Pathology of the Conjunctiva, Orbit, Lacrimal Gland, and Intraocular Tumors

Clinical Features

In children, papillomas are most commonly multiple and pedunculated, involving the fornix, caruncle, or eyelid margin, rarely involving the cornea. In adults, they are usually single and sessile, usually occurring at the limbus or bulbar conjunctiva. Papillomas commonly appear as exophytic, pink-red, strawberry-like papillary growths that may be pigmented. Human papillomavirus (HPV) has been detected in both pediatric (HPV 6) and adult (HPV 16) papillomas.

Pathologic Features

Typical findings show a benign papillomatous lesion composed of fibrovascular cores lined by squamous epithelium. The squamous epithelium is generally nonkeratinizing and the epithelial cells are usually only mildly atypical; goblet cells are present ( Fig. 15.5A–C ). Rarely, squamous papillomas may show an inverted growth pattern. Some papillomas have numerous melanocytes that impart a darker color to the lesion clinically. In lesions secondary to HPV infection, mild to focally moderate dysplasia of the epithelium may be present. Viral cytopathic effect due to HPV infection, including cytolasmic clearing and koilocytosis, may be identified.

Immunohistochemistry and In Situ Hybridization

Studies that may prove useful in diagnosing papillomas include p16, Ki-67, and in situ hybridization for HPV DNA. A p16 immunohistochemical stain most commonly reveals some dysplastic cells via nuclear and cytoplasmic reactivity ( Fig. 15.5D ). Ki-67 stain shows one or two basal cell layers in cycle; if moderate dysplasia is present, additional cells in cycle are present in the mid-epithelium. DNA in situ hybridization is positive for low-risk HPV DNA (probe for HPV 6/11) and/or high-risk HPV (probe HPV 16/18).

Differential Diagnosis

The main consideration, especially in adults, is a well-differentiated in situ or invasive papillary squamous cell carcinoma. The papillae in invasive squamous cell carcinoma are usually more broad-based or sessile and the epithelial lining is composed of dysplastic cells with lack of maturation, enlarged nuclei, prominent nucleoli, and mitotic figures present in the epithelium above the parabasal layer.

Treatment and Prognosis

Conjunctival papillomas often show spontaneous regression. However, recurrences are frequent (6%–27%). There is a variety of treatment options for treating large and symptomatic conjunctival papillomas. Surgical excision of the lesion and cryotherapy to the adjacent conjunctiva is the treatment of choice.

Clinical Features

Clinically, lesions can appear focal and well circumscribed or diffuse and poorly demarcated. Lesions are most commonly located within a sun-exposed interpalpe bral fissure, specifically in the nasal or temporal zones and the limbus ( Fig. 15.6A ). CIN usually appears as a fleshy, sessile, or mildly elevated lesion ( Fig. 15.6 ). If the growth is diffuse, it usually occurs in non-sun–exposed areas of the conjunctiva such as the fornix or palpebral conjunctiva and can appear gelatinous and less well defined.

Pathologic Features

Histopathology features comprise intraepithelial dysplasia originating in the basal layers extending toward the surface epithelium overlying areas of solar elastosis. These lesions can show different growth patterns, mainly keratinizing (leukoplakic), nonkeratinizing, or spindle cell, with actinic or papillomatous features. The epithelial cells may be small, large, spindle shaped, and clear, among others. CIN is graded as mild, moderate, or severe according to the degree of involvement of the epithelium. However, it can be challenging to accurately discern the degree of dysplasia in keratinizing lesions. In mild dysplasia (CIN1) the lesion involves the lower third of the conjunctival epithelium; moderate dysplasia (CIN2) shows involvement of up to two-thirds the conjunctival epithelium; and severe dysplasia (CIN3/carcinoma in situ) shows full-thickness epithelial involvement ( Fig. 15.6B and C ). A variant of squamous cell carcinoma, conjunctival keratoacanthoma, shows an acanthotic epithelial proliferation with cytologic atypia, an intact basement membrane, increased mitotic figures, and a central crater filled with keratin.

Immunohistochemistry and In Situ Hybridization

Studies that can be used to aid in the diagnosis of CIN are immunohistochemistry for p63, p16, and Ki-67, and in situ hybridization for HPV DNA. p16 may delineate the area of dysplasia if the lesion is HPV driven with diffuse nuclear and cytoplasmic staining ( Fig. 15.6D ). p63 stains both the involved and uninvolved epithelium; however, the involved area with CIN will show larger nuclei with p63 stain than the normal surrounding epithelium. Ki-67 stain is helpful in demonstrating the increased cells in cycle beyond the basal epithelial cell layer. DNA in situ hybridization for low-risk HPV DNA (probe for HPV 6/11) and/or high-risk HPV (probe HVP 16/18) may be helpful in demonstrating the presence of HPV infection and affect treatment options.

Differential Diagnosis

Differential diagnosis includes UV-related leukoplakic lesions of the limbal conjunctiva, intraepithelial sebaceous carcinoma, intraepithelial invasion by an adenocarcinoma, mucoepidermoid (adenosquamous) carcinoma, and primary acquired melanosis with atypia without pigment. In clinically leukoplakic lesions there is epithelial hyperplasia with acanthosis, parakeratosis, and squamous metaplasia with minimal atypia of the epithelium in an area overlying solar elastosis. The changes are nonspecific and can be related to sun exposure, vitamin A deficiency, xerosis of the conjunctiva, keratoconjunctivitis sicca, Sjögren syndrome, and radiotherapy. In an attempt at a less confusing and unifying terminology, this author adds lesions similar to actinic keratosis of the skin to the CIN nomenclature (CIN1). Intraepithelial involvement by sebaceous carcinoma of the conjunctiva can be especially challenging because if the tumor involves all the layers of the conjunctiva it can appear similar to squamous cell carcinoma in situ. In conjunctival sebaceous carcinoma the basal layer of the conjunctiva shows a normal population of basal cells that appear smaller than the larger, very atypical, malignant sebaceous cells with foamy cytoplasm and atypical mitoses found in the mid and upper layers of the epithelium. Oil Red O stain and/or adipophilin immunohistochemical stain to demonstrate intraepithelial fat globules is very helpful in the differential diagnosis of these cases. Epithelial membrane antigen (EMA) and androgen receptor (AR) stains may also be helpful in highlighting the malignant cells of sebaceous carcinoma.

Adenocarcinoma originating in the apocrine glands of Moll may rarely involve the conjunctiva and appear similar to a dysplasia or squamous cell carcinoma. Evidence of glandular formation with cells showing ample pink cytoplasm should raise the differential diagnosis. ER, BGF-15, and carcinoembryonic antigen (CEA) stains can be used to aid in the diagnosis of an apocrine adenocarcinoma. Mucoepidermoid (adenosquamous) carcinoma is comprised of atypical squamous cells with eosinophilic cytoplasm, arranged in sheets and cords, with interspersed mucous cells. Less commonly, primary acquired melanosis with atypia without pigmentation may be confused with a dysplastic or squamous lesion. Immunohistochemical staining with Mart-1, HMB-45, MITF-1, or S100 are helpful in differentiating CIN from a melanocytic lesion.

Treatment and Prognosis

Excision of the affected epithelium with cryotherapy of the margins is the standard treatment.

Clinical Features

The clinical presentation of invasive squamous cell carcinoma is similar to that of CIN. It occurs in the interpalpebral conjunctiva and displays a wide array of clinical appearances: circumscribed, diffuse and poorly delineated, gelatinous, sessile, or papillomatous mass ( Fig. 15.7A and B ) with varying degrees of surface keratinization ( Fig. 15.7C ). Large, dilated conjunctival blood vessels usually feed the mass. It can be locally invasive into the orbit, globe, and cornea, causing glaucoma and pain requiring enucleation. It can rarely metastasize in 1% to 2% of cases.

Pathologic Features

Squamous cell carcinoma is typically a well-differentiated neoplasm composed of abnormal squamous epithelial cells with increased mitoses and keratin production. Squamous cells might appear less differentiated with large, pleomorphic cells, giant cells, dyskeratosis, and abnormal mitoses. The tumor’s extension through the basement membrane of the conjunctival epithelium can be highlighted with periodic acid-Schiff (PAS) stain. Stromal invasion may be superficial or deep. Histological variants include spindle cell, basaloid, clear cell, and pigmented. Spindle cell variant of squamous cell carcinoma of the conjunctiva, although rare, tends to be more locally invasive than conventional squamous cell carcinoma and has a tendency to metastasize ( Fig. 15.7D ).

Immunohistochemistry

Staining for EMA (67%), high-molecular-weight keratin (HMWK; 100%), BRST-1 (25%), CEA (25%), and mucin-1 (75%) have been reported to be useful in the diagnosis of squamous cell carcinoma of the conjunctiva. p53 has been reported positive in squamous cell carcinoma in 78% of tumors; there is no definite link between p53 staining and HPV infection.

Differential Diagnosis

Squamous cell carcinoma should be differentiated from mucoepidermoid (adenosquamous) carcinoma arising in the conjunctiva or originating from the paranasal sinuses. Mucicarmine, Alcian blue, colloidal iron, and mucin-1 stains are useful in highlighting the mucus-secreting cells present in mucoepidermoid carcinoma. BRST-2, CK-7, CK-20, and low-molecular-weight keratin have been reported to stain positively in mucoepidermoid carcinoma and not squamous cell carcinoma. In contrast, EMA, HMWK, BRST-1, and CEA stain squamous cell carcinoma. Molecular analysis of the translocation t(11;19) (q12;p13), resulting in a fusion MECT1-MAML2 gene characteristically described in salivary gland tumors, may be used to aid in the diagnosis. However, this translocation has not been reported to date in conjunctival mucoepidermoid (adenosquamous) carcinomas. The spindle cell variant of squamous cell carcinoma may be indistinguishable from malignant fibroblastic proliferations on light microscopy alone. Immunohistochemical studies may be helpful in differentiating spindle cell carcinoma from sarcomas.

Treatment and Prognosis

The overall prognosis of squamous cell carcinoma is good. Complete surgical excision with alcohol corneal epitheliectomy, partial lamellar sclerokeratoconjunctivectomy, and double freeze-thaw cryotherapy to the surrounding conjunctival margins is advised. Recurrences may occur in up to 12.9% of cases, 6 to 12 months after the primary treatment. Recurrence does not seem to correlate significantly with age, gender, laterality, clinical appearance, or focality of the tumor at presentation. However, tumors larger than 5 mm in diameter, tumors extending more than 2 mm onto the cornea, and tumors with local invasion (corneal, scleral, intraocular, or orbital invasion) are associated with a higher risk of recurrence.

Pathologic Features

Histopathologically, mucoepidermoid carcinoma shows sheets and cords of large squamous epithelial cells with eosinophilic cytoplasm, and mucin-containing cells. The typical intermediate-size cells described in salivary and lacrimal gland tumors are not usually present in this tumor ( Fig. 15.8A ). In infiltrating areas, the neoplastic cells may surround pools of mucin ( Fig. 15.8B and C ). Mucicarmine, Alcian blue, PAS, and colloidal iron highlight the mucin-producing cells present in the lesion.

Differential Diagnosis

The main differential diagnosis is CIN and invasive squamous cell carcinoma of the conjunctiva. Other diagnostic possibilities include basal cell carcinoma involving the conjunctival epithelium and adnexal malignancies with clear cell change.

Immunohistochemistry and Molecular Genetics

BRST-2, CK-7, CK-20, and low-molecular-weight keratins stain the tumor cells positively in contrast to squamous cell carcinoma. In the salivary glands, mucoepidermoid carcinoma is uniquely characterized by a specific translocation t(11;19)(q12;p13), resulting in a fusion between the MECT1 and MAML2 genes. Although the incidence of this fusion in MEC varies, it is generally accepted that more than 50% of salivary gland mucoepidermoid carcinomas harbor MECT1-MAML2 . It has been reported that fusion-positive cases show significantly better survival than fusion-negative cases. This translocation has not been reported to date in mucoepidermoid (adenosquamous) carcinomas arising in the conjunctiva.

Treatment and Prognosis

Wide local excision with free surgical margins is the treatment of choice. The tumor shows higher rates of recurrences, orbital, and intraocular spread than squamous cell carcinoma. It can metastasize to regional lymph nodes, lungs, and bone.

Clinical Features

The conjunctival involvement appears clinically as diffuse thickening with loss of eyelashes and masquerades as an inflammatory disease, as in chronic keratoconjunctivitis ( Fig. 15.9A ).

Pathologic Features

Histologically, sebaceous carcinoma shows atypical cells with foamy cytoplasm, arranged singularly or in groups, present within the epithelium ( Fig. 15.9B ). The hyperchromatic cells have enlarged nuclei and are significantly larger than the surrounding normal basal keratinocytes. The malignant cells may spread to replace the entire epithelial thickness, and atypical mitotic figures are often present. ( Fig. 15.9C and D ). If the tumor cells replace the entire conjunctival epithelium, then differentiating it from a nonkeratinizing squamous cell carcinoma in situ can be challenging.

Histochemistry and Immunohistochemistry

Oil Red O on frozen or formalin-fixed tissue without processing is very helpful ( Fig. 15.9C , inset ). The typical immunohistochemical profile of sebaceous carcinoma is EMA, CK-7, CAM5.2, adipophilin, and variable AR positivity depending on the degree of differentiation. S100 and anti-alpha smooth muscle actin (SMA) are negative; Ber-EP4 stain is negative in most cases. p16 and p53 are useful in determining the extent of conjunctival intraepithelial spread. Both markers are expressed in the majority of cases. A subset of patients with phenotypic Muir-Torre syndrome (MTS)–related sebaceous tumors will have germline mutations in the DNA mismatch repair (MMR) genes hMSH2 , MSH6 , and hMLH1 . In MTS-associated tumors, particularly sebaceous adenoma and well-differentiated sebaceous carcinoma, up to 70% of patients have microsatellite instability, leading to the development of visceral malignancies, in particular colonic adenocarcinoma. The spectrum of cancers and the germline mutations characteristic of MTS have suggested it represents a phenotypic variant of hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome. Immunohistochemical panels including MLH1, MSH6, and PMS2 and MSH2 are important to rule out microsatellite instability. Although loss of MMR protein expression by immunohistochemistry is highly suggestive of germline mutations, it may also represent sporadic mutations in MMR genes; thus germline microsatellite instability testing is required to confirm the diagnosis.

Differential Diagnosis

The main differential diagnosis of intraepithelial sebaceous carcinoma includes in situ squamous cell carcinoma and basal cell carcinoma. The detection of AR and adipophilin positivity is most useful for differentiating sebaceous carcinoma from squamous cell carcinoma. Poorly differentiated squamous cell carcinoma typically shows EMA positivity and is negative for CEA, AR, CA19-9, adipophilin, and Ber-EP4. Basal cell carcinoma usually involves the conjunctiva from the eyelid and shows atypical basaloid cells that can be difficult to distinguish from sebaceous carcinoma. EMA, CA15-3, Ber-EP4, and adipophilin stains are most valuable in differentiating sebaceous carcinoma from basal cell carcinoma. Basal cell carcinoma is positive for Ber-EP4 and negative for CEA, EMA, CA15-3, and adipophilin.

Pinguecula

Pathologic Features

The overlying epithelium is often thin but may be acanthotic or dysplastic. The stromal collagen shows fragmentation and basophilic degeneration (elastotic degeneration) due to degenerated collagen fibers ( Fig. 15.10A ). Elastic stain may be used to highlight the elastotic degeneration of the stroma ( Fig. 15.10B ).

Pterygium

Clinical Features

A chalazion appears as a firm, tender, erythematous lump in the tarsal conjunctiva. It may break though the conjunctival epithelium or drain into the skin of the eyelid.

Pathologic Features

Chalazion is characterized by the presence of acute and chronic granulomatous inflammation ( Fig. 15.11A ) reacting to lipid material ( Fig. 15.11A , inset ). The inflammation is more in keeping with foreign body–type changes with loose granuloma formation and giant cells. Infectious organisms are usually not identified but a secondary infection can occur.

Differential Diagnosis

Differential diagnosis includes specific infections such as tuberculosis and cat-scratch disease, chronic granulomatous inflammatory processes such as sarcoidosis and rheumatoid nodule, and tumors, mainly sebaceous carcinoma. There is a wide array of infectious organisms that can involve the conjunctiva, including bacteria, fungi, mycobacteria, and parasites. Infectious etiologies are most commonly clinically suspected; cultures and specific stains for microorganisms can be performed to rule them out. Sarcoidosis may involve the conjunctiva in 7% to 17% of patients with ocular sarcoidosis. The classic histological findings are tight nonnecrotizing granulomas with giant cells ( Fig. 15.11B ). Asteroid and Schaumann bodies may be found within giant cells ( Fig. 15.11C ). The granulomatous inflammation in chalazion is loose when compared to sarcoidosis. Conjunctival involvement in patients with rheumatoid arthritis is very rarely seen. Typically a central area of necrosis surrounded by palisading histiocytes is present and is helpful in differentiating from a chalazion. Older patients with chronic blepharoconjunctivitis may harbor a sebaceous carcinoma. Sebaceous carcinoma most commonly involves the conjunctival epithelium in a pagetoid growth pattern; the cells are unmistakably malignant with nuclear hyperchromasia, foamy cytoplasm, and abnormal mitoses. Stains may be used to aid in differentiation, mainly adipophilin for fat droplets or Oil Red O.

Treatment and Prognosis

The typical management is hot compresses and good eyelid hygiene. If the lesion is symptomatic and does not resolve, incision and curettage is the management of choice.

Conjunctival Inclusion Cysts

Conjunctival inclusion cysts are in the great majority acquired, secondary to surgical or accidental trauma, foreign body, and chronic inflammation. Congenital inclusion cysts are rare.

Pathologic Features

The cysts are lined by nonkeratinizing squamous epithelium with variable amounts of mucus-secreting goblet cells ( Fig. 15.12A and B ). If there is pigment present in the basal epithelial layer of the cyst without melanocytic hyperplasia, then a diagnosis of cystic benign melanosis is rendered ( Fig. 15.13A–C ).

Accessory Lacrimal Gland Cysts (Dacryops)

An accessory lacrimal gland cyst represents a cyst of an accessory lacrimal duct and may be preceded by trauma, infection, or inflammation of the conjunctiva.

Pathologic Features

The lining of the cysts is composed of nonkeratinizing squamous epithelium with a basal layer of cuboidal cells and a superficial layer of cylindrical cells surrounded by a prominent fibrous stroma. In some cases a portion of an accessory gland is present in the surrounding tissue ( Fig. 15.14A and B ).

Conjunctival Choristomas

Most congenital lesions of the conjunctiva are choristomas: benign tissues foreign to the conjunctiva. Choristomas may be simple or complex depending on the presence of one or more types of histologically normal tissues, including skin, fat, bone, lacrimal gland, cartilage, and, rarely, respiratory type mucosa. Most choristomas are sporadic and nonhereditary. Dermolipoma is the most common choristoma of the conjunctiva, accounting for approximately 58% of lesions; dermoid is the next most frequent (25% of cases). Their distinction is based on clinical features. Dermolipomas and dermoids are often part of Goldenhar syndrome, which features auricular and vertebral abnormalities.

Pathologic Features

The histopathological features of both dermolipoma and dermoid are similar. Both are lined by stratified squamous epithelium, partially keratinized. In dermolipoma the stroma contains densely packed collagen fibers and fibroadipose tissue ( Fig. 15.15A ). In a dermoid the stroma shows dense collagenous tissue with pilosebaceous units, sweat glands, and fibrofatty tissue. In both, the stroma may contain bone, cartilage ( Fig. 15.16B ), and ectopic lacrimal gland tissue. Rarely, a dermoid may be cystic and composed of respiratory-like epithelium.

Acquired Lobular Capillary Hemangioma, Pyogenic Granuloma Type

Acquired lobular capillary hemangioma accounts for 18% of all the conjunctival vascular lesions. It is commonly seen at a traumatic wound site or near a suture line after surgery for chalazion, pterygium, strabismus, or enucleation. It can also occur as a primary response to a chalazion.

Capillary and Cavernous Hemangioma

Hemangiomas of the capillary type may be isolated ( Fig. 15.16A and B ) or associated with a large capillary hemangioma affecting the eyelid and periocular skin. They do not differ from capillary hemangiomas elsewhere. Cavernous hemangioma can be solitary or may occur in association with syndromes such as Sturge-Weber syndrome, diffuse neonatal hemangiomatosis, and blue rubber bleb nevus syndrome. They are composed of enlarged blood-filled vessels lined by endothelial cells arranged in a loose connective tissue stroma. Smooth muscle may be present in the walls of the wall vessel. The differential diagnosis includes other rare vascular tumors involving the conjunctiva, glomangioma, and Kaposi sarcoma.

Lymphangiectasia and Lymphangioma

The stroma of the conjunctiva usually has numerous lymphatic channels. If they become dilated and focally appear distinct from the rest of the conjunctiva, the term lymphangiectasia is appropriate ( Fig. 15.17A and B ). If the lesion forms a distinct mass, then the term lymphangioma is used.

Clinical Features

Complexion-associated melanosis is usually observed around the limbus bilaterally, unlike primary acquired melanosis without atypia. The pigmentation appears flat and noncystic. It can cover the conjunctiva extensively and the pigmentation may increase with age.

Pathologic Features

The conjunctival basal layer shows increased melanin pigmentation ( Fig. 15.18A ) often extending into the more superficial layers without an increase in melanocytes. Racial melanosis may be found in other biopsied lesions of the conjunctiva, including pinguecula, pterygium, squamous papilloma, and squamous intraepithelial neoplasia.

Differential Diagnosis

Primary acquired melanosis without melanocytic atypia is identical to racial melanosis on histology, showing increased melanin deposits in the basal epithelial layer without melanocytic hyperplasia ( Fig. 15.18B ). Racial melanosis is also very similar to freckles or ephelides, flat patches of epithelial pigmentation concentrated in the basal layer. In congenital ocular melanocytosis or oculodermal melanocytosis (nevus of Ota), episcleral and scleral deeply pigmented dendritic melanocytes with benign cytologic features are present. These findings are usually seen in the sclera overlying the uveal tract.

Treatment and Prognosis

The lesion is benign and does not require excision. The development of conjunctival melanoma is rare in darkly pigmented individuals.

Clinical Features

Conjunctival nevi present as slightly tan, fleshy, well-defined flat or raised nodules usually located in the interpalpebral bulbar conjunctiva, the plica semilunaris, the caruncle, or the eyelid margin. Conjunctival nevi are most commonly seen in patients with brown irides. They are usually darkly pigmented (65% of cases); they may be lightly pigmented (19% of cases) or less frequently nonpigmented (up to 16% of cases). Compound melanocytic nevi, very commonly seen in children and young adults, are the most common type, followed in frequency by subepithelial, junctional, and blue nevi. Based on photographic documentation over an average period of 11 years, 13% of benign nevi were found to change in color, and 8% changed in size. The changes are commonly due to cystic growth, progressive pigmentation of previously amelanotic areas, or increased intrinsic inflammation.

Predisposing Conditions

Melanocytic nevi are usually sporadic with no systemic manifestations. However, pigmented lentiginous lesions and nevi may be rarely associated with the Carney complex and dysplastic nevus syndrome.

Pathologic Features

Compound melanocytic nevi are the most common type, accounting for 70% to 78% of all nevi. Histopathology examination shows intraepithelial or junctional oval melanocytes (type A melanocytes) and, less commonly, sheets of oval to cuboidal cells (type B melanocytes); they show maturation with depth, with progressive evolution into neurotized spindle-like cells in the subepithelium (type C melanocytes). Conjunctival nevi may undergo evolutionary changes with nevus cells confined to the junctional area initially, and later the nests “drop off” into the substantia propia, eventually losing connection with the epithelium ( Fig. 15.19A and B ). These nevi are characterized by stromal entrapped conjunctival epithelium, epithelial cysts, and nests ( Fig. 15.19C ), present in up to 50% of cases. The cysts are more common in long-standing lesions, and when present they represent cystic compound melanocytic nevi . In young individuals, cystic compound nevi may be inflamed, with prominent chronic inflammatory infiltrate including plasma cells and eosinophils ( Fig. 15.20A ). Both the cystic component and inflammation may account for rapid clinical growth. In children and young adults, atypical features may be present in benign nevi. Nesting and a confluent growth pattern of the junctional intraepithelial melanocytic component may be present but is usually limited to the area directly overlying the subepithelial component. A lateral shoulder of the junctional proliferation may also be present ( Fig. 15.20B ). Another atypical feature is paradoxical reverse maturation, with melanocytes in the substantia propria showing larger nuclei and more cytoplasm than those present in the intraepithelial component ( Fig. 15.20C ). These features have been described as potential pitfalls in the diagnosis of juvenile cystic compound melanocytic nevi . Junctional conjunctival nevi show nests of melanocytic cell nests in the base of the epithelium (predominantly type A melanocytes); the lesion is seen in children but is rarely encountered in adults. In older individuals, a diagnosis of primary acquired melanosis is more likely and should be ruled out. Subepithelial nevi show predominantly type B or C nevomelanocytes in the substantia propria commonly arranged in nests with usual maturation toward the deeper portion of the lesion; atypical features are rarely seen. Cytoplasmic balloon cell change may be found in benign nevi ( Fig. 15.21A ). Conjunctival blue nevi appear as noncystic brown or black-blue masses in the stroma. The common blue nevus shows an inverted wedge-shaped configuration and is composed of a uniform population of pigmented dendritic cells or benign type C melanocytes without atypia ( Fig. 15.21B ). Cellular blue nevi show a biphasic cellular pattern with spindled to oval melanocytes with clear or finely pigmented cytoplasm surrounded by heavily pigmented dendritic melanocytes. Most lesions appear well circumscribed, although the cellular areas may emerge from the far deep portion extending vertically deep into the substantia propria with a dumbbell-shaped outline. Conjunctival Spitz nevus is rare. It appears clinically as a nonpigmented mass in the conjunctiva or caruncle area. It shows nests of large, polygonal, nonpigmented epithelioid cells located in the stroma with lymphoid infiltrate at the base of the lesion and no mitoses present. The pigmented spindle cell nevus of Reed , once considered a pigmented variant of spindle cell Spitz nevi, is now recognized by most authors as a distinct entity. Reed nevus is composed histologically of elongated spindle-shaped and nevoid cells with a benign biologic behavior ( Fig. 15.21C ). Histopathological features in common with Spitz nevi and in contrast with malignant melanoma include a relatively small size, lesion symmetry, uniformity of cell type, good circumscription, and maturation of cells from superficial to deep. Eosinophilic Kamino bodies resembling those seen in Spitz nevi may be found. In contrast to classic Spitz nevi, the lesion is usually heavily pigmented, with abundant coarse melanin granules in the lesional cells and epithelial cells, and mostly confined to the subepithelium or junctional component only. Cases of hypopigmented Reed nevus have been described.