In a previous issue of this journal an introduction to this series of articles on primary acquired melanosis of the conjunctiva was published. In it, the structure and content of this work is given and the motivation of the authors is explained.  The table of contents of the series is as follows:
Chapter 1: Anatomy and histology of the eyelid and conjunctiva
Chapter 2: History of melanoma in situ
Chapter 3: History of primary acquired melanosis
Chapter 4: Atlas of lesions diagnosed as primary acquired melanosis
Chapter 5: Examples from our own experience
Chapters 1 and 2 of this series, as well as parts 1 and 2 of chapter 3, appeared in preceding issues of this journal. [2,3,4,5] The following contribution represents part 3, the last part of chapter 3 of this work. Chapter 4 and 5 and the Afterword will appear in following issues of the journal.
Almut Böer-Auer, M.D.
Current concepts (2000-present)
In 2000, Demirci and colleagues reported on 12 patients with both conjunctival melanoma and primary acquired melanosis who were treated with mitomycin C.  Seven patients received mitomycin C only and 5 patients were managed by the drug along with excision and cryotherapy. In five patients, subconjunctival recurrences developed. Two patients underwent and three were treated conservatively. Regression was seen in 11 patients.
The results of a study on immunohistochemistry in conjunctival melanosis undertaken by Sahara et al. appeared in 2001.  The authors investigated immunoreactivity with S100, NKI/C3, and HMB45 of melanocytic lesions of the conjunctiva. Twenty melanomas arose in primary acquired melanosis and 22 melanomas originated in the absence of any pre-existing primary acquired melanosis. There were seven cases of primary acquired melanosis with atypia and nine cases of primary acquired melanosis without atypia. Also tested for immunoreactivity were 35 conjunctival nevi and four examples of racial melanosis. The coworkers found that S100 and NKI/C3 were expressed similarly in all lesions, with at least one of those markers being positive in 100% of the lesions examined and that HMB45 was expressed in 72.7% of primary melanomas and 85% of melanomas that appeared in the context of primary acquired melanosis; 42.8% of primary acquired melanosis with atypia expressed HMB45, whereas only 11.1% of cases of primary acquired melanosis without atypia expressed it and 8.5% of nevi. Racial melanosis did not express HMB45. The authors concluded that S100 and NKI/C3 are useful markers for assessing the extent of melanocytic lesions on the conjunctiva and that HMB45 immunoreactivity could assist in distinguishing of benign from malignant lesions of the conjunctiva, particularly those associated with primary acquired melanosis. No attention was given by the authors to either terminology or biologic nature of primary acquired melanosis was.
In 2002, Tuomaala et al. engaged the subject of frequency and outcome of conjunctival melanomas that first demonstrated invasive growth on the cornea without evidence of anything other on the conjunctiva than primary acquired melanosis.  They determined that 4 of 85 patients had “invasive tumors” confined strictly to the cornea. In three instances, the melanomas had been affiliated with primary acquired melanosis. The authors emphasized that none of the tumors recurred after local excision, even though two patients developed lesions of primary acquired melanosis at the very same site. No metastases were observed to have appeared during a median follow-up of 2 years and 5 months (range, 1 year 8 months-7 years 10 months). The authors were compelled to conclude that primary melanomas of the conjunctiva can grow on the cornea in the absence of anything other than acquired melanosis and they suggested the term “corneally displaced malignant conjunctival melanoma” for such lesions. The idea that acquired melanosis could be melanoma in situ in continuity with invasive melanoma of the conjunctiva and cornea did not seem to occur to them, even though they admitted that invasive melanoma on the cornea most likely developed from the adjacent acquired melanosis.
Pitz, in 2002, studied intermediate filament (IF) expression in 34 melanocytic tumors of the conjunctiva, 16 nevi, nine specimens of primary acquired melanosis (eight with and one without atypia), and nine melanomas. The pattern of expression differed from that seen in melanocytic tumors present on other body sites (including uveal melanomas) in that it expressed neither cytokeratins nor peripherin.  Whereas no significant differences could be demonstrated between benign and malignant melanocytic lesions, the “expression profile” seemed to support the conclusion that pigmented lesions of the conjunctiva differed from those on other surfaces of the body, as well as from intraocular melanomas.
In 2002, Rodriguez-Sains commented on the issue of pigmented conjunctival lesions in these words:
“The term benign melanosis is used to describe those pigmented conjunctival conditions that histopathologically show increased deposition of melanin granules in the basal layer of the conjunctiva; in essence this is what in dermatopathology would be termed a freckle. This condition is very typical in Blacks and darkly pigmented Caucasians, and is either secondary to chronic inflammation or irritation or may indeed be idiopathic. The lesions are flat and stationary., . . . Benign melanosis is seen exclusively on exposed bulbar conjunctiva . . . ”  About primary acquired melanosis, he opined thus: “Primary acquired melanosis (PAM) is used to describe irregular hyperpigmentation of the bulbar conjunctiva, occurring usually near the limbus. The pigment is commonly duffuse, tan to brown, almost always unilateral ad multifocal . . . In primary acquired melanosis one sees hyperpigmentation of the conjunctiva, which is diffuse with a course that waxes and wanes over many years. A horizontal growth phase exits for these excessive, at times atypical melanocytes that lasts many years, leading to a vertical growth phase at which the tumor acquires a potential for metastasis.” 
The author referred to Zimmerman as being the first one to suggest that the phrase“benign acquired melanosis” be applied to the horizontal growth phase and “malignant acquired melanosis” be employed for the vertical invasive phase. He also alluded to the work of Folberg et al., who had suggested that primary acquired melanosis should be devided into primary acquired melanosis with atypia with a 50% chance of developing melanoma and primary acquired melanosis without atypia unassociated with any risk for developing melanoma. Rodriguez-Sains remarked stated, however, that it had yet to be shown how many examples of so-called primary acquired melanosis without atypia go on to become primary acquired melanosis with atypia, he emphasizing that it is at times exceedingly difficult to classify junctional melanocytic lesions as benign, malignant, or premalignant. He invoked Ackerman et al. as the one who asserted that the term primary acquired melanosis be replaced by melanoma in situ and he quoted Jakobiec et al. who demonstrated that the clinical expression of primary acquired melanosis without atypia cannot be differentiated from that of primary acquired melanosis with atypia. Rodriguez-Sains concluded that “any acquired pigmented lesion of the conjunctiva in an adult should be biopsied” and he acknowledged straightforwardly “I therefore am in agreement with Ackerman who believes that all primary acquired melanosis is indeed melanoma in situ. It makes more sense to me to treat the melanoma in its pre-invasive stage, before the tumor acquires metastatic potential.”
In 2002, Lommatzsch and Werschnik  commented on melanoma of the conjunctiva having reviewed the literature pertinent to it. This is what they said:
“Conjunctival melanoma arises from primary acquired melanosis, from a preexisting nevus or “de novo” without any precursor at all.” About primary acquired melanosis the authors wrote (translated from the German): “The primary acquired melanosis (PAM) is an unilateral change characterized by diffuse mottled pigmentation that may vary in intensity. . . . it simulates ethnically caused pigmentation that ususally is bilateral. . . . Rarely does a melanoma develop from primary acquired melanosis without atypia, whereas primary acquired melanosis with cytologic atypia in 50% of instances may develop into melanoma. There is no clinical method by which primary acquired melanosis with atypia can be differentiated from primary acquired melanosis without atypia. . . . Biopsies from different sites of the lesion are required.” About cytopathologic criteria for identification of “malignant melanocytes” the co-workers opined thus: “Malignant melanocytes are typified by atypia (anisocytosis, nuclea polymorphism, nuclear polychromasia) and pleomorphism of cells, nuclei, and nucleoli. Mitoses are seen rarely.” They stated, too, that “Sometimes nest formation of melanoma cells is seen in deep areas of a tumor which indicates that the lesion developed from a melanocytic nevus. When the epithelium around a melanoma shows melanoma in situ or primary acquired melanosis (PAM) with atypia . . . then it can be assumed that PAM was the precursor of the melanoma.”
Shields and Shields addressed the matter of pigmented lesions of the conjunctiva in a review in 2004 that included all aspects of tumor ophthalmology, i.e., beginning with anatomy, diagnostic procedures, and character of various tumors.  About primary acquired melanosis they commented as follows:
“Primary acquired melanosis is an important benign conjunctival pigmented condition that can give rise to conjunctival melanoma. In contrast to conjunctival nevus, it is acquired in middle ages and appears diffuse, patchy, flat, and noncystic. In contrast to ocular melanocytosis, the pigment is acquired, located within the conjunctiva, and appears brown, not grey, in color. The pigmentation can wax and wane over time. In contrast to racial melanosis, primary acquired melanosis generally is found in fair-skinned individuals as an unilateral patchy condition. Histopathologically, primary acquired melanosis is characterized by the presence of abnormal melanocytes near the basal layer of the epithelium. Pathologists should attempt to classify the melanocytes as having atypia or no atypia based on nuclear features and growth pattern. primary acquired melanosis with atypia carries a nearly 50% risk for ultimate evolution into malignant melanoma whereas primary acquired melanosis without atypia carries nearly 0% risk for melanoma development . . . .” About conjunctival melanoma the authors wrote this: “Malignant melanoma of the conjunctiva most commonly arises from primary acquired melanosis, but it also can arise from a preexisting nevus or de novo. It typically arises in adults at a median age of 62 years, but rare cases of conjunctival melanoma in children have been recognized. . . . Histopathologically, conjunctival melanoma is composed of variably pigmented malignant melanocytes within the conjunctival stroma. There may be microscopic evidence of primary acquired melanosis or a nevus . . . “
In preparation of a review article on management of melanoma of the conjunctiva in 2004, Brownstein went through more than 100 articles about melanoma on that site.  He stated in his introduction that “Conjunctival melanoma is a potentially lethal neoplasm, with an average 10-year mortality rate of 30%.” and went on to say that “Recognition of their precursor lesions at an early stage is important.” Management recommended by him included the following: “Surgical excision with adjuvant cryotherapy and alcohol corneal epithelialectomy is usually effective in eradicating most of these lesions. Extensive cases of flat primary acquired melanosis with atypia may be managed with Mitomycin C.” About benign pigmented lesions of the conjunctiva, Brownstein made these remarks:
“The predominant benign conjunctival melanocytic lesions are composed of a variety of nevi and melanoses that also have a predilection for the perilimbal bulbar conjunctiva. Nevi are believed to be congenital lesions that are generally unilateral. . . . Dark brown melanotic pigmentation is normally observed in the conjunctiva,a condition referred to as racial melanosis, which is especially evident bilaterally from an early age in more heavily pigmented races. This condition is usually in the form of an excess production of melanin or hyperpigmentation by the melanocytes (forming an ephelis) or benign proliferation of melanocytes (forming a benign lentigo)” About melanosis, the author made these specific comments: “The terminology associated with melanosis is controversial, especially when melanosis is unilateral and acquired, in that this lesion can be a precursor of invasive melanoma. Some authorities have referred to this unilateral acquired pigmentation as precancerous melanosis, which in the past has led to inappropriate aggressive therapy – frequently exenteration (surgical excision of the orbital contents, including the eyes and eyelids). As a result, others have referred to these lesions as benign acquired melanosis, but this terminology had caused concern that the malignant potential of this condition may be overlooked. Because these lesions may show variable histological findings, the World Health Organization proposed the term primary acquired melanosis (PAM) with or without atypia for these lesions (see below).” In regard to the relationship of melanoma and primary acquired melanosis, the author summarized the data thus: “Approximately 75% of these neoplasms [melanomas] arise in an area of primary acquired melanosis with atypia that requires histopathologic examination for this diagnosis. When thickening of the conjunctiva is present in an area of primary acquired melanosis, the development of invasive malignant melanoma is a primary concern (Fig 3), although an inflammatory reaction to the primary acquired melanosis also may produce a similar clinical picture.” In the same paragraph Brownstein made these bewildering statements: “When primary acquired melanosis occurs as a bilateral condition, it is most often caused by histologically benign racial pigmentation (racial melanosis) that generally occurs in the first decade of life. It is less frequently associated with systemic conditions such as Addison’s disease”In regard to histopathologic features of primary acquired melanosis, the author averred that “Unilateral acquired primary acquired melanosis is more likely due to a proliferation of atypical melanocytes (the histological equivalent of atypical melanocytic hyperplasia, or melanoma in situ in dermatopathology) that subsequently can give rise to an invasive malignant melanoma.” And he proceeded thus: “While primary acquired melanosis without atypia does not progress to a malignant melanoma, almost 50% of cases of primary acquired melanosis with atypia result in an invasive malignant melanoma that may be multifocal within a median of 2.5 years from the time of biopsy for primary acquired melanosis with atypia until progression to melanoma.” About primary acquired melanosis without atypia he set forth these observations: “primary acquired melanosis without atypia is a frequent clinical finding that is often unilateral. In determining which lesions should be biopsied, clinical judgment based on history, clinical features, and evidence of growth must be used. Thirty six percent of the white population show some degree of primary acquired melanosis that may exhibit slow growth, especially in relation to puberty or pregnancy. Most authorities in ocular oncology advocate that it is safest to biopsy all primary acquired melanosis lesions showing any notable growth.”
Groh and co-workers, in 2003, reported on 13 patients with melanoma of the conjunctiva associated with primary acquired melanosis and who were treated with local chemotherapy following on incomplete excision of the tumors.  Regression of the tumor was observed in all cases after completion of the therapy. In three patients, a recurrence of the disease was observed, the eyelid being involved by the process. The authors conclude that “Prognosis of conjunctival malignant melanomas involving the lid margin (pT4) is poor.”
Tosi et al., in 2004, investigated by digital surface microscopy (DSM) pigmented lesions of the conjunctiva.  They studied 39 such lesions, among them being melanocytic nevi, primary acquired melanosis, and melanomas. Thirty parameters were assessed and organized into four categories: geometry, color, texture, and islands of color. By the recognition of change of pattern in repeated images recorded, the coworkers were able to identify one melanoma that developed in a lesion diagnosed previously as primary acquired melanosis. In addition, they put forth criteria for differentiation of benign pigmented lesions from melanoma and advised that digital surface microscopy simplified greatly follow-up of pigmented lesions of the conjunctiva.
Tatla and coworkers, in 2005, reported on 12 patients who presented themselves with metastases to regional lymph nodes after local treatment for conjunctival melanoma had failed.  Six of those 12 had primary tumors of the bulbar conjunctiva; the other tumors arose in the palpebral conjunctiva, caruncle, or fornix. Eleven melanomas were said to have derived from primary acquired melanosis. Eleven patients died from the effects of metastatic melanoma.
In 2006, Parra and colleagues shared their experience with nine melanocytic lesions associated with a pterygium.  Five lesions showed melanocytic lentiginous hyperplasia characterized by a linear melanocytic proliferation restricted to the basilar region of the epithelium that consisted of small melanocytes, occasionally dendritic, sometimes polyhedral, with an inconspicuous cytoplasm, small, round nuclei, and small or absent nucleoli. Those lesions were all diagnosed by them as primary acquired melanosis without atypia. In two patients, the authors took note of widespread melanocytic proliferation within the epithelium marked by melanocytes disposed both as solitary units and in nests, at all levels of the epithelium (“pagetoid spread”). The nests were said to be irregular in shape and size. Melanocytes themselves exhibited various shapes that ranged from small polyhedral to epithelioid with hyperchromatic, large, and pleomorphic nuclei. So-called “mitotic activity” was virtually absent. The surface epithelium was intact and no ulceration was observed. The findings were deemed by the authors to be primary acquired melanosis with atypia indicating thereby an increased “risk of developing melanoma.” They referred to the Folberg classification even though they admitted that “For generations, primary acquired melanosis has been a matter of controversy with ophthalmologists, ophthalmic pathologists and dermatopathologists, who have suggested different approaches to classify conjunctival pigmented lesions.”
A study utilizing in vivo confocal microscopy of pigmented lesions of the conjunctiva was undertaken by Messmer et al. in 2006 in an attempt to forge criteria for pigmented lesions of the conjunctiva by way of correlation with excisional specimens that were examined by histology and immunohistochemistry.  The coworkers observed that primary acquired melanosis with atypia, as well as melanomas, presented themselves with hyperreflective granules throughout the epithelium that differed only in size. In primary acquired melanosis without atypia and complexion-associated melanosis, the hyperreflective granules were confined to the basal layer of the epithelium. The authors concluded that “High correlations were found between in vivo confocal microscopy … and histology in the diagnosis of pigmented conjunctival lesions.”
Keijser et al, also in 2006, examined 294 smears from 182 patients with pigmented lesions of the conjunctiva and attempted to predict from the cytopathology of melanocytes in smears whether a particular pigmented lesion of the conjunctiva is melanoma or not. They correlated the cytologic features in smears with the results of histological examination of excisional specimens taken within 6 months of follow up. Smears were classified by them according to the following categories: grade 0 = insufficient material for diagnosis; grade 1 = normal conjunctival cells; grade 2 = melanocytes with mild atypia; grade 3 = melanocytes with moderate atypia, and grade 4 = melanocytes with severe atypia, and they found the sensitivity, specificity, positive predictive value and negative predictive value of exfoliative cytology to be 85%, 78%, 59% and 93%, respectively. The authors commented that “exfoliative cytology is a fast, easy and non-invasive technique that may be used in the evaluation of patients with a pigmented conjunctival lesion.”
In 2006, too, Chalasani and colleagues analyzed the role of topical chemotherapy for primary acquired melanosis and melanoma of the conjunctiva and cornea.  They reviewed 22 examples of primary acquired melanosis with atypia and 16 of melanoma of the conjunctiva that had been treated with mitomycin C. By way of introduction, they stated that “Primary acquired melanosis without atypia carries almost zero risk of malignant transformation” and “Primary acquired melanosis with atypia carries an almost 50% risk for eventual transformation into malignant melanoma.” The authors admitted that “any lesion suspicious for primary acquired melanosis with atypia or melanoma requires tissue diagnosis,” the extent of the obligation being defined by them as “excisional biopsy with adequate margins, usually at least 2 mm.” In addition, cryotherapy of margins was recommended as a standard regimen. For larger lesions, other options of treatment, such as brachytherapy, CO2 laser, and exenteration, were mentioned. After presenting their results of a review of the literature on usage of topical chemotherapy in primary acquired melanosis or melanoma of the conjunctiva, they went on to suggest topical mitomycin C as a worthy option for patients whose margins after excision of primary acquired melanosis or melanoma were positive for neoplastic cells.
In the same year, 2006, Pache et al. engaged the matter of expression of progesterone and estrogen receptors, p16, and MIB1-Ki67 in pigmented lesions of the conjunctiva.  They compared 69 conjunctival nevi, 5 examples of primary acquired melanosis, and two melanomas of the conjunctiva. No differences of expression were found among the different lesions.
In 2007, Sugiura et al. scrutinized 29 examples of what they diagnosed as primary acquired melanosis with atypia.  In their introduction, they mentioned that “primary acquired melanosis (PAM) is a clinical term applied to a subset of conjunctival melanoses which comprise a broad group of conditions associated with localized or diffuse macular pigmentation of the conjunctiva,” but admitted that histologic examination is necessary to confirm the clinical impression of primary acquired melanosis. The most recent WHO classification of conjunctival melanocytic lesions was cited by them wherein “primary acquired melanosis without atypia,” typified by epithelial pigmentation with only slight increase in the number of normal-appearing melanocytes and a benign clinical course is differentiated from “primary acquired melanosis with atypia” characterized by increase in density of melanocytes, variable degrees of cytopathologic or architectural atypia, and an increased risk for developing melanoma, which, in turn, is differentiated from “invasive melanoma.” In the classification of the WHO, Sugiura at al. noted properly that there was no mention of the term “melanoma in situ.” Twenty nine examples of pigmented lesions of the conjunctiva in which sections of tissue and “follow up” from 6 months to 12 years were available formed the basis of the study by Sugiura at al.. An attempt was made by them to distinguish between a low-risk and a high-risk group of “primary acquired melanosis with atypia” in which on the basis of morphologic features the risk for developing invasive melanoma could be predicted. Among those features were: more heterogenous architecture, epithelioid cytomorphology, vesicular nuclei, and prominent nucleoli. Of 29 lesions, 20 had recurred locally, 17 had demonstrated “invasion,” 4 lesions had metastasized. In their discussion, the authors mentioned that dermatopathologists (A.B. Ackerman et al. 1991) in the past had advised strongly that the term primary acquired melanosis be abandoned and replaced by melanoma in situ. The authors explained that reluctance in regard to treatment was probably the reason for ophthalmologists not to adopt this proposal, they fearing that it would lead to unnecessary ocular exenteration. Based on their own observations, however, Sugiura et al. agreed that at least lesions that fullfilled their criteria for “high-risk primary acquired melanosis with atypia” should be called melanoma in situ and they proposed that in that particular aspect the WHO classification should be revised in order to convey accurately the biologic nature of the lesion and to enable such patients to be “followed more closely.” They admitted, too, that all patients with primary acquired melanosis with atypia should be treated with the aim of eradication of all atypical cells.
Also in 2007, Keijser and colleagues studied 68 consecutive patients who had a conjunctival melanocytic lesion using biopore membrane impression cytology, as well as with exfoliative cytology, and, in 26 of them, by histopathology.  Twenty-three of 26 biopores and 20 of 24 smears were correlated with histopathologic findings. Biopore cytology gathered a higher number of cells and a greater density compared to exfoliative cytology; interpretation by a histopathologist was easier and faster. The authors acknowledged, however, that sampling of the fornix, caruncula, and of material from the eye of children is difficult with the biopore method and exfoliative cytology seemed to be the better method in those situations.
A retrospective study by Furdova concerned 70 patients with a pigmented lesion of the conjunctiva assessed over the course of a 10-year period.  Of these, 10 were diagnosed as primary acquired melanosis and one as a melanoma. Primary acquired melanosis was considered to be a precursor lesion of melanoma, a condition that required treatment in order to prevent the possibly of a lethal sequela.
Chen et al., sought, in 2007, the most effective dose of mitomycin C (MMC) in the treatment of primary acquired melanosis with atypia and advocated a single four day cycle of 0.02% MMC as being sufficient.  Anandajeya and co-workers, in 2008, also employed mitomycin C in a 56-year-old Caucasian man who had inferotemporal prominent melanotic conjuntival pigmentation in his right eye. Histopathologic evaluation disclosed melanoma of the conjunctiva that arose within primary acquired melanosis associated with atypia. The patient first underwent an incisional biopsy of the conjunctiva followed by two cycles of mitomycin C 0.04% eye drops supplemented by double-freeze thaw cryotherapy to residual loci of PAM. One year after this regimen, no residual conjunctival melanosis was evident, and visual acuity remained stable at 20/30.
Also in 2007, Shields et al addressed the risks for transformation of conjunctival primary acquired melanosis into melanoma. In a retrospective study of 311 cases they found that primary acquired melanosis without atypia or with mild atypia showed no progression et al to melanoma, whereas primary acquired melanosis with severe atypia showed progression to melanoma in 13% of instances. The “follow up” time for some of the patients was just three years. The authors also observed that the greater the extent of primary acquired melanosis in “clock hours,” the greater was the risk for transformation into melanoma.  They provided these definitions relevant to the subject:
“In this study, we chose to be inclusive and define primary acquired melanosis clinically as any acquired flat, noncystic pigmented lesion of the conjunctiva, cornea, or caruncle that lacks the typical features of localized nevus or racial melanosis. Although the differentiation of these 2 conditions from primary acquired melanosis is straightforward in most instances, there are occasional cases where this distinction is challenging both clinically and histopathologically. . . . We defined primary acquired melanosis histopathologically using a slight modification of the criteria employed in previous reports from the Armed Forces Institute of Pathology (AFIP). Primary acquired melanosis without atypia was defined as pigmentation of the conjunctival epithelium with or without benign melanocytic hyperplasia. Primary acquired melanosis with atypia was characterized by the presence of atypical melanocytic hyperplasia. Primary acquired melanosis with mild atypia was defined as atypical melanocytes confined to the basal layer of the epithelium. Primary acquired melanosis with severe atypia was defined as atypical melanocytic hyperplasia that extended into the more superficial nonbasal portion of the epithelium in a pagetoid fashion and/or contained epithelioid cells.” They admitted that “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” and suggested thatimmunohistochemical stains for melanocytic and epithelial markers can help to make this distinction. They continued to say, however, that “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.”
Matters of dispute about primary acquired melanosis were engaged by the authors thus:
“The terminology related to primary acquired melanosis has been controversial. Historically, Reese called the condition precancerous melanosis. Zimmerman 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 (PAM). . . . . Ackerman, a dermatopathologist, has challenged this terminology and believes that primary acquired melanosis should be called melanoma-in-situ, similar to lentigo maligna of the skin.” Then they proceeded to defend the nomenclature advocated by Zimmermann in these lines: “The term melanoma-in-situ could possibly apply to primary acquired melanosis with severe atypia, . . . but certainly not to all cases of primary acquired melanosis. We believe that the term melanoma-in-situ could unnecessarily alarm both clinicians and patients, particularly since many primary acquired melanosis lesions have little propensity to evolve into melanoma. The term primary acquired melanosis seems acceptable, since the condition is primary, acquired, and generally pigmented.”
In regard to treatment, the authors offered the following opinion: “Our philosophy for primary acquired melanosis management is based on long-term clinical experience and the results of this study. All patients with primary acquired melanosis (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 primary acquired melanosis 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. . . . If primary acquired melanosis 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 primary acquired melanosis, our approach is to perform small conjunctival map biopsies in each quadrant and double freeze thaw cryotherapy to all remaining areas of pigment. . . . Corneal primary acquired melanosis is managed with either alcohol epitheliectomy or topical Mitomycin C. Depending on subsequent clinical and histopathologic findings, supplemental treatment for residual or recurrent primary acquired melanosis might include in-office cryotherapy or topical chemotherapy using Mitomycin C. Plaque brachytherapy can be used in selected instances.”
Shields et al. ended their analysis of the entire topic thus: “In conclusion, primary acquired melanosis appears to be more common than generally believed. Small foci of primary acquired melanosis (The very same study of Shields et al. was published in yet another journal, in 2008. 
Also in 2008 appeared a study by Novais and coworkers.  They reviewed 10,675 human ophthalmic specimens that included 101 conjunctival melanocytic lesions among which were 50 nevi, 36 examples of primary acquired melanosis, and 15 melanomas. They came to these conclusions: “Depending of the degree of atypia, primary acquired melanosis can be a precursor to conjunctival melanoma. Clinically, it appears as a flat, ill defined, unilateral, patchy or diffuse, brown conjunctival lesion. Histopathological examination reveals an abnormal proliferation of melanocytes at the basal layer of the epithelium . . . . The differentiation between primary acquired melanosis with or without atypia is based on nuclear features and growth pattern. Such distinction is crucial because primary acquired melanosis with atypia is associated with a 50% risk of evolving into melanoma.” In their own histopathologic material the authors noted that conjunctival melanomas were observed most often in older persons than those who developed primary acquired melanosis or nevi and that primary acquired melanosis predisposing in 75% of melanomas.
Although the associates did not address controversies about terminology of primary acquired melanosis they did admit the following “Histologically, junctional nevi are difficult to distinguish from primary acquired melanosis with atypia. In those cases, age is the most important clue to establish the diagnosis. If the patient is a child or a young adult, the lesion is more likely to be a junctional nevus. On the other hand, if the lesion appears later in life and progresses slowly to a larger lesion, the diagnosis of primary acquired melanosis with atypia should be considered.”
In the same year, Damato and Coupland commented on commented on the matter as follows:
“This paper aims to stimulate debate on the terminology, classification, grading and staging of conjunctival melanosis and melanoma. We audited our results with 76 invasive conjunctival melanomas. . . . . Approximately 50% of invasive melanomas were associated with ‘primary acquired melanosis with atypia,’ a term which in our opinion underestimates the gravity of this disease. We also found deficiencies in the grading, terminology and classification of conjunctival melanocytic abnormalities. In summary, we suggest that the term ‘primary acquired melanosis’ be reserved for clinical diagnosis. Histologically, this abnormality can be categorized more precisely as either ‘hypermelanosis’ or ‘conjunctival melanocytic intraepithelial neoplasia (C-MIN).’ ‘Primary acquired melanosis without atypia’ can be termed more accurately as ‘C-MIN without atypia.’ In view of the high risk of invasive melanoma, we suggest that ‘primary acquired melanosis with atypia’ be termed ‘C-MIN’ with atypia, with the more severe changes regarded as melanoma in situ.” The authors suggested a scoring system based on horizontal and vertical spread and degree of severity of melanocytic atypia for diagnosis of what they called ‘C-MIN’ with atypia. 
Ackerman and Mones produced a monograph published in 2009 captioned Precanceroses: Cancers All!  As the title denotes, they asserted that all of the so-called precanceroses are really superficial cancers, among them being “lentigo maligna” and the analogue of it on the conjunctiva “primary acquired melanosis.” The authors decried the fact that after three quarters of a century, ophthalmologists and ophthalmopathologists continued to use the concept of primary acquired melanosis resulting in damage to patients.
Also in 2009 appeared a study by Furusato et al. that examined WT1 and Bcl2 expression in a variety of conjunctival melanocytic lesions including what the authors had classified as benign nevi, atypical nevi, primary acquired melanosis, and malignant melanomas. Immunohistochemical studies were performed with Bcl2, S100, HMB45, and Melan A antibodies. The authors found a graded increase in expression of WT1 in lesions with increasing atypia. Moreover, WT1 and HMB45 frequently showed diffuse and strong staining in atypical nevi, primary acquired melanosis with atypia, and malignant melanomas compared with benign lesions. The authors concluded that “Bcl2 is a highly sensitive immunohistochemical marker for melanocytic tumors of the conjunctiva” and that “HMB45 and WT1 staining distinguishes benign from malignant lesions.” 
Numerous case reports about primary acquired melanosis and conjunctival melanoma were published in the first decade of the 21st Century. In 2000,  Wenkel and coworkers reported on a 75-year-old woman who had a history of numerous recurrences of a melanoma on the conjunctiva that arose in “precancerous melanosis.” She had undergone multiple excisions and had received irradiation. Sections from the exenteration specimen revealed involvement of the iris and the conjunctiva by melanoma as well as the presence of primary acquired melanosis.
Demirci et al.  shared their experience with a 41-year-old patient who, for 20 years, had a pigmented lesion on the left eye. Clinically, the lesion looked like to the authors like primary acquired melanosis. Histopathologically however, it showed what the authors believed to be “dense infiltrates of heavily pigmented dendritic melanocytes” which they diagnosed as blue nevus. The photomicrograph in their report, however, shows changes more in keeping with regression of melanoma than with a “blue nevus.” The authors were concerned that in some loci cytopathologic attributes might indicate that the “blue nevus” had “transformed” to melanoma. According to the authors, “follow up” of 13 months had been uneventful.
In 2001, Paridaens and colleagues recorded their own experience with therapy of 4 patients with “invasive melanoma” proven histopathologically, the method of treatment being amniotic membrane transplantation.  In one patient, local recurrence of primary acquired melanosis was treated with topical mitomycin. The matter of management of conjunctival and corneal melanoma by surgical excision, amniotic membrane allograft, and topical chemotherapy also was considered by Shields et al.  A 40-year-old Caucasian woman with a 20 year-history of pigmentation of the conjunctiva was diagnosed eventually as having a large melanoma in continuity with melanosis of the adjacent bulbar conjunctiva and corneal epithelium. Histopathologic examination of sections from the excised specimen showed what the authors called “diffuse melanosis of the conjunctival epithelium with extensive invasion of the substantia propria . . . compatible with conjunctival melanoma.” They instituted a “combined method” of treatment for conjunctival melanoma employing surgical excision, amniotic membrane allograft, and topical chemotherapy with mitomycin C.
Schmidt et al. also focused on treatment of lesions of primary acquired melanosis.  A 65-year-old woman with a large lesion of acquired melanosis with atypia was treated with low dose of mitomycin C topically. A biopsy taken after that therapy revealed signs of residual melanosis thereby prompting the coworkers to repeated the treatment. The pigmentation continued to fade away and, on last follow up, it was almost gone. For the authors, the terms “melanocarcinoma in situ” and “primary acquired precancerous melanosis with atypia” were synonyms of primary acquired melanosis.
In a comment on the case report of Schmidt et al., Lommatzsch wrote (translated from the German) that “because a quarter of all melanomas of the conjunctiva develops from preexistent melanosis, it needs to be considered to treat PAM with atypia before transformation into malignant forms” and he added that “the correct diagnosis may be masked on histopathology when the biopsy is not taken from a distinctive area.”  Lommatzsch emphasized the need for prospective multicenter studies in order to develop better therapeutic strategies for primary acquired melanosis and he concluded with a quote from Henkind in 1978 to the effect that “much of what has been written about pigmented lesions of the conjunctiva is either anecdotal, speculative, or controversial.”
A 58-year-old patient of Yuen et al. had for 15 years primary acquired melanosis that then was treated with topical mitomycin after which there was complete resolution with no recurrence over a period of 26 months.  This was the concept of the authors in regard to the condition they treated “primary acquired melanosis without atypia is not felt to be associated with a high melanoma risk but may be a predecessor of primary acquired melanosis with atypia. However, primary acquired melanosis with atypia has been estimated to progress to melanoma in 46,4% of cases.”
Bajaj and colleagues, in 2003, reported on a 65-year-old patient who had tarsal conjunctival melanoma adjacent to irregular macular pigmentation that was interpreted histopathologically to be primary acquired melanosis with atypia.  The coworkers affirmed that the primary acquired melanosis had been present at least for five years. In their discussion, they wrote that “Although the exact genesis and progression of conjuctival melanoma is unknown, at least 75% of them arise from primary acquired melanosis and 20% in a conjunctival nevus.” And they continued to say that ” . . . primary acquired melanosis should . . . be eradicated using surgery, cryotherapy, laser ablation, brachytherapy, topical chemotherapy or a combination of these methods.”
In 2005, Colby and Nagel told of a 30-year-old black woman who had a 15-year history of a pigmented lesion on the superior limbus that extended to the bulbar conjunctiva.  The diagnosis histopathologically was“primary acquired melanosis with mild atypia” and the patient was simply followed. Five years later, the patient presented herself with a nodule. The diagnosis histopathologically then was “invasive malignant melanoma with adjacent primary acquired melanosis with severe atypia.” Adjuvant cryotherapy, as well as topical mitomycin C, were instituted. Although the authors claimed a good response to mitomycin C, the photomicrograph of a biopsy taken three years after mitomycin treatment shows single melanocytes distributed irregularly in the basal layer which were interpreted by the authors as “primary acquired melanosis with minimal atypia.”
In the same year, Duchateau et al. told of a 74-year-old woman who presented herself to an ophthalmologist because of bloody tears.  Examination revealed a large nodular melanoma hidden in the left superior fornix of the conjunctiva that, according to the authors, had developed on an unknown primary acquired melanosis. In their conclusion, the authors wrote that primary acquired melanosis sometimes takes a stable course but in other instances it is a precancer. They recommended that primary acquired melanosis be followed annually with complete inspection of the entire conjunctiva. When a change is observed, a biopsy becomes mandatory in order to determine the most appropriate treatment.
In 2005, Becerra and colleagues  reported on a 59-year-old woman with a pigmented mass in the inferior tarsal conjunctiva of the left eye that was continuous with diffuse, multifocal pigmentation involving the inferior half of the bulbar conjunctiva, fornix, and eyelid skin. Histopathologic examination of sections disclosed “conjunctival melanoma from primary acquired melanosis.” The pigmentation of the conjunctiva had been present for 15 years. A biopsy performed 6 years previously had been interpreted as “primary acquired melanosis without atypia,” and observation had been recommended by a dermatologist.
Also in 2005, Krohn and Monge  recorded two patients with primary acquired melanosis of the conjunctiva. One of them had melanocytes disposed in linear array in the basal layer. The authors thought that the melanocytes showed “moderate atypia” and the patient was treated with cryotherapy and the lesion resolved completely. The other had a pigmented lesion that histopathologically demonstrated irregular hyperplasia of melanocytes with marked atypia. The patient received cryotherapy followed by topical mitomycin treatment and resolution was complete.
In contrast, Kyto and Kivela  diagnosed a melanoma in situ of the conjunctiva in a 77-year-old woman who had presented herself with a nine month history of dark pigmentation in one eye. The nasal, temporal, and the upper conjunctiva showed a pigmented lesion that extended to the skin of the eyelid. The clinical diagnosis was “primary acquired melanosis of the conjunctiva with atypia” because the conjunctiva seemed not to be thickened and close follow-up was recommended. After 18 month in which the lesion was said to have been waxing and waning topical chemotherapy with mitomycin was initiated because of the extent of the melanosis. Fourteen months later, the lesion had resolved in part. Even though the authors seemed not to have performed a biopsy in their patient, they classified their patient as having “melanoma in situ.” In their opinion, primary acquired melanosis of the conjunctiva with atypia was a premalignant proliferation of melanocytes, typified histologically by large melanocytes with prominent nucleoli, which spread and form nests in the basal layer, and eventually throughout the epithelium. In their own patient, they believed the epithelium to be replaced by atypical melanocytes, that advanced stage of primary acquired melanosis being termed “conjunctival melanoma in situ” by them.
In 2006, Lin and Ferrucci  published their experience with a 72-year-old man who had recently developed a large, dark, elevated zone of conjunctival pigmentation at the medial canthus that extended onto the superior bulbar conjunctiva and superior palpebral conjunctiva of the left eye. A biopsy was taken and interpreted as “primary acquired melanosis with atypia.” According to the authors primary acquired melanosis was a unilateral patchy area of variably brown conjunctival pigmentation found most often in middle-aged or elderly white patients and “Although it is a benign condition, its significance lies with its potential for progression into conjunctival melanoma.” They acknowledged that the term primary acquired melanosis had been “adopted by the World Health Organization” and spelled out the characteristics of it as set forth by that organization, namely, “a flat, unilateral, patchy, golden yellow to brown area of conjunctival pigmentation.” In their discussion, however, the authors said that “When it [primary acquired melanosis] is present in a pediatric population, the pigmentation is generally considered congenital and is more likely to be a junctional nevus or compound nevus.” And proceeded as follows: “primary acquired melanosis can be divided into 2 categories: lesions that are likely to remain stable and lesions that are likely to covert to melanoma. This distinction cannot be made clinically but is based on histologic analysis.”
In regard to interpretation of histopathologic findings the authors mentioned that “primary acquired melanosis can be divided into 2 main groups: those without cytological atypia (primary acquired melanosis without atypia) and those with cytological atypia (primary acquired melanosis with atypia).” They defined “atypia” as an abnormality of a cell that is determined by cytologic features and growth patterns and which is related to the potential for malignancy. They continued to say that “Four types of atypical melanocytes may be found: small polyhedral cells, similar to classic melanocytes (containing small, round nuclei and barely perceptible cytoplasm); epithelioid cells (containing abundant eosinophilic cytoplasm); spindle cells (aligned so the long axes are parallel to the basement membrane of the epithelium); and dendritic cells (large cells with complex branching dendrites found along the basilar layer). Mixtures of these cell types are common and are considered polymorphous.”
In regard to histologic patterns encountered in primary acquired melanosis lesions, the authors mentioned “basilar hyperplasia (proliferation of melanocytes confined to the basilar layer of the epithelium),” “basilar nests (clusters of melanocytes anchored at the basilar layer that push up against the overlying epithelium without invading it),” “intraepithelial nests (clusters of melanocytes contained within the epithelium but not anchored to the basilar layers, as are basilar nests),” “pagetoid growth (individual melanocytes present within the suprabasilar layers of epithelium, regardless of cell type),” and “melanoma in situ (replacement of conjunctival epithelium by atypical melanocytes).”
In their opinion, the distinction between primary acquired melanosis with atypia and without atypia could be made by the presence or absence of melanocytic hyperplasia, the pattern of intraepithelial growth, and the presence or absence of epithelioid cells. They differentiated further between two types of “primary acquired melanosis without atypia,” one being simply an overproduction of melanin in the absence of melanocytic hyperplasia, the other being melanocytic hyperplasia with or without an increase in pigment. In those latter lesions, melanocytes were not atypical and did not migrate from their position at the base of the epithelium immediately above the basement membrane. The authors were convinced that “these lesions are unlikely to undergo malignant transformation.” And concluded as follows: “If atypia is present, treatment options include excision, cryotherapy, membrane graft, and topical chemotherapy. Even after treating PAM, close followup is necessary. The natural history of PAM is to wax and wane, and the lesion may recur. Thus, patients should be seen routinely to monitor for recurrence.”
Again in 2006, Bongiorno et al.  wrote of a 32-year-old patient who developed an amelanotic melanoma on the conjunctiva with no history of primary acquired melanosis. Histopathologially, there was an ulcerated nodule but “the melanoma did not have an intraepithelial component extending far beyond the margins of the deepest part.” The authors were adamant that “the histology of skin and conjunctival melanomas is noncomparable in all features” because “the conjunctiva does not contain a papillary dermis” and “any melanocytic lesions that invade the substantia propria corneae must be suspected a malignant melanoma.”
Also in 2006, Reddy and colleagues  reported on a 93-year-old woman with an elevated pigmented lesion on the conjunctiva that was next to a zone of increased pigmentation on the opposing tarsal conjunctiva, the changes on the latter conjunctival site being interpreted as “pseudomelanomatous alteration;” only melanophages were present. The alternative interpretation of complete regression of a melanoma was not considered as a differential diagnosis. The co-workers commented about the setting in which conjunctival melanoma developed in this sentence: “Although conjunctival melanoma commonly arises within primary acquired melanosis (with atypia), it should be differentiated from other pigmented lesions such as racial melanosis, conjunctival nevi, primary acquired melanosis without atypia, pigmented hidrocystomas, and pigmented squamous cell carcinomas.”
Three patients with melanoma of the conjunctiva with intraocular extension were discussed in 2007 by Sandinha et al.  who summarized as follows: “Three patients presented with primary conjunctival melanomas, which either arose at or later involved the limbus on a background of primary acquired melanosis.”
About their patient 1, they said that “Microscopy of the lesion revealed an epithelioid malignant melanoma with primary acquired melanosis with severe atypia in the adjacent conjunctiva.” The same patient experienced several local recurrences of the disease in the form of what the authors interpreted to be “primary acquired melanosis with mild atypia,” “malignant melanoma,” “amelanotic melanoma,” and “limbal malignant melanoma with focal spread into the overlying epithelium and infiltration of the corneal stromal lamellae” as well as “malignant melanoma invading the trabecular meshwork, iris and ciliary body.”
Their patient 2 had “a 15-year history of pigmentation of the right plica and caruncle that had recently increased in size.” The clinical appearance had been interpreted as primary acquired melanosis and the patient, therefore, merely was observed. Several years later, when the lesion had extended to the inferior cornea and lower fornix, it was biopsied. Histopathologic changes were interpreted as “malignant melanoma arising on a background of widespread primary acquired melanosis with severe atypia.” Cryotherapy was given and the lesion recurred locally one year later when again cryotherapy was applied. In the course, pigmentation continued to return locally and histopathologically they were diagnosed sequentially as “recurrent melanoma,”recurrent primary acquired melanosis,” residual primary acquired melanosis with severe atypia,” “recurrent malignant melanoma.”
The third patient was said to have “a 3-month history of a left epibulbar mass at the temporal limbus . . . associated with widespread pigmentary changes, suggestive of primary acquired melanosis involving the caruncle, plica, nasal bulbar conjunctiva and upper and lower tarsus.” Histopatholgic findings were interpreted as “malignant melanoma arising on a background of primary acquired melanosis.” Because the patient experienced several recurrences the eye, at last, was exenterated. Histopathology revealed “malignant melanoma covering the bulbar conjunctiva and cornea, with extensive intraocular spread and invasion through the sclera posteriorly to form an extraocular mass.” A preauricular lymph node also contained a metastasis of melanoma. The authors emphasized that “all three initial tumours arose on a background of primary acquired melanosis with atypia. Primary acquired melanosis with atypia is a multifocal disease and is not usually amenable to local surgery alone.” No mention was made to the fact that for other authors primary acquired melanosis was melanoma in situ.
Charbel Issa et al., in 2008, reported on two women (84 and 85 years old, respectively) with melanoma of the conjunctiva.  Both had a pigmented tumor close to the limbus and that was surrounded by pigmentation of the conjunctiva and the cornea. Following complete excision of the tumor, “conjunctival malignant melanoma arising from primary acquired melanosis” was diagnosed histopathologically. Treatment with mitomycin C eye drops was initiated and the tumor did not persist locally within the follow-up (24 and 6 months). The authors were compelled to advise that a patient with primary acquired melanosis required follow-up on a regular basis for the purpose of detecting “malignant transformation” at an early stage.
Finger et al, in 2008, commented on the use of topical interferon alfa-2b for conjunctival melanoma and primary acquired melanosis with atypia of five consecutive patients with biopsy-proven melanoma.  Two patients experienced recurrence of the tumors of the cornea eight and 13 months after local excision, cryotherapy, and topical mitomycin C. Two months after treatment with topical interferon alfa-2b, the lesions regressed without any side effects. Two other patients (who could not tolerate topical mitomycin C) were switched to topical interferon alfa-2b. They developed transient chemical conjunctivitis but no signs of recurrence (mean, 15 months of follow-up). The fifth patient had recurrent tumor despite having undergone numerous surgeries. That melanoma did not respond to topical interferon alfa-2b, nor did the patient tolerate the treatment; keratoconjunctivitis was induced by it. The authors concluded that conjunctival and corneal melanoma regressed after exposure to topical interferon alfa-2b and proposed that a larger-scale, longer-term study must be done to assess the efficacy and safety of it.
In 2009, Anandajeva et al. reported on a 56-year-old Caucasian man who was found to have prominent conjunctival pigmentation in his right eye. Histopathologic findings were interpreted as melanoma of the conjunctiva arising within primary acquired melanosis with atypia. The patient was treated by incisional conjunctival biopsy followed by two cycles of mitomycin C 0.04% eye drops and supplemental cryotherapy. At 1 year following this treatment, there was no clinically apparent residual conjunctival melanosis, and visual acuity remained stable at 20/30. 
In 2010, Stacy and coworkers told of 66-year-old woman with a history of neurofibromatosis type 1 who developed an extensive pigmentation of the left bulbar conjunctiva. Findings in a biopsy specimen demonstrated melanoma arising from primary acquired melanosis with atypia. Two excision and cryotherapy procedures did not completely eradicate the conjunctival pigment, which was then treated with topical mitomycin C. Subsequent biopsies and clinical examinations have revealed no remaining tumor. 
Review of the most recent literature pertinent to primary acquired melanosis of the conjunctiva reveals that an increasing number of articles focus more on noninvasive diagnostic procedures and eye preserving therapeutic strategies than on conceptual aspects of the condition. In regard to diagnostic procedures, exfoliative cytology, digital surface microscopy, and confocal microscopy were investigated. Not surprisingly, primary acquired melanosis with atypia, as well as melanoma, show similar features in regard to hyperreflective granules, which are absent in primary acquired melanosis without atypia and complexion-associated (racial) melanosis. Immunohistochemical studies contributed little to clarification of the issue except that MB45 seemed to stain only a small proportion of lesions diagnosed as primary acquired melanosis without atypia.
The idea of primary acquired melanosis being melanoma in situ hardly penetrated the literature of ophthalmology and ophthalmic pathology. As an example, Tuomaala et al. could not integrate the finding of invasive melanoma on the conjunctiva and the cornea connected to one another only by what they considered to be primary acquired melanosis, instead terming it “corneally displaced melanoma.” Some authors diagnosed conjunctival melanoma in situ as well as primary acquired melanosis with atypia as if those two lesions were different from one another and could be told apart. No criteria for differentiation, however, were provided. Others continued to affirm that primary acquired melanosis is benign and at most bore risk for transformation into melanoma. Some even stated that primary acquired melanosis could appear symmetrically, involve both eyes, and be present in persons with dark skin, a condition referred to by still others as “racial pigmentation.”
An exception is Rodriguez-Sains who agreed straightforwardly with Ackerman et al. that acquired melanosis is melanoma in situ and advised complete removal of it at the earliest stage of the process. In regard to what was called primary acquired melanosis without atypia, however, he questioned whether it really represented an early stage of primary acquired melanosis with atypia.
Based on their own study on primary acquired melanosis with atypia, Sugiura et al. suggested that the term melanoma in situ be adopted at least for what they called “high risk” primary acquired melanosis. Criteria cited by them for identification of such lesions read nearly identical to Reese’s description of “precancerous melanosis,” namely, epithelioid morphology, prominent nucleoli, and heterogenous architecture. None of those criteria are really new. What the authors picture in their article as “high-risk PAM with atypia” fullfills criteria for melanoma in situ. What the authors show as “low-risk PAM with atypia” , however, fullfills the very same criteria, abnormal melanocytes being present as solitary units not equidistant from one another along the basal layer and sometimes well above it. Differences between their “high-risk” and “low-risk” group seem to be marginal and a distinction between them unconvincing. Most remarkable in the study by Sugiura et al. is the high rate of recurrence, invasion, and metastasis in the 29 cases they investigated, that being a strong evidence for the malignant nature of the condition referred to by them as primary acquired melanosis.
In contrast, Shields and coworkers continue to use the nomenclature of primary acquired melanosis and insist that when atypia was absent or slight, such lesions had almost no risk of becoming melanoma. For lesions showing atypia, they estimate the risk to be much lower than in previous studies, namely 13%. It is difficult to explain such discrepancies other than by different interpretation of criteria for diagnosis. In this context, it is interesting to note that Shields et al. included several patients who were relatively young, who belonged to ethnic groups beside Caucasian or who had bilateral pigmentations. How exactly they were able to differentiate primary acquired melanosis from junctional nevi, racial melanosis, and congenital melanosis was not explained by them.
The suggestion of Damato et al., to rename primary acquired melanosis as “conjunctival melanocytic intraepithelial neoplasia (C-MIN)” is no improvement as it fails to denote the condition as either benign or malignant.
Of the numerous case reports published in recent years, some are impressive because of the clinical course of the patients. In several of them, macules were treated locally for years until, at last, metastases developed. In one patient, local metastases were interpreted to be blue nevi. Some colleagues who focussed on treatment of melanosis and melanoma of the conjunctiva advised novel approaches, such as amniotic membrane transplantation and topical interferone.
In the year 2010, the matter of conjunctival pigmented lesions is still replete with controversies, inconsistencies, and unsolved questions.
The observation that melanoma may develop in a longstanding slowly-growing macular pigmentations of the conjunctiva is a century old, but the criteria for identification of such flat lesions, clinically and histopathologically, differentiation of them from benign simulators, and appropriate treatment are still a matter of debate.
To some extent, the controversies are rooted in a confusing nomenclature. Beginning with precancerous and cancerous melanosis (Reese), continuing with benign and malignant acquired melanosis (Zimmermann), proceeding to primary acquired melanosis with and without atypia with and without invasion (Folberg), and ending with “high risk” and “low risk” primary acquired melanosis with atypia (Sugiura), the terminology impedes comprehension rather than facilitates it. The term primary acquired melanosis continues to be used today for both benign and malignant pigmented lesions of the conjunctiva.
In order to clarify the matter, it seems essential to extract facts on which authors from various disciplines have agreed, as well as to alert to arenas that still are in need of further research. These are some thoughts in those regards:
– If, together with an intraepithelial proliferation of melanocytes, cells of melanoma are present in the substabtia propria (or in the dermis), the lesion is an “invasive” melanoma. That diagnosis has important prognostic and therapeutic implications and, therefore, should be made straightforwardly without equivocation. Terms like “cancerous melanosis,” “malignant melanosis,” or “primary acquired melanosis with invasion” are misleading and should be eschewed scrupulously.
– If a proliferation of melanocytes is restricted to a surface epithelium, such a lesion can be either a junctional melanocytic nevus or a melanoma in situ. A diagnosis of melanoma in situ is based on criteria that are the very same in all epithelial structures of the body, namely, asymmetry, poor circumscription, predominance of melanocytes disposed as solitary units over nests, pagetoid pattern, and cytopathologic attributes such as pleomorphism of nuclei and prominent nucleoli. Such lesions in the past have been designated by various names, among them lentigo maligna, Hutchinson’s freckle, precancerous melanosis, and primary acquired melanosis with atypia, but all these terms fail to identify the lesion correctly as the melanoma it is and, therefore, deserve to be abandoned.
– If a melanoma in situ is biopsied, histopathologic findings may sometimes be subtle for many reasons, one being that it is still so early in the course that not a single nest has yet formed. In such a situation there may be only solitary melanocytes increased in number in the basal layer. Diagnosis then requires great aptitude, but it can be accomplished. When it cannot be on histopathologic grounds alone, it usually can be by careful clinicopathologic correlation. If that fails, another biopsy is indicated.
– Zones of regression of conjunctival melanoma may pose a problem in diagnosis. No increase in number of intraepithelial melanocytes may be discernible, only melanophages in patchy lichenoid array in the substantia propria. In such instances diagnosis may be accomplished in correlation with clinical findings.
– What kind(s) of lesions is/are included under the title of “benign acquired melanosis without atypia” has yet to be elucidated. While doubtlessly some of the lesions mentioned above (areas of single melanocytes or of regression of melanoma in situ) have been diagnosed as “acquired melanosis without atypia” the same diagnosis also was given to entirely benign lesions such as junctional nevi and racial melanosis.
– It remains to be clarified whether there are analogues of solar lentigo, ephelis, ink spot lentigo/benign melanosis of the mucous membranes, and simple lentigo on the conjunctiva. While simple lentigo just as a junctional melanocytic nevus is a melanocytic proliferation, all other lesions just mentioned are essentially epithelial in nature. No criteria for identification of such lesions on the conjunctiva are available so far and no criteria for differentiation of them from the subtle manifestations of melanoma mentioned above have been established. Studies on clinicopathologic correlation are required to resolve these questions.
In order to clarify the matter of what is called “primary acquired melanosis of the conjunctiva,” a comprehensive search of the literature was undertaken. In this historical perspective, studies, case reports, reviews, editorials, and letters to editors have been included because each individual publication conveys concepts put forward by the authors. The history is separated into 6 intervals of time, each of which is followed by a comment: Reports before 1937; Reese’s concept in 1937 and consequences up to 1959; Controversies in ophthalmology: Zimmermann and others, 1960-1975; Influence of skin pathology on concepts about conjunctival melanocytic lesions 1976-1990; Controversy continues: Ackerman and others, 1990-2000; and Current concepts beginning from the year 2000. This third part of the chapter presents the history beginning in the year 2000, as well as conclusions from all three parts of this chapter.
Almut Böer-Auer is a dermatopathologist at the Dermatologikum Hamburg, Germany. This article was reviewed by François Milette, M.D., and A. Bernard Ackerman, M.D. Contact author via email: firstname.lastname@example.org .
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