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The Surgical Pathology of Pigmented Conjunctival Melanocytic Lesions by oyc99684

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									The Surgical Pathology of Pigmented Conjunctival Melanocytic Lesions


Robert Folberg, MD
Frances B Geever Professor and Head
Department of Pathology
University of Illinois at Chicago
840 S Wood Street, Room 110 CSN
Chicago, IL 60612
rfolberg@uic.edu




USCAP 2007, San Diego
Companion Society Meeting: American Association of Ophthalmic Pathologists
Saturday Evening, March 24, 2007-02-04
1. Background
       a. In ophthalmic surgical practice, there is a compelling conflict between the need to
          eradicate cancer and the desire to preserve vision
                 i. Consequences and example:
                        1. It is not possible to excise pigmented conjunctival lesions with “adequate
                             margins” because the sacrifice of conjunctival goblet cells and accessory
                             lacrimal gland tissue may result in the a painful dry eye that
                             compromises vision
                ii. Fear of darkness – blindness – is a primal fear. Children are afraid of the dark.
                    Adults are afraid of losing their independence.
                        1. Most ophthalmologist have heard patients exclaim, “Doctor, I'd rather be
                             dead than blind!”
       b. Before the public awareness of AIDS and Alzheimer's disease as major public health
          issues, the Gallup Organization polled Americans asking the following question: What
          disease do you fear most?
                 i. In both the 1960s and 1970s, the most feared disease was cancer. The second
                    most feared disease was blindness.
                ii. Therefore, a patient who is confronted with a diagnosis of ocular cancer, is
                    confronted with two terrible fears. The surgeons who care for these patients must
                    balance two compelling needs.
               iii. And therefore, the surgical pathologist must be sensitive to the patient's
                    perspective and the therapeutic options.
2. Challenges to the Surgical Pathologist
       a. Understanding the unique microanatomy of the conjunctiva
       b. Appreciating and using the clinician's terminology
       c. Knowing the surgical and medical treatment of these disorders
3. Microanatomy of the Conjunctiva
       a. Bulbar conjunctiva
       b. Palpebral conjunctiva
                 i. Tightly tethered to the underlying tarsus
                        1. Therefore, even invasive lesions in this area appear clinically flat
       c. Fornix
                 i. A pseudostratified columnar epithelium with goblet cells. Do not mistake the
                    normal histology for dysplasia!
       d. Caruncle
                 i. Conjunctival mucosa with pilar units, sebaceous glands, and eccrine glands in
                    the submucosa
       e. The Limbus
                 i. The importance of Bowman's layer as a surgical pathology landmark
                ii. Most surface neoplasms of the conjunctiva that extend into the cornea remain
                    superficial to Bowman's layer
4. Handling the conjunctival resection at the limbus: be certain to take histological sections that run
   perpendicular to the limbus (bottom panel, right)
5. Conjunctival Nevi: Key teaching points
      a. Junctional nevi are seldom encountered and should only be diagnosed in young children
                 i. Pathologists who are tempted to render a diagnosis of junctional nevus should
                    consider the possibility of primary acquired melanosis with atypia, a melanoma
                    precursor
      b. Nevi only seldom encroach upon the cornea
                 i. Pigmented lesions that invade the cornea are not likely to be benign
      c. Be aware of the inflamed conjunctival nevus of childhood, a compound nevus with
          chronic inflammation populated by variable numbers of eosinophils
                 i. There is no counterpart to this lesion in cutaneous pathology as this is not a halo
                    nevus and bears no relation to vitiligo
6. Conjunctival melanoma and its precursors
      a. The overall mortality of conjunctival melanoma is 25%
      b. Clinical Terminology
                 i. Congenital melanosis oculi (also known as congenital ocular melanocytosis
                        1. Conceptually, this is a congenital nevus of the uvea
                        2. There may be an increased risk of uveal melanoma in the Causasian
                            population with this disorder (but not in Asians or African-Americans)
                        3. The sclera appears to be blue clinically because of the deep uveal
                            pigmentation (the Tyndall effect renders the melanin blue clinically)
                        4. The pigmentation is not in the conjunctiva
                ii. Secondary acquired melanosis
                        1. No risk of developing melanoma
                        2. Examples:
                                a. Complexion-associated pigmentation: bilateral conjunctival
                                    pigmentation in individuals with dark skin tone
                                b. Secondary to systemic disease (e.g., Addison's disease)
                                c. Secondary to topical medications (silver nitrate, epinephrine)
                                d. Other pigmentations (e.g., mascara)
               iii. Primary acquired melanosis
                        1. Meeting the following diagnosis criteria
                                a. unilateral
                                b. acquired
                                c. flat
                                d. brown pigmentation in a
                                e. fair-complexioned individual
              iv. Very Important - Key conceptual point
                        1. There are no clinical criteria to that permit the prediction of the histology
                            of conjunctival pigmented lesions that meet these five criteria!
                        2. Therefore, ophthalmologists have been taught to take biopsies from
                            every patient with a lesion that does meet these criteria.
      c. Pathology terminology
                 i. Primary acquired melanosis
                        1. Without atypia: hyperpigmentation of the conjunctiva with or without
                            melanocytic hyperplasia but without atypia
                                a. No likelihood of progression to melanoma
                                b. Cannot be called “lentigo” histologically – the conjunctiva lacks
                                    rete
                        2. With atypia: atypical intraepithelial melanocytic hyperplasia, with or
                            without pigmentation
                                a. 50-90% likelihood of progression to melanoma if not completely
                                    extirpated
      d. Questions for discussion
                 i. Primary acquired melanosis without atypia: Why isn't this called lentigo or
                    ephelis?
                ii. Primary acquired melanosis with atypia: Why isn't this called “melanoma in situ”?
iii. Answers
        1. Because there are no clinical criteria to allow for the separation of
            melanoma precursors from completely benign lesions,
        2. Because the nomenclature is shared between clinician and pathologist,
            and
        3. Because the nomenclature guides therapy


                             Unilateral, flat pigmented conjunctival lesion

                                            Clinical Diagnosis


                                                 PAM




                                                Biopsy




                        PAM without atypia                PAM with atypia

                                       Histological Diagnosis




                      PAM without atypia                          PAM with atypia

                        No progression to                        50-90% progression to
                           melanoma                                   melanoma



                                                                     Malignant
                                                                     Melanoma




                                                                   25% mortality
   7. ADASP Recommendations for Reporting Conjunctival Melanoma
         a. Indicate the location of the lesion
                  i. Melanomas arising in the fornix, palpebral conjunctiva, plica semilunaris, and
                     caruncle, tend to follow a more aggressive course than melanomas affecting and
                     confined to the bulbar conjunctiva and limbus
         b. Indicate the procedure undertaken to obtain tissue
                  i. Incisional biopsy (including “map” biopsy – the procurement of multiple small
                     biopsies from the conjunctiva)
                 ii. Excisional biopsy
                iii. Debridement of the corneal epithelium
         c. When present, indicate involvement of the
                  i. Episclera
                 ii. Corneal stroma
                iii. Orbital fat
         d. Thickness (depth)
                  i. Measured from the top of the epithelium to the deepest tumor cell in the
                     substantia propria
                         1. recall that the conjunctiva is not normally keratinized and a granular layer
                              is absent
         e. Measure of proliferation
                  i. Mitoses
                 ii. Proliferation index
         f. Margins
                  i. Completely removed
                 ii. Lateral margins involved but deep margin uninvolved
                iii. Deep margins involved but lateral margins uninvolved
                iv. Not complete either laterally or in depth
         g. Vascular invasion
                  i. None
                 ii. Lymphatics
                iii. Vascularity
                iv. Lymphatics and vascular

   8. Treatment options
          a. Excisional biopsy (compare with “map biopsy”)
          b. Cryotherapy
          c. Topical chemotherapy (mitomycin-C)
                    i. role of post-treatment biopsy
                   ii. mitomycin-C effects within the epithelium
   9. Final points
          a. The best treatment of conjunctival melanoma is its prevention through the appropriate
              treatment of conjunctival primary acquired melanosis with atypia, and
          b. The best treatment requires a partnership between the surgeon and the pathologist.


Suggested Additional Readings:

The General Surgical Pathology of Pigmented Conjunctival Lesions
   1. Jakobiec FA, Folberg R, Iwamoto T: Clinicopathologic characteristics of premalignant and
      malignant melanocytic lesions of the conjunctiva. Ophthalmology 1989;96:147-166.
   2. Folberg R, Jakobiec FA, Bernardino VB, Iwamoto T: Benign conjunctival melanocytic lesions:
      clinicopathologic features. Ophthalmology 1989;96:436-461.
   3. McDonnell JM, Carpenter JD, Jacobs P, Wan WL, Gilmore JE. Conjunctival melanocytic lesions
      in children. Ophthalmology 1989;96:986-993.
   4. Paridaens AD, Minassian DC, McCartney AC, Hungerford JL. Prognostic factors in primary
      malignant melanoma of the conjunctiva: a clinicopathological study of 256 cases. The British
      journal of ophthalmology 1994;78:252-259.

   5. Spencer WH, Folberg R: Conjunctiva. In Spencer WH (ed): Ophthalmic Pathology - An Atlas and
      Textbook, 4th edition, Philadelphia, WB Saunders, 1996. pp. 125-155.
   6. Farber M, Schutzer P, Mihm MC, Jr. Pigmented lesions of the conjunctiva. J Am Acad Dermatol
      1998;38:971-978.
   7. Anastassiou G, Heiligenhaus A, Bechrakis N, Bader E, Bornfeld N, Steuhl KP. Prognostic value
      of clinical and histopathological parameters in conjunctival melanomas: a retrospective study. Br
      J Ophthalmol 2002;86:163-167.
   8. Folberg R, Salomão DR, Grossniklaus HE, Proia AD, Rao NA, Cameron DJ: Recommendations
      for the reporting of tissues removed as part of the surgical treatment of common malignancies of
      the eye and its adnexa.
      Am J Clin Pathol 2003;119:179-164.
      Hum Pathol 2003;34:114-118.
      Mod Pathol 2003;16:725-730.
   9. Folberg R. Tumors of the eye and ocular adnexae. In Fletcher CM (ed). Diagnostic
      Histopathology of Tumors, 3rd Edition. Churchill Livingston, London (2007, in press).


Conjunctival Nevi
   1. Folberg R, Jakobiec FA, Bernardino VB, Iwamoto T: Benign conjunctival melanocytic lesions:
      clinicopathologic features. Ophthalmology 1989;96:436-461.
   2. Crawford JB, Howes EL, Jr., Char DH. Combined nevi of the conjunctiva. Arch Ophthalmol
      1999;117:1121-1127.
   3. Zamir E, Mechoulam H, Micera A, Levi-Schaffer F, Pe'er J. Inflamed juvenile conjunctival naevus:
      clinicopathological characterisation. Br J Ophthalmol 2002;86:28-30.



Primary acquired melanosis with and with out atypia and conjunctival melanoma
    1. Folberg, R, McLean, I W, Zimmerman, L E 1984 Conjunctival acquired melanosis and malignant
       melanoma. Ophthalmology 91: 673-678
   2. Folberg, R, McLean, I W, Zimmerman, L E 1985 Conjunctival malignant melanoma. Hum Pathol
      16: 136-1431.
   3. Jakobiec FA, Buckman G, Zimmerman LE, et al. Metastatic melanoma within and to the
      conjunctiva. Ophthalmology 1989;96:999-1005.
   4. Anastassiou G, Heiligenhaus A, Bechrakis N, Bader E, Bornfeld N, Steuhl KP. Prognostic value
      of clinical and histopathological parameters in conjunctival melanomas: a retrospective study. Br
      J Ophthalmol 2002;86:163-167.
   5. Gallardo MJ, Randleman JB, Price KM, et al. Ocular argyrosis after long-term self-application of
      eyelash tint. Am J Ophthalmol 2006;141:198-200.


The Nomenclature Debate
   1. Folberg, R, Jakobiec, F A, McLean, I W et al 1992 Is primary acquired melanosis of the
      conjunctiva equivalent to melanoma in situ? Mod Pathol 5: 2-5


Topics in Management
1. Tuomaala S, Eskelin S, Tarkkanen A, Kivela T. Population-based assessment of clinical
   characteristics predicting outcome of conjunctival melanoma in whites. Invest Ophthalmol Vis Sci
   2002;43:3399-3408.
2. Salomao DR, Mathers WD, Sutphin JE, Cuevas K, Folberg R. Cytologic changes in the
   conjunctiva mimicking malignancy after topical mitomycin C chemotherapy. Ophthalmology
   1999;106:1756-1760.
3. Pe'er J, Frucht-Pery J. The treatment of primary acquired melanosis (PAM) with atypia by topical
   Mitomycin C. Am J Ophthalmol 2005;139:229-234.
The Surgical Pathology of Pigmented Conjunctival Melanocytic Lesions


Robert Folberg, MD
Frances B Geever Professor and Head
Department of Pathology
University of Illinois at Chicago
840 S Wood Street, Room 110 CSN
Chicago, IL 60612
rfolberg@uic.edu


Summary Points:

   1. The surgical pathologist must be aware of the surgeon’s goal to preserve vision
      in addition to the extirpation of melanomas and their precursors,
   2. Therefore, the surgical pathologist must be aware of variations in the conjunctival
      microanatomy, the terminology shared by the surgeon and the pathologist, and,
      of course, the microscopic appearances of the spectrum of conjunctival
      pigmented lesions.
   3. Conjunctival melanoma is associated with a 25% mortality, and the best
      treatment of conjunctival melanoma is its prevention through extirpation of its
      precursor lesion – primary acquired melanosis with atypia.u
The Surgical Pathology of
 Pigmented Conjunctival
  Melanocytic Lesions

     Robert Folberg, MD
 University of Illinois at Chicago
               Background
Inherent conflicts of interest:
  Balancing the need to eradicate cancer
  with the desire to preserve vision

  – The Gallup Polls
  – “Doctor, I’d rather be dead than blind!”
     Challenges to the Surgical
            Pathologist

Understanding …
  – The conjunctival microanatomy
  – The ophthalmologist’s terminology
  – Surgical and medical approaches to treatment
Microanatomy of the Conjunctiva




    Bulbar       Palpebral    Fornix
  Conjunctiva   Conjunctiva
The Ocular Caruncle
Microanatomy of the Limbus




    Importance of Identifying Bowman’s Layer
Partnering with the Surgeon




   Surgical Techniques to Obtain Optimal Biopsy Material
                http://eyepath.comd.uic.edu
                  Click on Practical Tips
Conjunctival Nevi
      Conjunctival Nevi:
Clinicopathological Features
           Conjunctival Nevi:
       Histopathological Features




Subepithelial Nevus, Conjunctiva   Subepithelial Nevus, Caruncle
Conjunctival Nevi: Variants




       Blue Nevus, Bulbar Conjunctiva
Inflamed Juvenile Nevus
Conjunctival Nevi: Teaching Points
Junctional nevi are seldom if ever encountered
   Suspect melanoma precursor if melanocytes are confined to the
     epithelium

Nevi only very rarely encroach upon the cornea are almost
  never encountered in the palpebral conjunctiva
   Suspect melanoma in these topological contexts

Inflamed juvenile nevi are common
   Clinically present with growth which may reflect acquisition of the
      inflammatory component
   Not associated with halo nevus or vitiligo – entirely benign
    Conjunctival Melanoma,
    Melanoma Precursors,
      and the Pretenders




The mortality of conjunctival melanoma is 25%
   Conjunctival Melanoma and
          Precursors




Primary Acquired Melanosis   Malignant melanoma

                             Overall mortality: 25%
Primary Acquired Melanosis                   Congenital Melanosis




                                 Complexion-associated pigmentation
                                 Addison’s disease
                                 Peutz-Jegher’s Disease
                                 Topical Medications
                                 Others

  Secondary Acquired Melanosis
                          The Dilemma

      Unilateral flat conjunctival pigmentation in
              a fair-complexioned adult



There are no clinical criteria that allow separation of PAM without atypia
                             Hyperpigmentation         Hyperpigmentation
                             without melanocytic       with hyperplasia or
                             hyperplasia or atypia     atypia

                             Primary Acquired Melanosis without atypia




Primary Acquired Melanosis




                             Primary Acquired Melanosis with atypia
                      Terminology
Primary acquired melanosis without atypia
  Why don’t we call this “ephelis” or “lentigo”?

Primary acquired melanosis with atypia
  Why isn’t this called “melanoma in situ”?

Why?
  Because there are no clinical criteria to allow for the separation of
  melanoma precursors from completely benign lesions,
  Because the nomenclature is shared between clinician and
  pathologist, and
  Because the nomenclature guides therapy.
     Unilateral, flat pigmented conjunctival lesion

                 Clinical Diagnosis


                      PAM




                     Biopsy




PAM without atypia             PAM with atypia

               Histological Diagnosis
PAM without atypia    PAM with atypia


 No progression to   50-90% progression to
    melanoma              melanoma



                         Malignant
                         Melanoma




                       25% mortality
                             Hyperpigmentation         Hyperpigmentation
                             without melanocytic       with hyperplasia or
                             hyperplasia or atypia     atypia

                             Primary Acquired Melanosis without atypia




Primary Acquired Melanosis




                             Primary Acquired Melanosis with atypia
ADASP Protocol: Conjunctival Melanoma
             Treatment Options


Excision
  Limited option

Cryotherapy

Topical Chemotherapy
  Mitomycin-c eyedrops
  Role of post-treatment biopsy
    Histological mitomycin effect
The best treatment of
conjunctival melanoma is its
prevention through treatment
of PAM with atypia
The best treatment requires a
partnership between the
surgeon and the pathologist
Many of the clinical photographs used in this presentation first
appeared in the following articles:

Jakobiec FA, Folberg R, Iwamoto T: Clinicopathologic
characteristics of premalignant and malignant melanocytic lesions
of the conjunctiva. Ophthalmology 1989;96:147-166.
Folberg R, Jakobiec FA, Bernardino VB, Iwamoto T: Benign
conjunctival melanocytic lesions: clinicopathologic features.
Ophthalmology 1989;96:436-461.



Many of the photomicrographs used in this presentation originate
from the following source:

Folberg R. Tumors of the Eye and Ocular Adnexae (Chapter 29). In
Fletcher CF (ed). Diagnostic Histopathology of Tumors, 3rd edition.
Elsevier, March 2007.

								
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