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Pathology in cancer genetics

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					     Pathology in cancer genetics
     Indirect marker of a genetic profile of tumour.
          Risk assessment and management.




25/10/2011 05:21:20   Sameer Jhavar.The Institute of   1
                         Cancer Research, UK
     Pathology in cancer genetics
                          Genetic cause
                      (Hereditary)/ Sporadic
                                 Breast cancer



                                Ovarian cancer



                                 Bowel cancer



                                 Kidney cancer




25/10/2011 05:21:20   Sameer Jhavar.The Institute of   2
                         Cancer Research, UK
    Breast cancer: Medullary histology is significantly more common
                    in BRCA1 associated tumours

•    INTRADUCT CARCINOMA: PAPILLARY; COMEDO; CRIBRIFORM;
•    INFILTRATING DUCTAL CARCINOMA; PAPILLARY; NEUROENDOCRINE (80% of all invasive breast cancers)
•    LOBULAR CARCINOMA IN SITU
•    INFILTRATING LOBULAR CARCINOMA; MUCINOUS; SIGNET RING CELL (10% of all invasive breast cancers)
•    SECRETORY CARCINOMA
•    CARCINOMA IN PREGNANCY
•    SIGNET RING CELL CARCINOMA
•    MUCIN SECRETING CARCINOMA
•    IDC WITH CHONDROID METAPLASIA
•    MEDULLARY CARCINOMA (5-10% of invasive cancers)
•    TUBULAR CARCINOMA
•    CARCINOMA WITH SARCOID REACTION; WITH GRANULOMAS; WITH SQUAMOUS DIFFERENTIATION;
•    SCC WITH PSEUDOSARCOMATOUS STROMA
•    SCC WITH SPINDLE CELL STROMA
•    LEIOMYOSARCOMA
•    NEURILEMMOMMA
•    SARCOMA (MFH)
•    LYMPHOMA
•    LEUKEMIC INFILTRATE
•    SARCOMA (HEMAMGIOPERICYTOMA)
•    ANGIOSARCOMA




      25/10/2011 05:21:20                  Sameer Jhavar.The Institute of                              3
                                              Cancer Research, UK
Breast cancer: Medullary histology is significantly more common
                in BRCA1 associated tumours.


   • Medullary breast cancers: 13-24% have BRCA1 mutations

   • Non-medullary histology: 6% had BRCA1 mutations

  • In BRCA1 carriers—up to 20% breast cancers are of Medullary histology.

   •In BRCA2 carriers– up to 3% breast cancers are of Medullary histology.



                        Bisinger F et al, Can. Res, 1998, Eisinger F et al, JAMA, 1998 and Malone K et al JAMA,1998




  25/10/2011 05:21:20              Sameer Jhavar.The Institute of                                            4
                                      Cancer Research, UK
Breast cancer: Medullary histology is significantly more common
                in BRCA1 associated tumours




  a well-circumscribed mass mammographically.
  young women (younger than 35 years old) with breast cancer.
  finding of high-grade tumour cells arranged in a syncytial pattern with a pushing border. This pushing
  border is surrounded by a prominent lymphoplasmacytic infiltrate.
  If the tumour lacks these features, or has an invasive border or extensive necrosis, it may be better
  characterized as an atypical medullary carcinoma.

  25/10/2011 05:21:20                Sameer Jhavar.The Institute of                                       5
                                        Cancer Research, UK
Breast cancer: Medullary histology is significantly more common
                in BRCA1 associated tumours




  25/10/2011 05:21:20   Sameer Jhavar.The Institute of      6
                           Cancer Research, UK
Breast cancer: Medullary histology is significantly more common
                in BRCA1 associated tumours




  25/10/2011 05:21:20   Sameer Jhavar.The Institute of      7
                           Cancer Research, UK
          BRCA1 associated breast tumours: pathology in
                comparison to sporadic tumours

                    BRCA1                                                    Non-BRCA1
                       Invasive                                   Less invasive, less extent of pushing margins
                      High grade                                                   Low grade
  ER-ve, PR-ve, Her2-ve, p53 +ve, CK5/6, 14, 17 +ve
 (Derived from basal layer of the mammary epithelium)


                  High mitotic rates                                            Low mitotic rates


               Nuclear pleomorphism +                                      Nuclear pleomorphism less


                 Solid sheets of cells                                 Less extent of solid sheets of cells

                      Necrosis +                                                   Necrosis -

             Lymphocytic infiltrate ( LI) +                                          Less LI

                                                                      Invasive lobular type more common




25/10/2011 05:21:20                       Sameer Jhavar.The Institute of                                          8
                                             Cancer Research, UK
       BRCA2 associated breast tumours: pathology in
        comparison to sporadic tumours & genotype-
                  phenotype correlation

•   More heterogeneous,
•   999del5 (Icelandinc founder mutation) associated Breast cancer-Less tubule
    formation, more nuclear pleomorphism, higher mitotic rates.
•   BRCA2 associated breast cancers--: Continuous pushing margins, fewer tubules,
    lower mitotic counts,
•   Lobular and tubulolobular histology.




     25/10/2011 05:21:20       Sameer Jhavar.The Institute of                  9
                                  Cancer Research, UK
                                       Ovarian cancers

•      SEROUS CYSTADENOCARCNOMA
•      MUCINOUS CYSTADENOCARCINOMA
•      MESODERMAL MIXED TUMOURS
•      CLEAR CELL OR HYPERNEPHROID CARCINOMA
•      ENDOMETROID CARCINOMA
•      ENDODERMAL SINUS (MESONEPHRIC) TUMOUR/ YOLK SAC TUMOUR---GERM CELL
•      BRENNER TUMOUR; BENIGN AND MALIGNANT
•      DYSGERMINOMA (LIKE SEMINOMA IN MALES)----- GERM CELL
•      BENIGN CYSTIC TERATOMA
•      IMMATURE/ MALIGNANT TERATOMA
•      BENIGN CYSTIC TERATOMA (WITH MALIGNANT TRASNFORMATION)
•      GRANULOSA CELL TUMOUR---SEX CORD STROMAL TUMOUR
•      THECA-GRANULOSA CELL TUMOUR----SEX CORD STROMAL TUMOUR
•      SERTOLI CELL TUMOUR (ARRHENOBLASTOMA; ANDROBLASTOMA)----SEX CORD STROMAL
•      LEYDIG CELL TUMOUR----SEX CORD STROMAL
•      THECOMA
•      FIBROTHECOMA
•      FIBROMA
•      FIBROSARCOMA
•      HILUS CLL TUMOUR
•      BURKITTS LYMPHOMA
•      SECONDARY TCC
•      SECONDARY LEIOMYOSARCOMA
•      KRUKENBERGS
•      SECONDARY CARCINOID




    25/10/2011 05:21:20               Sameer Jhavar.The Institute of              10
                                         Cancer Research, UK
                        Ovarian cancers



• Serous tumours: resemble epithelium of
  fallopian tube. (BRCA ASSOCIATED): 30% OF ALL OVARIAN CANCERS
• Mucinous tumours: mimic mucosa of the
  endocervix. (HNPCC ASSOCIATED): (10% OF ALL OVARIAN CANCERS)
• Endometrioid carcinoma: similar to glands of
  the endometrium. (HNPCC ASSOCIATED) (20% OF ALL OVARIAN
     CANCERS)




25/10/2011 05:21:20    Sameer Jhavar.The Institute of             11
                          Cancer Research, UK
                                  Ovarian cancers




                                                        NO. (%) POSITIVE FOR MUTATIONS IN

               HISTOLOGY                        BRCA1           BRCA2                  Either
               Invasive (n = 515)               39 (7.6)        21 (4.1) 60 (11.7)
                      Serous (n = 341)         37 (10.9) 19 (5.6) 56 (16.4)
                      Endometrioid (n = 94)      2 (2.1)         2 (2.1)              4 (4.3)
                      Mucinous (n = 44)           0 (0)            0 (0)                0 (0)
                      Other (n = 36)              0 (0)            0 (0)                0 (0)
               Borderline (n = 134)               0 (0)            0 (0)                0 (0)
                                                                               Risch H et al, 2001, Am J Hum Gen.

25/10/2011 05:21:20              Sameer Jhavar.The Institute of                                           12
                                    Cancer Research, UK
                             Ovarian cancer:


 BRCA1 carriers: >90% cancers are of serous cystadenocarcinoma histology.


 Epithelial ovarian, papillary serous peritoneal primary, fallopian tube cancer:
 BRCA associated.

 Mucinous epithelial (could be HNPCC; NOT BRCA associated): ovarian
 cancer at age <30 years may be more likely to be due to HNPCC mutations
 (MSH2 and MLH1) and not due to BRCA1/2.

 Germ cell tumours of the ovary (NOT ASSOCIATED WITH BRCA): Living
 affected relative many years after a reported diagnosis could be an indication
 of the more curable non-epithelial ovarian cancer.




25/10/2011 05:21:20         Sameer Jhavar.The Institute of                         13
                               Cancer Research, UK
―stomach‖, ―womb‖, ―abdominal‖, cancers should raise the suspicion of ovarian
                                  cancer.
  Strenuous attempts to confirm the diagnosis of ovarian cancer should be made.


     Not associated with BRCA1 and BRCA2 mutations                              mucinous
                                                                                borderline


       Associated with BRCA1 and BRCA2 mutations                        epithelial ovarian cancer
                                                                      papillary serous primary peritoneal cancers
                                                                          fallopian tube cancer


                Associated with HNPCC                      very young onset, mucinous or endometroid ovarian
                                                                               cancer .
                                                           More likelihood of synchronous endometrial cancer.


               PJ syndrome and testicular feminisation    sex cord tumours (granulosa cell, theca-granulosa cell,
                      syndrome                           sertoli cell (arrhenoblastoma; androblastoma), leydig cell
                                                                                    tumor.
            Associated with Gorlins syndrome                                 ovarian fibromas




   25/10/2011 05:21:20                  Sameer Jhavar.The Institute of                                            14
                                           Cancer Research, UK
      Bowel cancer: inherited syndromes predisposing to CRC
    Disease                Colorectal lesion                     Pathology of polyp                 Gene involved

      FAP                 polyps (>100); CRC                         adenomatous                        APC

     HNPCC                 polyps (few); CRC                         adenomatous                  MLH1, MSH2, MSH3,
                                                                                                        PMS1

Juvenile polyposis               Polyps;                            hamatomatous                   BMP2R, SMAD4,
                                  CRC
Cowdens disease                  polyps                             hamatomatous                        PTEN


      PJS                     polyps; CRC                           hamatomatous                       STK11


Hereditary mixed              Polyps; CRC                 Uvenile polyps, hyperplastic polyps,      LOCALISED TO
   polyposis                                              adenomatous polyps, mixed polyps           UNKNOWN 6q
   syndrome
   Hereditary                 Polyps; CRC               Adenomatous polyps, serrated adenoma,          CRAC1
    colorectal
  adenoma and
   carcinoma
    sequence
  Hyperplastic                   polpys                 Serrated adenomas, hyperplastic polyps,      UNKNOWN
   polyposis                                                         mixed polyp


 MYH polyposis       Similar picture to classical FAP                                                   MYH


   25/10/2011 05:21:20                      Sameer Jhavar.The Institute of                                     15
                                               Cancer Research, UK
                                     Hamartomatous polyps
                JPS (BMP2R, SMAD4)                                       PJS (STK11)
Unilobulated, smooth                                          Inflammatory response not seen.
                                                                   Cystic dilatation not seen
Gross infiltration of the lamina propria by chronic
    inflammatory cells                                     Hypertrophy or hyperplasia of the smooth
                                                               muscle layer occurs extending in a
                                                               tree like fashion into the superficial
Cystic dilatation of glandular type structures lined by
    normal appearing columnar epithelium is                                epithelial layer.
    pathognomonic




    25/10/2011 05:21:20                   Sameer Jhavar.The Institute of                           16
                                             Cancer Research, UK
               Life time risk of other cancers in HNPCC


                             Cancer                               Lifetime risk (%)

                      Colorectal cancer (men)                            65-80

                  Colorectal cancer (women)                              30-70


                           Endometrial                                   40-60

                             Ovarian                                     4-12

                              Gastric                                    2-13

                           Urinary tract                                  4-6

                            Renal cell                                    3

                       Bile duct/gall bladder                             2

                           Small bowel                                    4-7




25/10/2011 05:21:20                     Sameer Jhavar.The Institute of                17
                                           Cancer Research, UK
                              Pathology of other cancers in HNPCC
        Cancer                     Lifetime risk (%)                     Histology in HNPCC            Histology in other genetic
                                                                                                               condition
Colorectal cancer (men)                   65-80                 Right sided, Mucinous, poorly diff,
                                                                solid cribriform growth, signet ring
                                                                cell type cancer, necrosis, marked
   Colorectal cancer                      30-70                  lymphocytic infiltration, lymphoid
       (women)                                                    aggregation at tumour margins.

      Endometrial                         40-60                  MLH1 associated = can be any            Classical endometrioid
                                                                  including Endometrioid type               ―undiffereniated‖
                                                                   MSH2 associated = non-
                                                                       endometrioid type
        Ovarian                            4-12                      Papilary epithelial, Serous,               serous
                                                                      mucinous, endometrioid
         Gastric                           2-13                             Intestinal type

      Urinary tract                        4-6                                   TCC

       Renal cell                            3                                   TCC                     Clear cell cancer: VHL
                                                                                                         Papillary tpe 1: HPRC
 Bile duct/gall bladder                      2

      Small bowel                          4-7

Underlined features form part of the Bethesda criteria for MSI testing



   25/10/2011 05:21:20                                 Sameer Jhavar.The Institute of                                             18
                                                          Cancer Research, UK
                             Kidney cancers:
  Clear cell (hereditary and sporadic), papillary (hereditary and sporadic)

Inherited mutations in MET oncogene are nearly always associated with
papillary renal cell cancer.
Inherited mutation in VHL tumour suppressor gene with clear cell renal
cancer.
Hereditary Papillary renal cell cancer (AD, multiple bilateral Type 1 papillary
renal tumours): c-met oncogene mutations and 95% duplication of
chromosome 7q
Sporadic Papillary renal cell cancer: 13% have c-met oncogene mutations
and 75% with duplication of 7q
VHL disease associated with mutations in VHL gene
Familial clear cell renal cancer: chromosome 3p translocation
Sporadic clear cell renal cancers: 57% VHL mutations and 98% LOH


25/10/2011 05:21:20          Sameer Jhavar.The Institute of                       19
                                Cancer Research, UK

				
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