Primary acquired melanosis of the conjunctiva has been the subject of changing concepts and controversy with regard to demographics, terminology, clinical definition, histopathologic definition, incidence, natural course, and management.1–29
This study was designed to address some of these issues.
Concerning demographics, PAM is mainly a condition of adult Caucasians, with a median age at diagnosis of 56 years (). However, in this series, classic PAM was seen in patients as young as 15 years of age. We have no explanation for the slight preponderance of females (62%). PAM does not occur exclusively in Caucasians. Of our 276 patients, 4% were non-Caucasian. In dark-skinned individuals, PAM must be differentiated from racial melanosis, which is usually bilateral and symmetrical.1
We have treated several African American patients who presented with aggressive conjunctival melanoma that had clearly arisen from PAM (unpublished observations). PAM is generally considered to be a unilateral disease. The finding that 13% of cases in this series were bilateral could partly be related to the fact that patients underwent a meticulous examination of both eyes, and small foci of PAM in the fellow eye were detected, recorded, and coded.
The terminology related to PAM has been controversial. Historically, Reese5
called the condition precancerous
objected to that term, since many cases had benign clinical and histopathologic features. He called it acquired
melanosis and divided it into stage I (benign acquired melanosis) and stage II (cancerous acquired melanosis). The World Health Organization subsequently adopted the term primary acquired melanosis
Folberg and associates4,8–12
used that term in several publications and established histopathologic criteria to predict which cases are more likely to progress to melanoma. Ackerman,13
a dermatopathologist, has challenged this terminology and believes that PAM should be called melanoma-in-situ
, similar to lentigo maligna of the skin. The term melanoma-in-situ
could possibly apply to PAM with severe atypia, which comprises 21% of biopsied lesions () and 8% of all cases of PAM seen in a clinical practice ( and ), but certainly not to all cases of PAM. We believe that the term melanoma-in-situ
could unnecessarily alarm both clinicians and patients, particularly since many PAM lesions have little propensity to evolve into melanoma. The term PAM
seems acceptable, since the condition is primary, acquired, and generally pigmented.
To date, there has not been a clear clinical definition of PAM. In this study, we chose to be inclusive and define PAM clinically as any acquired flat, noncystic pigmented lesion of the conjunctiva, cornea, or caruncle ( through ) that lacks the typical features of localized nevus or racial melanosis.1
Although the differentiation of these 2 conditions from PAM is straightforward in most instances, there are occasional cases where this distinction is challenging both clinically and histopathologically. The histopathologic definition of PAM is provided in the “Methods” section and is derived from the AFIP definitions.7–12
In some instances it may be extremely difficult to determine histopathologically if low-grade melanocytic hyperplasia is present or whether conjunctival pigmentation reflects melanin pigment within squamous epithelial cells. Immunohistochemical stains for melanocytic and epithelial markers can help to make this distinction in challenging cases. On the other hand, the results of this study suggest that this distinction actually is of little significance clinically because neither PAM without atypia nor PAM with mild atypia progresses to melanoma.
FIGURE 1 Primary acquired melanosis (PAM) with varying extent of involvement. A, PAM involving less than 1 clock hour of bulbar conjunctiva. B, PAM involving 4 clock hours of conjunctiva with slight corneal extension. C, PAM involving more than 6 clock hours of (more ...)
FIGURE 4 Transformation of primary acquired melanosis (PAM) into melanoma. A, At initial presentation, flat PAM was detected on the bulbar and forniceal conjunctiva. The lesion was removed and cryotherapy performed. It proved to be PAM with atypia. B, The patient (more ...)
The reported incidence of PAM varies greatly in different clinical settings. Motivated by the AFIP reports that recommended biopsy for most cases, Gloor and Alexandrakis14
attempted to establish the true incidence by screening all Caucasian patients over age 10 years who were referred to a cornea clinic for unrelated conditions. Using minimally stringent criteria for diagnosis, they concluded that PAM was present in 36% of adult Caucasians. They emphasized that many PAM lesions were small and did not require surgical biopsy, since the vast majority were not destined to transform into melanoma. In a report of 1643 conjunctival lesions from an ocular oncology practice, PAM comprised 11% of all conjunctival tumors and pseudotumors and 21% of pigmented conjunctival lesions.2
Nevus and melanoma were more common than PAM, reflecting referral bias for these more obvious and more suspicious conditions. Based on our experience and review of the literature, we believe the incidence of PAM actually is much higher than generally believed, because many lesions that meet the diagnostic criteria for PAM never come to clinical attention and may even be ignored by the patient and the physician.
The clinical features of PAM were elucidated in this study (). Most patients were asymptomatic or noticed only the patch of pigment. The extent of PAM was 3 clock hours or less in 76% and more than 3 clock hours in 23%. Corneal involvement with PAM was noted in 23%. The extent of PAM is best determined by making large detailed drawings during meticulous preoperative slit-lamp examination. Careful preoperative assessment is important because the precise extent of PAM is often less obvious in photographs or during intraoperative examination with the operating microscope. Accurate information concerning the extent of the lesion is critical in planning therapeutic strategies.
The natural course of PAM with regard to progression, recurrence, and evolution to melanoma has not been previously elucidated. In the frequently cited histopathologic series from the AFIP, the investigators reported that 32% of 41 eyes with PAM progressed to melanoma. If the PAM showed microscopic evidence of atypia, progression to melanoma occurred in 46%, but if there was no atypia, the chances were nil.8–11
The study included mainly cases that were referred to the AFIP for histopathologic diagnosis. Hence, they generally were larger lesions with more bothersome histopathologic features. The investigators concluded that biopsy or removal of all PAM lesions was warranted. However, that study did not include potential cases in the general population that were not subjected to biopsy.
Neither the studies of Folberg and associates7–11
nor the study of Gloor and Alexandrakis14
addressed the natural course of PAM following the initial clinical diagnosis. In this study, we attempted to address that question. All patients in our series had a lesion that appeared sufficiently suspicious to the referring ophthalmologist to prompt consultation at our ocular oncology center. Hence, this study presumably provides a somewhat more reliable estimate of the true risk of the progression of PAM to melanoma. However, this study also has selection bias, because lesions that are more suspicious clinically are more likely to be directed to a tertiary referral center.
The majority of PAM lesions in this series were small, allowing for observation (62%), and only 21% of these observed lesions showed enlargement during the course of follow-up ( and ). Hence, it appears that many small, bland lesions can cautiously be followed and are likely to remain stable and require no treatment.
Of the larger lesions that were managed by initial biopsy and cryotherapy (), 27% recurred and 3% eventually evolved to melanoma. The mean interval from initial surgery to recurrence was 19 months, and the mean interval to development of melanoma was 39 months. The latter observations stress the need for periodic long-term follow-up of all patients who have had observation or excision of PAM, particularly if histopathologic studies reveal atypia.
Some differences were found in the AFIP series and the WEI series with regard to PAM progression to melanoma (). In the WEI series that included all cases (observed and biopsied), the incidence of progression to melanoma was 4%. In comparing only cases with available histopathology, overall progression to melanoma was 32% in the AFIP series and 3% in the WEI series. Both studies found no progression to melanoma if there was no cytologic atypia.
With regard to the assessment of the effect of the degree of cellular atypia and progression to melanoma, the current WEI series attempted to use the same criteria for atypia and severe atypia that were used in the AFIP series. The lower incidence of progression to melanoma in the WEI series probably reflects a variety of factors, including the probable referral of cases with more severe histopathologic features to the AFIP in contradistinction to cases with no atypia or mild atypia. Furthermore, patients in the WEI clinical series were followed up periodically by the same group of experienced ocular oncologists, and residual or recurrent PAM was treated promptly before it progressed to a more advanced stage.
In the WEI series, Kaplan-Meier estimates showed that the rate of PAM enlargement in the initially observed group was 26% at 5 years, 35% at 10 years, and 43% at 15 years. The estimates for evolution into melanoma were 8% at 5 years, 12% at 10 years, and 21% at 15 years (). These findings show the slow but potentially malignant progression of PAM. In the initially biopsied group, Kaplan-Meier estimates showed that the rate of PAM recurrence was 52% at 5 years and 58% at 10 and 15 years, and the rate of melanoma development was 5% at 5 years and 11% at 10 and 15 years. Despite apparent resolution of PAM on clinical inspection after meticulous treatment by excisional or incisional biopsy followed by cryotherapy, patients should be followed closely, because PAM recurrence with melanoma development can pose a serious threat.
The greater the extent of PAM on the surface of the globe, the greater the risk for PAM recurrence following biopsy and the greater the risk for melanoma (RR 1.70) development ( and ). For example, in patients who were observed, PAM involving 4 clock hours carried a 6.8 times greater risk for melanoma development than PAM of only 1 clock hour. If PAM involved 12 clock hours, the risk for melanoma development was 20.4 times greater than with a 1-clock-hour lesion.
Our philosophy for PAM management is based on long-term clinical experience and the results of this study. All patients with PAM (or any conjunctival tumor) should have a large detailed drawing performed in the office using slit-lamp biomicroscopy. The surgical plan is made on the basis of this drawing. If PAM is confined to the bulbar conjunctiva and is less than 1 clock hour in extent, we generally recommend observation once or twice a year unless the patient requests excision. In this analysis, 62% of cases were managed with observation, the majority of which were small lesions ( and ). If PAM is 1 to 2 clock hours in extent, the patient is counseled and offered the options of observation or treatment with the advice that excision is probably preferable. If the lesion is greater than 2 clock hours in extent, we generally recommend complete surgical excision and cryotherapy for those up to 5 clock hours and wide incisional biopsy plus cryotherapy for larger lesions.
For more diffuse PAM, our approach is to perform small conjunctival map biopsies in each quadrant and double freeze thaw cryotherapy to all remaining areas of pigment.1,18–20
When extensive conjunctival tissue is removed and primary closure is difficult, amniotic membrane or buccal mucosal graft is employed.25,26
Corneal PAM is managed with either alcohol epitheliectomy or topical mitomycin C. Depending on subsequent clinical and histopathologic findings, supplemental treatment for residual or recurrent PAM might include in-office cryotherapy or topical chemotherapy using mitomycin C.20–22
Plaque brachytherapy can be used in selected instances.1
In conclusion, PAM appears to be more common than generally believed. Small foci of PAM (<1 clock hour) generally remain stable, but larger lesions carry greater potential for evolution into invasive melanoma. PAM without atypia and PAM with mild atypia carry almost no risk for progression into melanoma, whereas PAM with severe atypia shows 13% transformation to melanoma. Cautious, long-term follow-up is advised for all patients with PAM.