History
An 83-year-old woman who had a history of cicatricial pemphigoid of the left eye with symblepharon formation
developed a pigmented lesion on her left bulbar conjunctiva. The lesion was excised and diagnosed as a
junctional nevus. One and one half years later, she was noted to have a focal corneal pannus with a few
flecks of pigment and this was biopsied.
Diagnosis
Primary malignant melanoma of conjunctiva arising in primary acquired melanosis with atypia
Histopathology
Most of the tumor involves subepithelial tissues. The highly cellular neoplasm essentially is non-pigmented
and consists of spindle-shaped cells and small polyhedral cells. Nuclei are mild to moderately pleomorphic,
are without prominent nucleoli, have irregular nuclear membranes and scattered intracytoplasmic nuclear
inclusions. Rare epithelioid cells also are seen. Although occasional groups of spindle cells have a
nested arrangement, most cells infiltrate the subepithelial tissue diffusely. No maturation is observed.
Only rare mitotic figures are visible. Scattered plasma cells are evident throughout the lesion, with some
neutrophils identified superficially. The epithelium covering the neoplasm is attenuated and in areas
contains groups of tumor cells. A portion of corneal stroma is present at the bottom of the biopsy. Tumor
involves resection margins.
Previous biopsies from this patient showed left conjunctival primary acquired melanosis (PAM) with atypia
(nested basilar pattern without epithelioid cells) and lentigo maligna in the region of the eyebrow.
Discussion
Primary melanomas of conjunctiva are uncommon tumors, constituting approximately 2% of eye malignancies1
and are second in frequency of conjunctival malignancies to squamous cell carcinoma.2 For comparison, in
1987 in Sweden there were 2 conjunctival melanomas for 70 uveal melanomas and 1243 skin melanomas.3
Conjunctival melanomas typically affect middle-aged to older white individuals, rarely arising in childhood
(approximately 0.4%4 to 1%5 of conjunctival melanomas are encountered in individuals younger than 20
years of age) and exceptionally in blacks6 or Asians. Studies generally have shown that between 56%5,7,8
and 75%3,9 of melanomas originate from PAM with the remainder occurring in pre-existing nevi or de
novo. A few individuals with the dysplastic nevus syndrome have developed conjunctival melanoma10 but a
relationship between these two conditions, although postulated, has not been established conclusively. In
Shields et al's study of 150 patients with conjunctival melanoma, 2 patients had the dysplastic nevus
syndrome, 7 had a history of cutaneous melanoma and 8 had lentigo maligna of the eyelid.5 Patients with
ocular/oculodermal melanocytosis (nevus of Ota) are not at increased risk for conjunctival melanoma although
they are for uveal melanoma.11
Clinically, primary conjunctival melanomas may be variably pigmented thin or nodular lesions, solitary and
well circumscribed or, in the case of tumors arising in PAM, multifocal and diffuse. Mean tumor size was 8
mm at the base with a thickness of 2 mm in Shields et al's analysis of 150 conjunctival melanoma patients.5
In De Potter et al's study,7 88% of these tumors were pigmented while 12% were amelanotic;
Paridaens et al reported 4 amelanotic melanomas arising from PAM sine pigmento (PAM without pigment).12
Lack of pigment can impart a reddish appearance to the lesion, a situation noted especially in recurrent
melanomas that can lead to a mistaken clinical impression of pyogenic granuloma.5 Features to suggest
malignant transformation in a pre-existing pigmented conjunctival lesion include increasing thickness,
altered pigmentation, the development of prominent blood vessels, extension on to cornea and tethering of
normally mobile conjunctiva to underlying sclera. Tumors occurring in a nevus or de novo usually are found
in bulbar conjunctiva in the interpalpebral fissure whereas those arising in PAM may be located anywhere.
Thus the former are more readily noticed by patients while the latter may go undetected until the tumor
becomes quite large.
Although it has been attempted, the consensus is that the classification of cutaneous melanomas does not
apply to conjunctival melanomas and Clark's levels cannot be used.1,13,14 Histologic factors, such as
origin, cell type, thickness, diameter, mitotic rate, lymphatic invasion, associated inflammatory infiltrate
and accompanying epithelial involvement, as well as clinical factors, such as location, age, and gender,
have been analyzed for prognostic implications, with controversial results. This may be due to the
generally small number of cases analyzed, to the different clinical and histologic features assessed and to
the varying methodologies employed. Further, some factors seem to be interdependent and the significance of
each finding alone is uncertain.
Histologically, conjunctival melanomas may be composed of spindle cells, epithelioid cells or a mixed
population but the majority of tumors are mainly or entirely epithelioid. It appears that predominantly or
purely epithelioid cell tumors may have a worse prognosis than pure spindle cell melanomas.3,8,15
Intraepithelial involvement can accompany invasive tumor, and, if pagetoid spread or diffuse replacement of
epithelium is seen, Folberg et al's study suggested a worse prognosis;9 however, the presence or absence
of PAM overall did not alter survival. In contrast, Shields et al observed in their series of patients that
melanoma without accompanying PAM was a risk factor for death.5 Vascular space involvement, typically
lymphatic, may also be demonstrated, a finding associated with a 4-fold increase in death rate.8 Mitotic
activity varies from rare to frequent although its correlation with prognosis is controversial, with some
claiming prognostic importance3 but others not.8 Similar controversy exists over the significance of
an inflammatory infiltrate.8,16 Almost all conjunctival melanomas stain positively for HMB, S100,17,18 A103
which recognizes melan-A/MART-1,17 and NKI/C318
Tumor diameter and site appear to have some relevance as prognostic indicators, with large (greater than 10
mm in diameter3 or affecting more than one quadrant of bulbar conjunctiva)1 or multifocal15
melanomas involving the fornix, palpebral conjunctiva, caruncle, plica, lid margins or cornea having an
increased mortality.8,9,16 The prognostic value of thickness is controversial: findings have ranged
from tumor depth being not significant,3 to less than 0.8 mm,9,11 1.5mm,14,15 2 mm1 and 4 mm8
being the thickness to separate low-risk from high-risk melanoma. Tumor thickness appears to be related to
diameter and location in terms of prognostic relevance.1,8,15 Age and gender do not affect prognosis.
Overall survival rate for conjunctival melanoma is 77% to 88% at 5 years1,7 and 70% to 76% at 10 years.1,3
Treatment is generally surgical: local excision for small tumors, with or without cryotherapy, and
exenteration for larger, more advanced ones. Enucleation is not used to treat conjunctival melanoma. Close
follow-up of locally excised melanomas is required since at least one-third of cases recur. The effect of
recurrence on prognosis is a matter of dispute with one study claiming it was the only factor correlating
with metastasis7 while another found it did not affect survival.3 Conjunctival melanomas most
commonly first metastasize to preauricular and cervical lymph nodes but can show wide hematogenous systemic
spread.5,9 Occasional tumors exhibit local extension to paranasal sinuses and nasal cavity.8
Differential diagnosis of primary conjunctival melanoma includes primary conjunctival tumors of
non-melanocytic origin that have acquired pigment, particularly in individuals with dark skin. Primary
conjunctival melanoma also must be distinguished from metastatic melanoma, either from a conjunctival
melanoma elsewhere or rarely from a distant cutaneous melanoma.19 The former represents local lymphatic
metastasis and in one study of 52 patients with invasive conjunctival melanomas, 6 exhibited this
phenomenon; five of these patients later developed regional or distant metastases.15 Cutaneous melanomas
which metastasize to conjunctiva typically do so in the setting of widespread dissemination, including
multiple facial lesions, but exceptionally, a single amelanotic conjunctival tumor may be the first evidence
of metastatic spread from a cutaneous melanoma. Other malignancies metastatic to conjunctiva are less
likely to cause diagnostic confusion with melanoma and are extremely rare.20
Primary acquired melanosis (PAM) is a flat, intraepithelial, variably brown pigmentary change in conjunctiva
which primarily is unilateral and affects middle-aged, white individuals. Clinically PAM may wax and wane
in size and pigmentation, although not spontaneously resolve, for an indefinite period. Occasional cases of
PAM sine pigmento have been reported;12,15 these can be difficult to follow clinically and may be
diagnosed only when a malignant melanoma evolves. In general, PAM first affects bulbar conjunctiva but over
a period of years may spread to palpebral conjunctiva, fornices, plica, cornea and lacrimal drainage system.
For histopathologic evaluation, small lesions are biopsied in their entirety while larger lesions are
sampled in multiple areas.
Microscopically, PAM represents a proliferation of melanocytes normally present in conjunctival epithelium.
Based on pattern of growth and the presence or absence of cytologic atypia, PAM can be classified as PAM
with atypia or PAM without atypia. This is an important prognostic decision because studies have shown that
PAM without atypia rarely progresses to melanoma while approximately 50% of PAM with atypia eventuates in
melanoma.21 Thus PAM without atypia may be followed clinically while PAM with atypia requires further
therapy. Also, PAM without atypia rarely recurs but PAM with atypia can recur if it has been incompletely
removed or if it involves the cornea. Treatment of large foci of PAM with atypia can pose problems since
substantial areas of conjunctiva cannot be excised or ablated without producing a dry eye which can lead to
infections, corneal ulcer and ultimately loss of vision. Surgical excision with or without cryotherapy,
topical chemotherapy (Mitomycin C), conjunctival autografts, or amniotic membrane transplantation has been
tried with varying degrees of success. With regard to Mitomycin C, pathologists need to be aware of its
persistent effects in post treatment biopsies - variable epithelial atrophy and thinning, dyskeratosis,
keratinization, nuclear pyknosis or enlargement, chromatin smudging, cytoplasmic eosinophilia, single cell
necrosis and subepithelial inflammation - as these can cause confusion with residual disease or recurrence.22,23
PAM without atypia consists of an increased number of melanocytes which do not have prominent nucleoli or
hyperchromasia and which are confined to the basal layer of the conjunctival epithelium. The melanocytes
are typically polyhedral cells with scant cytoplasm and small round nuclei.21 PAM with atypia must be
assessed with regard to pattern of epithelial involvement and the type of melanocytic cells.
Intraepithelial involvement by melanocytic cells may occur along the basilar layer, as basilar nests, nests
throughout the epithelium, single cells throughout the epithelium (pagetoid spread) and almost total
replacement of the epithelium. It has been shown that 75% of PAM with a non-basal intraepithelial
arrangement of atypical cells have resulted in melanoma.21 Atypical melanocytic cells may be small
polyhedral cells, spindle cells, large dendritiform melanocytes or epithelioid cells. The latter are
particularly significant since 90% of PAM with epithelioid cells have developed melanomas.21 The mean
time from clinical detection of pigment to melanoma occurring is approximately 7 years while the mean time
from biopsy with diagnosis of PAM with atypia to melanoma is 2.5 years.21
Clinical differential diagnosis of PAM includes secondary acquired melanosis which encompasses pigmentation
developing in conjunctival inflammation, infection and systemic diseases (e.g. Addison's disease) as well
as complexion-associated pigmentation ("racial" pigmentation). This occurs, generally bilaterally with
forniceal sparing, in individuals with dark complexions. Conjunctival pigmented lesions, termed
conjunctival lentigines by dermatologists, can be seen in two familial lentiginosis syndromes: in
approximately one quarter of patients with Carney's complex, sometimes in association with eyelid myxomas,
and in Peutz-Jeghers syndrome. There is no increased incidence of primary acquired melanosis in the
dysplastic nevus syndrome.24
Histologic difficulties with PAM include distinguishing it from invasive melanoma, from pagetoid spread of
carcinoma and from junctional nevi. Conjunctival epithelium may be tangentially sectioned (particularly if
the biopsy was not fixed flat), may appear polypoid in plica and fornices, or may exist as conjunctival
cysts or downward epithelial proliferations; PAM with atypia affecting such epithelium may give the false
impression of melanocytic cells involving substantia propria. Sebaceous carcinoma may spread in a pagetoid
fashion within conjunctival epithelium and may be confused with PAM with atypia. Junctional nevi occur in
childhood while PAM is found in middle-aged individuals. Therefore a melanocytic lesion resembling a
junctional nevus in someone beyond thirty years of age is almost always PAM. Also, nevi do not show
pagetoid spread and almost never extend on to cornea, in contrast to PAM.
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