Melanocytic nevi

Melanocytic nevi (also called nevocellular nevi, nevus cell nevi) are classified as hamartomas or neoplasms depending on whether the lesions are congenital or acquired. Conjunctival melanocytic nevi usually become clinically apparent in childhood, appearing as unilateral circumscribed pigmented lesions on the perilimbal interpalpebral bulbar conjunctiva, frequently incorporating small, clear epithelial cysts (Fig 5-19A). Melanocytic nevi are also common in the caruncle. They occur in the palpebral conjunctiva only in rare instances; pigmented lesions in this area are typically intraepithelial acquired melanosis or melanoma.

Amelanotic nevi of the conjunctiva are melanocytic nevi containing no pigment, meaning they have a pinkish appearance, which makes clinical diagnosis more challenging. The pigmentation and size of a nevus may increase during puberty, at which point the lesion may become noticeable.

Histologically, conjunctival melanocytic nevi are neoplasms composed of nests or sheets of nevus cells (specialized melanocytes) with benign features, including round to oval, uniformly staining nuclei and a moderate amount of cytoplasm. Epithelial cysts are often encountered within the stromal component of a nevus. The presence of these cysts within the stromal component of a nevus is typically indicative of a benign lesion.

Like cutaneous melanocytic nevi, conjunctival nevi undergo evolutionary changes with age. In the initial, junctional phase (usually in the first and second decades of life), nevus cells are arranged in nests (theques) at the interface (junction) between the epithelium and the stroma (Fig 5-19B). As the nevus evolves and proliferates, the nests descend into the stroma and eventually may lose connection with the epithelium. Nevus cells residing exclusively at the epithelial–stromal junction are called junctional nevi, whereas nevi located exclusively in the stroma are termed subepithelial or stromal nevi; nevi with both junctional and subepithelial components are designated as compound nevi. In an older individual, the presence of a junctional component in a conjunctival nevus may represent malignant transformation.

Figure 5-19 Conjunctival melanocytic nevus. A, Clinical appearance with characteristic cystic areas (arrows).B, Histologically, the nevus cells have round, oval, or pear-shaped nuclei with a moderate amount of cytoplasm, mostly arranged in nests (arrowheads). Nevus cells are also present at the epithelial–stromal junction (arrow); hence, this is a compound nevus. Note the epithelial inclusion cysts (asterisks) within the lesion, correlating with the clinical appearance.

(Part B courtesy of George J. Harocopos, MD.)

An inflamed juvenile conjunctival nevus is a compound nevus that typically becomes apparent in childhood or adolescence and clinically often appears to grow rapidly, which is suggestive of malignancy. Histologically, the aggregates of nevus cells are surrounded and invaded by lymphocytes, plasma cells, and often eosinophils. This lesion may be misinterpreted histologically as malignant if the pathologist is not familiar with it.

Another form of melanocytic nevi that may occur in the conjunctiva is a blue nevus. Clinically, it appears as a dark blue–gray to blue-black nodule. Its melanocytes have a spindle cell morphology, similar to that of nevus cells seen in the uveal tract, and tend to contain a large amount of cytoplasmic melanin. Ocular and oculodermal melanocytosis, which is more often seen in dark-complexioned individuals, occurs deep to the conjunctiva, in the episclera and sclera, and consists of aggregates of dendritic melanocytes (Fig 5-20).

Intraepithelial melanosis

Conjunctival melanosis is a clinical term for localized or diffuse acquired pigmentation of the conjunctiva that occurs within the epithelium. Histologically, the term melanosis can be confusing, as it does not make a distinction between increased melanin content in epithelial cells and proliferation of melanocytes. These different etiologies of conjunctival pigmentation are more appropriately referred to as intraepithelial nonproliferative melanocytic pigmentation (a condition in which usually a small number of conjunctival basal dendritic melanocytes synthesize increased amounts of melanin that is transferred to surrounding basal epithelial cells) and intraepithelial melanocytic proliferation without atypia (a condition in which increased numbers of normal-appearing dendritic melanocytes—hyperplasia or early neoplasia—are generally confined to the basal epithelial layers in a linear arrangement).

Figure 5-20 Ocular melanocytosis. A, Clinical photograph illustrating slate-gray patches of pigmentation of the scleral surface. B, Histologic examination shows an increased population of intensely pigmented spindle and dendritic melanocytes in the deep episclera (E), sclera (S), and uveal tract (U).

(Part A courtesy of Gabriela M. Espinoza, MD; part B courtesy of George J. Harocopos, MD.)

The classification of and terminology used for various forms of melanosis are the subjects of debate. Conjunctival melanosis can be divided into primary, secondary, and complexion-associated forms (Fig 5-21). Secondary and complexion-associated melanoses generally do not involve melanocytic proliferation, only increased pigment production. PAM involves melanocytic proliferation and thus has a risk of progression to malignancy. An understanding of the nomenclature and processes that apply to pathologic diagnosis is important when management of these lesions is considered. Equally important is communicating the suspected clinical diagnosis to the pathologist, as proper interpretation of histologic findings is greatly enhanced by that knowledge.

Figure 5-21 Schematic representation of the spectrum of non-nevoid pigmented lesions of the conjunctiva. Small brown dots denote melanin. A, Complexion-associated melanosis represents a nonproliferative melanocytic process in which a normal number of melanocytes produce an increased amount of melanin that is transferred to the surrounding basal epithelial cells. There is an increase in pigment but no change in cell numbers or morphology. B, Primary acquired melanosis (PAM) without atypia or with mild atypia (conjunctival melanocytic intraepithelial neoplasia [C-MIN] 1, 2) refers to low-grade lesions in which there is both increased pigment production and an increased number of melanocytes but no or very mild change in melanocyte morphology. C, PAM with moderate to severe atypia (C-MIN 3, 4, 5). There is increased pigment production, an increased number of melanocytes, and migration of melanocytes into the more superficial epithelial layers. Morphology of melanocytes is atypical. D, Melanoma in situ (C-MIN >5) with full-thickness replacement of the epithelium by morphologically atypical melanocytes shows an increased nucleocytoplasmic ratio.

(Illustration by Cyndie C. H. Wooley.)

Secondary acquired melanosis Conjunctival pigmentation with mild increase in normal melanocytes (reactive melanosis of the conjunctiva) may be triggered by another conjunctival lesion (eg, squamous papilloma or carcinoma) or by underlying conjunctival inflammation.

Complexion-associated melanosis Complexion-associated melanosis (also called benign epithelial melanosis, racial melanosis, primary conjunctival melanosis) appears as bilateral flat patches of brown pigmentation with irregular margins, typically involving the bulbar conjunctiva in individuals with dark skin pigmentation (Fig 5-22A). Streaks and whorls of melanotic pigmentation may extend onto the peripheral cornea, a condition called striate melanokeratosis. The caruncle and palpebral conjunctiva may also be involved. Histologically, there is increased pigmentation primarily in the basal epithelial cells, and the epithelial melanocytes are normal in number and cytomorphology (hence the proposed new term hypermelanosis) (Fig 5-22B).

Primary acquired melanosis PAM is divided into PAM without atypia and PAM with atypia. PAM characteristically presents as a unilateral melanotic macule or patch in middle-aged light-skinned individuals. The lesion may remain stable, or it may wax and wane over a number of years. It is impossible to clinically distinguish PAM without atypia from PAM with atypia; these lesions can be distinguished only histologically. The recommendations regarding when to observe PAM versus when to perform biopsy are controversial. However, clinical findings such as larger size (3 clock-hours or more) and a caruncular, forniceal, or palpebral location portend a worse prognosis. Recommendations for incisional/excisional biopsy of PAM are discussed in BCSC Section 8, External Disease and Cornea.

The terminology and classification used for non-nevoid intraepithelial melanocytic proliferations are unique to the conjunctiva and have been subjects of ongoing debate. Specifically, the terms PAM with and without atypia are not used to describe other tissues. Also, the grading of mild, moderate, and severe atypia is somewhat subjective. To mirror the terminology used for cutaneous lesions and perhaps more accurately predict prognosis, several other classification schemes have been suggested for these intraepithelial melanocytic proliferations. The other main classification scheme is the conjunctival melanocytic intraepithelial neoplasia (C-MIN) scoring system, which is more complex and assigns a score of 1–10 according to the horizontal and vertical extent of epithelial involvement. PAM with atypia and C-MIN are considered synonymous terms for describing intraepithelial melanocytic neoplasia. The recently published World Health Organization (WHO) Classification of Tumours of the Eye proposes a simplified classification that grades intraepithelial melanocytic neoplasia as either low grade or high grade.

The PAM with/without atypia classification is familiar to most ophthalmologists and has generated more published information linked to prognosis and risk of metastasis than have other classification systems. Thus, despite the histologic ambiguity of the term melanosis, this classification is still the most commonly used system for grading and prognostication of intraepithelial melanocytic proliferations and is described here (see Figs 5-21, 5-22).

PAM without atypia is characterized by an increased number of cytologically unremarkable melanocytes arranged linearly along the basal epithelial layer, with the pigment localized mainly to the epithelial cells (see Fig 5-22E, F). In PAM with atypia, melanocytes are increased in number and may be cytologically atypical with a bloated appearance or pleomorphic nuclei. The melanocytes migrate into the superficial layers of the epithelium (see Fig 5-22H–J). These melanocytes form discohesive intraepithelial nests and migrate as individual cells or small clusters into the more superficial epithelium (ie, pagetoid spread). They may completely replace the epithelium (ie, melanoma in situ). Migration of melanocytes into the more superficial layers of the epithelium and cytologic atypia occur to varying degrees and are graded by the pathologist as mild, moderate, or severe (see Fig 5-22). Features of severe cytologic atypia include mitotic activity, nesting, pagetoid spread, cellular enlargement, epithelioid cell morphology, prominent nucleoli, and enlarged hyperchromatic nuclei. IHC stains for melanocytes, such as Melan A, HMB-45, and MITF, ideally complexed with a red chromogen, often highlight the presence and extent of melanocytic proliferation.

PAM with mild atypia carries minimal, if any, risk of malignant transformation. In contrast, PAM with moderate or severe atypia (see Fig 5-22G–J) and melanoma in situ (see Fig 5-22G, K, L) carry a significant risk (approximately 10%–15%) of progression to melanoma.

Table 5-1 summarizes the clinical features of common nonmalignant melanocytic conjunctival lesions. Table 5-2 summarizes the histology of non-nevoid pigmented lesions of the conjunctiva and correlations with the clinical nomenclature and histologic classification schemes. See also BCSC Section 8, External Disease and Cornea.

• Conway RM, Graue GF, Pelayes DE, et al. Conjunctival melanoma. In: American Joint Committee on Cancer (AJCC). AJCC Cancer Staging Manual. 8th ed. Springer; 2017: 803–813.

• Damato B, Coupland SE. Conjunctival melanoma and melanosis: a reappraisal of terminology, classification and staging. Clin Exp Ophthalmol. 2008;36(8):786–795.

• Margo C, Coupland SE, Moulin A, Roberts F. Melanocytic tumours of the conjunctiva and caruncle. In: Grossniklaus HE, Eberhart CG, Kivelä TT, eds. WHO Classification of Tumours of the Eye. 4th ed. International Agency for Research on Cancer (IARC); 2018.

• Shields JA, Shields CL, Mashayekhi A, et al. Primary acquired melanosis of the conjunctiva: risks for progression to melanoma in 311 eyes. The 2006 Lorenz E. Zimmerman lecture. Ophthalmology. 2008;115(3):511–519.e2.

Conjunctival melanoma

Approximately 50%–70% of cases of conjunctival melanoma arise from PAM with atypia (Fig 5-23); the remainder develop from a nevus or are de novo. Melanomas are usually nodular and can involve any portion of the conjunctiva. The nodule may be pigmented or amelanotic (15%–25% of conjunctival melanomas). Conjunctival melanomas metastasize to regional lymph nodes in 25% of patients, as well as to the lungs, liver, brain, bone, and skin. The overall mortality rate in these cases ranges from 15% to 30%. Clinical features associated with a worse prognosis include

• nonbulbar conjunctival location (ie, plica semilunaris/caruncle, forniceal or palpebral conjunctiva)

• increased tumor thickness (>1.8 mm)

• involvement of the eyelid margin

Figure 5-22 Spectrum of non-nevoid pigmented lesions of the conjunctiva. A, Clinical appearance of complexion-associated melanosis (benign epithelial melanosis). B, Histology of complexion-associated melanosis with morphologically unremarkable melanocytes confined to the basal epithelial layer. C, Immunohistochemical (IHC) staining for SOX-10, a melanocyte marker, demonstrates a normal number of melanocytes. D, Clinical photograph of PAM without atypia or with mild atypia (C-MIN 1, 2). E, Histology of PAM without atypia demonstrating a linear pattern of morphologically typical pigmented melanocytes in the basal layer of the epithelium. F, SOX-10 IHC stain demonstrates an increase in the number of melanocytes restricted to the deeper epithelial layers. G, Clinical photograph demonstrating the appearance of PAM with moderate to severe atypia (C-MIN 3, 4, 5) involving many clock-hours and/or melanoma in situ (C-MIN >5). These 2 degrees of atypical melanosis cannot be distinguished clinically. H, Histology of PAM with moderate atypia (C-MIN 3, 4, 5). Note the cells with round dark nuclei in the more superficial epithelial layers. I, MITF-1 IHC stain, another marker of melanocytes, stains melanocytes red and highlights the atypical pattern of melanocytic growth. J, Histology of PAM with severe atypia (C-MIN 5) with nests of atypical pigmented melanocytes in the more superficial layers of the epithelium. K, Histology of melanoma in situ (C-MIN >5). Note the full-thickness replacement of conjunctival epithelium with atypical, largely nonpigmented melanocytes with small, dark nuclei. L, Melan-A IHC stain, also a marker for melanocytes, demonstrates full-thickness replacement of conjunctival epithelium with atypical melanocytes (red-staining cells). Note: The clinical appearance of PAM/C-MIN of various stages can be indistinguishable; thus, these lesions usually require biopsy for a definitive diagnosis.

(Parts A and D courtesy of George J. Harocopos, MD; part G courtesy of Vahid Feiz, MD; all other parts courtesy of Tatyana Milman, MD.)

Table 5-1 Clinical Comparison of Nonmalignant Melanocytic Lesions of the Conjunctiva

Table 5-2 Non- nevoid Pigmented Lesions of the Conjunctiva

Figure 5-23 Melanoma arising from PAM with atypia. A, Clinical photograph. Note the elevated melanoma nodule adjacent to the limbus, arising from a background of PAM (diffuse, flat, brown pigmentation). Also note the prominent vascularity. B, Histologic examination shows melanoma (asterisk) arising from PAM (arrows).

(Part A courtesy of Morton E. Smith, MD; part B courtesy of Tatyana Milman, MD.)

When clinical suspicion for melanoma is high, referral to a surgeon with extensive experience in excision and treatment of ocular surface tumors should be considered because the outcome for the patient with incomplete excision is poor.

Occasionally, extrascleral extension of an anterior uveal melanoma presents as an episcleral/conjunctival mass that may mimic a primary conjunctival melanoma. Extrascleral extension of anterior uveal melanoma should be included in the differential diagnosis, particularly for a nonmobile pigmented or amelanotic episcleral nodule overlying the ciliary body that has sentinel vessels but without surrounding PAM (Fig 5-24). A complete eye examination, including gonioscopy and dilated ophthalmoscopy, should always be performed in any patient with a conjunctival mass. In individuals with darker complexions, conjunctival SCC is occasionally associated with reactive pigmentation masquerading as melanoma.

Histologically, the atypical melanocytes in melanoma range from spindle to polyhedral to epithelioid. The atypical cells may replace the epithelium only with an intact basement membrane (melanoma in situ, C-MIN >5), involve both the epithelial layer and the stroma, or involve just the stroma (invasive melanoma). The morphological cell types present in conjunctival melanoma do not have the same prognostic significance that they have in uveal melanoma. Rather, as in cutaneous melanoma, depth of invasion has a stronger correlation with prognosis. Mitotic figures may be present and are more frequent in more aggressive lesions.

Figure 5-24 Melanoma of the ciliary body with extrascleral extension, presenting as an ocular surface mass. Note that there is no PAM surrounding the nodule, a clue that the lesion might have an intraocular origin. Also note that the lesion is associated with deep episcleral/scleral vessels (sentinel vessels, arrow) and does not obscure the overlying conjunctival vessels. This indicates that the lesion is deep to the conjunctiva.

(Courtesy of J. William Harbour, MD.)

IHC stains for melanocytes, such as Melan A, HMB-45, and MITF, may be helpful in diagnostically challenging cases. In addition, identification of tumor-specific biomarkers has enhanced the assessment of conjunctival melanoma. For example, mutations in the BRAF gene, present in 30%–50% of conjunctival melanomas, can be a predictor of metastasis. Identification of melanoma biomarkers is also important in treating disease that has spread beyond the ocular surface, as targeted therapies against biomarkers are currently available. See also BCSC Section 8, External Disease and Cornea.

• Shields CL, Chien JL, Surakiatchanukul T, Sioufi K, Lally SE, Shields JA. Conjunctival tumors: review of clinical features, risks, biomarkers, and outcomes—the 2017 J. Donald M. Gass Lecture. Asia-Pac J Ophthalmol. 2017;6(2):109–120.

Excerpted from BCSC 2020-2021 series: Section 4 - Ophthalmic Pathology and Intraocular Tumors. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.