Primary acquired melanosis (PAM) is an acquired conjunctival lesion characterized by patchy black-brown pigmentation due to abnormal proliferation of melanocytes. It can occur anywhere on the conjunctiva. Unlike nevus, it is a flat pigmented lesion without elevation.
In addition to primary acquired melanosis without known cause, pigmentation may also occur due to chronic inflammation such as allergic diseases, irritation from cosmetics or chemicals, or after surgery (secondary melanosis). PAM refers to primary lesions without these secondary causes.
PAM itself is not necessarily malignant. PAM without atypia is benign with low risk of malignant transformation. On the other hand, PAM with atypia is a precancerous lesion that transforms into conjunctival malignant melanoma in about 25-50% of cases. It is important to confirm the presence of atypia by biopsy.
PAM is broadly classified into two groups based on the presence or absence of histological atypia. Recently, it is also called conjunctival melanocytic intraepithelial lesion (C-MIL) and has been reorganized in the WHO classification 3).
| PAM classification | Corresponding C-MIL | Risk of malignant transformation |
|---|---|---|
| PAM without atypia | Low-grade C-MIL | Low (rarely transforms) |
| PAM with atypia, mild | Intermediate-grade C-MIL | Moderate |
| PAM with atypia, severe | High-grade C-MIL / melanoma in situ | Approximately 25–50% |
A C-MIN score of 5 or higher is considered melanoma in situ and requires more aggressive treatment2).
It accounts for 11% of all conjunctival lesions2). It most commonly occurs in middle-aged and older Caucasians and is almost always unilateral. Since approximately 60–75% of conjunctival malignant melanomas arise from PAM, it is particularly important as a precancerous lesion. The incidence is lower in East Asians compared to Caucasians.
A characteristic course of PAM is the “wax and wane” phenomenon, where pigmentation repeatedly increases and decreases 2). Even if the pigmentation becomes lighter or disappears, the lesion itself has not disappeared. Overlooking this point may lead to the mistaken belief that the condition has healed, resulting in neglect of follow-up.
No. PAM shows a waxing and waning pattern. Even if the pigmentation becomes lighter, the lesion has not disappeared, and pathological lesions often remain. The same applies after mitomycin C treatment; after pigmentation disappears, mapping biopsy is necessary to confirm eradication.
If the following changes occur, promptly consult a specialist and consider biopsy:
The direct cause of PAM is not clear, but it is based on abnormal proliferation of melanocytes within the epithelium. Unlike secondary melanosis (described below), it occurs without a specific external cause.
Pigmented lesions with the following triggers are not PAM but are classified as secondary melanosis:
Since the conjunctiva is directly exposed to ultraviolet (UV) light, UV exposure is considered a risk factor. The reason it is more common in Caucasians is that they have less melanin, resulting in a weaker UV filter effect.
First, the morphology, color, borders, and presence of elevation of the lesion are evaluated in detail using a slit-lamp microscope. Eyelid eversion must always be performed to examine the fornix and palpebral conjunctiva.
Anterior segment OCT can evaluate the depth of the lesion and whether it is confined to the epithelium. It is visualized as a hyperreflective lesion.
Since PAM shows “wax and wane,” regular photographic documentation from the initial visit is the basis for follow-up. It objectively tracks changes in pigment distribution.
This is the gold standard for definitive diagnosis of PAM and determining treatment strategy.
A map biopsy is a biopsy technique in which pigmented lesions of the conjunctiva are systematically collected from multiple sites. By mapping the distribution of atypia throughout the lesion, the extent and degree of atypia can be accurately determined. The presence and degree of atypia are the most important factors in deciding the treatment strategy (observation or excision).
Evaluation of markers by immunohistochemistry is useful for definitive diagnosis and differentiation between benign and malignant lesions3).
| Marker | Significance | Notes |
|---|---|---|
| PRAME | Most powerful marker of malignancy | Positive in PAM with atypia / melanoma1) |
| Ki-67 | Proliferation index | High value suggests malignancy |
| p16 | Tumor suppressor | Loss suggests malignancy1) |
| S100, SOX10, HMB45 | Common melanocytic markers | Cannot distinguish benign from malignant |
Treatment strategy for PAM is determined by the presence and degree of histological atypia.
PAM without atypia
Strategy: Observation.
Content: Continue regular slit-lamp microscopy and photographic documentation.
Frequency: Follow-up every 3 to 6 months is recommended.
Consideration for excision: If there are cosmetic issues or changes during follow-up, perform excision and pathological examination.
PAM with atypia
Strategy: Active treatment intervention.
Mild atypia: Excision ± cryotherapy.
Severe atypia (melanoma in situ): Wide excision + cryotherapy + MMC topical therapy.
Common: Regular follow-up for all cases (early detection of malignant transformation).
Topical chemotherapy is performed for histologically proven PAM with atypia.
As an alternative to mitomycin C, topical administration of IFNα-2b is used. Its advantage over MMC is that it does not cause limbal stem cell deficiency.
Not necessarily. For PAM without atypia, regular observation is the basic approach. On the other hand, PAM with atypia is a precancerous lesion, so active treatment such as excision or topical chemotherapy is recommended. The standard procedure is to determine the treatment plan after confirming the presence or absence of atypia by biopsy.
The essence of PAM is abnormal proliferation of melanocytes within the conjunctival epithelium. The stage without invasion into the subepithelial tissue is called “intraepithelial” lesion, and when invasion occurs, it is diagnosed as malignant melanoma.
In modern concepts, PAM is understood as a spectrum called C-MIL (conjunctival melanocytic intraepithelial lesion) 3).
Benign melanosis → low-grade C-MIL → high-grade C-MIL → melanoma in situ → invasive melanoma
This spectrum exists, and PAM with atypia corresponds to intermediate to high-grade C-MIL.
Malignant transformation from PAM with atypia has been reported to involve TERT promoter mutation (c.-124C>T) 2). This mutation leads to activation of telomerase reverse transcriptase, promoting cell immortalization and malignant transformation. It has also been associated with high tumor mutational burden.
PAM accounts for approximately 60–75% of the origins of conjunctival malignant melanoma. This indicates that if PAM is left untreated or overlooked, it can progress to invasive malignant melanoma, underscoring the importance of early diagnosis and appropriate management.
International standardization of the C-MIL classification system and C-MIN scoring is progressing 3). This is expected to improve diagnostic reproducibility among pathologists and enhance the accuracy of treatment selection based on the degree of atypia.
Immunohistochemistry panels combining markers such as PRAME, p16, and Ki-67 are enabling reclassification of lesions previously considered “indeterminate” 1). This may allow more accurate determination of the need and timing for biopsy.
Non-invasive monitoring techniques using anterior segment OCT and in vivo confocal microscopy are being developed. They are expected to serve as means to evaluate PAM progression in real time without biopsy.
Eder et al. (2024) showed that in 5 cases of atypical conjunctival melanocytic proliferative lesions that were difficult to evaluate by routine histology, reclassification was possible using a combination of immunohistochemistry panel (PRAME, p16, HMB45, Ki-67, etc.) and FISH analysis 1). The potential of microRNA profiling for differentiating benign from malignant lesions has also been suggested.
Research is advancing on molecular profiling, including TERT promoter mutations, to individually predict the risk of transformation from PAM to melanoma 2). In the future, personalized treatment strategies based on molecular risk assessment are expected to become possible.
