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

Biopsy

Clinical Diagnosis

PAM

PAM without atypia PAM with atypia

Histological Diagnosis

PAM without atypia PAM with atypia

No progression to melanoma

50-90% progression to 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 The Surgical Pathology of Pigmented Pigmented ConjunctivalConjunctival

MelanocyticMelanocytic LesionsLesions

Robert Robert FolbergFolberg, MD, MDUniversity of Illinois at ChicagoUniversity of Illinois at Chicago

BackgroundBackground

Inherent conflicts of interest: Inherent conflicts of interest: Balancing the Balancing the needneed to eradicate cancer to eradicate cancer with the with the desiredesire to preserve visionto preserve vision

–– The Gallup PollsThe Gallup Polls–– ““Doctor, IDoctor, I’’d rather be dead than blind!d rather be dead than blind!””

Challenges to the Surgical Challenges to the Surgical PathologistPathologist

Understanding Understanding ……–– The The conjunctivalconjunctival microanatomymicroanatomy–– The ophthalmologistThe ophthalmologist’’s terminologys terminology–– Surgical and medical approaches to treatmentSurgical and medical approaches to treatment

Microanatomy of the ConjunctivaMicroanatomy of the Conjunctiva

Bulbar Conjunctiva

PalpebralConjunctiva

Fornix

The Ocular The Ocular CaruncleCaruncle

Microanatomy of the Microanatomy of the LimbusLimbus

Importance of Identifying Bowman’s Layer

Partnering with the SurgeonPartnering with the Surgeon

Surgical Techniques to Obtain Optimal Biopsy Material

http://eyepath.comd.uic.edu

Click on Practical Tips

Conjunctival Nevi

ConjunctivalConjunctival Nevi: Nevi: ClinicopathologicalClinicopathological FeaturesFeatures

ConjunctivalConjunctival Nevi: Nevi: HistopathologicalHistopathological FeaturesFeatures

Subepithelial Nevus, Conjunctiva Subepithelial Nevus, Caruncle

ConjunctivalConjunctival Nevi: VariantsNevi: Variants

Blue Nevus, Bulbar Conjunctiva

Inflamed Juvenile NevusInflamed Juvenile Nevus

ConjunctivalConjunctival Nevi: Teaching PointsNevi: Teaching Points

JunctionalJunctional nevi are seldom if ever encounterednevi are seldom if ever encounteredSuspect melanoma precursor if Suspect melanoma precursor if melanocytesmelanocytes are confined to the are confined to the

epitheliumepithelium

Nevi only very rarely encroach upon the cornea are almost Nevi only very rarely encroach upon the cornea are almost never encountered in the never encountered in the palpebralpalpebral conjunctivaconjunctivaSuspect melanoma in these topological contextsSuspect melanoma in these topological contexts

Inflamed juvenile nevi are commonInflamed juvenile nevi are commonClinically present with growth which may reflect acquisition of Clinically present with growth which may reflect acquisition of the the

inflammatory componentinflammatory componentNot associated with halo nevus or Not associated with halo nevus or vitiligovitiligo –– entirely benignentirely benign

Conjunctival Melanoma, Melanoma Precursors,

and the Pretenders

The mortality of conjunctival melanoma is 25%

ConjunctivalConjunctival Melanoma and Melanoma and PrecursorsPrecursors

Primary Acquired Melanosis Malignant melanoma

Overall mortality: 25%

Primary Acquired Melanosis Congenital Melanosis

Secondary Acquired Melanosis

Complexion-associated pigmentation

Addison’s disease

Peutz-Jegher’s Disease

Topical Medications

Others

The Dilemma

Unilateral flat conjunctival pigmentation in a fair-complexioned adult

There are no clinical criteria that allow separation of PAM without atypia

Primary Acquired Melanosis without atypia

Hyperpigmentationwithout melanocytichyperplasia or atypia

Hyperpigmentationwith hyperplasia or atypia

Primary Acquired Melanosis

Primary Acquired Melanosis with atypia

TerminologyTerminologyPrimary acquired Primary acquired melanosismelanosis without without atypiaatypia

Why donWhy don’’t we call this t we call this ““ephelisephelis”” or or ““lentigolentigo””??

Primary acquired Primary acquired melanosismelanosis with with atypiaatypiaWhy isnWhy isn’’t this called t this called ““melanoma in situmelanoma in situ””??

Why?Why?Because there are no clinical criteria to allow for the separatiBecause there are no clinical criteria to allow for the separation of on of melanoma precursors from completely benign lesions,melanoma precursors from completely benign lesions,

Because the nomenclature is shared between clinician and Because the nomenclature is shared between clinician and pathologist, andpathologist, and

Because the nomenclature guides therapy.Because the nomenclature guides therapy.

Unilateral, flat pigmented conjunctival lesion

Biopsy

Clinical Diagnosis

PAM

PAM without atypia PAM with atypia

Histological Diagnosis

PAM without atypia PAM with atypia

No progression to melanoma

50-90% progression to melanoma

Malignant Melanoma

25% mortality

Primary Acquired Melanosis without atypia

Hyperpigmentationwithout melanocytichyperplasia or atypia

Hyperpigmentationwith hyperplasia or atypia

Primary Acquired Melanosis

Primary Acquired Melanosis with atypia

ADASP Protocol: ADASP Protocol: ConjunctivalConjunctival MelanomaMelanoma

Treatment OptionsTreatment Options

ExcisionExcisionLimited optionLimited option

CryotherapyCryotherapy

Topical ChemotherapyTopical ChemotherapyMitomycinMitomycin--cc eyedropseyedropsRole of postRole of post--treatment biopsytreatment biopsy

Histological Histological mitomycinmitomycin effecteffect

The best treatment of The best treatment of conjunctivalconjunctival melanoma is its melanoma is its prevention through treatment prevention through treatment of PAM with of PAM with atypiaatypia

The best treatment requires a The best treatment requires a partnership between the partnership between the surgeon and the pathologistsurgeon and the pathologist

Many of the clinical photographs used in this presentation firstappeared in the following articles:

Jakobiec FA, Folberg R, Iwamoto T: Clinicopathologiccharacteristics 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 originatefrom 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.