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                                                                                                                                                       Journal of the Italian Society of Anatomic Pathology
                                                                                                                                                       and Diagnostic Cytopathology,
                                                                                                                                                       Italian Division of the International Academy of Pathology
                                                                                                                                                        ORIGINAL ARTICLES
                                                                                                                                                        313 The role of 2D bar code and electronic cross-matching in the reduction
                                                                                                                                                            of misidentification errors in a pathology laboratory. A safety system assisted
                                                                                                                                                            by the use of information technology
                                                                                                                                                            G. Fabbretti
                                                                                                                                                                                                                                                     Vol. 103 December 2011
                                                                                                                                                        318 Cytologic re-evaluation of negative effusions from patients with malignant
                                                                                                                                                            mesothelioma
                                                                                                                                                            V. Ascoli, D. Bosco, C. Carnovale Scalzo

                                                                                                                                                        325 Intra-operative frozen section technique for breast cancer: end of an era
                                                                                                                                                            E. Manfrin, A. Remo, F. Falsirollo, G.P. Pollini, A. Parisi, A. Nottegar, F. Bonetti

                                                                                                                                                        331 The diagnostic accuracy of cervical biopsies in determining cervical lesions: an audit
                                                                                                                                                            J. Wang, M. El-Bahrawy

                                                                                                                                                        337 “Combined” desmoplastic melanoma of the vulva with poor clinical outcome
Periodico bimestrale – POSTE ITALIANE SPA - Spedizione in Abbonamento Postale - D.L. 353/2003 conv. in L. 27/02/2004 n° 46 art. 1, comma 1, DCB PISA




                                                                                                                                                            G. Collina

                                                                                                                                                        CASE REPORTS
                                                                                                                                                        340 Tuberculosis of superficial lymph nodes, a not so rare event to consider in diagnosis.
                                                                                                                                                            A case in an elderly male
                                                                                                                                                            A. Merante, M.R. Ambrosio, B.J. Rocca, A.M. Condito, A. Ambrosio, M. Arvaniti,
                                                                                                                                                            G. Ruotolo

                                                                                                                                                        343 Adenolipoma of the skin
                                                                                                                                                            S. Karoui, T. Badri, R. Benmously, E. Ben Brahim, A. Chadli-Debbiche, I. Mokhtar,
                                                                                                                                                            S. Fenniche

                                                                                                                                                        346 Adenomatous transformation in a giant solitary Peutz-Jeghers-type hamartomatous
                                                                                                                                                            polyp
                                                                                                                                                            F. Limaiem, S. Bouraoui, A. Lahmar, S. Jedidi, S. Aloui, S. Korbi, S. Mzabi
Aut. Trib. di Genova n. 75 del 22/06/1949




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Journal of the Italian Society of Anatomic Pathology
and Diagnostic Cytopathology,
Italian Division of the International Academy of Pathology


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CONTENTS                                                                     of help in the diagnostic work-up of patients with effusions suspi-
                                                                             cious for mesothelioma.
Original articles
                                                                             Intra-operative frozen section technique for breast cancer:
The role of 2D bar code and electronic cross-matching                        end of an era
in the reduction of misidentification errors in a pathology
laboratory. A safety system assisted                                         E. Manfrin, A. Remo, F. Falsirollo, G.P. Pollini, A. Parisi,
by the use of information technology                                         A. Nottegar, F. Bonetti
G. Fabbretti                                                                 Data on 2436 primary breast carcinomas diagnosed between 1992
                                                                             and 2006 were collected to evaluate the rate of frozen section pro-
Introduction. Mismatching of patients and specimens can lead to              cedures performed over time. Frozen section procedures performed
incorrect histopathological diagnoses. Most misidentification errors
                                                                             to evaluate resection margins for conservative surgery or sentinel
in laboratories occur during the manual pre-laboratory and labora-
tory phases. In the past few years, we have examined this vital and          node status were excluded. Over time, there was a decrease in the
challenging issue in our unit and introduced appropriate procedures.         use of frozen sections indistinctly extended to all pT cancer catego-
Recently, we have paid special attention to the problem of speci-            ries. The rate of cancers diagnosed with frozen sections was 51.2%
men mix-ups in the gross examination phase and the mismatching of            in 1999, and 0% in 2005-2006. In the same period, the adoption
blocks and slides in the cutting phase.                                      of cytology and core biopsy for breast cancer diagnosis increased
Objective. We have focused on the reduction of the potential sources         from 40% in 1992 to more than 90% since 1999. In an audited
of mismatching of specimen containers, tissue blocks and slides,             diagnostic activity on breast pathology, the routine use of frozen
focusing in particular on the most critical steps which are gross cut-       sections on primary lesions was considered inappropriate, particu-
ting and preparation of microtome sections.                                  larly in assessment of clinically non-palpable lesions, and should be
Design. A 2D bar code directly printed on the labels of specimen contain-    limited to cases with inadequate pre-surgical sampling.
ers, and directly printed onto cassettes and slides, is now being used; in
addition, the system performs an electronic cross-check of tissue blocks
and slides, which is managed by the laboratory information system.
                                                                             The diagnostic accuracy of cervical biopsies in determining
Results. The present system permits full sample traceability from            cervical lesions: an audit
the moment samples reach the laboratory to the issuing of the final          J. Wang, M. El-Bahrawy
report. Indeed, the LIS records samples, blocks and slides in real time      Objective. The present audit was carried out to assess the diag-
throughout the entire procedure, as well as the operator’s name, and         nostic accuracy of cervical punch biopsy during colposcopy in
the date and time each individual procedure is done. This facilitates        comparison with diagnosis from subsequent cone excision.
later monitoring of the entire workflow.
                                                                             Design and setting. Retrospective analysis was performed by
Conclusions. The introduction of 2D bar code and electronic cross-
checking represents a crucial step in significantly increasing the safe      examining the histopathology reports for paired cervical punch
management of cases and improving the quality of the entire work             biopsies and cervical cone excisions for cases reported from April
process.                                                                     2004 to March 2005 (when cervical biopsies and cones were
                                                                             reported by general pathologists) and from January to December
                                                                             2008 (when reporting by specialist gynaecological pathologists
Cytologic re-evaluation of negative effusions from patients                  was instituted).
with malignant mesothelioma
                                                                             Sample. 150 women had both cervical punch and cone biopsies
V. Ascoli, D. Bosco, C. Carnovale Scalzo                                     performed in the 2004-2005 period, while 149 women had both
Background. Cytology is a controversial means of diagnosing                  biopsies performed in 2008.
malignant mesothelioma due to the high rates of negative sam-                Main outcome measures and results. In 2004-5, the rate of con-
ples. The aim of the present study was to review effusions origi-            sistent diagnosis was 68.7%, compared with 75.8% in 2008. This
nally reported as “negative” in patients with histologically-proven          was due to a decrease in the rates of overdiagnosis (16.7% vs.
mesothelioma to evaluate possible pitfalls.                                  14.8%) and underdiagnosis (14.7% vs. 9.4%), which was statisti-
Methods. We reviewed the cytologic slides of 25 specimens                    cally significant. The sensitivity rates for 2004-5 and 2008 were
that refer to 15 epithelioid, 5 biphasic, 4 sarcomatoid and 1 well-          87.5% and 89.7%, and the specificity rates for the same periods
differentiated papillary mesotheliomas. For comparison, we also              were 39.8% and 39.4% respectively.
reviewed 23 specimens from non-neoplastic conditions. For each               Conclusions. This audit highlights the importance of planning
effusion, we evaluated the background and calculated a score con-            patient management on the basis of co-ordinated information
sidering the following items: amount of mesothelial cells, archi-            from smear results, history, colposcopy findings and cervical
tectural pattern and atypical features, and a revised diagnosis was          biopsies. The introduction of specialist gynaecological histopa-
rendered.                                                                    thology reporting has significantly improved the rates of consis-
Results. More than half of the effusions initially called “nega-             tent diagnosis.
tive” (but mesothelioma by histology) were considered atypical/
suspicious (false-negative diagnosis); the remaining cases were              “Combined” desmoplastic melanoma of the vulva with poor
true-negative or inadequate. Almost all effusions initially called           clinical outcome
“negative” (but non-neoplastic by histology) were considered
negative. The only item that seems to discriminate between the               G. Collina
two groups is atypia of mesothelial cells.                                   Desmoplastic melanomas in an unusual variant of melanoma that
Conclusions. The present study has highlighted the following pit-            usually occurs in sun-damaged skin of elderly people. Desmopla-
falls: (i) to report effusions devoid of mesothelial cells as negative       sia may be the prominent features of the lesion or represent a por-
that instead should be reported as inadequate/non-diagnostic; (ii)           tion of an otherwise non-desmoplastic melanoma; these latter are
to underestimate low cellular effusions containing atypical meso-            called “combined” desmoplastic melanoma. Desmoplastic mela-
thelial cells or high cellular effusions containing bland mesothe-           nomas of the vulva are rare. Herein, we report a case of “com-
lial cells with a morular pattern; (iii) to consider that an inflamma-       bined” DM of the labia minor consisting of a superficial spitzoid
tory background may obscure a scant number of mesothelial cells.             component and a deeper spindle desmoplastic component. Protein
A categorized system (inadequate (M1), negative (M2), atypical               S-100 expression was ubiquitous, while MART-1 and HMB-45
(M3) and suspicious (M4)) for reporting effusion cytology may be             were limited to the superficial spitzoid component and were nega-
tive in desmoplastic areas. Notably, the nodal metastasis retained      eccrine sweat glands inside the fat proliferation. A 32-year-
the same biphasic pattern seen in the primary tumour. The patient       old woman presented to our department with a slow-growing,
died of widespread metastatic disease 3 years after diagnosis.          painless subcutaneous soft tumour located on the upper part of the
                                                                        right thigh. Microscopically, there was lobulated adipose tissue
                                                                        proliferation with well-differentiated eccrine glands and ducts
Case reports                                                            in the periphery and centre of the nodule. These features were
                                                                        suggestive of ALS.
Tuberculosis of superficial lymph nodes, a not so rare event            ALS is a rare microscopic variant of cutaneous lipoma having
to consider in diagnosis. A case in an elderly male                     similar clinical features to lipoma. The most frequent locations
                                                                        of this tumour are thighs (as in our patient), shoulders, chest
A. Merante, M.R. Ambrosio, B.J. Rocca, A.M. Condito,                    and arms. Histologically, the tumour is composed of lobulated
A. Ambrosio, M. Arvaniti, G. Ruotolo                                    adipose tissue with larger and more prominent lobules than
Tuberculosis (TB) is still one of the most frequent infectious          those in normal subcutaneous adipose tissue. A well-developed
diseases worldwide. Until the 1990s, Western European countries         capsule may also be identified. Eccrine glands and ducts, without
showed a low frequency of TB infection, but the rise of immigration     proliferative changes, are well-differentiated within the adipose
has led to a rapid increase in its occurrence. In the elderly,          tissue.
TB is emerging as a significant health problem (age-related             Differential diagnosis of adenolipoma includes the common
decline of the cell-mediated immunity, associated illnesses, use        lipoma and its variants, skin tag and other hamartomatous lesions,
of immunosuppressive drugs, malnutrition, poor life conditions),        such as nevus lipomatosus superficialis, and the lipomatous
although its detection and diagnosis is not easy also considering its   variant of eccrine angiomatous hamartoma.
subclinical presentation. Almost 70% of all TB infections in Italy
are found in the lungs; 50% of the extrapulmonary infections affect
lymph nodes. Due to the low incidence of superficial tuberculous        Adenomatous transformation in a giant solitary
lymphadenitis without pulmonary manifestations, the possibility         Peutz-Jeghers-type hamartomatous polyp
of a TB aetiology is often not taken into consideration in the          F. Limaiem, S. Bouraoui, A. Lahmar, S. Jedidi, S. Aloui,
differential diagnosis of lymphadenopathy, resulting in significant     S. Korbi, S. Mzabi
delay of appropriate treatment.                                         Solitary Peutz-Jeghers-type polyp is a rare hamartomatous polyp
Herein, we describe the case of a 78-year-old male with nocturnal       without associated mucocutaneous pigmentation or a family his-
fever, weakness, night sweats, loss of weight and decay in general      tory of Peutz-Jeghers Syndrome. It is usually encountered in the
condition. The patient had a past medical history of prostate           small intestine, but rarely involves the rectum. A 27-year-old
adenocarcinoma treated with hormone therapy.The past medical            previously healthy female patient presented with a two-month
history in association with clinical findings and laboratory data       history of rectal bleeding. The patient had neither mucocu-
(anaemia, high titers of fibrinogen and reactive c-protein) led         taneous pigmentation nor a family history of gastro-intestinal
to the suspect of metastatic adenocarcinoma. Only histological          polyposis. Endoscopic examination revealed a solitary lobular
and molecular biology findings allowed us to make a correct             polypoid lesion in the lower rectum. The polyp was sessile and
diagnosis of TB.                                                        measured 15 cm in diameter. As histological examination of
                                                                        the biopsy specimen was suggestive of adenoma, endoscopic
                                                                        polypectomy was performed. Histologically, this polyp had an
Adenolipoma of the skin
                                                                        arborizing muscular network originating from the muscularis
S. Karoui, T. Badri, R. Benmously, E. Ben Brahim,                       mucosa, and was covered by well organized mucosa with sev-
A. Chadli-Debbiche, I. Mokhtar, S. Fenniche                             eral foci of dysplastic glands. The final pathological diagnosis
Adenolipoma of the skin (ALS) is an uncommon histological               was solitary Peutz-Jeghers type hamartomatous polyp with ade-
variant of lipoma, characterized by the presence of normal              nomatous transformation.
pathologica 2011;103:313-317




                                                                  Original article



  The role of 2D bar code and electronic cross-matching
        in the reduction of misidentification errors
   in a pathology laboratory. A safety system assisted
           by the use of information technology
                                                            G. FABBRETTI
                                   U.O. Anatomia Patologica e Citologia, Ospedale Infermi, Rimini, Italy



                                                                   Key words

                 Mismatch errors • Risk management • 2D Barcode technology • Safety management of patient specimens



                                                                   Summary

Introduction. Mismatching of patients and specimens can lead                being used; in addition, the system performs an electronic cross-
to incorrect histopathological diagnoses. Most misidentification            check of tissue blocks and slides, which is managed by the labora-
errors in laboratories occur during the manual pre-laboratory and           tory information system.
laboratory phases. In the past few years, we have examined this             Results. The present system permits full sample traceability
vital and challenging issue in our unit and introduced appropriate          from the moment samples reach the laboratory to the issuing
procedures. Recently, we have paid special attention to the prob-           of the final report. Indeed, the LIS records samples, blocks and
lem of specimen mix-ups in the gross examination phase and the              slides in real time throughout the entire procedure, as well as
mismatching of blocks and slides in the cutting phase.                      the operator’s name, and the date and time each individual pro-
Objective. We have focused on the reduction of the potential                cedure is done. This facilitates later monitoring of the entire
sources of mismatching of specimen containers, tissue blocks and            workflow.
slides, focusing in particular on the most critical steps which are         Conclusions. The introduction of 2D bar code and electronic
gross cutting and preparation of microtome sections.                        cross-checking represents a crucial step in significantly increas-
Design. A 2D bar code directly printed on the labels of specimen            ing the safe management of cases and improving the quality of
containers, and directly printed onto cassettes and slides, is now          the entire work process.



Introduction                                                                incorrectly-recorded laterality and anatomical sites.
                                                                            Another two steps in the procedure that are particularly
Since the publication of “To err is human” in 1999 1,                       prone to error are the gross and cutting phases, which
substantial work has been done to reduce factors that                       are characterized by sample mix-ups and block and slide
contribute to errors in medical and surgical pathology                      mismatching errors.
practice. Procedures in the histopathology unit involve                     A significant reduction in the number of misidentifica-
multistep processes with several handoffs of materi-                        tion errors on accession was achieved in 2008 with the
als, which are all potential sources of error 2. Errors that                elimination of handwritten requests and handwritten
may occur at any stage of processing vary in frequency,                     labels, and by the introduction of an order entry with
depending on the laboratory. Several papers have been                       electronic requests and labels. In addition, direct print-
published that analyze and propose solutions 3-5. Over                      ing of cassettes and slides by automatics printers inter-
the past five years, we have approached this challenging                    faced with the laboratory information system produced
issue in our laboratory, with particular focus on the pre-                  a considerable reduction in block and slide mismatching
laboratory and laboratory phases.                                           errors.
The most critical step is the accession phase, which is                     However, data analysis in 2009 revealed continuing
characterized by incorrect patient identifications and                      block and slide mismatching. For this reason, at the be-




 Acknowledgements                                                             Correspondence
 The author is grateful to the entire Pathology Unit Staff; particular        Giovanna Fabbretti, U.O. Anatomia Patologica e Citologia,
 thanks are given to Luigi Santucci, Director of the Information              Ospedale Infermi, via Settembrini 2, 47900 Rimini, Italy - E-mail:
 Technology Department, and to Francesco Graziani, Rina Velati                giovanna.fabbretti@auslrn.net
 and Carla Zucca of Dedalus SpA.
314                                                                                                                   g. fabbretti




ginning of 2010, a 2D bar code was introduced, which          Fig. 1. cassettes and slides with a directly printed 2D bar code
is directly printed onto container labels, cassettes and      and accession code number. Slides also show readable text: name
                                                              of institution, type of stain (he: yellow slides and immunostains
slides, in order to reduce mismatching in the gross ex-       for Ki-67, progesterone and oestrogen receptors: white charged
amination and cutting phases. This new technology is          slides) name and surname of patient.
also an effective means of improving sample traceability
during the workflow.
The purpose of the present work is to discuss the highly
reliable work procedure we have developed, which fully
utilizes the benefits of information technology.


Materials and methods
The entire process was reorganised in May 2008 when
a new laboratory information system (LIS, Armonia
Dedalus, SpA, Italy) was integrated with the Hospital
Information System (HIS; Trak-care, Traksystem, Aus-
tralia), with an HL7 interface for receiving orders from
physicians through HIS order entry. This eliminated the
need for handwritten requests and handwritten container
labels. At the same time, the LIS was interfaced with the
cassette and slide printers (Leica Microsystems, Ban-        matching of a block and its associated slides. It is im-
nockburn, IL) to handle cassette and slide printing case-    possible for two identically identified blocks or slides to
by-case during the gross and cutting phases; this avoids     exist. For example, if a slide is printed and then the same
the need for manual code transcription. All of the above     slide is printed again, the first slide printed is identified
has been described in detail in a previous publication 6.    in the 2D bar code as 11-I-13500A21 and the second one
Since 2010, the LIS has used a 2D bar code and has been      11-I-13500A22.
interfaced with both cassette and slides printers (a Lei-    This is of fundamental importance and is a key point
ca printer in the Cytology Lab and Slide Mate printers       regarding matching of blocks and slides.
[Thermo Fisher Scientific, Waltham, MA] at the Cutting       Each workstation in our unit is equipped with a PC,
Station); the LIS also has been integrated with a Leica      monitor and scanner. We have also equipped each cut-
BOND-III instrument, which fully automates immuno-           ting station with small slide printers to avoid the need to
histochemistry work; 2D bar codes are directly printed       preprint slides. The LIS manages each individual step
onto immunohistochemistry slides at the cutting station:     via the 2D bar code regarding the processing of samples,
the BOND-III reads the 2D slide bar codes. Extensive         blocks and slides by recording the name of the operator
bar code printing testing and validation for cassettes and   and the date and time of the step; in this way, each single
slides was conducted by Leica, Thermo Fisher Scien-          case is traceable during the entire work procedure.
tific and Dedalus, and for scanner configuration by the      The LIS furthermore records any error or problem de-
Dedalus Company and Metrologic Instruments Inc. We           tected at any stage in the workflow. This function is
chose the Metrologic MS1690 Focus, which is an om-           quick and easy to access by using a keyboard; in this
nidirectional scanner capable of reading all standard 1D     function, a list of predetermined parameters are dis-
and 2D bar codes.                                            played: e.g. error or problem type, possible corrective
During set up, we carried out ping testing on cassettes      action, date, time and operator. Cases where an error has
and slides. No input failure occurred. Bar code misread-     been detected are marked by a special icon, so that the
ing may be caused by poor quality cassette and slide ma-     pathologist is alerted and can check the validity of the
terials, which can cause variations in printing quality.     corrective actions taken before diagnosis.
We always test any new material that will be used.           Errors and problems are subdivided in the following
The following are printed on cassettes: the accession        way: accession errors, specimen errors or problems, and
code (e.g. 11-I-11340), specimen container letter (e.g.      misidentification during the processing procedure. Each
A, B, C), subpart block number (e.g. 1, 2) and a 2D bar      subgroup is further divided into other sub-categories (e.g.
code, which includes a progressive printing number           misidentification during gross examination, embedding,
(Fig. 1).                                                    cutting, etc.). This system permits rapid analysis of col-
The following is printed on the slides as human readable     lected data. Once a month, a specially trained technical
text: accession code (e.g. 11-I-13800), patient name and     staff member evaluates data trends.
surname, type of stain (e.g. HE, PAS), the name of our       The unit’s workflow, which is bar code based, is de-
unit (Anat Pat, RN); in addition there is a 2D bar code,     scribed in a consistent and easy-to-read manner.
which also encodes a progressive printing number.            1. Accession phase: after a double check to verify that
The progressive printing number, found in both slide             data on the electronic request corresponds to that on
and cassette 2D bar codes, is essential for the univocal         the medical report that accompanies specimens (e.g.
role of 2D bar coDe anD electronic croSS-matching in the reDuction of miSiDentification errorS                                                     315



 Fig. 2. Downloaded request form and adhesive labels attached to                  for sentinel lymph nodes, yellow for small biopsies,
 specimen containers. above: patient data; middle: the two sub-                   blue for lymph nodes, pink for skin biopsies and
 mitted specimens: 1) skin from the lumbo-sacral region; 2) skin                  green for surgical specimens), section number, and
 from the patient’s hip and clinical information; below: the space
 occupied by detached labels.                                                     the routine stains or immunostains, if provided. The
                                                                                  default setting may be modified at any time during
                                                                                  the process. Cassettes are directly printed (Leica Mi-
                                                                                  crosystems, Bannockburn, IL) case-by-case during
                                                                                  gross examination. The printing process is quick and
                                                                                  easy.
                                                                               3. Tissue embedding phase: after processing each cas-
                                                                                  sette is read by the scanner before embedding the tis-
                                                                                  sue. The LIS displays the following: code number,
                                                                                  tissue type, fragment number and notes, if recorded
                                                                                  during gross examination, including operator name,
                                                                                  date, time and status (Fig. 4); after reading, the cas-
                                                                                  sette’s status is changed from processing to executed.
                                                                                  When all samples related to a single case are embed-



                                                                                 Fig. 4. tissue embedding station: the cassette is read by the scan-
                                                                                 ner. the liS displays all relevant information and shows a list of
   bronchoscopy, endoscopic report, etc.), the case is                           embedded cassettes.
   entered into the LIS by scanning a bar code on the
   paper copy of the electronic request, determining
   the recovery of the request from HIS (Fig. 2). The
   LIS provides a lab worksheet with number (e.g.
   11-I-14500) both as readable text and as a bar code
   (Fig. 3), and also provides labels for specimen con-
   tainers in readable text as well as a 2D bar code.
   Once a misidentification error is detected, the case
   is rejected and it will be processed after the error has
   been corrected.
2. Gross examination phase: the specimen containers
   are moved to the gross bench for sectioning and re-
   cording of macroscopic findings. Our LIS provides
   many predetermined parameters for each anatomi-
   cal site and each medical procedure; for example,
   the topographic code (SNOMED), the number and
   colour of the cassette (orange for urgent cases, white
                                                                                 Fig. 5. cutting station: the cassette is read by the scanner, the liS
                                                                                 shows all tissue block information (patient name and surname,
 Fig. 3. an internal lab worksheet: accession number and 1-di-                   code number, tissue type, number of fragments, embedded
 mensional bar code and adhesive labels for specimen containers                  status, operator and date) and the slide mate printer prints the
 with a 2-dimensional bar code.                                                  relevant information on the slide.
316                                                                                                             g. fabbretti




   ded in cassettes, the case status is changed from gross     because the clinical information was not concordant
   executed to embedded. The LIS sequentially shows a          with histological appearance. In other cases, the slide
   list of all embedded cassettes on the monitor in the        samples clearly did not correspond with the anatomical
   work session, and, if required, supplies a printed          site indicated in the request when viewed under the mi-
   list.                                                       croscope. Another particularly important result achieved
4. Cutting phase: just before cutting, the operator reads      by the introduction of 2D bar coding is the introduction
   the block’s bar code with the scanner, and the slide        of automated tracing; it is now possible in real time, to
   printer prints all the associated slides; after section     trace a specimen container or missing block and locate
   cutting (and only at this time - before it is picked        it immediately.
   up) the slide is read by the scanner. If the slide does     Indeed, the LIS manages the workflow, step by step, re-
   not match the block, a message error on the moni-           cording the operator’s name, date and time of each single
   tor alerts the operator (Fig. 5). The LIS displays the      step. We are now able to know what is happening in real
   changing status of the slide from requested to vali-        time, and to take immediate action to locate a misplaced
   dated only if the slide matches correctly. When all         container or block.
   slides related to a single case are validated, the case’s
   status is changed from embedded to cut.
5. Checkout phase: at the end of the entire work flow          Discussion
   procedure, there is the final check before delivering
   slides to the referring pathologist. Each slide is read     The case-by-case direct printing of bar code numbers
   by the scanner, and when all slides of a single case        on cassettes and slides by automated printers managed
   (routine stain, special stains and immunostains) are        by the LIS prevents errors caused by handwritten labels
   ‘pinged’ the case is ready to be sent for medical ex-       and by transcription. Checking correspondence between
   amination.                                                  the code number on container labels and the cassette at
                                                               the gross station and between block and the slide at the
                                                               cutting station was previously done visually and was
Results                                                        therefore subject to error caused by fatigue and lack of
                                                               concentration.
The results achieved have been particularly good and of        Even if the mismatch rate was low in the gross exami-
significant importance. Since the introduction in 2010         nation and cutting phases, and in keeping with data re-
of 2D bar codes on container labels, we have not had a         ported in recent literature 7, an error that mismatches a
single case of sample mix up in the gross examination          slide to the wrong patient can have serious consequences
phase in a total of 26,964 histological cases. In the gross    on clinical outcome.
examination phase, each case begins with a reading             For this reason, we worked closely with the LIS provider
of the 2D bar code on the container label, and the LIS         to design a system that would prevent this type of error.
makes it impossible for a code number that is different to     The result is that we have up-graded our LIS with the
the case number in question to be printed on a cassette.       introduction of 2D bar codes on labels of specimen con-
In contrast, in 2009 we had 10 errors in a total of 26,961     tainers, and direct printed on cassettes and slides. The
(0.03%) cases that involved mismatch of samples from           biggest leap in improved quality was achieved by the
the same patient.                                              introduction of electronic cross-match managed by LIS.
Additionally, in the cutting phase we have had no mis-         Another important advance is that there is now sample
match since automatic cassette and slide cross checking        traceability throughout the entire workflow.
was made possible by the introduction of 2D bar codes          In a recent paper, Zarbo et al. 8 describes a workflow
in 2010 (26,964 histological cases; 80,571 tissue blocks).     dependent on bar code reading and illustrates the use of
In contrast in the same period in 2009, we had 32 mis-         traditional bar codes on specimen container labels, in
matches from a total of 26,961 cases (0.11%) (80,361           specific labels for slides and use 2D bar code only for
tissue blocks) caused by the transfer of sections from one     cassettes.
block to a mismatched slide. Data analysis showed that         Unfortunately, in their laboratory, electronic requests
mismatch errors were more or less equally distributed          are not yet employed and cases are accessioned manu-
between routine cutting (14 cases) and re-cutting. There       ally from handwritten requisitions, which are often in-
was a slightly greater error prevalence for re-cutting (18     complete and unclear, as noted by Dimenstein 9. The
cases), where the errors involved cases with similar code      labelling of slides represents an additional manual step
numbers (e.g. 09-I-23715 and 09-I-23915); 12 of 18 er-         that is time consuming, prone to error and finally more
rors involved specimens from different patients, and 4 of      expensive than directly printing on them.
18 involved different specimens from the same patient.         The electronic checking introduced in the cutting sta-
Of the 14 routine cutting mismatch errors, 10 involved         tion overcomes the problem of operators failing to fol-
different patients. None of the errors for either the gross    low standard procedures, which was an issue that Zarbo
examination or the cutting phase resulted in adverse con-      emphasized in his report. The LIS prevents proceeding
sequences for the patient, as they were detected during        to the next case and alerts the operator is procedures are
subsequent steps. The errors were noticed in some cases        not followed. Furthermore, if the slide’s bar code is not
role of 2D bar coDe anD electronic croSS-matching in the reDuction of miSiDentification errorS                                                   317



read by the scanner, the case is not validated. The intro-                     procedure, and not later in the pathology lab by a member
duction of electronic cross checking of blocks and slides                      of administration or technical staff. During gross tissue
is an effective means of preventing inevitable human er-                       examination, LIS case data can be accessed by reading
rors in the cutting phase caused by fatigue, lack of con-                      the 2D bar code on container labels, avoiding mix-up of
centration and heavy workload.                                                 specimens; the direct printing of cassettes one case at a
During the development of this project, the only con-                          time avoids the need for them to be prepared in advance
cern was the possible increase in processing times. How-                       and eliminates the risk of confusing cassettes from dif-
ever, during the first three weeks after the adoption of                       ferent patients. The direct printing of slides, one block at
the new workflow we experienced only a small delay                             a time, at the moment of cutting of sections, eliminates
in slide delivery, which was caused by the need to train                       the need for labelling, which is a time consuming step.
all operators; such training is obviously necessary when                       More importantly, it also eliminates a potential source of
introducing new organizational procedures. All techni-                         error because traditional labelling is a manual procedure
cal staff have very positively accepted this new working                       that is visually checked. Furthermore, labelling is more
procedure. In addition, in recent years much has been                          expensive than direct printing of slides. The introduction
accomplished in training all operators in risk manage-                         of electronic cross-checking using 2D bar codes directly
ment, and on-going work has been done with the entire                          printed onto blocks and slides represents a very important
team to identify the causes of mismatching and improv-                         qualitative leap. In our experience, it represents the best
ing workflow. The knowledge of when, where and why                             method for avoiding block and slide mismatching.
misidentification errors occur, which is a fundamental                         The redesigned workflow with 2D bar codes has an-
prerequisite for their successful reduction, has been fa-                      other advantage: real time case traceability throughout
cilitated by the LIS, which allows quick, easy and com-                        the entire procedure. Gradually we redesigned the entire
plete error reporting at each step of the work flow, as                        workflow procedure over a period of years. The support
previously described.                                                          we received from top management was crucial for its
In summary, the work over the last few years has been                          success. In our experience, no single piece of technology
focused on simplifying workflow procedures as much as                          can eliminate errors in a complex system such as a pa-
possible by utilizing information technology, and the em-                      thology work flow composed of multiple handoffs. Each
ployment of bar coding to minimize operator caused error.                      laboratory has to consider the individual requirements of
The process was streamlined by eliminating some poten-                         their own workflow.
tially error prone procedures, most importantly eliminat-                      The LIS and bar code technology play a leading role in
ing manual accession input in the LIS by using a direct                        making the entire process far safer. However, there is
electronic request entry. It is important to note that in this                 also the need for standard operating procedures for each
manner, the patient and his or her samples are correctly                       step, accompanied by an efficient system of recording
identified at the time they are taken, in the place they are                   errors for every phase (pre-lab, lab and post-lab) and rig-
taken and by the clinician who performed the medical                           orous daily compliance with all procedures.


References                                                                         gical pathology: an 18-mounth experience. Am J Clin Pathol
                                                                                   2010;134:466-70.
1
    Kohn LT, Corrigan JM, Donaldson MS, eds. To err is human:                  6
                                                                                   Fabbretti G. Risk management: correct patient and specimen iden-
    building a safer health system. Washington, DC: National Acad-                 tification in a surgical pathology laboratory. The experience of
    emies Press 1999.                                                              Infermi Hospital, Rimini, Italy. Pathologica 2010;102:96-101.
2
    Nakhleh RE. Error reduction in surgical pathology. Arch Pathol             7
                                                                                   Nakhleh RE, Idowu MO, Souers RJ, et al. Mislabeling of cases,
    Lab Med 2006;130:630-2.                                                        specimens, blocks, and slides: a college of American pathologists
3
    Zarbo RJ, D’Angelo R. The Henry Ford Production System: effec-                 study of 136 institutions. Arch Pathol Lab Med 2011;135:969-74.
    tive reduction of process defects and waste in surgical pathology.         8
                                                                                   Zarbo RJ, Tuthill JM, D’Angelo R, et al. The Henry Ford Produc-
    Am J Clin Pathol 2007;128:1015-22.                                             tion System: reduction of surgical pathology in process misidenti-
4
    D’Angelo R, Zarbo RJ. The Henry ford Production System: mea-                   fication defects by bar code-specified work process standardisa-
    sures of process defects and waste in surgical pathology. Am J                 tion. Am J Clin Pathol 2009;131:468-77.
    Clin Pathol 2007;128:423-9.                                                9
                                                                                   Dimenstein IB. Letter to the Editor. Am J Clin Pathol
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    Layfield LJ, Anderson GM. Specimen labelling errors in sur-                    2009;132:975-6.
pathologica 2011;103:318-324




                                                              Original article



              Cytologic re-evaluation of negative effusions
              from patients with malignant mesothelioma
                                       V. ASCOLI, D. BOSCO, C. CARNOVALE SCALZO
            Dipartimento di Scienze Radiologiche, Oncologiche e Anatomo-patologiche, Sapienza Università di Roma, Italy



                                                              Key words

                          Mesothelioma • Cytology • Serous effusion • Reactive mesothelium • Diagnostic pitfalls



                                                               Summary

Background. Cytology is a controversial means of diagnosing             suspicious (false-negative diagnosis); the remaining cases were
malignant mesothelioma due to the high rates of negative sam-           true-negative or inadequate. Almost all effusions initially called
ples. The aim of the present study was to review effusions origi-       “negative” (but non-neoplastic by histology) were considered
nally reported as “negative” in patients with histologically-proven     negative. The only item that seems to discriminate between the
mesothelioma to evaluate possible pitfalls.                             two groups is atypia of mesothelial cells.
Methods. We reviewed the cytologic slides of 25 specimens that          Conclusions. The present study has highlighted the following pit-
refer to 15 epithelioid, 5 biphasic, 4 sarcomatoid and 1 well-          falls: (i) to report effusions devoid of mesothelial cells as negative
differentiated papillary mesotheliomas. For comparison, we              that instead should be reported as inadequate/non-diagnostic; (ii) to
also reviewed 23 specimens from non-neoplastic conditions.              underestimate low cellular effusions containing atypical mesothelial
For each effusion, we evaluated the background and calculated           cells or high cellular effusions containing bland mesothelial cells with
a score considering the following items: amount of mesothelial          a morular pattern; (iii) to consider that an inflammatory background
cells, architectural pattern and atypical features, and a revised       may obscure a scant number of mesothelial cells. A categorized sys-
diagnosis was rendered.                                                 tem (inadequate (M1), negative (M2), atypical (M3) and suspicious
Results. More than half of the effusions initially called “nega-        (M4)) for reporting effusion cytology may be of help in the diagnos-
tive” (but mesothelioma by histology) were considered atypical/         tic work-up of patients with effusions suspicious for mesothelioma.



Introduction                                                            Therefore, any information that could lend support to
                                                                        the possibility to suspect a diagnosis of MM in a fluid
Since most malignant mesothelioma (MM) first present                    sample should be considered.
with a pleural/peritoneal effusion 1, cytologic analysis                We present herein the experience of our laboratory on
represents the primary diagnostic approach. However,                    25 cases of histologically-proven MM in which cyto-
cytologic diagnosis of MM is notoriously challenging                    logic diagnosis on effusions was originally reported
with a sensitivity ranging from 30% to 80% 1-4. This                    as negative for malignancy. Based on the re-examina-
variability mainly reflects the lack of experience of pa-               tion of cytology specimens, we investigated the type
thologists with this rare malignancy and the complex-                   of errors, if any, and produced a scoring system that
ity in interpretation of the changes in mesothelial cells,              might be helpful in detecting mesothelioma cells. For
the main pitfall being the resemblance of mesothelioma                  comparison, 23 negative effusions from histologically-
cells to normal or reactive mesothelial cells. The lack of              demonstrated non-neoplastic conditions were also re-
a dedicated technical approach to the handling of effu-                 examined.
sions is also the source of errors such as improper collec-
tion and processing of effusions fluids 5.
The topic of whether cytology should be an acceptable                   Materials and methods
means of diagnosing MM is controversial 6, but a role for
cytology cannot be excluded, also because cytology may                  From a series of 109 histologically proven cases of MM
be the only source of pathological material available.                  (all with a previous effusion examined) that were diag-



                                                                          Correspondence
                                                                          Valeria Ascoli, Dipartimento di Scienze Radiologiche, Oncologiche
                                                                          e Anatomo-patologiche, Sapienza Università di Roma, viale Regina
                                                                          Elena 324, 00161 Roma, Italy - Tel. +39 06 44703550 - Fax
                                                                          +39 06 49973376 - E-mail: e-mail: valeria.ascoli@uniroma1.it
cytologic re-evaluation of negative effuSionS from patientS with malignant meSothelioma                                                        319


Tab. I. Scoring system.
      Cytological features                                                   Score
 1.   mesothelial cellularity                                                from 0 to 3 points (0 = absent, 1 = scarce, 2 = moderate,
                                                                             3 = abundant)
 2.   architecture of mesothelial cells                                      from 1 to 2 points (1 = single, 2 = single & clusters)
 3.   atypical features of mesothelial cells (anisonucleosis,                from 1 to 7 points
      multinucleation, atypical mitosis, macronucleoli,
      cytomegalia, vacuolation of the cytoplasm, presence
      of squamoid cells)



nosed in our institution (Azienda Ospedaliera Policlinico                           There were two main patterns: neutrophil plentiful
“Umberto I”, Roma) over a 9-year period, we retrieved                               (Fig. 1), and small lymphocyte plentiful (Fig. 2). In
25 cases in which the original cytology report was “nega-                           effusions with abundant neutrophils, there was also a
tive for malignancy”. Fourteen cases were first effusions                           large amount of fibrin and necrosis obscuring meso-
and 11 were recurrent effusions. The final histologic di-                           thelial cells, when present (Fig. 3).
agnosis was as follows: epithelioid MM (n = 15), well-                        •     Mesothelial cells. In 6 specimens, mesothelial cells
differentiated papillary mesothelioma (n = 1), biphasic                             were absent (inadequate/non-diagnostic specimens);
MM (n = 5) and sarcomatoid MM (n = 4). Twenty-one                                   in the other 19 specimens, mesothelial cells were
were MM of the pleura and 4 of the peritoneum.                                      present (adequate specimens). Of these 19 adequate
Cytological material consisted of conventional smears                               specimens, 12 effusions were scarcely cellular and 7
stained with Papanicolaou and Giemsa stains. None of                                moderate-to-abundant cellular.
the 25 specimens had been processed by the cell block                         •     Mesothelial architecture. Mesothelial cells were seen
technique. Also, immunocytochemistry had not been re-                               either as scattered single cells (n = 11, Figs. 1-4) or as an
quested.                                                                            admixture of single and clustered cells (n = 8, Fig. 5).
The cytological slides were reviewed by the three                             •     Mesothelial atypical features. Of the 19 adequate
coauthors who were non-blinded to the original di-                                  specimens, 5 effusions showed mesothelial with no
agnosis, and the following cytological features were                                atypical features. The other 14 effusions showed
considered: 1) background, defined in terms of in-
flammatory cells (lymphocytes, neutrophils, mixed
inflammatory cells) and the presence of necrosis;                                 Fig. 1. Single mesothelial cells surrounded by neutrophils; note
2) mesothelial cellularity, defined as absent, scarce,                            cytomegalia, multinucleation and prominent nucleoli. histology
                                                                                  revealed epithelial mesothelioma. cytodiagnosis on revision: m4/
moderate, and abundant; 3) mesothelial cell architec-                             suspicious.
ture, the arrangement of mesothelial cells in clusters/
morulae or as individual cells; 4) mesothelial atypi-
cal features, including anisonucleosis, atypical mi-
tosis, binucleation/multinucleation, macronucleoli,
cytomegalia, vacuolation of the cytoplasm and pres-
ence of squamoid cells.
We calculated a score for each effusion considering the
amount of mesothelial cells, architecture of mesothelial
cells and number of atypical features (Tab. I). Based on
morphological features and taking into account the total
score, we formulated a revision diagnosis. To verify the
performance of the scoring system, we also reviewed 23
effusion specimens from histologically-demonstrated
non-neoplastic pleural conditions.


Results
Cytological revision
Group negative by cytology/mesothelioma by histology
The main features of cytological revision of the 25 MM
cases together with the corresponding histological sub-
types are reported in Table II, and in Figures 1-4.
• Background. All effusion samples were character-
   ized by a variable amount of inflammatory cells.
320                                                                                                                                  v. aScoli et al.




Tab. II. revision of 25 effusions with an original cytologic diagnosis of “negative for malignancy” and a final histologic diagnosis of “malignant
mesothelioma”.
 Histologic                                Cytological revision                                           Diagnosis on revision
 subtype
                   Background                          Mesothelial cells
                  Inflammatory        Amount        Architecture      Atypical      Total
                     Cell Type                                        features      Score
 epithelial        lymphocytes            0              na               na           0              inadequate/non-diagnostic (m1)
 epithelial         neutrophils           0              na               na           0              inadequate/non-diagnostic (m1)
 epithelial         neutrophils           0              na               na           0              inadequate/non-diagnostic (m1)
 epithelial         neutrophils           0              na               na           0              inadequate/non-diagnostic (m1)
 Sarcomatous       lymphocytes            0              na               na           0              inadequate/non-diagnostic (m1)
 epithelial            mixed              0              na               na           0              inadequate/non-diagnostic (m1)
 epithelial        neutrophils/           1               1                0           2                        negative (m2)
                    necrosis
 epithelial            mixed              1               1                0           2                        negative (m2)
 Sarcomatous       neutrophils/           1               1                0           2                        negative (m2)
                    necrosis
 Sarcomatous           mixed              1               1                0           2                        negative (m2)
 Sarcomatous       lymphocytes            1               1                0           2                        negative (m2)
 biphasic          lymphocytes            1               1                1           3                        atypical (m3)
 epithelial        lymphocytes            1               1                1           3                        atypical (m3)
 epithelial        lymphocytes            1               1                2           4                        atypical (m3)
 biphasic          lymphocytes            1               1                2           4                        atypical (m3)
 biphasic          lymphocytes            2               2                1           5                        atypical (m3)
 epithelial        lymphocytes            2               1                2           5                        atypical (m3)
 epithelial        lymphocytes            1               2                2           5                        atypical (m3)
 biphasic          lymphocytes            1               1                3           5                        atypical (m3)
 epithelial            mixed              2               2                2           6                       Suspicious (m4)
 biphasic          lymphocytes            1               2                3           6                       Suspicious (m4)
 epithelial            mixed              2               2                2           6                       Suspicious (m4)
 epithelial       mixed/necrosis          2               2                2           6                       Suspicious (m4)
 wDpm                  mixed              3               2                2           7                       Suspicious (m4)
 epithelial         neutrophils           2               2                4           8                       Suspicious (m4)

na = not applicable
wDpm = well-differentiated papillary mesothelioma




    often multinucleation and macronucleoli and cyto-                      (n = 1), and with no atypical nuclear features. The back-
    megalia (Figs. 1, 3), also in addition to vacuolation of               ground of the smears was heavily inflammatory; often
    the cytoplasm and squamoid cells (Fig. 4); the least                   there were granulocytes and also abundant necrosis. The
    frequent atypical features were anisonucleosis and                     overall score was 2.
    mitosis.                                                               M3-Atypical mesothelial cells of undetermined signifi-
Upon revision, we attributed the 25 effusions to 4 cat-                    cance. We included 8 effusions in this category charac-
egories: M1 (inadequate), M2 (negative), M3 (atypical)                     terized by scarce rather than moderate mesothelial cellu-
and M4 (suspicious).                                                       larity; mesothelial cells were seen as single cells (n = 6)
M1-Inadequate/non-diagnostic. We included 6 cases in                       more than in clusters (n = 2); mesothelial cells showed
this category that were completely devoid of mesothe-                      a few atypical nuclear features; the inflammatory back-
lial cells. The background of the smears was heavily in-                   ground was mainly represented by lymphocytes (Fig. 2).
flammatory (granulocytes or lymphocytes). The overall                      A single case included in this category was highly cel-
score was 0.                                                               lular, but anisonucleosis was the only atypical feature
M2-Negative. We included 5 cases with a low number                         of mesothelial cells. The overall score was between 3
of mesothelial cells lying singly (n = 4) or in clusters                   and 5.
cytologic re-evaluation of negative effuSionS from patientS with malignant meSothelioma                                                         321



 Fig. 2. Single atypical mesothelial cell surrounded by numerous                Fig. 4. Single atypical mesothelial cells surrounded by abundant
 lymphocytes. histology revealed biphasic mesothelioma. cytodi-                 inflammatory cells; note many orangiophilic squamoid cells. his-
 agnosis on revision: m3/atypical.                                              tology revealed epithelial mesothelioma. cytodiagnosis on revi-
                                                                                sion: m4/suspicious.




 Fig. 3. abundant necrosis, fibrin, inflammatory cells; there were
 only very rare single atypical mesothelial cells. histology revealed
 biphasic mesothelioma. cytodiagnosis on revision: m4/suspi-
 cious.




                                                                                Fig. 5. clusters of mesothelial cells with bland atypical features.
                                                                                histology revealed epithelial mesothelioma. cytodiagnosis: on re-
                                                                                vision m4/suspicious.




M4-Suspicious mesothelial cells. We included 6 effu-
sions characterized by moderate/abundant mesothelial
cellularity; in all specimens, there were clusters of me-
sothelial cells (Fig. 5); the number of nuclear atypical
features was variable. The overall score was > 5.
Group negative by cytology/negative by histology
The main features of the cytological revision of the 23
non-neoplastic cases are reported in Table III.
• Background. All effusion samples were character-
    ized by a variable amount of inflammatory cells.
• Mesothelial cells. In a single specimen, mesothelial
    cells were absent (inadequate/non-diagnostic speci-
    men); most other specimens contained a moderate
    amount of mesothelial cells.
• Mesothelial architecture. Mesothelial cells were seen
    either as scattered single cells or as an admixture of
    single and clustered cells.
• Mesothelial atypical features. Of the 22 adequate
    specimens, effusions showed no atypical features
322                                                                                                                                v. aScoli et al.




Tab. III. revision of 23 effusions with an original cytologic diagnosis of “negative for malignancy” and a final histologic diagnosis of “benign
hyperplasia of mesothelial cells/no evidence of malignancy”.
 Histology                                                     Cytological revision                                 Diagnosis on revision
                                  Background                              Mesothelial cells
                                 Inflammatory          Amount        Architecture      Atypical     Total Score
                                    Cell Type                                          features
 no malignancy                     neutrophils             0              na              na              0              inadequate/
                                                                                                                      non-diagnostic (m1)
 no malignancy                        mixed                1               1               0              2               negative (m2)
 no malignancy                    lymphocytes              1               1               0              2               negative (m2)
 no malignancy                        mixed                1               1               0              2               negative (m2)
 no malignancy                        mixed                1               1               0              2               negative (m2)
 no malignancy                    lymphocytes              2               1               0              3               negative (m2)
 no malignancy                        mixed                1               1               1              3               negative (m2)
 no malignancy                        mixed                2               2               0              4               negative (m2)
 no malignancy                        mixed                2               1               1              4               negative (m2)
 no malignancy                        mixed                3               1               1              5               negative (m2)
 no malignancy                        mixed                2               2               1              5               negative (m2)
 no malignancy                    lymphocytes              2               2               1              5               negative (m2)
 no malignancy                        mixed                2               2               1              5               negative (m2)
 no malignancy                    lymphocytes              2               2               1              5               negative (m2)
 no malignancy                    lymphocytes              2               2               1              5               negative (m2)
 no malignancy                    lymphocytes              2               2               1              5               negative (m2)
 no malignancy                    lymphocytes              2               2               1              5               negative (m2)
 no malignancy                    lymphocytes              2               2               1              5               negative (m2)
 no malignancy                        mixed                2               2               1              6               negative (m2)
 no malignancy                    lymphocytes              2               2               2              6               negative (m2)
 no malignancy                    lymphocytes              3               2               1              6               negative (m2)
 no malignancy                    lymphocytes              3               2               1              6               negative (m2)
 no malignancy                        mixed                2               2               2              6               negative (m2)

na: not applicable.




    (n = 6), a single atypical feature (n = 14) or two atypi-             cases. These effusions represent diagnostic errors (false-
    cal features (n = 2).                                                 negative diagnoses) because they contained atypical me-
Upon revision, we attributed the 23 effusions to 2 cat-                   sothelial cells. When excluding 6 inadequate specimens
egories, M1 (inadequate) and M2 (negative).                               (24%), the remaining 5 cases (20%) were confirmed as
M1-Inadequate/non-diagnostic. We included a single                        negative for malignancy, and were not diagnostic errors
case in this category that was completely devoid of me-                   (true-negative diagnoses) by cytology.
sothelial cells. The background of the smears was heav-                   The scoring system is not particularly useful in sepa-
ily inflammatory (granulocytes).                                          rating the effusions due to non-neoplastic conditions
M2-Negative. We included 22 cases with a moderate                         from effusions due to mesothelioma. However, there
number of mesothelial cells lying singly or in clusters                   is a bias of case selection in the MM group. In fact,
and with no atypical nuclear features or minimal atypi-                   effusions due to MM were cases were that had been
cal features. The background of the smears was inflam-                    called “negative” in earlier diagnosis; it is likely that
matory. The overall score was between 2 and 6.                            effusions containing clear-cut mesotheliomatous cells
                                                                          would give a higher score. Architectural features seem
                                                                          to be a non-informative variable, and the amount of
Discussion                                                                mesothelial cells does not discriminate between the
                                                                          two groups; rather, it seems that more abundant meso-
Our results showed that the cytologic revision of speci-                  thelial cells characterize the “negative” effusions more
mens previously reported as negative (but mesothelioma                    than “false negative effusions” due to mesothelioma.
by histology) provided a different diagnosis in 56% of                    Atypical features are probably the most useful charac-
cytologic re-evaluation of negative effuSionS from patientS with malignant meSothelioma                                              323



teristics in the daily practice to discriminate between                       sediment); (iii) the absence of immunocytochemistry
the two groups.                                                               (because cell blocks are not routinely prepared in our
Based on our diagnosis on revision, we propose that                           laboratory in case of negative effusions).
effusions containing atypical mesothelial cells should                        Taking into account histology, effusions that also re-
be called at the very least “effusions containing atypi-                      mained negative on revision included three of four sar-
cal mesothelial cells of undetermined significance”                           comatous MM of the present series; this finding is not
(M3 category); those effusions containing abundant                            unexpected and is a well-know feature in the cytologic
mesothelial cells with a morular pattern with some                            literature (mesothelial cells are entrapped in the fibrous
atypical features should be called “suspicious for me-                        tissue). Among the suspicious/M4 effusions, there was
sothelioma” (M4 category). The M3/atypical and M4/                            a case of well-differentiated peritoneal mesothelioma
suspicious effusions are at variance more on the basis                        (WDPM), which is an uncommon subtype of mesothe-
of the amount of mesothelial cells and on the basis of                        lioma characterized by superficial spreading of papillary
cell grouping, rather than on the number of atypical                          formations lined by bland epithelioid cells that can be a
nuclear features. We also propose, similar to thyroid/                        source of false-negative cytologic diagnoses. However,
breast and cervical cytology, a system for reporting ef-                      this entity should be recognized by cytology in highly
fusion cytology that could be of help in the diagnostic                       cellular effusions and reliably be called suspicious for
work-up of fluids for mesothelioma: inadequate (M1),                          mesothelioma 8 9.
negative (M2), atypical (M3) and suspicious (M4), as
recently reported 3.
Although we are aware of the limits of cytology in di-                        Conclusions
agnosis of mesothelioma, and confirmed herein, the
present study has allowed us to focus on the follow-                          1. More than half of effusions due to mesothelioma that
ing pitfalls: (i) To call negative those effusions that are                      were initially called “negative for malignancy” are
devoid of mesothelial cells; these effusions should be                           false-negatives on revision. The remaining cases are
called inadequate/unsatisfactory, non-diagnostic. Any                            either true negatives (very scarce cellularity) or inad-
specimen with no mesothelial cells to be evaluated                               equate (absence of mesothelial cells).
should be unsatisfactory for evaluation, as in thyroid                        2. Cytology may aid in diagnosis in patients with epi-
and cervical cytology. (ii) To pay little attention to low                       thelioid and biphasic MM, but not in patients with
cellular effusions containing atypical mesothelial cells                         sarcomatoid MM.
dispersed as single cells. Several conditions limit exfo-                     3. Obscuring inflammatory background (lymphocytes,
liation of diagnostic cells into effusions (recurrent ef-                        neutrophils) and necrosis may hamper diagnostic
fusions, non-epithelial mesothelioma). Any specimen                              evaluation of atypical mesothelial cells.
with abnormal cells should be satisfactory for evalu-                         4. Currently, to limit the number of false-negative diag-
ation, as for cervical/thyroid cytology. In such cases,                          nosis, we ask clinicians to send the total amount of
a note should be added indicating that the presence of                           fluid that is actually collected to increase the amount
mesothelioma cannot be excluded. (iii) To not take into                          of cells. We carefully process effusion fluid to rou-
account high cellular effusions with a striking morular                          tinely prepare cell-blocks, as strongly recommended
pattern of mesothelial cells of bland appearance. An-                            by most experts.
other pitfall is the heavy inflammatory background that                       5. As in thyroid/breast and cervical cytology, a catego-
may hamper the diagnosis by obscuring the scant num-                             rized system for reporting effusion cytology may be
ber of mesothelial cells. In the atypical/M3 category,                           of help in the diagnostic work-up of fluids for meso-
we noticed that inflammatory cells were mainly lym-                              thelioma (inadequate [M1], negative [M2], atypical
phocytes; interestingly, it is known that mesothelioma                           [M3] and suspicious [M4]).
can be heavily infiltrated with many immune effector                          6. The scoring system adopted in this study (evaluating
cells, with T-lymphocytes constituting the major part                            the amount of mesothelial cells, architectural pattern
of inflammatory cells 7. Other factors (data not shown)                          and atypical features of mesothelial cells) is not par-
that may have contributed to the diagnostic pitfall are:                         ticularly useful in separating effusions due to non-
(i) the scarce amount of fluid examined respect to                               neoplastic conditions from those due to mesothe-
the amount of fluid evacuated implying hypocellular                              lioma; nevertheless, atypical features are probably
specimens; (ii) the improper specimen processing (ex-                            the most useful characteristics in the daily practice to
cess of blood and insufficient concentration of cellular                         discriminate between the two groups.
324                                                                                                                                v. aScoli et al.




References                                                                5
                                                                              Whitaker D. The cytology of malignant mesothelioma. Cytopathol-
                                                                              ogy 2000;11:139-51.
1
    Di Bonito L, Falconieri G, Colautti I, et al. Cytopathology of ma-    6
                                                                              Sheaff M. Should cytology be an acceptable means of diagnosing
    lignant mesothelioma: a study of its patterns and histological bas-
                                                                              malignant mesothelioma? Cytopathology 2010;22:3-4.
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2
    Renshaw AA, Dean BR, Antman KH, et al. The role of cytologic
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                                                                              Hegmans JP, Hemmes A, Hammad H, et al. Mesothelioma envi-
    evaluation of pleural fluid in the diagnosis of malignant mesothe-        ronment comprises cytokines and T-regulatory cells that suppress
    lioma. Chest 1997;111:106-9.                                              immune responses. Eur Respir J 2006;27:1086-95.
3
    Rakha EA, Patil S, Abdulla K, et al. The sensitivity of cytologic
                                                                          8
                                                                              Ikeda K, Suzuki T, Tate G, et al. Cytomorphologic features of
    evaluation of pleural fluid in the diagnosis of malignant mesothe-        well-differentiated papillary mesothelioma in peritoneal effusion:
    lioma. Diagn Cytopathol 2010;38:874-9.                                    a case report. Diagn Cytopathol 2008;36:512-5.
4
    Sherman ME, Mark EJ. Effusion cytology in the diagnosis of            9
                                                                              Haba T, Wakasa K, Sasaki M. Well-differentiated papillary
    malignant epithelioid and biphasic pleural mesothelioma. Arch             mesothelioma in the pelvic cavity. A case report. Acta Cytol
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pathologica 2011;103:325-330




                                                               Original article



                     Intra-operative frozen section technique
                          for breast cancer: end of an era
            E. MANFRIN, A. REMO*, F. FALSIROLLO, G.P. POLLINI**, A. PARISI, A. NOTTEGAR, F. BONETTI
  Department of Pathology and Diagnosis, Section of Surgical Pathology, G.B. Rossi Hospital, University of Verona; * Surgical Pathology
    Unit, Mater Salutis Hospital, ULSS21, Legnago (VR); ** Department of Surgery, G.B. Rossi Hospital, University of Verona, Italy



                                                                Key words

             Frozen sections • Intraoperative diagnosis • Breast cancer • Core needle biopsy • Fine needle aspiration cytology



                                                                 Summary

Data on 2436 primary breast carcinomas diagnosed between 1992            in 1999, and 0% in 2005-2006. In the same period, the adoption
and 2006 were collected to evaluate the rate of frozen section pro-      of cytology and core biopsy for breast cancer diagnosis increased
cedures performed over time. Frozen section procedures performed         from 40% in 1992 to more than 90% since 1999. In an audited
to evaluate resection margins for conservative surgery or sentinel       diagnostic activity on breast pathology, the routine use of frozen
node status were excluded. Over time, there was a decrease in the        sections on primary lesions was considered inappropriate, particu-
use of frozen sections indistinctly extended to all pT cancer catego-    larly in assessment of clinically non-palpable lesions, and should be
ries. The rate of cancers diagnosed with frozen sections was 51.2%       limited to cases with inadequate pre-surgical sampling.


Introduction                                                             intraoperative assessment of a suspicious breast lesion,
                                                                         while an important role is still reserved to the evaluation
The frozen section technique was first introduced by                     of resection margins 22-24 and status of sentinel lymph
Wilson in 1905 for intraoperative diagnosis of breast                    nodes 25-27.
carcinoma 1. In subsequent years, intraoperative frozen                  In the literature, only limited data have been collected
section examination was established as a reliable pro-                   with the aim of objectively defining the decreasing use
cedure for the rapid histologic evaluation of surgical                   of FS. The aim of the current study was to analyse the
breast specimens 2-6. Advances in radiology, pathology,                  frequency of FS utilization in primary breast cancer se-
surgical techniques, medical oncology and radiotherapy                   ries over a period of 15 years, and to evaluate the influ-
have changed the diagnostic and therapeutic approaches                   ence of clinical and pathological variables on results.
to breast cancer. Nowadays, different therapeutic strate-
gies to breast cancer are available and tailored treatment
for each individual patient is guided by detailed clinical               Materials and methods
and pathological data available before surgery. Over the
years, the flow-chart referred to the assessment of breast               Data on a large series of consecutive breast cancers, de-
lesions has been progressively shifted from intraopera-                  tected outside a screening program and surgically treated
tive procedures to pre-surgical diagnostic techniques, as                in “G.B. Rossi” University Hospital in Verona between
imaging guided fine-needle aspiration cytology (FNAC)                    January 1992 to December 2006 were extracted from
and core needle biopsy (CNB) or vacuum-assisted gun                      files of the Breast Cancer Registry and the Department
needle biopsy (VAB) 7-13. The diffusion of mammogra-                     of Pathology of the same institution. The rate of breast
phy has increased the detection of small cancers (< 1 cm)                cancers submitted to FS for intraoperative diagnostic
as well as proliferative, low grade atypical lesions for                 purpose were retrieved from computerized diagnostic
which intraoperative frozen sections (FS) should not be                  files of the Department of Pathology. Frozen section
considered mandatory 4-6 14-18. In this scenario, FS has lost            procedures performed to evaluate resection margins for
its role as the first line diagnostic method guiding the                 conservative surgery or sentinel node status were ex-
surgical strategy on primary breast lesions 19-21 through                cluded. According to the purpose of the present analysis,



                                                                           Correspondence
                                                                           Erminia Manfrin, Department of Pathology and Diagnosis,
                                                                           University of Verona, piazzale L.A. Scuro, 37134 Verona, Italy -
                                                                           Tel. +39 045 8124810 - Fax +39 045 8027136 - E-mail: erminia.
                                                                           manfrin@univr.it
326                                                                                                                          e. manfrin et al.




 Fig. 1. Distribution of the breast cancer detection rate according to pt classification and year of detection.




cancers were stratified according to the year of detec-                   cancers were submitted to FS, but in 2005 and 2006,
tion, “in situ” or invasive cancer histology, lesion size                 no primary breast lesion was assessed with FS (Fig. 2).
measured on the histological slide and expressed in pT                    The progressively decreasing use of FS began in the
category according to the American Joint Committee on                     middle of the 1990’s. At the beginning of the 2000’s,
Cancer (AJCC) 28. To match the number of cancers his-                     the requests for FS on primary breast lesions registered
tologically diagnosed and the number of needle biopsies                   a nearly vertical decrease (Fig. 2). The decreasing use
performed to gain a pre-surgical diagnosis, pathologi-                    of FS on primary breast cancers involved all pT cancer
cal files were also searched for pre-operative diagnostic                 categories (Fig. 3). From 1992 to 1999, the rate of can-
procedures performed on primary breast lesions during                     cers submitted to FS was significantly influenced by
the same period.                                                          cancer size with more FS performed on cancers larger
                                                                          than 1 cm (FS rate in pT1c cancers: 40%; FS rate in

Results
                                                                          Tab. I. frozen section procedures performed on 2434 primary breast
Between January, 1992 and December 2006, 2434 pri-                        cancers between 1992 and 2006.
mary breast cancers were collected at the Department                                              Cancer series    Frozen Section rate
of Pathology of the University of Verona (Tab. I). Inva-                   Year                       n. 2434                %
sive breast cancers accounted for 85.6% (2,084 cases)                      1992                         117                 51.3
and “in situ” cancers for 13.5% (329 cases). In 0.9%
of cases, the invasive or “in situ” type was not speci-                    1993                         139                 48.2
fied (21 cases). Over the years, the detection rate of                     1994                         105                 48.5
invasive breast cancers smaller than 2 cm (pT1mic-a,                       1995                         125                 44.0
pT1b, pT1c) showed a progressive increase balanced                         1996                         120                 39.1
by the decreasing detection rate of cancers larger than
                                                                           1997                         155                 29.0
2 cm (pT2+) (Fig. 1). Changes in the distribution in
the detection rate of breast cancer in favour of small                     1998                         195                 25.6
lesions were observed during the middle of the 1990’s,                     1999                         175                 22.8
but a higher detection rate was registered in 1999 and                     2000                         222                 12.1
continued in subsequent years, favoured by the intro-
                                                                           2001                         207                  1.0
duction of the breast cancer screening program and
more participation of women in non-organized mam-                          2002                         186                  0.0
mography tests. From 1999, the detection rate of “in                       2003                         129                  6.2
situ” carcinoma showed an increase that was almost                         2004                         162                  3.7
always greater than 15% (Fig. 1). The rate of FS per-                      2005                         219                   0
formed yearly on primary breast lesions progressively
decreased over time (Tab. I). In 1992, 50% of detected                     2006                         178                   0
frozen SectionS for breaSt cancer DiagnoSiS                                                                                     327



 Fig. 2. yearly rate of breast cancers submitted to frozen section analysis between 1992 and 2006 in our institution.




pT2+ cancers: 48.7%). In the 2000’s, the FS rate was                     the needle sampling procedures performed. The rate of
less than 2.5% in all pT cancer categories (Fig. 4).                     cancers submitted to a pre-surgical sampling procedure,
Data on pre-surgical diagnostic procedures performed                     either FNAC and CNB, increased exponentially since
on surgically treated lesions were completely avail-                     1995 (Fig. 5), which was balanced by the decreasing use
able for screen-detected breast cancers and have been                    of FS (Fig. 2).
previously published 10-11. All screen-detected breast
cancers were assessed with FNAC or CNB before sur-
gery. FNAC was adopted as a first-line method to obtain                  Discussion
cytological smears from suspicious lesions with an ac-
curacy that was well within the thresholds proposed by                   The results of the current study about the use of FS on
European guidelines for quality assurance in breast can-                 primary breast lesions during 15 years of surgical pa-
cer screening programmes 29. Briefly, the FNAC positive                  thology activity (1992-2006), have shown the progres-
predictive value for a malignant diagnosis was 99.3%,                    sive disuse of this technique in our institution. A rate as
the inadequate rate from cancer (IRc) was 2.4% and the                   high as 50% of primary breast cancers were submitted to
false-positive rate (FPR) was 0.5%.                                      FS in 1992, but at present no cancers are assessed with
Data on pre-surgical sampling diagnostic procedures                      FS in an intraoperative setting (Tab. I).
performed on clinically detected cancers were avail-                     For many years, the diagnosis of breast cancer was guid-
able for about 60% of all cases for years between 1992                   ed by the intraoperative assessment of suspicious lesions
and 1997, but for subsequent years (1998-2006) more                      by frozen sections. After long-lasting scientific discus-
of 90% of cases were furnished with information about                    sions about accuracy of FS on breast lesions, pathologists



 Fig. 3. rate of breast cancers submitted yearly to frozen section analysis according to cancer size.
328                                                                                                                            e. manfrin et al.




 Fig. 4. rate of cancers submitted to frozen section analysis according to cancer size in the 1990’s (blue column) and 2000’s (pink column).




achieved an overall agreement on the appropriate setting in              Screening programmes favour the detection of lower
which FS should be adopted 14 15 17 18 21 30-32. Trained person-         graded, smaller sized breast cancers as well as pre-inva-
nel and accurate selection of lesions to be submitted to FS              sive lesions and pure microcalcifications for which the
evaluation limited the false–negative rate to as less than 1%,           feasibility of intraoperative consultation has been evalu-
and the number of deferred diagnoses to less than 5% 2 6 21.             ated, but not routinely recommended 3 33. Studies sug-
The appropriateness of FS examination for diagnosis of                   gest that FS for these breast lesions may have a lower
mammographically-detected lesions has been subject of                    accuracy and may impair the results of definitive histol-
controversy, and most authors have concluded that frozen                 ogy from paraffin-embedded tissue due to freezing arte-
section examination should be limited to cases with distinct             facts 14-17 34 35.
gross lesions larger 1.0 cm 16 17. As a consequence, the per-            In the current cancer series, the beginning of the screen-
centage of breast specimens evaluated by frozen sections                 ing activity coincided with the growing detection of can-
has decreased over the years. A review of data from Ben                  cers smaller than 1 cm and the decreasing rate of cancers
Taub Hospital (Houston, USA) documented that, between                    larger than 2 cm (Fig. 1). However, only 8% of breast
1985 and 1995, 20% to 35% of all intraoperative consulta-                cancers collected from 1999 to 2006 were screen-detect-
tions sent to frozen section analysis were from the breast,              ed, and assume that the “positive” effect of screening
but this decreased to 4-8% in the 2000’s 21.                             programmes in stimulating women to perform mam-
In our institution, the decreasing use of FS, already de-                mography examinations favoured the improved detec-
tectable in the middle of 1990’s, registered an accelera-                tion of small breast cancers even in a female popula-
tion at the beginning of 2000’s in concomitance with the                 tion that was not invited to screening represents 92% of
beginning of screening programme activity (Fig. 2).                      the current series. The overall detection rate for cancers


 Fig. 5. rate of breast cancer submitted yearly to pre-surgical needle sampling between 1992 and 2006 in our institution.
frozen SectionS for breaSt cancer DiagnoSiS                                                                                                      329



smaller than 1 cm shifted from 12-18% between 1992                          solved cases sent to FS. The type of breast lesion on
and 1996 to 20- 40% in subsequent years.                                    mammograms or ultrasound (focal, parenchymal distor-
The growing number of small breast lesions may be a                         tion, calcifications) and the confidence of the radiolo-
cause of the reduced use of FS. The sensitivity of frozen                   gist or pathologist with a needle sampling technique are
section diagnoses of breast lesions after the introduction                  guiding the modality to obtain diagnostic samples from
of a national programme in mammographic screening                           breast lesions 8-10, reducing costs 13 and limiting the use
in Luxembourg dropped from 92.3% in 1990 to 87.6%                           of FS to those cases in which a pre-surgical diagnosis is
in 1998, the negative predictive value from 95.7% to                        not adequate.
88.3%, and invasive breast cancers ≤ 1 cm increased                         A preoperative core or fine-needle biopsy may eliminate
from 14.2% to 22.3% (p < 0.01). Breast frozen section                       unnecessary surgery and significantly reduce costs 38-40.
examinations in 1990 compared to those in 1998 de-                          The study of sentinel lymph node and schemes of neo-
clined from 70.7% to 62.2% 20.                                              adjuvant chemotherapy that increase breast conserva-
Nevertheless, the decreasing use of FS is not completely                    tion surgery, disease-free and overall survival in patients
explained by the increased detection rate of small cancers                  with complete pathological response 41, favoured the
less than 1 cm. In current series, the decreasing rate of FS                adoption of core needle biopsy for histological dem-
performed on primary breast cancers was observed in all                     onstration of breast carcinoma and for the assessment
pT cancer categories (Fig. 2). The comparison between                       of a biological cancer profile predictive of response to
the FS rate performed on breast cancers collected between                   medical therapy. In addition, preoperative diagnosis of
1992 and 1999 and the FS rate in cancer series between                      invasive breast cancer increases the likelihood of clean
2000 and 2006, stratified according to cancer size, high-                   margins at definitive surgery 38-40. This reduces the need
lights that in the 2000’s FS was exceptionally performed                    for a two-stage procedure and improves both surgical
for diagnostic purpose on primary breast cancers, what-                     and oncological outcomes 42 43.
ever the cancer size (Fig. 3). This is far more interesting                 Advances in surgical techniques, oncology, pathology,
for our analysis, especially if it is considered that in 2005               radiotherapy and radiology have influenced a new vi-
and 2006, on a total of 397 cancers, no FS was performed                    sion for treatment of breast cancer and reduced surgical
(Tab. I), even if 60% of detected cancers were larger than                  trauma. The current results confirm that drastic changes
1 cm and potentially amenable to FS (Fig. 1).                               have occurred in the management of breast lesions, with
The strictly adherence to guideline recommendations                         more patients evaluated in a pre-operative setting. After
favouring pre-surgical, image-guided needle assessment                      more than 100 years from its first adoption as a rapid
of breast suspicious lesions to avoid unnecessary sur-                      method for breast cancer diagnosis 1, the use of frozen
gery 29, aided the widespread adoption of FNAC, CNB                         sections is no longer considered for primary breast le-
and VAB to obtain a diagnosis on mammographically                           sions. In an audited diagnostic activity on breast pathol-
detected breast lesions 36. In a multidisciplinary approach                 ogy, the routine use of FS on primary lesions is inappro-
to breast lesions, biopsy techniques provided optimal di-                   priate, particularly in the assessment of clinically non-
agnostic accuracy with a sensitivity between 93% and                        palpable lesions. Its use should be limited to cases with
100% and a specificity between 98% and 100% 10 30-32,                       inadequate pre-surgical sampling quantified in no more
which undoubtedly influenced the reduction of unre-                         than 5% of surgically removed cancers 29.


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pathologica 2011;103:331-336




                                                             Original article



                The diagnostic accuracy of cervical biopsies
                  in determining cervical lesions: an audit
                                                     J. WANG, M. EL-BAHRAWY
                           Department of Histopathology, Hammersmith Hospital, Imperial College London, UK



                                                             Key words

                                     Cervix • Biopsy • Colposcopy • Dysplasia • Cancer • Screening



                                                              Summary

Objective. The present audit was carried out to assess the diag-       Main outcome measures and results. In 2004-5, the rate of con-
nostic accuracy of cervical punch biopsy during colposcopy in          sistent diagnosis was 68.7%, compared with 75.8% in 2008. This
comparison with diagnosis from subsequent cone excision.               was due to a decrease in the rates of overdiagnosis (16.7% vs.
Design and setting. Retrospective analysis was performed by            14.8%) and underdiagnosis (14.7% vs. 9.4%), which was statisti-
examining the histopathology reports for paired cervical punch         cally significant. The sensitivity rates for 2004-5 and 2008 were
biopsies and cervical cone excisions for cases reported from April     87.5% and 89.7%, and the specificity rates for the same periods
2004 to March 2005 (when cervical biopsies and cones were              were 39.8% and 39.4% respectively.
reported by general pathologists) and from January to December         Conclusions. This audit highlights the importance of planning
2008 (when reporting by specialist gynaecological pathologists         patient management on the basis of co-ordinated information
was instituted).                                                       from smear results, history, colposcopy findings and cervical
Sample. 150 women had both cervical punch and cone biopsies            biopsies. The introduction of specialist gynaecological histopa-
performed in the 2004-2005 period, while 149 women had both            thology reporting has significantly improved the rates of consis-
biopsies performed in 2008.                                            tent diagnosis.



Introduction                                                           opsy, the patient then undergoes cervical cone or loop
                                                                       excision.
In the UK, a cervical screening program has been imple-                Therefore, accurate diagnosis on the biopsy taken at col-
mented since the 1980s, and the advantages of cervical                 poscopy is key in directing further management of the
screening are well documented, with a decrease in both                 patient. Despite the importance of this key step in the
incidence and mortality from cervical cancers. Despite                 patient pathway, there have been few studies examin-
its success, cervical screening by cytology is not always              ing the reliability of cervical punch biopsies. One study
reliable. It has been established that the average screen-             analysed 352 cases and showed that there was a concor-
ing sensitivity and specificity of cervical cytology is                dance rate of only 66% between the histological diagno-
about 61-66% and 82-91%, respectively 1 2. However, a                  ses of punch biopsies and the results of the subsequent
positive cervical cytology result is only the first step in            loop excision of the cervix 3. In another study of 107
the pathway towards definitive diagnosis and treatment                 cases, cervical punch biopsy was compared to cytology.
of a cervical lesion. The current practice in the UK is                It was found that there was a consistency rate of 63%
that a patient with a cytology result confirming defi-                 between cervical punch biopsies and cones 4.
nite dyskaryosis or with repeated borderline change                    We investigated the accuracy of reporting of cervical bi-
requires referral to colposcopy. At colposcopy, the                    opsies taken at colposcopy, which would influence the
cervix is visualized and a punch biopsy is often taken                 subsequent management of patients. Moreover, the prac-
for histological examination. If high grade cervical                   tice of histopathologists as a whole is moving towards
intraepithelial neoplasia (CIN) or cervical glandular                  specialist reporting. It also remains to be seen if such a
intraepithelial neoplasia (CGIN) is confirmed on bi-                   move improves the accuracy of cervical punch biopsy



 Acknowledgements                                                        Correspondence
 M. El-Bahrawy is grateful for support from the NIHR Biomedical          Mona A. El-Bahrawy, Department of Histopathology, Imperial
 Research Centre funding scheme. J. Wang receives funding from           College London, Hammersmith Hospital, DuCane Road, London
 the NIHR Clinical Lecturer scheme.                                      W12 0NN UK - Tel. 020 8383 3442 - Fax 020 8383 8141 - E-mail:
                                                                         m.elbahrawy@imperial.ac.uk
332                                                                                                        J. wang, m. el-bahrawy




diagnosis. In this audit, we investigated the diagnostic         of high-grade squamous intra-epithelial lesions (HSIL).
accuracy of cervical biopsies performed at a gynaeco-            The same situation also applies for CIN2/3 and CGIN.
logical cancer centre. The accuracy of diagnosis in two          However, CIN1 and human papilloma virus (HPV) in-
different periods was analysed, a period during which            fections were categorized separately, despite the similar
the diagnosis of cervical biopsies and cones was done by         management plans and the common Bethesda classifica-
general pathologists, and a period after specialist report-      tion of low-grade SIL (LSIL). This is because these le-
ing by gynaecological histopathologists was instituted           sions have previously had different management strate-
and the vast majority of cervical biopsies were reported         gies in the UK. In addition, a diagnosis of CIN (difficult
by specialists.                                                  to grade) or an inadequate sample at cervical biopsy was
                                                                 deemed to be consistent with any CIN grade in the cone
                                                                 excision. However, a biopsy diagnosis of CIN (difficult
Methods                                                          to grade) and a subsequent cone diagnosis of HPV only
                                                                 or benign conditions was considered overdiagnosis.
Patients                                                         In addition to comparing the reporting accuracy be-
This is a retrospective study of histopathology reporting        tween the two periods, the results were categorized into
on cervical punch biopsies and cones during two periods.         whether the reporting of the cervical punch biopsy was
The earlier period was from 1 April 2004 to 31 March             done by specialist gynaecological histopathologists, or
2005, and the later period was from 1 January 2008 to            by general histopathologists.
31 December 2008. Only patients who had both a cervi-
                                                                 Standards
cal biopsy and a subsequent cone biopsy reported at the
Department of Histopathology, Hammersmith Hospital,              There have not been any previous publications that have
during the periods defined were included.                        dealt in detail with the problem of overdiagnosis or un-
                                                                 derdiagnosis in cervical biopsies. However, Boonkilit et
Data collection                                                  al. have shown in their series that there is a concordance
For each pair of specimens, pathology reports were re-           rate of 66% between cervical biopsy results and cones 3.
trieved and the following data collected: type of speci-         For the purposes of the present audit, therefore, we have
men, consultant histopathologist (general or specialist)         considered a consistent diagnosis rate of 60% to be ac-
reporting the case and diagnosis. In cases where the             ceptable. Also, Thompson et al. have shown that there
diagnosis fell between two categories, the higher grade          was a negative diagnosis in cone excisions of 28-68% 5.
diagnosis was recorded, as in most cases further man-            Thus, an overdiagnosis rate of less than 25% was con-
agement would be based on the higher grade disease.              sidered acceptable.
As examples, for the purpose of this audit in a punch
                                                                 Statistical analysis
biopsy reported as showing CIN 2-3, the diagnosis was
considered as CIN 3 and for a punch biopsy where the             To determine if the number of consistent diagnoses and
diagnosis is CIN 1 and CGIN, the diagnosis was CGIN.             the number of either over- or underdiagnoses were sig-
Based on the diagnoses of the biopsies and cones, each           nificantly different between the two periods of reporting,
pair of specimens was categorized as having consistent           a chi-square test was performed. A significant difference
diagnoses, overdiagnoses or underdiagnoses. Situations           in reporting accuracy was if the p value was < 0.05.
of overdiagnosis and underdiagnosis are summarized in            Finally, to calculate the sensitivity, specificity, positive
Table I.                                                         predictive value (PPV) and negative predictive value
For the audit purposes, since CIN2 and CIN3 are both             (NPV) for the two reporting periods, each diagnosis was
high grade lesions which have similar management pro-            categorized into positive results (high-grade lesions or
tocols, a biopsy of CIN2 with a subsequent cone excision         higher, including CIN2, 3, CGIN and invasive cancer) or
showing CIN3, or vice versa, was classified as consistent        negative results (low-grade or benign lesions, including
diagnosis. This is in line with the Bethesda classification      CIN1, HPV, atypia or inflammation). This classification
                                                                 was based on the management protocols for the diag-
                                                                 nosis, with high-grade lesions being an indication for a
Tab. I. criteria for overdiagnosis and underdiagnosis.
                                                                 cone excision. Biopsy samples which were CIN (diffi-
Overdiagnosis Criteria
                                                                 cult to grade) or inadequate were classified as consistent
cin2 or 3                           cin1/hpv/benign conditions   with the cone diagnosis (as described above).
cin1                                hpv/benign conditions
cin (difficult to grade)            hpv/benign conditions
                                                                 Results
Underdiagnosis Criteria
cervical punch biopsy               cone biopsy                  Cervical biopsy and cone results
cin1                                cin2 or 3
                                                                 From April 2004 to March 2005, a total of 744 cervi-
hpv                                 cin 1, 2 or 3
                                                                 cal punch biopsies were reported. Of these, 150 cervical
cin (any grade)                     invasive carcinoma           biopsies had subsequent cone biopsies done in the same
benign conditions/atypia            hpv/cin/invasive carcinoma   period. The mean age of patients was 32 years (range
DiagnoStic accuracy of cervical biopSieS                                                                                              333



21-77 years). In 2008 (January to December), the total                   Fig. 1. case 1: cervical punch biopsy showed cin3 (a, X100), and
number of cervical punch biopsies was 514, with 149                      the subsequent cone only showed inflammation (b, X100). case
of patients having subsequent cone biopsies. The mean                    2: the cervical punch biopsy showed no definite features of dys-
age of the patients for this period was 31 years (range                  plasia (c, X100) and the subsequent cone showed cin2 (D, X100).

23-70).
In 2004-2005, the histological diagnoses of cervical bi-
opsies were 13 CIN1, 64 CIN2, 42 CIN3, 2 CIN difficult
to grade, 5 CGIN, 5 invasive carcinoma, 6 HPV and 13
benign lesion (e.g. cervicitis). Among the cone biopsies,
there were 27 CIN1, 45 CIN2, 50 CIN3, 4 CGIN, 10
invasive carcinoma, 7 HPV and 7 benign lesion. The
percentages of high-grade lesions diagnosed by cervical
biopsies and at cone excision were 78.7% and 72.7%,
respectively. Figure 1 shows examples of the different
diagnoses in cervical punch and cone biopsies.
In 2008, among the cervical biopsies, there were 13 CIN1,
89 CIN2, 29 CIN3, 1 CIN difficult to grade, 2 CGIN, 3 in-
vasive carcinoma, 2 HPV and 10 benign. Among the cone
biopsies, there were 21 CIN1, 65 CIN2, 45 CIN3, 2 CGIN,
3 invasive, 2 HPV and 10 benign lesion. The percentages
of high-grade lesions diagnosed
by cervical biopsies and at cone        Fig. 2. (a) rates of over- and under- and correct diagnosis in the years 2004-5 and 2008. (b)
excision were 83.2% and 77.2%,          Sensitivities, specificities, ppv and npv in both periods.
respectively.
Sensitivity and specificity of re-
porting
For the reporting period 2004-5,
the sensitivity of the cervical bi-
opsy was 87.5%, the specificity
was 39.5%, the PPV was 81.0%
and the NPV was 51.7%. In
2008, the respective values were
89.7%, 39.4%, 83.9% and 52%.
The results are shown in Figure
2A.
Consistency of reporting
The results were categorized
into cervical biopsies that were
consistent with cone diagnosis,
overdiagnoses or underdiag-
noses. The results are shown in
Tables II, III and IV respective-
ly. There was an increase in the
percentage of consistent diagno-
ses in 2008 (75.8%) compared
with 2004 (68.7%), with de-
crease in both the incidences of
over- (14.8% vs 16.7%) and un-
derdiagnoses (9.4% vs 14.7%).
The results are presented in
Figure 2B.
Considering cases of overdiag-
nosis in the original cervical bi-
opsy, an important subset were
those diagnosed as high grade
lesions on the cervical biopsy,
but subsequently found to be low
grade or benign lesions on cone
334                                                                                                                   J. wang, m. el-bahrawy




excision. For this subset, it was also found that there was                  sies reported by general pathologists in 2004-2005, the
a decrease from 15.3% in 2005 to 13.4% in 2008 (high-                        incidences of consistent diagnosis, overdiagnosis and
lighted in bold in Table III).                                               underdiagnosis were 68.1%, 17.0% and 14.8%, respec-
In 2004-5, only 15 of 150 (10%) cases were reported by                       tively. In contrast, for biopsies undergoing specialist re-
specialist gynaecological pathologists. In contrast, 123                     porting in 2008, the incidences of consistent diagnosis,
of 149 (83%) cases were reported by specialist patholo-                      overdiagnosis and underdiagnosis were 76.4%, 14.6%
gists in 2008. The results show that for the cervical biop-                  and 8.9%, respectively.



Tab. II. number of consistent diagnoses between cervical biopsies and cones.
Punch Biopsy Diagnosis Cone Diagnosis                                2004              % of total          2008           % of total
cin1                           cin1                                    5                      3.3           4                  2.7
cin2                           cin2                                    45                     30.0          70                47.0
cin3                           cin3                                    35                     23.3          27                18.1
inv                            inv                                     5                      3.3           3                  2.0
cgin                           cgin                                    3                      2.0           1                  0.7
naD/infl/meta                  naD/infl/meta                           3                      2.0           5                  3.4
others                         others                                   7                     4.7            3                 2.0
 cin 2/3                        cgin                                   (1)                                  (2)
 cgin                           cin2/3                                 (1)
 cin(difficult to grade)        cin2/3                                 (1)                                  (1)
 inadequate                     cin/inv                                (4)
total                                                                 103                     68.7         113                75.8
naD: no abnormality detected; infl: inflammation; meta: metaplasia; inv: invasive carcinoma



Tab. III. number of overdiagnoses in cervical biopsies compared with cones.
Punch Biopsy Diagnosis Cone Diagnosis                                2004              % of total          2008           % of total
cin2/3                 cin1                                           17                 11.3               16              10.7
cin2/3                         hpv                                     3                      2.0           0                  0.0
cin2/3                         naD/infl/meta                           3                      2.0           4                  2.7
cin3                           cin2                                    0                      0.0           0                  0.0
cin1                           hpv                                     1                      0.7           1                  0.7
cin (difficult to grade)       hpv                                     1                      0.7           0                  0.0


cin1                           atypia                                  0                      0.0           1                  0.7
total                                                                  25                     16.7          22                14.8
naD: no abnormality detected; infl: inflammation; meta: metaplasia; inv: invasive carcinoma



Tab. IV. number of underdiagnoses in cervical biopsies compared with cones.
Punch Biopsy Diagnosis Cone Diagnosis                                2004              % of total          2008           % of total
cin1                           cin2/3                                  6                      4.0           7                  4.7
cin2                           cin3                                    0                      0.0           0                  0.0
hpv                            cin                                      6                     4.0            2                 1.3
                               (cin1)                                  (2)                                  (1)
                               (cin2/3)                                (4)                                  (1)
cin                            inv                                      4                     2.7            0                 0.0
(cin3)                                                                 (3)
(cin1)                                                                 (1)
naD/infl/meta                  cin/inv                                  5                     3.3           4                  2.7
                               (inv)                                   (1)
                               (cin2/3)                                (2)                                  (4)
                               (cin1)                                  (2)
naD/infl/meta                  hpv                                      1                     0.7           1                  0.7
atypia
total                                                                  22                     14.7          14                 9.4
naD: no abnormality detected; infl: inflammation; meta: metaplasia; inv: invasive carcinoma
DiagnoStic accuracy of cervical biopSieS                                                                               335



Statistical analysis                                            the basis of smear results of high grade dyskaryosis, per-
To determine if there was a difference in the incidence         sistent low grade dyskaryosis or a colposcopic impres-
of over- and underdiagnosis between the two periods             sion of high grade lesion. This highlights the importance
of reporting, Pearson’s chi-square test was applied. A          in which biopsy diagnoses are considered in context of
statistically significant improvement in the rate of over-      the cervical smear and colposcopy results, thus leading
diagnosis was found cChi-square = 346, p = 0.03) and            to a cone excision despite a negative or low grade bi-
underdiagnosis (chi-square = 375, p < 0.01).                    opsy, if indicated.
                                                                The overdiagnosis rate is considered more critical, as it
                                                                leads to cone excisions even if smear results and col-
Discussion                                                      poscopic impression are not consistent. In our study,
                                                                the rate of overdiagnoses of high grade lesions was de-
Cervical punch biopsy is an essential component in cervi-       creased from 15% to 13% from the first to the second
cal screening, yet it has limitations despite targeted sam-     period of study. This is significant, as cone excisions can
pling at colposcopy and care in specimen processing and         be associated with complications (although rare), and
reporting. A previous study showed that 33% of directed         hence should be avoided if not indicated.
biopsies did not detect the high-grade lesion found in the      It must be stated that the discrepancy between punch
cone 6, while 40% of random biopsies were able to detect        biopsy diagnosis and cone biopsy does not necessarily
high grade dysplasia. Assessment of cervical cone biop-         imply an incorrect interpretation by the pathologist in all
sies also has its challenges. In one study, 99 negative cones   cases. In some instances, the lesions are small and may
were reviewed and 21 cases were subsequently found to           be totally removed by the biopsy, and hence may not be
be positive for dysplasia or malignancy 7. In another study,    represented in the subsequent cone. Also, although very
of 95 negative cone biopsies 25 on subsequent review or         informative and accurate in the majority of cases, cervi-
resectioning were found to have significant lesions 5.          cal punch biopsies have their inherent limitations. It is
In this study, we investigated the accuracy of cervical         possible that the biopsied part of the cervix at colposcopy
punch biopsy reporting, as compared with subsequent             does not target the area of actual abnormality, and hence
diagnosis of cone excision specimens. We show that              the dysplasia is not detected due to an erroneous site of
the rate of consistent diagnoses has increased from             sampling. Improvements which may increase the accu-
2004 to 2008, from 68.7% to 75.8%. This was due to              racy of the biopsy include four quadrant biopsies 9 and
a statistically significant decrease in both the rates of       studying histological sections taken at multiple levels for
over- and underdiagnoses. The reason for this improve-          thorough histological assessment 10. A fact that must also
ment is most likely due to a change in the practice of          be acknowledged is that in some cases there is justifiable
reporting cervical biopsies, from that by general his-          interobserver variability. Some biopsies are difficult to
topathologists in the general pool of specimens, to             interpret due to being small, partially traumatised, poor-
specialist reporting by gynaecological histopatholo-            ly orientated or even showing very subtle changes that
gists, which was the only change in laboratory practice         require much experience and may well initiate interob-
between both periods. In a previous study examining             server variability. Recent developments to improve the
positive cones to determine the accuracy of biopsies 8,         diagnosis of cervical biopsies, as well as cervical smears,
of 355 biopsy-proven cases of dysplasia, 323 had a              include HPV genotyping for high risk HPV subtypes
subsequent positive cone. With 22 negative cones, the           and immunohistochemistry for p16INK4a 11 12. These
PPV was 91%. However, when only high grade lesions              additional tests have been shown to aid in the diagno-
on pre-cone histology or cytology were analysed, 277            sis of CIN in equivocal and difficult cases. For example,
of 371 cases had a positive cone diagnosis, giving a            p16INK4a has been shown to significantly improve the
sensitivity of 74.7%. Our current study therefore was           interobserver agreement between pathologists for punch
comparable with a sensitivity of 89.7% and a PPV of             biopsies 12.
83.9% with specialist reporting.
Two other previous studies compared the consistency be-
tween the pre-cone diagnosis and the cone excision. The         Conclusion
consistency rate between cervical biopsy and cone exci-
sion pathological diagnoses was 66.2% in one study 3            In conclusion, the role of cervical biopsy is essential but
and 63% in another 4. Our study showed a comparable             still has its limitations. As recommended by the National
consistency rate in the first period, but in the second         Health Service (NHS) cervical screening programme, it
period where specialist reporting was implemented, the          is essential that patient management is based on co-ordi-
rate was increased to over 75%.                                 nated information of smear results, history, colposcopy
It is important to note that in our cohort cases with under-    findings and cervical biopsy results. It is recommended
diagnosis still underwent cone biopsies, although these         that these specimens are reported by specialist gynaeco-
diagnoses will not lead to a cone excision if considered        logical pathologists, which have been shown to be ad-
in isolation. In these cases, the cone was performed on         vantageous in increasing the diagnostic accuracy.
336                                                                                                                           J. wang, m. el-bahrawy




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    Coste J, Cochand-Priollet B, de Cremoux P, et al. Cross sectional         Gynecol Oncol 2009;115:493-6.
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                                                                              Golbang P, Scurry J, de Jong S, et al. Investigation of 100 consecutive
    man papillomavirus DNA testing for cervical cancer screening.             negative cone biopsies. Br J Obstet Gynaecol 1997;104:100-4.
    BMJ 2003;326:733.
                                                                         8
                                                                              Spitzer M, Chernys AE, Shifrin A, et al. Indications for cone biopsy:
2
    Kulasingam SL, Hughes JP, Kiviat NB, et al. Evaluation of human           pathologic correlation. Am J Obstet Gynecol 1998;178(1 Pt 1):74-9.
    papillomavirus testing in primary screening for cervical abnor-
    malities: comparison of sensitivity, specificity, and frequency of
                                                                         9
                                                                              Cagle AJ, Hu SY, Sellors JW, et al. Use of an expanded gold stan-
    referral. JAMA 2002;288:1749-57.                                          dard to estimate the accuracy of colposcopy and visual inspection
                                                                              with acetic acid. Int J Cancer 2010;126:156-61.
3
    Boonlikit S, Asavapiriyanont S, Junghuttakarnsatit P, et al. Cor-
    relation between colposcopically directed biopsy and large loop
                                                                         10
                                                                              Fadare O, Rodriguez R. Squamous dysplasia of the uterine cervix:
    excision of the transformation zone and influence of age on the           tissue sampling-related diagnostic considerations in 600 consecu-
    outcome. J Med Assoc Thai 2006;89:299-305.                                tive biopsies. Int J Gynecol Pathol 2007;26:469-74.
4
    Heatley MK, Bury JP. The correlation between the grade of dys-       11
                                                                              Sigurdsson K, Taddeo FJ, Benediktsdottir KR, et al. HPV geno-
    karyosis on cervical smear, grade of cervical intraepithelial neo-        types in CIN 2-3 lesions and cervical cancer: a population-based
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                                                                              Horn LC, Reichert A, Oster A, et al. Immunostaining for p16INK4a
5
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pathologica 2011;103:337-339




                                                            Original article



         “Combined” desmoplastic melanoma of the vulva
                  with poor clinical outcome
                                                            G. COLLINA
                         Unit of Anatomic Pathology, Department of Oncology, Maggiore Hospital, Bologna, Italy



                                                             Key words

                           Desmoplastic melanoma • “Combined” • Vulva • Immunohistochemistry • Protein S100



                                                             Summary

Desmoplastic melanomas in an unusual variant of melanoma              superficial spitzoid component and a deeper spindle desmoplas-
that usually occurs in sun-damaged skin of elderly people. Des-       tic component. Protein S-100 expression was ubiquitous, while
moplasia may be the prominent features of the lesion or rep-          MART-1 and HMB-45 were limited to the superficial spitzoid
resent a portion of an otherwise non-desmoplastic melanoma;           component and were negative in desmoplastic areas. Notably,
these latter are called “combined” desmoplastic melanoma. Des-        the nodal metastasis retained the same biphasic pattern seen in
moplastic melanomas of the vulva are rare. Herein, we report          the primary tumour. The patient died of widespread metastatic
a case of “combined” DM of the labia minor consisting of a            disease 3 years after diagnosis.



Introduction                                                          Materials and methods
Melanoma represents the second most frequent malig-                   The excised material was fixed in 10% formalin and em-
nancy of the vulva. These neoplasms occur mostly in                   bedded in paraffin. Deparaffinized 5-µm-thick sections
post-menopausal women and are generally diagnosed                     were stained with haematoxylin and eosin. Immunohis-
when they ulcerate and discharge blood 1. Vulvar des-                 tochemistry was performed using the Ventana System
moplastic melanomas are uncommon, and only a few                      employing the following antibodies: protein S100 (Ven-
cases have been documented 1-4. Herein, we report a                   tana ready to use), MART-1 [Melan-A (A-103), Ventana
case of “combined” desmoplastic and spitzoid mela-                    ready to use], HMB-45 (Cell Marque ready to use), actin
noma.                                                                 [muscle-specific (HHF35) Cell Marque ready to use].


Clinical history                                                      Results
A 73-year-old female sought medical attention for an                  A 0.3 cm punch biopsy showed a hyperplastic epider-
ulcerated nodule of the right labia major. A biopsy was               mis with atypical melanocytes localized at the dermal-
performed and a diagnosis of melanoma was rendered.                   epidermal junction (Fig. 1). The upper dermis was in-
Two weeks later she underwent surgical excision. The                  filtrated by epithelioid and pleomorphic melanocytes.
skin ellipse measured 2.5 × 2 cm and was centred by                   Dilated capillaries reminiscent of Spitz lesion were also
a grey ulcerated nodule measuring 2 cm in diameter.                   present (Fig. 2). The skin ellipse showed a polypoid, ul-
Sentinel lymph node procedure was performed and a                     cerated and hypopigmented tumour (Fig. 3). The lesion
right inguinal lymph node was removed. The sentinel                   was composed of single or grouped melanocytes, which
lymph was metastatic. Complete inguinal lymphoad-                     reached the upper layer of the epidermis.
enectomy failed to show other metastases. The patient                 In the deeper part of the dermis, the epithelioid compo-
died of widespread metastatic disease 3 years after di-               nent merged with spindle neoplastic cells interspersed
agnosis.                                                              among dense collagen bundles (Fig. 4) which represent-



                                                                        Correspondence
                                                                        Guido Collina, Unit of Anatomic Pathology, Department of
                                                                        Oncology, Maggiore Hospital, l.go B. Nigrisoli 2, 40133 Bologna,
                                                                        Italy - Tel. +39 051 6478908 - Fax +39 051 6478660 - E-mail:
                                                                        guido.collina@ausl.bologna.it
338                                                                                                                              g. collina




Fig. 1. punch biopsy shows ulcerated and hyperplastic epidermis          Fig. 4. in the deep part of the lesion, neoplastic melanocytes
and neoplastic cells expanding the superficial dermis, revealing oe-     are spindled and immersed in a desmoplastic stroma, which
dema and dilated vessels.                                                shows increased mucin.




  Fig. 2. neoplastic melanocytes are either epithelioid either spin-    Fig. 5. S100 protein diffusely stained neoplastic melanocytes in
  dled. lymphocytes in groups and dilated vessels are also present      both the epithelioid and spindle component in the desmoplastic
  (left side).                                                          area.




 Fig. 3. melanoma has polypoid conformation with dumbbell               Fig. 6. Strong mart 1 immunostaining in the epithelioid superfi-
 features and reaches the deep dermis almost approaching the            cial melanocytes, while spindled melanocytes, including those of
 sub-cutaneous fat.                                                     the desmoplastic area, were negative.




ed 40% of the entire lesion. Features of neurotropism                  spindle cells (Fig. 6), which were nonetheless faintly
and angiotropism were present.                                         positive; HMB-45 stained only a few epithelioid mel-
Protein S100 was ubiquitous (Fig. 5), while MART-1                     anocytes. Smooth muscle actin was negative.
strongly stained the epithelioid melanocytes of the spit-              The micro-staging of this lesion showed it to fall into
zoid component of the upper part of the lesion that were               the poor prognosis category (i.e. 5.7 mm in Breslow’s
almost negative in the desmoplastic areas except for rare              thickness, ulceration and the number of mitosis was at
“combineD” DeSmoplaStic melanoma of the vulva with poor clinical outcome                                                                  339



    Fig. 7. metastatic-inguinal-sentinel-lymph node: the biphasic          or replacement nerve bundles typical of this melanoma
    patter of primary lesion is also preserved in the metastasis, epi-     subtype 6.
    thelioid melanocytes are localized on the left, while the desmo-       DM/neurotropic melanomas of the vulva are uncom-
    plastic area is evident on the right.
                                                                           mon, and similar to mucosal melanomas, have a dismal
                                                                           prognosis 4.
                                                                           We report a case of “combined” DM of the labia mi-
                                                                           nor consisting of a superficial spitzoid component and a
                                                                           deeper spindle desmoplastic component. S-100 expres-
                                                                           sion was ubiquitous, while MART-1 and HMB-45 were
                                                                           limited to the superficial spitzoid component and were
                                                                           negative in desmoplastic areas. Notably, the nodal me-
                                                                           tastasis retained the same biphasic pattern seen in the
                                                                           primary tumour. This is infrequent considering that in a
                                                                           series of 55 DM only 2% showed lymph-node metasta-
                                                                           ses 7. Complete lymphoadenectomy failed to show other
                                                                           metastatic lymph nodes. The patient died 3 years later
                                                                           due to widespread metastases.
least 6 per mm2). The lymph node showed metastatic                         There is still controversy on the prognosis of DM. Early
deposits composed of either spitzoid or desmoplastic ar-                   studies suggested an aggressive behaviour than conven-
eas (Fig 7).                                                               tional melanomas, while others documented DM with a
                                                                           more favourable clinical course 5
                                                                           Busam et al. 8 suggested that pure desmoplastic mela-
Discussion                                                                 nomas thicker than 4 mm have a better prognosis when
                                                                           compared with combined DM and conventional mela-
Desmoplastic melanoma (DM) is a rare variant of                            nomas of the same thickness. In their study, only 3 of
spindle cell melanoma that usually occurs in the sun-                      26 patients with pure DM died of disease compared to
damaged skin of elderly patients. Conley et al. first de-                  the experience of their institution, where 25% of patients
scribed DM in 1971 as “a variant of spindle cell mela-                     died for thick conventional melanomas in 3 years. Our
noma which elicits the production of abundant colla-                       patient seems to confirm that thickness and the presence
gen” 5. Reed and Leonard further expanded the original                     of “combined” histological components represent valu-
description and documented the extensive infiltration                      able prognostic indicators of poor outcome.


References                                                                 5
                                                                               Conley J, Lattes R, Orr W. Desmoplastic malignant melanoma (a
                                                                               rare variant of spindle cell melanoma). Cancer 1971;28:914-36.
1
     Byrne PR, Maiman M, Mikhail A, et al. Neurotropic desmoplastic mel-   6
                                                                               Reed JG, Leonard DD. Neurotropic melanoma: a variant of des-
     anoma: a rare vulvar malignancy. Gynecol Oncol 1995;56:289-93.            moplastic melanoma. Am J Surg. Pathol 1979;3:301-11.
2
     Warner TF, Hafez GR, Buchler DA. Neurotropic melanoma of the          7
                                                                               de Almeida LS, Requena L, Rutten A, et al. Desmoplastic malig-
     vulva. Cancer 1982;49:999-1004.                                           nant melanoma : a clinicopathologic analysis of 113 cases. Am J
3
     Mulvany NJ, Sykes P. Desmoplastic melanoma of the vulva. Pa-              Dermatopathol 2008;30:207-15.
     thology 1997;29:241-5.                                                8
                                                                               Busam KJ, Mujumdar U, Hummer AJ, et al. Cutaneous desmo-
4
     Rogers RS 3 , Gibson LE. Mucosal, genital, and unusual clinical
                  rd                                                           plastic melanoma: reappraisal of morphologic heterogeneity and
     variants of melanoma. Mayo Clin Proc 1997;72:362-6.                       prognostic factors. Am J Surg Pathol 2004;28:1518-25.
pathologica 2011;103:340-342




                                                                  case repOrt



 Tuberculosis of superficial lymph nodes, a not so rare
event to consider in diagnosis. A case in an elderly male
      A. MERANTE, M.R. AMBROSIO1, B.J. ROCCA1, A.M. CONDITO2, A. AMBROSIO3, M. ARVANITI4, G. RUOTOLO
    Head Physician Geriatric Unit, “Pugliese-Ciaccio” Hospital, Catanzaro, Italy; 1 Department of Human Pathology and Oncology,
 Pathological Anatomy Section, University of Siena, Italy; 2 Emergency Medicine Unit, “Pugliese-Ciaccio” Hospital, Catanzaro, Italy;
           3
             University “Magna Graecia” of Catanzaro, Italy; 4 Microbiology Section, University “Federico II”, Napoli, Italy



                                                                 Key words

                                                    Tuberculosis • Mycobacterium • PCR



                                                                  Summary

Tuberculosis (TB) is still one of the most frequent infectious dis-      aetiology is often not taken into consideration in the differential
eases worldwide. Until the 1990s, Western European countries             diagnosis of lymphadenopathy, resulting in significant delay of
showed a low frequency of TB infection, but the rise of immigra-         appropriate treatment.
tion has led to a rapid increase in its occurrence. In the elderly, TB   Herein, we describe the case of a 78-year-old male with nocturnal
is emerging as a significant health problem (age-related decline of      fever, weakness, night sweats, loss of weight and decay in gen-
the cell-mediated immunity, associated illnesses, use of immuno-         eral condition. The patient had a past medical history of prostate
suppressive drugs, malnutrition, poor life conditions), although its     adenocarcinoma treated with hormone therapy. The past medical
detection and diagnosis is not easy also considering its subclinical     history in association with clinical findings and laboratory data
presentation. Almost 70% of all TB infections in Italy are found         (anaemia, high titers of fibrinogen and reactive C-protein) led to
in the lungs; 50% of the extrapulmonary infections affect lymph          the suspect of metastatic adenocarcinoma. Only histological and
nodes. Due to the low incidence of superficial tuberculous lymph-        molecular biology findings allowed us to make a correct diagnosis
adenitis without pulmonary manifestations, the possibility of a TB       of TB.



Introduction                                                             numerous. It is well known that the age-related decline
                                                                         of the cell-mediated immunity (thymus, lymph node
Tuberculosis (TB) is still one of the most frequently-                   and spleen involution) may cause reactivation of latent
occurring infectious diseases worldwide. According                       infections. Moreover, the presence of associated ill-
to the World Health Organization (WHO) 1, approxi-                       nesses such as diabetes mellitus, chronic renal failure,
mately one-third of the world’s population is current-                   diffuse parenchymal lung diseases, certain malignan-
ly infected with tubercle bacilli, while 8 million new                   cies, as well as the use of immunosuppressive drugs
cases of active disease develop each year and 3 million                  (e.g. corticosteroids), may further impair cell-mediated
patients die 2. Until the 1990s, Western European coun-                  immunity, increasing the risk of reactivation. Adverse
tries showed a rather low frequency of TB infection,                     social factors, such as malnutrition, poor living condi-
but the rise of immigration has led to a rapid increase                  tions as well as staying in nursing homes also affect the
in its occurrence 3. Furthermore, it is well known that                  elderly much more frequently than younger individu-
TB can be associated with diseases that depress the                      als 4 5. In the former, TB is not easy to detect and di-
immune system, such as leukaemia or HIV, affecting                       agnose because it does not manifest so clearly in these
specific age groups (infants, elderly). In the elderly, TB               individuals. In fact, symptoms (loss of weight, night
is emerging as a significant health problem. It may be                   sweats, weakness, anorexia, mild fever) are often non-
either exogenous or endogenous in origin, with the lat-                  specific and may be attributed to age-related changes 6.
ter representing over 90% of cases and consisting of re-                 The presence of other chronic diseases may confuse the
activation of dormant disease in the lungs or elsewhere                  clinical picture, and often the patient is unable to give
in the body 4. Predisposing factors in the elderly are                   an accurate account of symptoms.



                                                                           Correspondence
                                                                           Maria Raffaella Ambrosio, Department of Human Pathology and
                                                                           Oncology, Pathological Anatomy Section, University of Siena, via
                                                                           delle Scotte 6, 53100 Siena, Italy - Tel. +39 0577 233236 - Fax
                                                                           +39 0577 233235 - E-mail: maradot@libero.it
tuberculoSiS of Superficial lymph noDeS, a not So rare event to conSiDer in DiagnoSiS                                                     341



Apart from general diagnostic problems, there are diffi-                         cay of general conditions, for a few weeks. The patient
culties regarding the recognition of TB affecting various                        suffered from chronic obstructive airway disease and
sites. In fact, almost 70% of all TB infections in Italy 7                       cerebral vasculopathy. Moreover, he had a history of
are found in the lungs; of the remaining extrapulmonary                          prostatic adenocarcinoma treated with hormone thera-
infections, approximately 50% affect lymph nodes. Due                            py as well as a pacemaker. On physical examination,
to the low incidence of tuberculous lymphadenitis with-                          a swelling of a right laterocervical lymph node was
out pulmonary manifestations, the possibility of TB is                           observed. In particular, the node was tender, mobile
often not taken into consideration in the differential di-                       and painful with irregular borders. Blood pressure
agnosis of lymphadenopathy, resulting in a significant                           was 110/60 mmHg, heart rate 94 beats per min (bpm)
delay of appropriate treatment.                                                  and body temperature was 38.1°C. Laboratory data
Unfortunately, very little clinical data is available on                         revealed hyperleucocytosis (5.9 × 103/mm3) with ab-
the diagnosis and therapy of lymph node TB in Western                            solute neutrophilia (neutrophils 78.3%, lymphocytes
countries 8. However, owing to the immigration that has                          13.3%), normochromic normocytic anaemia (haemo-
taken place over the last decades, there is a renewed in-                        globin 10.5 g/dl, mean corpuscular volume 88 μm3)
terest in the disease.                                                           with an increase of acute phase proteins (C-reactive
                                                                                 protein-PCR, procalcitonin, fibrinogen). To rule out
                                                                                 a metastatic adenocarcinoma of the prostate or lym-
Case report                                                                      phoproliferative disorder, a lymph node ultrasound
                                                                                 imaging (US) of the neck and a whole body CT-scan
A 78-year-old male was admitted to the Geriatrics                                were performed. The US revealed an enlarged (7 cm
Unit of Catanzaro Hospital for the onset of nocturnal                            in maximum diameter), inhomogeneous lymph node
fever, weakness, night sweats, loss of weight and de-                            with a hyperechoic centre, and on this basis, tubercu-


  Fig. 1. effacement of lymph node architecture by large granulomas, with central necrosis, surrounded by epithelioid giant cells in a pali-
  saded arrangement (a, haematoxylin-eosin [h&e], original magnification [om] 10x); the giant cells show large, clear, slightly reticulated,
  c-shaped nuclei (b, h&e om 20x). positivity for ziehl-neelsen stain (c, zn om 20x) and pcr for mycobacterium tuberculosis (d).
342                                                                                                                              a. merante et al.




lous lymphadenopathy was suspected. Shortly after, a                    not decreased and accounts for almost 7.5% of all patients
Mendel-Mantoux test as well as sputum and urinalysis                    infected by mycobacterium tuberculosis. Nevertheless, it
were carried out with negative results.                                 seems that tuberculous lymphadenopathy is not taken into
Histological and microbiological analyses of the lymph                  consideration in Western countries and diagnosis is per-
node were also conducted by US-guided fine-needle as-                   formed only by histological examination 12.
piration (FNA). One aliquot of FNA sample was fixed                     In the present case, the past medical history (prostatic
in 95% ethyl alcohol and stained by Giemsa for cyto-                    adenocarcinoma), in association with clinical findings
logic analysis. Immunohistochemistry for CKAE1/AE3                      (fever associated with vague and non-specific symp-
and PSA was made. Another aliquot was used for mi-                      toms) and laboratory data (anaemia, high titres of fi-
croscopic detection of the microorganism using Ziehl-                   brinogen and PCR) led to the suspect of metastatic ad-
Neelsen (ZN) stain as well as agar and radioactive cul-                 enocarcinoma. Only histological and molecular biology
ture (BACTEC). To assess the genotype of the mycobac-                   findings allowed us to make a correct diagnosis. Dif-
terium, polymerase chain reaction (PCR) and the IS6110                  ferential diagnosis of granulomatous lymphadenopathy
restriction-fragment-length-polymorphism (RFPL) were                    includes sarcoidosis (well-defined, non-caseating granu-
performed using standard methods 9.                                     lomas with a ring of collagen), atypical mycobacterial
Lymph node architecture was effaced by the presence of                  infections (less granulomatous changes with more acute
large granulomas, sometimes confluent, with central necro-              inflammation, sometimes with abscess formation and a
sis (Fig. 1a). A number of epithelioid cells (arranged in a             histiocytic proliferation of spindle cells mimicking an
palisaded architecture), multinucleated giant cells of Lang-            inflammatory pseudotumor), lepromatous lymphadenitis
hans type and, occasionally, foreign body type in between,              (rare, non-caseating granulomas with numerous foamy
encircling caseosis and bordered by lymphocytes and plas-               macrophages replacing the paracortical regions and con-
ma cells, were surrounded by thick fibrous layers (Fig. 1b).            taining abundant intracellular organisms) and Hodgkin
CKAE1/AE3 and PSA were negative. ZN and PCR for                         lymphoma (non caseating granulomas in the paracorti-
mycobacterium tuberculosis were positive (Fig. 1c-d).                   cal areas, Reed-Stemberg and Hodgkin cells).
On the basis of the morphological and molecular biol-
ogy findings, a diagnosis of tuberculous lymphadenopa-
thy was made.                                                           Conclusion
Treatment with isoniazid, rifampicin and pyrazinamide
was established, according to the recommendations of                    It is important to bear in mind that TB infection, although
the American Thoracic Society 10, with immediate im-                    infrequent, may be the cause of a lymphadenopathy. In
provement of clinical conditions. One month later, the                  elderly patients, a delay in diagnosis represents a seri-
patient developed hepatotoxicity, and isoniazid and ri-                 ous problem since TB is curable only when treatment is
fampicin was replaced with rifabutin.                                   established at an early stage 4.
                                                                        The pathological examination of lymph nodes plays a criti-
                                                                        cal role in diagnosis. In fact, although from a clinical view-
Discussion                                                              point there may be some confusion as to whether an enlarged
                                                                        lymph node is due to TB or to other benign or malignant
TB remains one of the leading infectious diseases, caus-                lymphadenopathies, the histological picture is characteristic
ing significant morbidity and mortality worldwide 11. Al-               and diagnosis is readily established by biopsy examination
though the reporting of new TB infections has declined                  of the lymph node. Moreover, the demonstration of Koch’s
steadily over time, the frequency of lymph node TB has                  bacillus using Ziehl-Neelsen stain and PRC is definitive.


References                                                              7
                                                                             Ministero della Salute - DG della Prevenzione Sanitaria. Ufficio
                                                                             V - Malattie Infettive e Profilassi Internazionale.
1
    Geldmacher H, Taube C, Kroeger C, et al. Assessment of lymph        8
                                                                             Cailhol J, Decludt B, Che D. Sociodemographic factors that con-
    node tuberculosis in Northern Germany: a clinical review. Chest          tribute to the development of extrapulmonary tuberculosis were
    2002;121:1177-82.                                                        identified. J Clin Epidemiol 2005;58:1066-71.
2
    Baussano I, Cazzadori A, Scardigli A, et al. Clinical and demo-     9
                                                                             van Embden JD, Cave MD, Crawford JT, et al. Strain identifica-
    graphic aspects of extrathoracic tuberculosis: experience of an          tion of Mycobacterium tuberculosis by DNA fingerprinting: rec-
    Italian university hospital. Int J Tuberc Lung Dis 2004;8:486-92.        ommendations for a standardized methodology. J Clin Microbiol
3
    Brudey K, Driscoll JR, Rigouts L, et al. Mycobacterium tubercu-          1993,31:406-9.
    losis complex genetic diversity: mining the fourth international    10
                                                                             Ramón-García S, Ng C, Anderson H, et al. Synergistic drug combi-
    spoligotyping database (SpolDB4) for classification, population          nations for tuberculosis therapy identified by a novel high through-
    genetics and epidemiology. BMC Microbiol 2006,6:23.                      put screen. Antimicrob Agents Chemother 2011;55:3861-9.
4
    Sood R. The problem of geriatric tuberculosis. Journal of Indian    11
                                                                             World Health Organization. Global tuberculosis control: Surveil-
    Academy of Clinical Medicine 2004;5:156-62.                              lance, Planning, Financing. Geneva, WHO Report; 2008.
5
    Salvado M, Garcia-Vidal C, Pilar Vazquez P, et al. Mortality of     12
                                                                             Montoro E, Rodriguez R. Global burden of tuberculosis. In:
    Tubercolosis in very old people. J Am Geriatr Soc 2010;58:18-22.         Palomino JC, Leão SC, Ritacco V, eds. Tuberculosis 2007,
6
    Zevallos M, Justman JE. Tubercolosis in the elderly. Clin Geriatr        from basic science to patient care. Kamps and Bourcillier 2007,
    Med 2003;19:121-38.                                                      pp. 263-81.
pathologica 2011;103:343-345




                                                               case repOrt



                                       Adenolipoma of the skin
    S. KAROUI, T. BADRI, R. BENMOUSLY, E. BEN BRAHIM*, A. CHADLI-DEBBICHE*, I. MOKHTAR, S. FENNICHE
Department of Dermatology, Habib Thameur Hospital, Faculty of Medicine, University of Tunis El Manar; * Department of Pathology,
                      Habib Thameur Hospital, Faculty of Medicine, University of Tunis El Manar, Tunisia



                                                              Key words

                                  Adenolipoma • Perisudoral lipoma • Eccrine glands • Lipoma • Skin



                                                               Summary

Adenolipoma of the skin (ALS) is an uncommon histological var-        of this tumour are thighs (as in our patient), shoulders, chest and
iant of lipoma, characterized by the presence of normal eccrine       arms. Histologically, the tumour is composed of lobulated adipose
sweat glands inside the fat proliferation. A 32-year-old woman        tissue with larger and more prominent lobules than those in nor-
presented to our department with a slow-growing, painless sub-        mal subcutaneous adipose tissue. A well-developed capsule may
cutaneous soft tumour located on the upper part of the right thigh.   also be identified. Eccrine glands and ducts, without proliferative
Microscopically, there was lobulated adipose tissue proliferation     changes, are well-differentiated within the adipose tissue.
with well-differentiated eccrine glands and ducts in the periphery    Differential diagnosis of adenolipoma includes the common
and centre of the nodule. These features were suggestive of ALS.      lipoma and its variants, skin tag and other hamartomatous lesions,
ALS is a rare microscopic variant of cutaneous lipoma having          such as nevus lipomatosus superficialis, and the lipomatous vari-
similar clinical features to lipoma. The most frequent locations      ant of eccrine angiomatous hamartoma.



Introduction                                                            Fig. 1. painless nodule on the right upper thigh.

Adenolipoma of the skin (ALS) is an uncommon histo-
logical variant of lipoma characterized by the presence
of normal eccrine sweat glands inside a fat proliferation.
We report a new case with a review the literature.


Case report
A 32-year-old woman presented to our department with
a slow-growing, painless nodule on her thigh. Cutane-
ous examination showed a subcutaneous soft tumour of
1.5 cm in diameter located on the upper part of the right
thigh. The lesion was covered by an erythematous skin,
with no palpable thrill (Fig. 1). A diagnosis of lipoma
was suspected. Surgical excision of the tumour and the
overlying skin was performed.
Gross examination revealed a soft, yellow, lobulated mass
measuring 3 cm in greatest diameter. Microscopically, the             Discussion
nodule was composed of adipose tissue proliferation with
distinct lobulation within the tumour. Well-differentiated            Several variants of lipoma were described according to
eccrine glands and ducts were seen in the periphery and               their location and morphology. In a lipoma, the adipose
centre of the nodule. No capsule was seen and no architec-            tissue may be associated with other proliferative or non-
tural or cytological alteration was noticed in these glands           proliferative tissues, such as in angiolipoma and fibrol-
(Fig 2). These features were suggestive of ALS.                       ipoma 1.

                                                                        Correspondence
                                                                        Talel Badri, Department of Dermatology, Habib Thameur Hospital,
                                                                        8, rue Ali Ben Ayed, 1008 Tunis, Tunisia - Tel. +216 98 829300 -
                                                                        Fax +216 71 399115 - E-mail: talel_badri@yahoo.fr
344                                                                                                                 S. Karoui et al.




 Figs. 2A, B. well-differentiated eccrine glands and ducts, with-
                                                                    thigh (especially its upper part) and buttock (n = 16). The
 out proliferative changes, within the adipose tissue (haematoxy-   other reported locations are: the shoulder region (n = 3),
 lin and eosin, X40).                                               abdomen (n = 2), periungual region (n = 2), female ex-
                                                                    ternal genitalia (n = 2), axillary region (n = 1), lower lip
  A                                                                 (n = 1), supraclavicular region (n = 1), arm (n = 1), hip
                                                                    (n = 1) and breast (n = 1) 2-10.
                                                                    Histologically, the tumour is composed of lobulated adi-
                                                                    pose tissue with larger and more prominent lobules than
                                                                    those in normal subcutaneous adipose tissue. Unlike our
                                                                    patient, a well-developed capsule may also be identified.
                                                                    Eccrine glands and ducts, without proliferative changes,
                                                                    are well-differentiated within adipose tissue 2 3. Only one
                                                                    case of ALS with apocrine glandular cystic component
                                                                    has been reported in a 40-year-old female patient with an
                                                                    axillary tumour 8.
                                                                    The frequency of adenolipoma might be underestimated,
                                                                    especially when sectioning of lesions can miss the few
                                                                    glandular components or when it is impossible to precise-
                                                                    ly locate eccrine glands within fragmented specimens.
  B                                                                 When the eccrine glands have a peripheral location in
                                                                    specimens, it may be also difficult to affirm whether the
                                                                    glands are within the tumour or are contained in adjacent
                                                                    normal structures 2 4.
                                                                    The histological differential diagnosis of adenolipoma
                                                                    includes common lipoma and its variants, skin tag, also
                                                                    in addition to other hamartomatous lesions, such as ne-
                                                                    vus lipomatosus superficialis and the lipomatous variant
                                                                    of eccrine angiomatous hamartoma 11 12.
                                                                    Adenolipoma usually has a similar clinical presentation
                                                                    to common lipoma. The size of adenolipoma appears to
                                                                    be smaller than that of common lipomas, probably be-
                                                                    cause of its superficial location that can lead to earlier
                                                                    symptoms. A subcutaneous lipoma may have a hernia-
                                                                    tion within the dermis. In this latter case, the eccrine
                                                                    glands are compressed and displaced rather than incor-
In 1993, Hitchcock et al. described an entity of lipoma             porated into the lesion as in ALS 2.
in a series of 9 patients that had never been reported pre-         Skin tag with a fatty stroma is also a differential diagno-
viously. It was a rare microscopic variant of cutaneous             sis. In this tumour, the eccrine glands are rather located
lipoma composed of large lobules of mature adipocytic               on both sides of the pedicle rather than within the fatty
tissue admixed with eccrine ducts and glands. This tu-              component 3.
mour was called “adenolipoma of the skin” 2.                        Nevus lipomatosus superficialis has a different clini-
Ait-Ourhrouil and Grosshans reported, in 1997, a sec-               cal feature. It presents as congenital multiple papules or
ond series of 11 cases 3. They postulated that this lesion          nodules. Microscopically, it shows ectopic adipose tis-
develops from the peripheral adipose tissue of eccrine              sue with fibrous tissue in the papillary and reticular der-
glands and suggested the name perisudoral lipoma. In-               mis. The density of the collagen bundles, the abundance
cluding our patient, the total number of ALS reported               of fibroblasts and its vascularity are more prominent
cases, in the English and French literature is 31 (Tab.             than in normal skin 2 11.
I) 2-10. The tumour often has the appearance of a usual             Eccrine angiomatous hamartoma is usually an isolated
lipoma. Occasionally, the clinical presentation is sug-             congenital lesion showing a preponderance of eccrine
gestive of skin tag, neurofibroma or a hamartomatous                and vascular proliferation, which are absent in ALS 2 12.
lesion. The delay between tumour occurrence and the                 ALS is a fatty-tissue proliferation that includes and
first medical evaluation ranges from 6 months (in our               moves the normal eccrine glands to the centre of the tu-
case) to more than 10 years 3 5. The average size calcu-            mour. This glandular component does not show any pro-
lated from our literature review is 2.7 cm 2-10. There is           liferative changes. Its location on the upper thigh, as in
a female preponderance (22:9), and the average age at               our patient, may allow clinical suspicion of ALS which
diagnosis is 47.8 years 2-10. ALS is mainly located on the          should be confirmed by histological findings.
aDenolipoma of the SKin                                                                                                                       345



    Tab. I. Summary of the reported cases of alS.
    Reference                     Age (years)       Sex            Location                          Size                     Duration
    hitchcock 1993 2                   25           m                arm                             1 cm                        n/a
                                       61           m                thigh                           n/a
                                       44            f             Shoulder                          6 cm
                                       33            f          Supraclavicular                     1.5 cm
                                       37           m              Shoulder                          4 cm
                                       39            f               thigh                          0.8 cm
                                       52            f               thigh                          1.5 cm
                                       25            f               thigh                          4.4 cm
                                       75           m                thigh                           4 cm
    ait-ourhrouil 1997 3               63            f               thigh                        1 to 3 cm                   > 10 years
                                                                                              (average: 2.5 cm)
                                       55           m              Shoulder                                                    5 years
                                       71           m             abdomen                                                     > 10 years
                                       61            f              buttock                                                    2 years
                                       44            f              buttock                                                  many years
                                       49            f                hip                                                    many years
                                       61           m                thigh                                                     2 years
                                       63            f              breast                                                   many years
                                       48            f               thigh                                                   many years
                                       54            f               thigh                                                   many years
                                       48           m             abdomen                                                        n/a
    rongioletti 1997 4                 41            f               thigh                          2.7 cm                   many years
                                       25            f               thigh                           2 cm                      5 years
    chadli-Debbiche 2001 5             34            f               thigh                           8 cm                      11 years
    ide 2003 6                         57            f             lower lip                         2 cm                      3 years
    bichert 2004 7                     67            f    periungual (middle finger)                 n/a                     many years
                                       48           m       periungual (great toe)                  0.8 cm                       n/a
    Del agua 2004    8
                                       45            f               thigh                          2.5 cm                       n/a
    antunez 2005 9                     40            f          axillary region                     3.7 cm                       n/a
    pantanowitz 2008     10
                                       41            f            left groin                        1.5 cm                   many years
                                       44            f            right vulva                        2 cm                      4 years
    present case                       32            f           upper thigh                         3 cm                     6 months




References                                                                   7
                                                                                  Richert B, André J, Choffray A, et al. Periungual lipoma: about
                                                                                  three cases. J Am Acad Dermatol 2004;51(Suppl 2):S91-3.
1
     Abensour M, Jeandel C, Heid E. Lipomes et lipomatoses cutanés.          8
                                                                                  Atunez P, Santos-Briz A, Munoz E, et al. Cutaneous apocrine cys-
     Ann Dermatol Venereol 1987;114:873-82.                                       tic adenolipoma. Am J Dermatopathol 2005;27:240-2.
2
     Hitchcock M, Hurt M, Santa Cruz D. Adenolipoma of the skin: a           9
                                                                                  Pantanowitz L, Henneberry J, Otis C, et al. Adenolipoma of the
     report of nine cases. J Am Acad Dermatol 1993;29:82-5.                       external female genitalia. Int J Gynecol Pathol 2008;27:297-
3
     Ait-Ourhrouil M, Grosshans E. Le lipome périsudoral. Ann Der-                300.
     matol Venereol 1997:124;845-8.                                          10
                                                                                  Del Agua C, Felipo F. Adenolipoma of the skin. Dermatol Online J
4
     Rongioletti F, Santa Cruz D. L’adénolipome cutané. Ann Derma-                2004;10:9.
     tol Venereol 1997;124:855-6.                                            11
                                                                                  Dotz W, Prioleau PG. Nevus lipomatous cutaneus superficia-
5
     Chadli-Debbiche A, Ben Brahim E, Mzabi-Regaya S. Le lipome                   lis: a light and electron microscopic study. Arch Dermatol
     périsudoral: une observation confirmant cette nouvelle entité. Ann           1984;120:376.
     Pathol 2001;21:289-90.                                                  12
                                                                                  Donati P, Amantea A, Balus L. Eccrine angiomatous hamartoma:
6
     Ide F, Mishima K, Saito I. Adenolipoma of the lip. Br J Derma-               a lipomatous variant. J Cutan Pathol 1989;16:227-9.
     tol 2003;148:606-7.
pathologica 2011;103:346-349




                                                               case repOrt



           Adenomatous transformation in a giant solitary
             Peutz-Jeghers-type hamartomatous polyp
                        F. LIMAIEM, S. BOURAOUI, A. LAHMAR, S. JEDIDI, S. ALOUI, S. KORBI, S. MZABI
                           Department of Pathology Mongi Slim Hospital, Sidi Daoued La Marsa (2046), Tunisia



                                                              Key words

                               Peutz-Jeghers-type polyp • Hamartoma • Adenomatous transformation • Rectum



                                                               Summary

Solitary Peutz-Jeghers-type polyp is a rare hamartomatous polyp       lesion in the lower rectum. The polyp was sessile and measured
without associated mucocutaneous pigmentation or a family his-        15 cm in diameter. As histological examination of the biopsy
tory of Peutz-Jeghers Syndrome. It is usually encountered in the      specimen was suggestive of adenoma, endoscopic polypectomy
small intestine, but rarely involves the rectum. A 27-year-old pre-   was performed. Histologically, this polyp had an arborizing mus-
viously healthy female patient presented with a two-month his-        cular network originating from the muscularis mucosa, and was
tory of rectal bleeding. The patient had neither mucocutaneous        covered by well organized mucosa with several foci of dysplastic
pigmentation nor a family history of gastro-intestinal polyposis.     glands. The final pathological diagnosis was solitary Peutz-Jegh-
Endoscopic examination revealed a solitary lobular polypoid           ers type hamartomatous polyp with adenomatous transformation.



Introduction                                                          nation, the patient’s skin including the perioral area was
                                                                      unremarkable and oral mucosa appeared normal. En-
Solitary Peutz-Jeghers-type polyps (PJP) are uncommon                 doscopic examination revealed a lobular and polypoid
hamartomatous lesions without associated mucocutane-                  lesion in the lower rectum measuring 15 cm in diam-
ous pigmentation or a family history of Peutz-Jeghers                 eter (Fig. 1). A biopsy of this polyp was performed and
Syndrome (PJS) 1 2. They are most frequently encountered              histological examination revealed findings suggestive of
in the small intestine, but rarely involve the rectum. Al-            an adenoma with low-grade intra-epithelial neoplasia.
though several cases of solitary PJP have been reported in            Endoscopic resection of the entire polyp was performed.
the literature, it is still unclear whether solitary PJP repre-       Histopathologically, the excised polyp had an arborizing
sents an incomplete form of PJS or a different entity 3. In           muscular network originating from the muscularis mu-
this paper, the authors report a new case of solitary Peutz-          cosa (Fig. 2) and was covered by well organized mucosa
Jeghers-type hamartomatous polyp with several foci of                 with hyperplastic (Fig. 3) and cystically dilated glands
glandular dysplasia revealed by rectal bleeding. To the               (Fig. 4). Several foci of dysplastic glands displaying
best of our knowledge, only 31 cases (Tab. I) of color-               low-grade intra-epithelial neoplasia were also identified
ectal solitary Peutz-Jeghers-type hamartomatous polyps                (Fig. 5). Thorough and careful examination of differ-
have been published in the English language literature to             ent sections of the entire polyp did not reveal any addi-
date, and adenomatous transformation has never been de-               tional adenocarcinomatous foci. After endoscopic treat-
scribed in solitary rectal PJP before.                                ment, no concomitant lesions were found elsewhere. At
                                                                      present, the patient is still on follow-up.

Clinical history
                                                                      Discussion
A 27-year-old previously healthy female patient with no
family history of gastro-intestinal polyposis, presented              A Peutz-Jeghers polyp (PJP) in a patient without muco-
with a two-month history of rectal bleeding. On exami-                cutaneous pigmentation or family history of PJS is called



                                                                        Correspondence
                                                                        Faten Limaiem, Department of Pathology, Mongi Slim Hospital-La
                                                                        Marsa- Tunisia - Tel. +216 96 55 20 57 - E-mail: fatenlimaiem@
                                                                        yahoo.fr
aDenomatouS tranSformation in a Solitary peutz-JegherS-type polyp                                                                    347



 Fig. 1. endoscopic examination revealing a lobular rectal polyp.   Fig. 3. cystically dilated glands were identified within the polyp.
                                                                    (haematoxylin & eosin; original magnification x 25).




                                                                    Fig. 4. hyperplastic glands composed of tall columnar absorp-
  Fig. 2. arborizing network of smooth muscle and connective        tive cells and goblet cells. (haematoxylin & eosin; original mag-
  tissue surrounding abundant normal glands. (haematoxylin &        nification x 25).
  eosin; original magnification x 10).




an isolated or solitary PJP 4. Whenever a PJP is found, it
is important to rule out a diagnosis of PJS on the basis of         Fig. 5. foci of dysplastic glands were noticed within the polyp
                                                                    (haematoxylin & eosin; original magnification x 25).
WHO criteria: (1) three or more histologically confirmed
PJPs; (2) any number of PJPs with a family history of
PJS; (3) characteristic, prominent, mucocutaneus pig-
mentations with a family history of PJS; (4) any number
of PJPs and characteristic, prominent, mucocutaneous
pigmentation 3. In our case, histological examination
showed the characteristic features of PJP, but the patient
did not fulfil WHO criteria for PJS diagnosis (negative
family history for PJS and absence of mucocutaneous
pigmentation), and was therefore considered to have a
solitary PJP. Solitary Peutz-Jeghers polyps are extremely
rare, with an estimated incidence of 1:120,000 5. They
are found most frequently in the small intestine, but al-
so occur in the large bowel and stomach 6 7. A Medline
search of the English language literature revealed only
three well-documented cases of solitary Peutz-Jeghers-
348                                                                                                                              f. limaiem et al.




Tab. I. cases of colorectal solitary peutz-Jeghers type polyps reported in the literature.
 Author/year                  Number         Age (years)         Location         Size (cm)     Presentation            Treatment
                              of cases          sex
 Suda 17 (1988)                   20         mean age =          colorectal           na              na                    na
                                             55.1 years
                                             males: 74%
 handa 12 (1990)                   1              na               colon              na              na                    na
 yamanaka    18
                  (1991)           1              na         transverse colon         na              na                    na
 muto 9 (1993)                     1              na               colon              na              na                    na
 nakayama    13
                  (1996)           1             64/m         lower rectum        2x1.5 x 1.5    bloody stools       transanal surgical
                                                                                                                         resection
 oncel 4                           5             46/m             Sigmoid             1.5         Screening       endoscopic polypectomy
 (2003)
                                                 68/m             Sigmoid             2.5         Screening       endoscopic polypectomy
                                                 46/m             Sigmoid              2          Screening       endoscopic polypectomy
                                                 33/f             Sigmoid              2        rectal bleeding   endoscopic polypectomy
                                                 56/m             cecum                2          Screening       endoscopic polypectomy
 Jaremko 19 (2005)                 1             19/m           Descending            na          colo-colonic      Subtotal colectomy
                                                                  colon                         intussusception
 itaba 20 (2009)                   1             50/m             Sigmoid             1.8         Screening       endoscopic polypectomy
 garces 21 (2011)                  1              na              rectum              na              na                    na
 limaiem (2011)                    1             27/f         lower rectum            15        rectal bleeding   endoscopic polypectomy
na: not available




type hamartomatous polyp of the rectum (Tab. I). The                        low malignant potential 11. However, some reports have
largest colorectal PJP reported in literature had a size of                 described areas of neoplastic change, such as adeno-
2.5 cm compared to 15 cm in our patient. Gastrointestinal                   matous or carcinomatous change in solitary PJP 9 12-14.
hamartomatous polyps in patients with PJS have a dis-                       Patients with PJS are at increased risk of developing
tinct histological appearance with interdigitating smooth                   both intestinal and extraintestinal malignancies. Since
muscle fibres forming a characteristic branching tree pat-                  solitary PJP are rare, it is not known whether there is
tern (arborization) 8. They display a frond-like elongated                  any increased risk for other malignancies, as observed
epithelial component and cystic gland dilatation extend-                    in PJS. In 50–94% of patients with PJS, a mutation of
ing into the sub-mucosa or muscularis propria. Peutz-                       the LKB1/STK11 gene is found. Conversely, no muta-
Jeghers-type polyps are histologically identical to those                   tion of the LKB1/STK11 gene was found in two cases
in Peutz-Jeghers syndrome, although some authors have                       of solitary PJP in which genotyping was carried out 15 16.
pointed out that solitary Peutz-Jeghers-type polyps tend                    Unfortunately, we were not able to carry out genotyping
to exhibit less branching of the muscularis mucosae than                    in our case.
in the familial form 9 10.                                                  In summary, a case of solitary Peutz-Jeghers-type polyp
The main difficulty in defining the true entity of these                    with adenomatous transformation is reported herein. Our
solitary hamartomatous polyps lies in the small number                      case is unique in that it is the largest solitary PJP report-
of published cases, some of which provide little clinical                   ed in literature involving the rectum which is an exceed-
information. Because of the absence of involved family                      ingly rare location. It is still unclear whether a solitary
members, the lack of mucocutaneous pigmentation char-                       Peutz-Jeghers polyp (PJP) is an incomplete form of PJS
acteristic of PJS and the presence of a solitary polyp, a                   or a separate entity. Whether there is an increased risk
solitary PJP might be a disease entity distinct from PJS.                   of cancer in patients with solitary Peutz-Jeghers-type
There is, however, controversy about the occurrence of                      polyps is uncertain, but periodic surveillance in young
solitary PJPs 1 5. In most case reports and series, clini-                  patients would seem appropriate 4. Available data are
cal and histological criteria were not fully documented                     extremely limited, and it is difficult to draw firm con-
and there was usually no extended follow-up 11. Hamar-                      clusions regarding management of patients with solitary
tomatous polyps are generally considered to have very                       polyps 5.
aDenomatouS tranSformation in a Solitary peutz-JegherS-type polyp                                                                                349



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350                                                                                                pathologica 2011;103:350-356




                                  Index Volume 103, No. 1-6

Issue 1                                                              S. Squillaci, R. Marchione, M. Piccolomini
February 2011                                                   40   An unusual case of signet ring cell adenocarcinoma
                                                                     of the prostate
ORIGINAL ARTICLE                                                     L. Reggiani Bonetti, M. Lupi, E. Stauder,
1   Realistic technician staffing requirements in                    S. Bergamini, M. Scuri, A. Maiorana
    a histopathology laboratory via an innovative               43   Subcutaneous Ewing sarcoma/PNET as a second
    workload method                                                  cancer in a previously irradiated young patient.
    M. Bergamaschi, G. Coccini                                       An uncommon type of post-irradiation soft tissue
                                                                     sarcoma
ANATOMY FOR HISTOPATHOLOGISTS                                        M. Bruno, G.I. D’Antona, G. Vita, G. Perrone,
4  Muscle spindle and Pacinian corpuscle: conceptions,               F. Fiordelisi, M. Bisceglia
   misconceptions, and the far-fetched hypothesis of an         46   Nodular extramedullary hematopoiesis involving the
   experienced surgical pathologist                                  adrenal gland.
   M. Bisceglia, S. Bisceglia, M.L. Bisceglia                        An uncommon cause of adrenal “incidentaloma”
                                                                     M. Salemme, R. Rodella, S. Fisogni, F. Facchetti
CASE REPORTS                                                    50   Ductal carcinoma of the prostate metastatic to the
8   Long pedunculated colonic polyp with                             skin
    diverticulosis: case report and review of the literature         G. Collina, C. Reggiani, G. Carboni
    M.R. Ambrosio, B.J. Rocca, A. Ginori, A. Barone, M.
    Onorati, S. Lazzi                                           LETTER TO THE EDITOR-IN-CHIEF
11 Amniotc band syndrome: a case report                         52 Needle core biopsy should replace fine needle
    A.M. Buccoliero, F. Castiglione, F. Garbini,                    aspiration cytology in ultrasound-guided sampling of
    D. Moncini, E. Lapi, E. Agostini, P. Fiorini, G.L. Taddei       breast lesions
14 Partial nodal involvement by marginal zone                       B. Brancato, M. Scialpi, T. Pusiol, M.G. Zorzi,
    lymphoma. Use of IGK gene rearrangement analysis                D. Morichetti, F. Piscioli
    in diagnostic work-up
    A. Gazzola, E. Sabattini, C. Mannu, F. Bacci,
    C.A. Sagramoso sacchetti, P. Artioli, L. Chilli,            Issue 3
    G. Da Pozzo, M. Piccioli, B. Falini, S.A. Pileri,           June 2011
    P.P. Piccaluga
19 Morphological analysis of three extrathoracic                ORIGINAL ARTICLES
    bronchogenic cysts simulating neoplasms                     53 Autoptic and echocardiographic findings in
    M. Lupi, L. Reggiani bonetti, E. Stauder, S. Bettelli,          seven foetuses with congenital heart anomalies,
    A. Maiorana                                                     lung lobation defects and normal visceroatrial
22 Renal leiomyoma                                                  arrangement
    N. Mashali, A.T. Awad, G. Trevisan, M. El-bahrawy               F. Angiero, V. Fesslova, T. Rizzuti, M. Stefani
25 Melanoma of the nipple. An additional case                   61 Solitary extramedullary plasmacytoma of the thyroid
    V. Mourmouras, M.R. Ambrosio, M. Onorati,                       gland associated with multinodular goiter: case
    B.J. Rocca, N. Di mari, F. De luca, C. Miracco                  report and review of the literature
                                                                    G. Puliga, L. Olla, G. Bellisano, N. Di Naro,
                                                                    M. Ganau, M.L. Lai, G. Faa, G.A. Tolu
Issue 2                                                         64 Sebaceous carcinoma of the vulva: critical approach
April 2011                                                          to grading and review of the literature
                                                                    T. Pusiol, D. Morichetti, M.G. Zorzi
ORIGINAL ARTICLE
27 Teaching anatomical pathology in the undergraduate           CASE REPORTS
    curriculum in Medicine: the experience of ‘C                68 Pleomorphic giant cell ductal carcinoma of the
    Course’, Sapienza University, Rome                              breast
    P. Gallo, G. D’Amati, C. Di Gioia, C. Giordano                  D. Tacchini, M.G. Mastrogiulio, L. Vassallo,
                                                                    A. Ginori
CASE REPORTS                                                    71 A solitary pilar leiomyoma of the trunk
32 Cystic sebaceous lymphadenoma of the parotid                     R. Benmously-Mlika, F. Ishak, S. Ben Jennet,
    gland: case report and review of the literature                 H. Hammami, T. Badri, I. Mokhtar, S. Fenniche
inDeX volume 103, no. 1-6                                                                                       351


73     Malignant proliferating trichilemmal cyst of the   CASE REPORTS
       scalp: histological aspects and nosology           299 Histogenetic and taxonomic considerations
       A. Khaled, M. Kourda, B. Fazaa, J. Kourda,             on a case of post-traumatic bizarre parosteal
       S. Ben Jilani, M. Ridha Kamoun, R. Zermani             osteochondromatous proliferation (BPOP)
                                                              M. Filotico, A. Altavilla, S. Carluccio
LETTER TO THE EDITOR-IN-CHIEF                             304 Reactive pseudo-glandular mesothelial hyperplasia
77 Reliability of K-ras mutational analysis on                in testis tunica vaginalis: a case report
    cytological samples from metastatic colorectal            N. Di Naro, G. Puliga, L. Olla, G.A. Tolu
    cancer                                                307 Incidental finding of peripheral B-cell non-
    C. Bozzetti, F.V. Negri, N. Naldi, R. Nizzoli,            Hodgkin lymphoma, lymphocytic/CLL type, of the
    B. Bortesi, V. Zobbi, C. Azzoni, E.M. Silini,             gallbladder in a patient with chronic cholecystitis
    A. Ardizzoni                                              H. Imenpour, M. Castagnola, G. De Silva, S. Zupo,
                                                              M. Truini, E. Merlo, L. Anselmi
                                                          311 Nodular hidradenoma in a 19-year-old woman
Issue 4                                                       R. Benmously-Mlika, M. Jones, H. Hammami,
August 2011                                                   N. Labbene, A. Debbiche, I. Mokhtar, S. Fenniche

ATTI DI CONGRESSO
79 Congresso Nazionale SIAPEC-IAP                         Issue 6
    Palermo, 27-29 Ottobre 2011                           Decmber 2011

                                                          ORIGINAL ARTICLES
Issue 5                                                   313 The role of 2D bar code and electronic cross-
October 2011                                                  matching in the reduction of misidentification errors
                                                              in a pathology laboratory. A safety system assisted
ORIGINAL ARTICLES                                             by the use of information technology
271 Primary synovial sarcoma of the kidney. A case            G. Fabbretti
    report with pathologic appraisal investigation and    318 Cytologic re-evaluation of negative effusions from
    literature review                                         patients with malignant mesothelioma
    A. Pitino, S. Squillaci, C. Spairani, M.F. Cosimi,        V. Ascoli, D. Bosco, C. Carnovale Scalzo
    E. Feyles, D. Ricci, F. Bardari, M. Graziano,         325 Intra-operative frozen section technique for breast
    F. Morabito, F. Cesarani, M. Garruso, M. Belletti,        cancer: end of an era
    K. Beierl, K.M. Murphy                                    E. Manfrin, A. Remo, F. Falsirollo, G.P. Pollini,
279 Oncocytic carcinoma of the parotid gland: case            A. Parisi, A. Nottegar, F. Bonetti
    report and review of the literature                   331 The diagnostic accuracy of cervical biopsies in
    T. Pusiol, D. Morichetti, M.G. Zorzi                      determining cervical lesions: an audit
                                                              J. Wang, M. El-Bahrawy
SPECIAL ARTICLE                                           337 “Combined” desmoplastic melanoma of the vulva
290 Epidemiological changes in breast tumours in Italy:       with poor clinical outcome
    the IMPACT study on mammographic screening                G. Collina
    programmes
    Impact Working Group                                  CASE REPORTS
                                                          340 Tuberculosis of superficial lymph nodes, a not so
GUIDELINES AND CHECK LISTS                                    rare event to consider in diagnosis. A case in an
294 Breast cancer and primary systemic therapy.               elderly male
    Results of the Consensus Meeting on the                   A. Merante, M.R. Ambrosio, B.J. Rocca,
    recommendations for pathological examination and          A.M. Condito, A. Ambrosio, M. Arvaniti, G. Ruotolo
    histological report of breast cancer specimens in     343 Adenolipoma of the skin
    the Marche Region                                         S. Karoui, T. Badri, R. Benmously, E. Ben Brahim,
    A. Santinelli, M. De Nictolis, V. Mambelli,               A. Chadli-Debbiche, I. Mokhtar, S. Fenniche
    R. Ranaldi, I. Bearzi, N. Battelli, C. Mariotti,      346 Adenomatous transformation in a giant solitary
    L. Fabbietti, S. Baldassarre, G.M. Giuseppetti,           Peutz-Jeghers-type hamartomatous polyp
    G. Fabris                                                 F. Limaiem, S. Bouraoui, A. Lahmar, S. Jedidi,
                                                              S. Aloui, S. Korbi, S. Mzabi
352                                                                                                                                                     author inDeX




                                                               Author Index

Abbona G.C., 143, 201                     Bar E., 151                                Bono F., 162                              Carboni G., 50
Acconcia A., 240                          Barbagli L., 190                           Bono L., 139, 212                         Cardone C., 181
Achille G., 187                           Barbareschi M., 140, 157, 171, 215, 216    Bonzanini M., 80                          Carducci A., 265
Adami G., 158                             Barbato A., 140                            Bordoni A., 163                           Carella R., 157, 171
Addati T., 150, 187, 226                  Barberis M., 125, 156, 219                 Bortesi B., 77                            Carlà T.G., 234
Afeltra A., 138                           Barbiano di Belgiojoso G., 214             Bortul M., 148                            Carli F., 221
Agostinelli C., 119, 168                  Barbieri D., 153                           Borzillo A., 248                          Carluccio S., 299
Agostini E., 11                           Barbieri P., 201                           Borzomati D., 165, 193, 194, 229          Carnovale Scalzo C., 318
Al Omoush T., 148                         Bardari F., 271                            Bosco A., 165                             Carolei D., 246
Alabiso O., 156                           Barnabei A., 202                           Bosco D., 318                             Carolina A.F., 199
Alaggio R., 165, 186                      Barollo S., 189                            Bosi A., 179                              Carosi I., 177, 207, 239
Albertoni L., 236                         Baron L., 147                              Bosisio F.M., 161, 223, 231               Carosi M., 202, 232, 251
Alesiani F., 197                          Barone A., 8, 195, 211, 230                Botta C., 147                             Carrieri G., 170
Alessandrini L., 147, 225                 Barreca A., 162                            Botta G., 135, 205                        Carroccio A., 164
Allegra E., 247                           Barresi G., 187, 231                       Botti G., 107, 110, 136, 140, 144, 146,   Carru C., 152
Allegrini S., 156, 192, 261               Barresi V., 187, 231                           153, 164, 217, 218, 239, 240, 241,    Caruso C., 138
Allia E., 100, 253                        Bartoletti R., 266                             245, 263, 264                         Caruso F., 129
Alò P.L., 170, 176, 188                   Bartolommei S., 265                        Bouraoui S., 346                          Caruso R., 233, 238
Aloui S., 346                             Bartoloni G., 96                           Bove G., 239                              Caruso S., 214
Altavilla A., 299                         Battaglia A., 228                          Boveri E., 197                            Casadio C., 157
Altomare V., 229                          Battaglia G., 235                          Bovo G., 161, 162, 243                    Cascone P., 141
Amato M., 161, 165                        Battelli N., 294                           Bozzetti C., 77                           Casini B., 217, 232
Amato T., 195                             Battolla E., 160                           Braccischi A., 169, 184, 229              Casoria A., 245
Ambrosio A., 230, 260, 340                Bearzi I., 294                             Bragantini E., 171, 216                   Casorzo L., 147, 259
Ambrosio M.R., 8, 25, 124, 181, 190,      Becchina G., 94, 167, 194, 241             Brancato B., 52                           Cassina E., 231
    195, 210, 211, 212, 230, 238, 260,    Bega O., 255                               Brandi M.L., 213                          Cassoni P., 162, 228
    265, 340                              Beierl K., 271                             Brazzarola P., 144                        Castagnola M., 307
Amico P., 165                             Belardinelli V., 147, 225                  Bresaola E., 157                          Castellano I., 100, 228
Amore F., 165                             Bellan C., 195, 210, 230, 238              Brisigotti M., 175, 216                   Castiglia M., 182, 190
Amoroso A., 138                           Bellavia T., 203                           Brollo A., 158                            Castiglione F., 11, 155, 205
Ancona E., 161, 235                       Bellei E., 169                             Brunelli C., 193, 194                     Castrista M., 239
Andreini L., 216                          Belletti M., 271                           Brunelli F., 146                          Cataldo I., 192, 237
Andreozzi A., 147                         Bellevicine C., 145, 173, 190, 200,        Brunelli M., 139, 204, 213, 216, 217      Catalucci A., 186, 208
Andronico G., 203                             202, 243                               Brunello E., 204, 216, 217                Catarini M., 197
Angelucci D., 172                         Bellini R., 261                            Bruno M., 43                              Cattoretti G., 161, 162, 231
Angiero F., 53                            Bellis D., 143, 159, 201                   Bruzzone M., 250                          Cavalli T., 213
Annaratone L., 221                        Bellisano G., 62                           Buccoliero A.M., 11, 155                  Cavani A., 229
Anniciello A., 140                        Belluso D., 159                            Buffa C., 144                             Cavazza A., 111, 157
Anniciello A.M., 107, 140                 Belmonte B., 142, 177, 182                 Bufo P., 144, 171, 185, 188, 240, 246,    Cavedon E., 189
Anselmi L., 307                           Beltrami V.R.L., 135, 205, 260                 247, 262                              Cè S., 248
Anselmi M., 208                           Ben Brahim E., 343                         Buglioni S., 148, 217                     Ceciliani E., 252
Antinori S., 112, 113                     Ben Jennet S., 71                          Buonaguro F.M., 83                        Centrone M., 150, 187
Antona J., 156, 192                       Ben Jilani S., 73                          Buonaguro L., 83                          Cerasola G., 203
Antonelli M., 96                          Ben-Dor D., 177                            Burgio U., 199                            Cernic S., 158
Antonini D., 159                          Benerini Gatta L., 215, 261                Burioni R., 113                           Cerrone M., 107, 110, 140, 146, 217,
Anzalone R., 145                          Benevolo M., 234, 251                      Butera D., 150                                218, 241, 245, 263, 264
Apicella P., 146                          Benmously R., 343                          Buttitta F., 126, 155, 158, 203           Certo G., 219, 236, 253
Appetecchia M., 202                       Benmously-Mlika R., 71, 311                                                          Cesarani F., 271
Aprile G., 163                            Bensi T., 201                              Cabibi D., 142, 177, 182, 190, 218, 236   Cesarini E., 150
Aquino G., 110, 164, 171, 245, 246, 263   Beretta Anguissola G., 188                 Cacciatore M., 164, 167, 197              Cesinaro A.M., 180
Aragona F., 177, 182                      Bergamaschi M., 1, 174                     Cadei M., 131, 215, 261                   Chadli-Debbiche A., 343
Arborea G., 202, 206, 245, 249, 255       Bergamini S., 40, 169                      Cagiano S., 144, 185, 246, 247            Chella A., 155, 203
Arcaini L., 196, 197                      Bertazzoni G., 265                         Cai T., 266                               Chiapparini L., 157
Arcuri P., 190                            Bertolaso A., 200                          Caldara A., 215                           Chiaramonte A., 195
Ardizzoni A., 77                          Bertolotti A., 261                         Caldarella A., 146                        Chiarello G., 152, 154, 189, 251
Arena R., 210                             Betta P.G., 201                            Callea M., 161, 165                       Chicchinelli N., 140
Arena V., 135, 148, 149, 214              Bettelli S., 19, 180, 215                  Caltabiano R., 98, 186, 247, 261          Chilli L., 14
Arisio R., 100                            Biancalani M., 146, 174                    Calvaruso M., 164, 167, 197               Chilosi M., 144, 191, 200, 204, 213,
Arnoffi J., 232                           Bianchi G., 169                            Calvisi G., 135, 143                          216, 217
Arrigoni C.V., 231                        Bianchi P., 175                            Camerlingo R., 217                        Chiusa L., 100, 162, 228
Artioli P., 14                            Bianchi S., 146                            Campaner M., 258                          Cianci R., 138
Arvaniti M., 340                          Bianco M., 206, 207                        Campisi V., 232                           Cicchinelli I., 135, 143
Ascierto P., 140                          Biasi O., 219                              Canciglia R., 194                         Cimino G., 195
Ascoli V., 318                            Biggeri A., 228                            Candia S., 148                            Cimmino A., 137, 168, 202, 208, 245
Asioli S., 166                            Bisceglia M., 4, 43, 177, 182, 183, 186,   Canessa P.A., 160                         Cintorino M., 211, 212, 265
Asselti M., 225, 226, 237                     195, 206, 207, 216, 249                Cannata N., 238                           Cirese V., 116
Avallone A., 240                          Bisceglia M.L., 4                          Cannizzaro C., 139, 213                   Citraro L., 200
Awad A.T., 22                             Bisceglia S., 4                            Cantaloni C., 140, 157, 215               Ciuffetelli V., 175, 263
Azzolina V., 210                          Boccardo S., 166, 221                      Cantile M., 107, 110, 140, 146, 164,      Claudio B., 217
Azzoni C., 77                             Boccuzzo G., 225                               217, 218, 239, 240, 241, 245, 263,    Clemente C., 105
                                          Bogina G., 99, 217                             264                                   Clemente R., 236
Bacci F., 14, 119                         Boldorini R., 156, 192, 261, 262           Capano R., 239, 240, 241                  Coccia A., 253
Bacigalupo A., 179                        Bollito E., 128                            Capella S., 159                           Coccini G., 1
Bacigalupo B., 160                        Bolner A., 171                             Capelli P., 191, 192                      Coccini G., 174
Badri T., 71, 343                         Bombonato M., 232                          Caponio M.A., 150                         Cocuzza S., 261
Baffa R., 235                             Bonanni B., 219                            Caporalini C., 204, 205                   Colantoni A., 159
Bagnoli A., 175                           Bonanno A., 233                            Cappadona S., 228                         Colao A., 202
Baldassarre S., 294                       Bonanno E., 148, 159                       Cappellesso R., 232                       Colasante A., 172, 259
Baldelli R., 202                          Bondi A., 87, 130                          Cappello F., 145                          Colato C., 144, 178
Baldini D., 148                           Bonello L., 162                            Capulli M., 186                           Coletti G., 175, 263
Balistreri M., 161, 189, 235              Bonetti F., 216, 217, 220, 325             Caraglia M., 263                          Colli S., 160, 166, 221
Balmativola D., 221                       Bonifacio D., 79                           Caramella D., 137                         Collina F., 146, 217, 218
Balzarini P., 215, 261                    Bonifacio M., 200                          Carbone A., 149                           Collina G., 50, 337
author inDeX                                                                                                                                                  353


Colombo M.P., 197                         Dell’Orto P., 156                     Ferretti M., 252                           Giantomassi F., 197
Colombo P., 223                           Dell’Osa E., 198                      Ferretti S., 88                            Giardina C., 222
Colonna A., 158                           Della Pace L., 239, 256               Ferro A., 215                              Giardini R., 114
Colonna P., 200                           Delrio P., 240                        Ferro P., 160, 166, 221                    Giarnieri E., 154
Comin C.E., 155, 204, 205                 De Maglio G., 182, 216                Ferrone S., 107                            Gigante A., 138, 211
Condito A.M., 340                         Demarchi A., 264                      Fesslova V., 53                            Gigantino V., 263, 264
Conte P.F., 215                           Denti A.M., 157                       Feyles E., 271                             Giglio A., 234
Contini M., 152                           Dessanti P., 166                      Fiaccavento R., 135                        Gilioli E., 204
Convertino C., 148                        Di Bella C., 223                      Fiandrino G., 122                          Gillio Tos A., 253
Coppola R., 161, 165, 193, 194, 229       Di Bello C., 162                      Ficarra G., 215                            Ginori A., 8, 68, 211
Corini F., 169, 184, 229, 243, 245        Di Bonito L., 79, 148                 Ficarra V., 139                            Gioioso A., 150
Cormio L., 170                            Di Bonito M., 146, 217, 218           Ficial M., 213                             Giordano C., 27
Corrao S., 145                            Di Carlo A., 234                      Filardo A., 254                            Giordano T., 238
Corrente A., 255                          Di Clemente D., 202, 206, 245, 249,   Filotico M., 299                           Giotta F., 225, 226
Corsi F., 239                                 255                               Fiordelisi F., 43, 216                     Giovagnini G., 175
Cosci E., 230                             Di Clemente L., 263                   Fiore G., 168, 206, 245, 249               Giovagnoli M.R., 82, 154
Cosimi M.F., 271                          Di Cristofano C., 148                 Fiorentino M., 128                         Girardi G., 205, 260
Cossu-Rocca P., 152                       Di Domenico M., 185                   Fiorini P., 11                             Girelli M.E., 189
Costa A., 238                             Di Filippo F., 217                    Fiorito C., 253                            Girlando S., 171, 215
Costantini B., 197                        Di Francesco A., 225                  Fisogni S., 46                             Girolomoni G., 178
Costanza G., 203                          Di Gioia C., 27                       Floccari F., 234                           Giudici F., 79, 148, 213
Costarelli L., 148                        Di Gregorio C., 231                   Flora M., 147                              Giuffra V., 137, 209
Covelli C., 249                           Di Leo A., 228                        Florena A.M., 164, 167, 197                Giuffrè G., 85
Covello R., 202                           Di Lorenzo, I., 251                   Floridi D., 205                            Giuliani M., 234
Coverlizza S., 264                        Di Lorito A., 172, 198, 200, 259      Foltran L., 163                            Giuliani S., 140
Crescenzi A., 148                         Di Marco F., 199                      Fondi C., 179                              Giunchi F., 128
Crippa S., 163, 233                       Di Mari N., 25                        Fontana V., 160                            Giurato E., 186
Crisafulli C., 233                        Di Matteo F.M., 193, 194              Fontecchio G., 137, 209                    Giuseppetti G.M., 294
Crisman G., 135, 143, 146, 175, 196,      Di Nardo P., 135                      Fornaciari A., 137                         Giusiani S., 137
    234, 263, 266                         Di Naro N., 62, 304                   Fornaciari G., 137, 138, 209               Gobbo S., 139, 191, 192, 213, 216
Croce A., 159, 172, 200                   Di Stasio E., 135                     Fornari A., 128                            Gomes V., 148
Croce C.M., 235                           Di Tonno C., 157                      Foscolo A.M., 254                          Gorji N., 166
Crocetti E., 146                          Diamanti L., 169, 184, 229            Francavilla S., 263                        Goteri G., 197, 252
Crucitti P., 87, 161                      Dimitri L., 239                       Franceschini M.C., 160, 166, 221           Grammatica L., 187
Cuorvo L., 215                            Dinelli M.E., 161, 162                Francesconi A., 202, 232                   Grandi C., 171
Curcio E., 163                            Diodoro M., 232                       Francia di Celle P., 162                   Grasso M.A., 207
Curcio M.P., 110                          Discepoli S., 146, 266                Franco C., 122                             Gravina G.L., 138, 209
Curti T., 266                             Doglioni C., 112                      Franco G., 197                             Graziano M., 271
                                          Dominici M., 215                      Franco R., 107, 110, 136, 140, 144, 171,   Graziano P., 157
D’Agruma L., 183                          Donà M.G., 234, 251                       185, 227, 239, 245, 263, 264           Greco M., 195
D’Alterio C., 239                         Donadio M., 228                       Franco V., 142, 164, 167, 236              Greco P., 87, 165
D’Amati G., 27, 148                       Donnini I., 179                       Frattini M., 156, 163, 233                 Greggi S., 153
D’Amuri A., 234                           Doring C., 196                        Frossi B., 164, 197                        Gri G., 164
D’Angelo A., 169, 184, 229                                                      Fulcheri E., 250, 257                      Grigolato P.G., 131, 215, 261
D’Angelo G., 172                          Eccher A., 204                        Fulciniti F., 140, 150                     Grillo L.R., 148
D’Angelo P., 199                          Eccher C., 215                        Fumagalli C., 156, 219                     Grimaldi B., 138
D’Angelo V., 207                          Egarter-Vigl E., 258                  Fusi C., 179                               Grottola A., 265
D’Antona G.I., 43                         El-Bahrawy M., 22, 331                                                           Guadagno E., 189
D’Antuono T., 158                         Epifani A., 234                       Gaeta L.M., 194, 229                       Guarneri V., 215
D’Armiento M., 93                         Esposito A., 129, 134                 Galardi F., 228                            Guarnotta C., 142, 164, 167, 190, 197
D’Eredità G., 222                                                               Galasso M., 235                            Guerrieri A.M., 222
D’Urso P.I., 137, 208                     Faa G., 62                            Galletta F., 164                           Guetti L., 155, 158, 203
Da Pozzo G., 14                           Fabbietti L., 294                     Galliani C., 182, 186, 249                 Gugliotta P., 147
Dal Mas A., 148                           Fabbretti G., 175, 313                Galliani C.A., 206                         Guidi S., 179
Dal Santo M., 131                         Fabbro M., 232                        Galliani M., 211                           Gulino A., 167
Dalla Palma P., 80, 118, 140, 171, 215,   Fabris G., 294                        Galligioni E., 215                         Gurrera A., 186
    216                                   Facchetti F., 46, 123, 168            Gallo D., 154                              Gustinelli A., 262
Danza K., 227                             Facchini G., 263                      Gallo E., 217                              Gustinucci D., 150
Daprile R., 220, 225, 227, 237            Facciolo F., 202                      Gallo P., 27                               Guzzardo V., 161, 225
David S., 145                             Fadda G., 81, 152, 154, 189, 251      Galuppini F., 189                          Guzzetti S., 220
De Bernard M., 235                        Faggiano A., 202                      Galzio R.J., 208
De Carolis S., 251                        Falconieri G., 163, 216               Gambacorta M., 232                         Hammami H., 71, 311
De Chiara A., 164                         Falini B., 14, 119                    Ganau M., 62                               Hansmann M.L., 196
De Giorgi V., 142                         Falsirollo F., 325                    Gandolfo S., 170, 172                      Hartmann S., 196
De Luca C., 202                           Fara D., 263                          Garbini F., 11                             Hofmann W.P., 196
De Luca F., 25, 212                       Fara Tanjona H., 156                  Garofalo A., 232                           Huhtamo E., 261
De Luca N., 177                           Faraggiana T., 138, 211               Garruso M., 271
De Maglio G., 147, 158, 163               Farina M., 107, 140                   Gaudio F., 202, 245                        Iaccarino A., 190
De Marco L., 253                          Farinati F., 236                      Gazzola A., 14                             Iannucci A., 204
De Miglio M.R., 152                       Farinetti A., 180, 248, 265           Genderini F., 214                          Icardi M., 201
De Murtas F., 239, 245                    Farruggia P., 199                     Genovese F., 94, 167, 194, 241             Ieni A., 187
De Nictolis M., 294                       Fasanella S., 140                     Genta R.M., 236                            Ientile D., 238, 255
De Pangher Manzini V., 158                Fasola G., 158, 163                   Gentile R., 90, 166, 191                   Ilardi G., 141, 180, 240, 246, 248
De Pellegrin A., 79, 148                  Fassan M., 86, 161, 189, 235, 236     Gessi M., 97                               Imenpour H., 307
De Rosa G., 141, 144, 180, 190, 240,      Fassina A., 125, 232                  Ghiringhello B., 253, 260                  Impara G., 234
    246, 248                              Fazaa B., 73                          Giacalone B., 94, 167                      Imperiale D., 144
De Rosa N., 200                           Fazioli F., 164                       Giacomelli L., 161, 225                    Inghirami G., 119, 162, 167
De Salvo L., 217                          Fedele F., 233                        Giallombardo D., 182, 190, 236, 242        Ingravallo G., 137, 168, 202, 208, 222
De Santis R., 249                         Fedeli F., 160, 166, 221              Giammaresi C., 139, 212                    Intrieri T., 146
De Silva G., 307                          Federico S., 253                      Gianatti A., 147                           Ioli A., 175
Deambrogio C., 253                        Felicioni L., 155, 158, 203           Giannakakis K., 138, 211                   Ionna F., 245
Debbiche A., 311                          Fenniche S., 71, 331, 343             Giannatempo G., 195                        Iop A., 158
Del Conte A., 158                         Fenocchio D., 220                     Giannatiempo R., 176, 185, 227, 239,       Ishak F., 71
Del Vecchio M., 169, 184, 229             Ferdeghini M., 144                        264                                    Isimbaldi G., 231
Del Vecchio M.T., 190, 210, 230           Feriozzi S., 211                      Giannini A., 146, 228
Del Vescovo V., 157                       Ferraiuolo P., 140                    Giannone A.G., 218                         Jaffrain-Rea M.L., 208
Delfino C., 179                           Ferrantelli A., 139, 211, 212         Giannone G., 150, 187, 225                 Jedidi S., 346
Dell’Antonio A., 148                      Ferraris A.M., 221                    Gianquinto D., 221                         Jones M., 311
354                                                                                                                                                   author inDeX




Kacerovská D., 259                         Manini C., 151, 253, 264                 Miracco C., 25                           Ozben T., 169
Karoui S., 343                             Manna A., 140                            Miraglia M.C., 242
Kasal A., 258                              Mannella E., 266                         Miranda G., 209                          Pacella E., 257
Kazakov D., 259                            Mannone T., 114                          Mittica G., 228                          Pacenti L., 190
Khaled A., 73                              Mannu C., 14                             Mokhtar I., 71, 311, 343                 Paci E., 146
Korbi S., 346                              Mannucci S., 210                         Molinari F., 233                         Paganotti A., 156, 192
Kourda J., 73                              Manta C., 160                            Molinaro L., 162, 222                    Pagliarulo M., 234
Kourda M., 73                              Manzotti M., 156                         Molo S., 122                             Paglierani M., 142, 147
Kuppers R., 196                            Marampon F., 138, 186, 209               Monari E., 169                           Pagni F., 223
                                           Marandino F., 217                        Moncelsi S., 152, 251                    Palamara G., 234
La Mantia E., 110, 136                     Marasà L., 199, 211                      Moncini D., 11                           Palatini J., 235
La Rocca G., 145                           Marasà S., 203, 242                      Mondaini N., 266                         Palazzoni G., 214
Labate A., 219, 236, 253                   Marasco A., 254                          Monego G., 135                           Palermo A., 188
Labbene N., 311                            Marazzi F., 214                          Monga G., 156                            Palma F., 187
Lagrasta C., 147                           Marchelle G., 147, 225                   Monticelli A., 185, 227, 239, 264        Palumbieri G., 246, 257
Lahmar A., 346                             Marchesini G., 252                       Montironi P.L., 151                      Palumbo M., 206, 245, 255
Lai M.L., 62                               Marchetti A., 109, 155, 158, 203         Montironi R., 128                        Palummo N., 210
Lambertenghi D., 228                       Marchiò C., 221, 228                     Montrone T., 202, 206, 222, 245, 249,    Panniello G., 177
Lanzafame S., 186, 261                     Marchione M., 228, 248                       255                                  Pannone G., 144, 171, 185, 188, 240,
Lapi E., 11                                Marchione R., 32                         Morabito F., 271                              246, 247, 262
Larato C., 253                             Marcolini L., 191, 192, 220, 237         Morassi F., 154                          Papagerakis P., 262
Lastilla G., 182                           Margiotta D., 138                        Moretto D., 234                          Papagerakis S., 262
Latini A., 234                             Margiotta M., 175                        Morichetti D., 52, 64, 141, 180, 181,    Papaleo N., 151
Lattanzio G., 198, 200                     Mariani M., 197                              222, 258, 279                        Papotti M., 128, 157
Lauricella C., 232                         Mariani N., 201                          Morosetti M., 211                        Pappalettera F., 170
Lazzi S., 8, 124, 181, 195, 230, 238       Mariani S., 162                          Mosca A., 139                            Para P., 175
Leardo T., 253                             Maricosu E., 152                         Mottolese M., 148, 217                   Paradiso A., 148, 220, 227, 237
Leocata P., 135, 143, 146, 175, 196,       Marinelli C., 198                        Mourmouras V., 25, 181, 238, 260         Parafioriti A., 182
    234, 263, 266                          Maringhini S., 210                       Mucilli F., 155, 158, 203                Parente P., 235
Leonardi E., 147, 215                      Mariotti C., 294                         Munari E., 200, 213                      Parenti R., 186
Leonardo E., 148                           Marra F., 146                            Mura A., 152                             Parisi A., 144, 191, 192, 220, 237, 325
Leoncini L., 124, 195                      Marra L., 185, 217, 240, 263, 264        Murari R., 176, 188                      Parracino T., 206
Leone B.E., 223                            Marsico A., 170, 172                     Muroni M.R., 152                         Parravicini C., 112
Leone G., 259, 261                         Martellani F., 79, 148                   Murphy K.M., 271                         Pasqualini F., 177
Leoni P., 197                              Martignoni G., 139, 204, 213, 216, 217   Musa M., 159                             Pasquinelli G., 183
Lepanto D., 219                            Martin V., 163                           Muscarella L., 183                       Pasquini P., 148
Li Cavoli G., 139, 211, 212                Martinesi M., 266                        Muscatiello N., 166                      Passamonti B., 150
Libener R., 201                            Maruzzi M., 206                          Mustacchi G., 148                        Passantino R., 139, 211, 212
Liberati M., 259                           Marzano A.L., 225, 226                   Muti P., 148                             Paulli M., 122, 196
Libretti L., 231                           Marzi S., 186, 208                       Mzabi S., 346                            Pazzagli M., 142
Liguori G., 107, 110, 146, 164, 217, 218   Mascolo M., 141, 180, 246, 248                                                    Pecciarini L., 147
Limaiem F., 346                            Mashali N., 22                           Nagar C., 94, 167, 194, 241              Pecorari M., 265
Liotta R., 191                             Masiero E., 158, 163                     Naldi N., 77                             Pederzoli A., 175
Liuzzi M., 222                             Massa P., 254                            Nania A., 238                            Pedica F., 191, 192
Lo Cunsolo C., 147                         Massarelli G., 152, 168                  Nanni N., 265                            Pedicillo M.C., 247
Lo Mele M., 147, 225                       Massi D., 106, 142, 179                  Nannini R., 216                          Pedretti P., 179
Loda M., 128                               Mastrogiulio M.G., 211, 230, 238         Napoli A., 222                           Pedron S., 217
Lomazzo G., 135                            Mastrogiulio M.G., 68                    Napoli P., 238                           Pelella A., 239, 240
Longhi E., 112                             Mataca E., 153                           Nasorri F., 229                          Pelizzo M.R., 189
Longo F., 165, 245                         Materazzi S., 179                        Nassini R., 179                          Pellegrini W., 168
Lora V., 178                               Matter M., 136                           Natale G., 144                           Pellis G., 148
Lorenzi L., 168                            Mattioli E., 226                         Navone R., 170, 172                      Pelosi G., 125, 157
Losito N.S., 153                           Mattoni M., 171, 185, 188, 246, 247,     Nebuloni M., 177, 214                    Penitente E., 172, 198, 259
Losito S., 245                                262                                   Negri F.V., 77                           Pennacchia I., 135, 149, 214
Lotta R., 166                              Maura E., 170                            Negri G., 154, 258                       Pennelli G., 189, 236
Lucchini C., 220                           Mazza S., 151                            Nesi G., 213, 266                        Pensiero V., 138
Lucchini V., 231                           Mazzer M., 163                           Nicastro A., 176, 185, 227, 239, 264     Pentenero M., 170, 172
Luchini C., 191, 192                       Mazzitelli R., 236                       Nicola M., 122                           Pepe P., 127
Lucioni M., 122, 196                       Mazzola S., 151                          Nicolini M., 175                         Pepi M., 155, 213
Ludwig K., 161                             Mazzon E., 219, 236, 253                 Nirchio V., 166, 170, 239, 256           Perdonà S., 263
Luparia P., 253                            Mazzucchelli L., 163, 233                Nitti D., 236                            Pericoli M.N., 148
Lupi M., 19, 40, 248                       Menia E., 154                            Nizzoli R., 77                           Perracchio L., 148, 232
Lupo C., 133                               Menis J., 158                            Nocita A., 151, 254                      Perrone G., 43, 161, 165, 193, 194, 229
Lusiardi M., 157                           Mennilli S., 134                         Nogales F.F., 152                        Pescarmona E., 202, 217, 232, 251
Lutrino S., 163                            Merante A., 260, 340                     Noto S., 170                             Pessina S., 156
                                           Mercurio C., 209                         Nottegar A., 204, 216, 217, 325          Petitti T., 211
Macario M., 220                            Merlo E., 307                            Novara G., 139                           Petroni S., 150, 225, 226
Macciocu E., 154                           Mescoli C., 236                          Novelli L., 155, 204, 205                Pettinato G., 145
Macilotti M., 140                          Mesiti M., 219                           Nozzoli C., 179                          Peveling-Oberhag J., 196
Macor P., 167                              Messerini L., 155, 204, 205              Nucifora M., 233                         Piacentini F., 215
Macrì L., 220, 221                         Messina V., 238                          Nugnes L., 176, 185, 227, 239, 264       Pica E., 176
Maglione A., 176, 185, 227, 239, 264       Mezzapelle R., 156, 192                                                           Piccaluga P.P., 14, 119, 167, 197
Magro G., 101, 165, 186, 259, 261          Mezzaroba N., 167                        Oackman C., 228                          Piccioli M., 14
Maio V., 179                               Mian C., 189                             Ober E., 79, 148                         Piccioni D., 175
Maione M.P., 176, 185, 227, 239, 264       Miani L., 252                            Olianas R., 152                          Piccolomini M., 32, 228, 248
Maiorana A., 19, 40, 169, 180, 215, 248    Micali S., 169                           Olla L., 62, 304                         Pietribiasi F., 101
Maiorano E., 202                           Michal M., 259                           Onetti Muda A., 138, 161, 165, 193,      Pignata S., 153, 263
Malapelle U., 145, 200, 202, 243           Micheletti M., 170                           194, 211, 229                        Piiper A., 196
Malatesta S., 155, 158, 172, 198, 200,     Micheli F., 173                          Onorati M., 8, 25, 181, 190, 195, 210,   Pilato B., 226
   203, 259                                Micheli P., 173                              211, 212, 230, 238, 260, 265         Pileri S.A., 14, 119, 167, 168
Maletta F., 220, 253                       Migaldi M., 180, 248, 265                Opocher G., 189                          Pili F., 152
Malfettone A., 220, 227, 237               Miglio U., 156, 192                      Oppressore D., 176, 185, 227, 239, 264   Pimpinelli F., 234
Mambelli V., 169, 184, 229, 245, 294       Miglionico L., 249                       Oranges T., 179                          Pimpinelli N., 179
Mamo M., 236                               Migliore M., 186                         Orecchia S., 201                         Pinzani P., 142
Manfrin E., 216, 217, 220, 237, 325        Mignogna C., 103, 238, 255               Orlando E., 203, 242                     Pioner R., 258
Mangerini R., 221                          Mikuz G., 128                            Orvieto E., 147, 225                     Pirozzi G., 217, 241
Mangia A., 220, 227, 237                   Mirabella A., 136                        Ottelli Zoletti F., 228                  Pisano C., 153
Mangiapia M., 200                          Mirabella C., 170                        Ottoveggio G., 94, 167, 194, 241         Piscioli F., 52, 141
author inDeX                                                                                                                                                      355


Piscuoglio S., 136                        Rostan I., 170, 172                      Sibau A., 158                              Unti E., 145, 199, 210, 241, 251
Pistillo M.P., 160, 166, 221              Rotellini M., 155, 204, 205              Silini E.M., 77                            Uras M.G., 152
Pitino A., 271                            Rotolo U., 139, 211, 212                 Silvano Costa S., 153                      Urbani V., 209
Pizzamiglio S., 148                       Rubini V., 150                           Silvestrini M., 171                        Urso C., 146
Pizzi G., 254                             Ruco L., 148                             Simoncelli S., 215
Pizzi M., 161, 189, 235, 236              Rudà R., 228                             Simone G., 150, 187, 220, 225, 226,        Vago G., 214
Pizzolitto S., 158, 163                   Rugge M., 86, 147, 161, 189, 225,            227, 237                               Vairo M., 182
Polci R., 211                                235, 236                              Simonetti A., 228                          Valduga F., 171
Pollini G.P., 325                         Ruisi R., 251                            Simoni A., 266                             Valentino A., 203, 242
Poloni A., 197                            Ruol A., 161                             Sivori M., 160                             Vandone A., 100
Ponte R., 257                             Ruotolo G., 260, 340                     Sollima L., 135, 143                       Vanoni V., 171
Ponz de Leon M., 231                      Russo A., 176, 185, 217, 227, 239, 264   Somma A., 189                              Vanzati A., 243
Popescu O., 150, 226                      Russo D., 173, 177                       Somma P., 173                              Varone V., 145, 173, 243
Porta C., 139                             Russo L., 239, 264                       Spagnoli L.G., 159                         Vasquez E., 247, 259
Possanzini P., 156, 219                   Russo S., 187, 202                       Spairani C., 271                           Vassallo L., 68, 211
Postiglione M., 176, 185, 227, 239, 264                                            Sparano L., 136                            Vassarotto E., 225
Potortì I., 191                           Sabatini A.M., 265                       Spina D., 195                              Vazzana N., 198
Pozzilli P., 188                          Sabattini E., 14, 119                    Spirito A., 206                            Vecchio F.M., 149, 214
Prestipino J., 101                        Sabbatini R., 252                        Spoladore C., 225                          Vecchio G.M., 165, 186
Priano R., 175                            Sabino A., 165                           Squillaci S., 32, 228, 248, 254, 271       Vecchione M.L., 141, 246, 248
Privitera E., 147                         Saccardi R., 179                         Staffolani M., 252                         Veggiani C., 156, 192, 262
Pucillo C., 164, 197                      Sacchini, A., 265                        Staiano M., 150                            Vellone V.G., 152, 154, 189, 251
Pugliese F., 138, 211                     Sacco O., 107                            Staibano S., 106, 141, 180, 240, 246,      Ventura L., 137, 138, 186, 208, 209
Puliga G., 62, 304                        Sagramoso Sacchetti C.A., 14                 248                                    Venturoli S., 153
Pusiol T., 52, 64, 141, 180, 181, 222,    Salatiello M., 202                       Stauder E., 19, 40                         Verderio P., 148
    258, 279                              Salemme M., 46                           Stefani M., 53                             Verdun di Cantogno L., 147
Puzzo L., 247                             Salvatore C., 220, 227                   Steinmeyer A., 266                         Vermi W., 123
                                          Salvatorelli L., 165, 186                Stigliano V., 232                          Vezzosi V., 146
Quero C., 187, 225                        Salvi S., 147, 166, 221                  Stio M., 266                               Viale G., 100
                                          Salvianti F., 142                        Stramazzotti D., 197, 252                  Vianello F., 189
Rabitti C., 193                           Salvio M., 201                           Stufano V., 156                            Viberti L., 85, 143, 201, 220
Raffaelli M., 189                         Salvioni D., 223                         Sulfaro S., 158                            Vigani A., 160
Ragazzini T., 130                         Sampaoli I., 175                         Sullo L., 170                              Vigevani E., 158
Ramieri M.T., 148, 176, 188               Sanchez Mete L., 232                                                                Vigliar E., 173, 243
Ranaldi R., 294                           Sangaletti S., 197                       Taborro R., 184, 245                       Vigna S., 147
Rappa F., 145                             Sangapur R., 225                         Tacchini D., 238                           Villani E., 234
Rattotti S., 196                          Sanguedolce F., 188, 247, 262            Tacchini D., 68                            Villari N., 137
Ravanini P., 261                          Santantonio R., 258                      Taddei G.L., 11, 155                       Vindigni C., 195
Re P., 201                                Santi R., 213, 266                       Taglieri D.M., 219, 236, 253               Viola P., 155, 158, 172, 198, 200, 203,
Re R., 197                                Santinelli A., 147, 294                  Tallarico E., 151, 254                         259
Realdon S., 235                           Santini D., 229                          Tallarigo F., 151, 228, 248, 254           Visca P., 202
Reggiani Bonetti L., 19, 40, 169, 180,    Santonastaso C., 241                     Tallini G., 147                            Vita G., 43
    215, 231, 248, 265                    Santopietro R., 181, 230, 238            Tancredi G., 205                           Vitale A., 214
Reggiani C., 50                           Santoro A., 144, 171, 185, 188, 189,     Taraglio S., 144                           Vitale A.R., 266
Reitano R., 170                               240, 246, 247, 262                   Tarquini E., 251                           Vitale R., 248
Relli V., 136, 140                        Sapia M.C., 210                          Tasso G., 177                              Vitarelli E., 231
Remo A., 220, 325                         Sapino A., 100, 147, 162, 220, 221,      Tatangelo F., 239, 240, 241                Vitiello A., 137
Resta L., 137, 206, 208, 245, 249, 255        228, 253                             Tavani E., 114                             Vitolo D., 148
Riboni R., 122                            Saponaro C., 220, 227, 237               Tempia Valenta G., 172                     Vittoria E., 217
Ribotta M., 135, 205, 260                 Sarnelli G.C., 201                       Terracciano L., 89, 136                    Vocaturo A., 234, 251
Ricci A., 186                             Sartore Bianchi A., 232                  Terrenato I., 148, 217                     Vocaturo G., 251
Ricci D., 271                             Sartori M., 192                          Testi R., 144                              Volinia S., 235
Ricci M., 216                             Satarpia L., 228                         Tolu G.A., 62, 304                         Volpe A., 159
Ricci R., 214                             Scacchi C., 157                          Tomasi A., 169
Ricco R., 168, 202                        Scaffa C., 153                           Tommasi S., 226                            Wang J., 331
Rider-Stark J., 128                       Scaglione, G., 167                       Tondat F., 162
Ridha Kamoun M., 73                       Scala C., 250                            Tonelli F., 213                            Zacchi A., 79, 148
Ridolfo A.L., 112                         Scala S., 239                            Tonello C., 112                            Zagami M., 229
Righi A., 259                             Scamarcio R., 168                        Tonini G., 229                             Zagarrigo C., 139
Righi D., 161, 194                        Scambia G., 152, 251                     Toppino D., 162                            Zamboni G., 191, 217
Rinaudo C., 159                           Scaramuzzino F., 190, 230                Torelli L., 79, 148                        Zamò A., 200
Riotta S., 255                            Scarcella S.V., 137, 208                 Tornesello M.L., 83                        Zamparese R., 169, 184, 229, 243, 245
Rivasi F., 153, 261, 262                  Scarpino S., 148                         Tornillo L., 91, 136                       Zanatta L., 147
Rizzi C., 158                             Scatena C., 142                          Torrisi A., 186, 259                       Zanconati F., 79, 148
Rizzuti T., 53                            Schillaci L., 177                        Tortorella S., 247, 262                    Zandonà L., 148
Rocca B.J., 8, 25, 124, 181, 190, 195,    Schillaci O., 142, 182                   Tortorici C., 139, 212                     Zanellato E., 163, 233
    210, 211, 212, 230, 238, 260, 265,    Schmidt A., 196                          Tosoni A., 214                             Zangrandi A., 147
    340                                   Schurfeld K., 124                        Tralongo V., 94, 167, 194, 241             Zanin T., 133
Rocco G., 136                             Scialpi M., 52                           Trapani F., 136                            Zaninotto G., 161, 235
Rodella R., 46                            Sciarrotta M.G., 155, 158, 203           Trappolini S., 197                         Zannoni G.F., 102, 152, 154, 189, 251
Rodolico V., 182                          Scibetta N., 145, 199, 210, 241, 251     Treves C., 266                             Zanus G., 232
Rollo F., 234, 251                        Scimeca M., 159                          Trevisan G., 22                            Zarrelli N., 249
Romanelli D., 163                         Scivetti A., 206                         Tricarico F., 166                          Zawada L., 214
Romano A., 79, 148                        Scognamiglio G., 107, 136, 140, 146,     Tricarico N., 177                          Zeppa P., 243
Romano M.F., 180                              153, 218                             Trincheri N.F., 201                        Zermani R., 73
Romano S., 180                            Scrima M., 110                           Triolo R., 215                             Zeuzem S., 196
Romeo G., 138                             Scuri M., 40                             Tripodi S., 190, 210, 211, 212, 230, 265   Zinellu A., 152
Roncalli M., 92                           Segala D., 139, 204, 213                 Tripodo C., 164, 167, 197                  Zito Marino F., 110
Roncella S., 160, 166, 221                Senatore S.A., 234                       Trizzino A., 199                           Zizzi A., 197
Ronchetti L., 234                         Senetta R., 228                          Trodella L., 229                           Zobbi V., 77
Ronco G., 253                             Sentinelli S., 232                       Trombatore M., 182, 190, 236               Zolfanelli F., 146
Rosa M., 211                              Serra A., 261                            Trombetta I., 209                          Zorzi M.G., 52, 64, 141, 180, 181, 222,
Rosai J., 182                             Serriello I., 211                        Troncone G., 125, 145, 173, 189, 190,          258, 279
Rossano V., 151                           Servino L., 261                              200, 202, 243                          Zuccotti G.F., 205, 260
Rossi Degl’Innocenti D., 155              Setta S., 172                            Truglia M.C., 228                          Zuegel U., 266
Rossi E.D., 81, 152, 154, 189, 251        Sgambato A., 180, 248, 265               Truini M., 166, 221, 307                   Zummo G., 145
Rossi G., 109, 136, 157                   Sgariglia R., 243                        Tuccari G., 187                            Zupo S., 307
Rossi R., 137, 208                        Siano M., 141, 180, 240, 246, 248
356                                                                                                                Key worDS inDeX




                                             Key words index

2D Barcode technology                313    G                                            O
                                            Gallbladder lymphoma                   307   Ovary                                19
A                                           Giant cells                             68
Adenocarcinoma                        40
Adenolipoma                          343                                                 P
Adenomatous transformation           346    H                                            Pacinian Corpuscle                    4
Adnexal tumour                       311    Hamartoma                              346   Pathological examination           294
Adrenal                               19    Hashimoto’s disease                     61   PCR                                340
Adrenal gland                         46    Hereditary spherocytosis                46   Perineurium                           4
Amniotc band syndrome                 11    Hidradenoma                            311   Peripheral neuroectodermal tumor     43
Apocrine                             311    Histogenesis                            32   Perisudoral lipoma                 343
Autoptic examination                  53    Histological report                    294   Personnel workload                    1
                                            Histopathology laboratory                1   Peutz-Jeghers-type polyp           346
                                            Hodgkin’s disease                       43   Pilar leiomyoma                      71
B                                           Hyperplasia                            304   Post-irradiation sarcoma             43
Biopsy                               331                                                 Prenatal diagnosis                   53
Bizarre paraosteal chondromatous                                                         Primary systemic therapy           294
proliferations (BPOP)                299    I                                            Prostate                         40, 50
Breast                                68    IGK                                    14    Protein S100                       337
Breast cancer                   294, 325    Immunohistochemistry         25, 279, 337
Bronchogenic cyst                     19    Incidentaloma                          46    R
                                            Intraoperative diagnosis              325    Reactive mesothelium                318
                                                                                         Rectum                              346
C                                                                                        Renal neoplasms                     271
Cancer                               331    K                                            Retroperitoneum                      19
CD 138                                61    Kappa chains                            61   Risk management                     313
Cervix                               331    Kidney                                  22
Cleft palate                          11    K-ras                                   77
Clinical governance                    1                                                 S
Colonic polyp                          8                                                 Safety management of patient
Colorectal cancer                     77    L                                               specimens                        313
Colposcopy                           331    Leiomyoma                               22   Salivary gland cancer               279
Combined                             337    Lip                                     11   Screening                           331
Congenital heart anomalies            53    Lipoma                                 343   Sebaceous carcinoma                  64
Core needle biopsy                   325    Lung lobation defects                   53   Sebaceous lymphadenoma               32
Cytology                             318    Lymphoma                               307   Sebaceous neoplasm                   64
                                                                                         Second cancer                        43
                                                                                         Serous effusion                     318
D                                           M                                            Signet ring cell                     40
Desmoplastic melanoma                 337   Malignant oncocytoma                   279   Skin                                343
Diagnostic pitfalls                   318   Malignant proliferating trichilemmal         Skin metastases                      50
Differential diagnosis            68, 271      cyst                                 73   Smooth muscle tumour                 71
Diverticular polyps                     8   Malignant proliferating trichilemmal         Solitary extramedullary plasmacytoma 61
Diverticulosis                          8   tumour                                  73   Stomach                              19
Ductal carcinoma                   50, 68   Mammography                             52   Synovial sarcoma                    271
Dysplasia                             331   Medical Education                       27   SYT/SSX gene fusion                 271
                                            Melanoma                                25
                                            Meningoencephalocele                    11   T
E                                           Mesothelial                            304   Teaching Anatomical Pathology        27
Eccrine glands                       343    Mesothelioma                           318   Technician                            1
Efficiency                             1    Mismatch errors                        313   Thyroid gland                        61
Ewing’s sarcoma                       43    Molecular biology                       14   Tuberculosis                        340
Extracardiac anomalies                53    Multinodular goiter                     61   Tumour                               22
Extramedullary hematopoiesis          46    Muscle Spindle                           4   Tunica vaginalis                    304
Extranodal lymphoma                  307    Mycobacterium                          340

                                                                                         U
F                                           N                                            Undergraduate curriculum in Medicine 27
Fine needle aspiration biopsy          77   Needle core biopsy                      52
Fine needle aspiration cytology   52, 325   Neoadjuvant chemotherapy               294
Foetal echocardiography                53   Nipple                                  25   V
Frozen sections                       325   Nodal marginal zone lymphoma            14   Vulva                               337
                                            Nose                                    11   Vulva cancer                         64
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