—  SHORT COURSE  —

OPHTHALMIC PATHOLOGY FOR THE NON-SPECIALIST


CASE 3 – COMPOUND CYSTIC NEVUS OF CONJUNCTIVA

J. Godfrey Heathcote, M.B.,Ph.D.  —  Janice R. Safneck, M.D.




History
A 9-year-old girl was noted to have an enlarging pigmented lesion in bulbar conjunctiva at 3 o'clock adjacent to the limbus.

Diagnosis
Compound nevus of conjunctiva

Histopathology
Nests of nevus cells are observed within conjunctival epithelium, within the walls of conjunctival inclusion cysts and subepithelially. The nests connect to the basal layer of the epithelium and there is no evidence of single cell intraepithelial spread. Cells within the nests vary from tightly to loosely cohesive, the latter apparent in the superficial junctional component where this change may be partly artefactual. Nevus cells range from polyhedral and epithelioid superficially to lymphocytoid in deeper aspects of the lesion, indicating some maturation. Even subepithelially, many nevus cells are arranged in nests. The intraepithelial component extends for a short distance beyond the subepithelial component at one edge. No mitoses are encountered in the nevus cells. Multiple cystic inclusions of conjunctival epithelium, some filled with eosinophilic material, are prominent.


Case 3, Slide 6 - Compound Cystic Nevus of Conjunctiva: Gross photograph of conjunctival nevus showing a tan lesion measuring 7 x 3 x 2 mm. Suture designates medial and nasal margin.
Case 3, Slide 7 - Compound Cystic Nevus of Conjunctiva: Epithelial inclusion cysts and nevus cells within epithelium and subepithelial tissue.

Discussion
Pigmented lesions of conjunctiva may be melanocytic or non-melanocytic in origin, with the former including nevi, acquired melanosis (primary and secondary) and malignant melanoma.

Nevi are the most common benign tumors of conjunctiva. They may be congenital but most are considered acquired and develop during the first two decades of life. Conjunctival nevi almost exclusively involve bulbar conjunctiva, plica and caruncle with a small percentage arising from lid margin. Elevated pigmented lesions of palpebral conjunctiva very rarely may be nevi but the vast majority of pigmented tumors located in this area represent melanoma or primary acquired melanosis (PAM).1 

Clinically, approximately 70% of conjunctival nevi are pigmented while the remaining 30% are amelanotic or show only very minimal pigmentation.2  They are of variable size, range from flat to polypoid, and are generally well circumscribed although sometimes diffuse but not multifocal. A feeder vessel may be evident in conjunctival nevi; however, proliferation of vessels around the base of a pigmented lesion is a feature of conjunctival melanoma. Conjunctival nevi are freely movable, in contrast to melanomas which may be fixed due to invasion of the episcleral tissues. Cystic inclusions of conjunctival epithelium within nevi are characteristic of 50 to 80% of these lesions and can be so prominent as to result in a clinical diagnosis of lymphangioma/lymphangiectasia.

Most nevi are removed because of enlargement3  but studies show they are also excised due to changes in pigmentation and for cosmetic reasons. It is generally agreed that the risk of malignant transformation is so minimal as to not justify removal for this reason alone. Guidelines indicate that any suspected nevus should be excised if atypically located (in fornices or palpebral conjunctiva), if growing significantly, if there is neovascularization or prominent inflammation or if pigmentation has changed.3  In one large study,3  approximately one half of excised nevi were submitted to the laboratory with a diagnosis other than nevus, e.g., tumor NOS, melanoma, PAM, foreign body and hemangioma.

The majority of conjunctival nevi are classical junctional, compound or subepithelial (intrastromal) in type. Junctional nevi occur in children and only rarely are identified in adults. In one study of conjunctival lesions in adults, just 2% of nevi were junctional4  and even the accuracy of this assessment has been questioned;2  indeed, any purely junctional nevomelanocytic lesion resembling a nevus in an adult is almost always PAM. In comparison, another study evaluating excised melanocytic lesions in children found 21% of nevi to be junctional.5  Typically, junctional nevi are flat, and microscopically, nevus cells are polygonal/epithelioid, cohesive and arranged in intraepithelial nests. Occasional junctional nevi may have a more "active appearance" with somewhat looser cellular cohesion and a rare mitotic figure,6  nonetheless; no single cell penetration of epithelium is seen.

In both children and adults, approximately 75% of excised nevi are compound with nevus cells in both epithelium and substantia propria. This contrasts with 3.5% subepithelial nevi in children5  versus 15% in adults,4  indicating maturation of nevi with the passage of time. Compound and subepithelial nevi range from thin to polypoid, depending partly on the location of the lesion. Perilimbal lesions are typically minimally thickened because the substantial propria is thin and episcleral tissues act as a barrier to growth.6  Histologically, nevus cells can be seen in nests both intra- and sub-epithelially and vary from polygonal/epithelioid superficially to lymphocytoid and sometimes fusiform in the depths of the lesion. As with cutaneous nevi, conjunctival nevus cells mature with descent into deeper zones of the subepithelial component. Rare conjunctival nevi may show neuroid formations but none has been reported to display regression and replacement by fibrous tissue as have those in the skin2  The deepest cells in a compound or subepithelial conjunctival nevus are typically non-pigmented except in black individuals who have pigmentation of nevus cells regardless of depth, but in whom conjunctival melanoma is exceedingly rare. Approximately 7% of conjunctival nevi contain pleomorphic or multinucleated nevus cells.5  Mitotic figures are extremely rare to non-existent.

Cysts lined by conjunctival epithelium and downward epithelial proliferations are present in up to 80% of conjunctival nevi, compared to epidermal cysts in just 1% of cutaneous nevi. Nests of nevus cells may be seen basally in conjunctival epithelial cyst walls; this is still considered a junctional component. Conjunctival cysts may increase in size due to mucin from goblet cells, resulting in an enlarging lesion which clinically can suggest malignant transformation.

A prominent lymphoplasmacytic response is present in 25 to 28% of nevi,5,6  particularly in adolescents and young adults,2  and is not suspicious for malignant transformation. Halo nevi, as seen in skin, have not been reported in conjunctiva. Melanophages may be present and on occasion, may account for changes in pigmentation seen clinically.1  However, foreign body reaction and/or ossification, as observed in facial cutaneous nevi, are absent in conjunctival nevi.7 

Ninety-five percent of conjunctival nevi stain positively for S100 protein in both intraepithelial and subepithelial components8  while NKI/C3 is positive in over 98% of conjunctival nevi.9  Conjunctival melanoma, the main differential diagnosis for compound and subepithelial conjunctival nevi, exhibits similar findings with these markers. Conjunctival melanomas also are typically strongly positive for HMB 45.8-10  In contrast, nevi are less reliably HMB 45 positive (409  to 95%)8  with Glasgow et al10  noting substantial staining of the subepithelial component while Steuhl et al8  did not. Despite these staining differences, it is generally agreed that HMB 45 cannot be used to reliably differentiate benign from malignant melanocytic lesions.8-10 

Unusual nevi including balloon cell, Spitz, epithelioid cell, blue and cellular blue nevi, have been documented in conjunctiva2,11  as has one case of pigmented spindle cell nevus of Reed.12  All these nevi show histologic features similar to their counterparts in skin. Combined nevi, a mixture of standard nevocytic and spindle-shaped blue nevus cells, were thought to be exceedingly rare in conjunctiva but a recent study by Crawford et al suggests they are much more common than previously appreciated.13  The dysplastic nevus syndrome and its relationship to conjunctival nevi is controversial. Rodriguez-Sains14  reported, on clinical examination, a 7-fold increase in conjunctival nevi in patients with the dysplastic nevus syndrome compared to controls but Seregard et al15  found no difference in incidence. Further, unlike in skin, no reliable clinical or histologic criteria for diagnosing dysplastic nevi in conjunctiva exist.2 

According to one study, 2.7% of conjunctival nevi recur.3  Limbal lesions are more likely to exhibit this behavior because they are technically more difficult to excise. If a conjunctival nevus extends to resection margins on first removal, there is no need to re-excise the lesion. However, any recurrence should be excised and submitted for histologic examination.

Differential diagnosis of conjunctival nevi involves not only histological findings but also clinical information, particularly with regard to separating a nevus from PAM. Junctional nevi can be histologically identical to PAM; however, the former occur almost exclusively in childhood while PAM arises in middle-aged individuals. Therefore, a junctional melanocytic lesion in an individual older than 30 years of age is likely PAM. Also, nevi may be focal or diffuse but not multifocal as PAM is. The edges of conjunctival nevi are typically well defined and, except in children, the subepithelial and intraepithelial components stop simultaneously. In an adult, extension of the intraepithelial portion of a melanocytic lesion beyond the subepithelial part should raise the question of PAM in association with a nevus or a conjunctival melanoma in association with PAM. Nevus cells are typically cohesive and, in junctional nevi, occur in nests surrounded by conjunctival epithelium; the cells of PAM with atypia often lack cohesion and do not usually have the same relationship to the epithelium that nevus cells do, i.e. large clusters separated by vertical pillars of epithelium. Intraepithelial spread of single cells and small cell clusters is not a feature of nevi and should suggest PAM with atypia.

Conjunctival nevi also must be distinguished from conjunctival melanoma. The former, although most frequently perilimbal in location, almost never involve the cornea, apparently because of its tightly ordered connective tissue structure. Therefore, pigmented limbal lesions extending on to the cornea raise the question of malignant melanoma. Conjunctival melanoma is exceptionally rare in childhood. Only 0.4% of conjunctival melanomas occur in individuals less than 20 years of age.5  Therefore enlarging pigmented lesions in this age group almost always are nevi. In contrast to nevi histologically, conjunctival melanomas show no evidence of maturation, have variable numbers of mitotic figures, and have pigmented cells even in the deepest aspect of the lesion.

Consideration of the aforementioned clinical and histological features enables definitive diagnosis of the vast majority of conjunctival nevi and melanomas. However, rare melanocytic proliferations exist, particularly in young individuals, which exhibit indeterminate findings on microscopy and cannot be reliably classified even by experienced ophthalmic pathologists.16 

Other conjunctival lesions simulating melanocytic disorders clinically include a wide array of conditions such as pigmented squamous papillomas and carcinomas, drug-related pigmentation, foreign bodies, mascara deposits, soft tissue lesions, conjunctival cysts, lymphoid salmon patches, pigmented fungi, and pterygia. Individuals with dark complexions can develop pigmentation of almost any conjunctival lesion.

References

  1. Buckman G, et al. Melanocytic nevi of the palpebral conjunctiva. An extremely rare location usually signifying melanoma. Ophthalmology 1988;95:1053-1057.
  2. Folberg R, et al. Benign conjunctival melanocytic lesions. Clinicopathologic features. Ophthalmology 1989;96:436-461.
  3. Gerner N, et al. Conjunctival naevi in Denmark 1960 - 1980. Acta Ophthalmol Scand 1996;74:334-337.
  4. Grossniklaus HE, et al: Conjunctival lesions in adults. A clinical and histopathologic review. Cornea 1987;6:78-116.
  5. McDonnell JM, et al: Conjunctival melanocytic lesions in children. Ophthalmology 1989;96:986-993.
  6. Jay B. Naevi and melanomata of the conjunctiva. Br J Ophthalmol 1965;49:169-204.
  7. Knox WF, et al: Foreign body giant cell reactions and ossification associated with benign melanocytic naevi. J Clin Pathol 1993;46:72-74.
  8. Steuhl K, et al: Significance, specificity and ultrastructural localization of HMB-45 antigen in pigmented ocular tumors. Ophthalmology 1993;100:208-215.
  9. Hitzer S, Bialasiewicz AA, Richard G. Immunohistochemical markers for cytoplasmic antigens in acquired melanosis, malignant melanomas, and nevi of the conjunctiva. Klin Monatsbl Augenheilkd 1998;213:230-237.
  10. Glasgow BJ, McCall LC, Foos RY: HMB-45 antibody reactivity in pigmented lesions of the conjunctiva. Am J Ophthalmol 1990;109:696-700.
  11. Kantelip B, et al. A case of conjunctival Spitz nevus: review of literature and comparison with cutaneous locations. Ann Ophthalmol 1989;21:176-179.
  12. Seregard, S. Pigmented spindle cell naevus of Reed presenting in the conjunctiva. Acta Ophthalmol Scand 2000;78:104-106.
  13. Crawford JB, Howes EL Jr., Char DH. Combined nevi of conjunctiva. Arch Ophthalmol 1999;117:1121-1127.
  14. Rodriguez-Sains RS. Ocular findings in patients with dysplastic nevus syndrome. An update. Dermatol Clin 1991;4:723-728.
  15. Seregard S, et al. Prevalence of primary acquired melanosis and nevi of the conjunctiva and uvea in the dysplastic nevus syndrome. A case-control study. Ophthalmology 1995;102:1524-1529.
  16. Grossniklaus HE, Margo CE, Soloman AR. Indeterminate melanocytic proliferations of the conjunctiva. Arch Ophthalmol 1999;117:1131-1136.