Primary Acquired Melanosis Research Articles

Therapy of melanocytic conjunctival tumors

Clinical experience of our single center in dealing with pigmented epibulbar lesions - melanocytic conjunctival tumors is presented. Since 2008 we use the topical treatment with mitomycin C (MMC) as an alternative or adjunctive method for excision in the treatment of melanocytic neoplasia of the conjunctiva. The retrospective case series of 85 patients with pigmented lesions of the conjunctiva - melanocytic conjunctival tumors, histopathologically examined in the period 2001-2010 is presented. Since 2008 we started to apply MMC in the treatment of primary acquired melanosis (PAM) and dysplastic nevi. We apply MMC topically directly after an excision as 2-times five minutes application. In 85 patients with pigmented lesions of the conjunctiva histopathological findings after excision of the lesion showed in 68 (80 %) cases melanocytic nevocelullar nevus, out of which 55 cases were combined and 13 cases were junctional nevi. In 60 (80 %) cases of melanocytic nevi atypia was found in 25 patients (42 %), nevus without atypia was present in 35 cases (58 %). PAM with atypia was found in 16 patients (classified since 2000). During the period of application of MMC we diagnosed only one patient with primary conjunctival melanoma. There was no presence of relapse of the pigmented lesion either after primary excision or after excision with MMC. Resection of more than one quadrant of bulbar conjunctiva in patients with pigmented lesions of the conjunctiva in cases of conjunctival nevus with atypia and PAM with atypia combined with topical MMC chemotherapy is an alternative therapy for residual pigmented lesions. There was no presence of relapse of pigmentation in area of excision with or without using MMC during the surgery in patients with PAM. The number of our patients is not sufficient yet to draw a conclusion (Fig. 6, Ref. 21).

Recurrent Primary Acquired Melanosis With Atypia Involving a Clear Corneal Phacoemulsification Wound

To report a case of corneal primary acquired melanosis (PAM) with atypia after cataract surgery. Retrospective case report with literature review. Excision of an elevated pigmented conjunctival lesion was performed at the time of cataract extraction by clear corneal phacoemulsification by an outside surgeon. Histopathologic examination revealed PAM with atypia. Three months after the initial surgery, recurrent melanosis involving the peripheral corneal epithelium was noted, with extension of pigment into the corneal stroma through the paracentesis site. Excision of the involved corneal epithelium and the adjacent conjunctiva was performed, and microscopically recurrent PAM with atypia was confirmed. Adjuvant cryotherapy was applied at the time of surgery, and topical mitomycin C was given postoperatively. Repeat biopsies revealed no remaining malignancy, and the intrastromal pigment has disappeared during 18 months of follow-up. We present this case to illustrate the importance of complete evaluation and treatment of potentially atypical melanocytic conjunctival lesions before proceeding with elective intraocular surgery.

Epistaxis or epiphora as sign for extension of a conjunctival melanoma: a series of six patients with nasolacrimal recurrence

Abstract Purpose To characterize malignant conjunctival melanomas with extension and recurrence in the nasolacrimal system Methods Localization of the primary tumor and recurrences of 210 conjunctival melanomas treated in the Netherlands were reviewed for orbital and nasal tumors (1978‐2008). On the basis of these cases and literature data, characteristics for nasolacrimal system extension and metastasis were reviewed. Results Six patients (3%) showed a recurrence of the primary conjunctival melanoma in the nasolacrimal system. Two of the six primary tumors were limbal tumors, the other four were diffuse tumors involving the fornix. In all six patients, the primary conjunctival melanomas were associated with primary acquired melanosis (PAM). During follow‐up period (mean 11.6 ± 3 years; median 8.7 years) two patients developed metastases, and died during follow‐up. Conclusion Patients should be advised to contact the treating ophthalmologist in the case of symptoms of epiphora, nose obstructions and epistaxis, especially non‐bulbar and diffuse cases associated with PAM.

Topical mitomycin C chemotherapy in the management of ocular surface neoplasia: a 10-year review of treatment outcomes and complications

IntroductionThe use of topical mitomycin C (MMC) has gained popularity in the management of ocular surface neoplasia. The aim of this study is to determine outcomes and complications following such...

Clinical and pathological features of 26 cases of conjunctival melanoma

To improve the knowledge of clinical and pathological features of conjunctival melanoma, in order to have an early diagnosis and treatment. Retrospective cases analysis. The clinical and pathological features of 26 cases of conjunctival melanoma were analyzed. These cases were treated from May in 1985 to June in 2007 in Tianjin Eye Hospital. Routine pathological examination and immunohistochemical staining of S-100 and HMB-45 were performed. The mean age was 53.4 years and ranging from 30.0 - 83.0 years. In these cases, 11 cases arose from primary acquired melanosis (PAM), 8 cases from conjunctival nevi or melanocytoma and 7 cases occurred de novo. Fourteen cases involved tarsal and bulbar conjunctiva, 6 cases involved bulbar conjunctiva only, 4 cases involved tarsal conjunctiva only and 2 cases were located at the limbus. Twenty two cases were epitheloid-cell-type melanoma, 4 cases were mixed-cell-type melanoma. There were 3 amelanotic melanomas, the tumor cells were positively stained with S-100 and HMB-45. The follow-up period was 1-18 years postoperatively in 14 cases. Among them, 12 cases showed 1-3 recurrences, 3 cases with preauricular lymph node metastasize, 1 cases with preauricular and submandibular lymph nodes metastasize; and 4 cases died from systematic extension or hepatic metastasis. Conjunctival melanoma mainly arises from malignant transformation of PAM or conjunctival nevi and consists of epitheloid melanotic tumor cells. The neighbor intraepithelial invasion and recurrence are common, particularly in diffuse type of tumors or tumors arising from PAM.

Limbal Stem Cell Deficiency after Topical Mitomycin C Therapy for Primary Acquired Melanosis with Atypia

To describe the incidence, characteristics, risk factors, and clinical outcome of limbal stem cell deficiency (LSCD) resulting from topical treatment with mitomycin C (MMC) for primary acquired melanosis (PAM) with atypia. Retrospective, observational case series. Patients with LSCD who had been managed with topical MMC for PAM with atypia at the Ocular Oncology Service at the Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel, between 2000 and 2007. Retrospective chart review of all patients with PAM with atypia was performed. Impression cytologic analysis of the corneal and conjunctival epithelium was performed in patients suspected of having LSCD. Evaluation of risk factors for LSCD, including demographic characteristics, MMC dosage, and length of treatment; and clinical and visual outcome of patients diagnosed with LSCD. Limbal stem cell deficiency was identified in 5 (23.8%) of 21 patients. The mean age+/-standard deviation of the 5 patients was 61.8+/-12.7 years compared with 43.7+/-16.1 years in patients in whom this complication did not develop (P = 0.025). Longer treatment periods of MMC were noted in eyes in which LSCD developed (78.4+/-24.8 days) compared with eyes without LSCD (37.7+/-3.1 days; P = 0.07). In 3 patients, spontaneous partial resolution of the LSCD was noted. High-dose topical MMC for PAM with atypia may be associated with a relatively high incidence of LSCD. Mitomycin C concentration and treatment regimen should be reevaluated to improve the safety of this treatment protocol.

Histological criteria for grading of atypia in melanocytic conjunctival lesions

To develop a standardised protocol for grading atypia in melanocytic conjunctival lesions (MCL), mainly primary acquired melanosis (PAM) and inflamed juvenile conjunctival naevi (IJCN) and to establish prognostic parameters for progression to malignant melanoma (MM). A retrospective non-randomised study of 304 patients with MCL was conducted. Histological slides of MCL diagnosed as conjunctival naevus (CN; 222 cases), PAM (42 cases), and IJCN (40 cases) were reviewed. A scoring method of atypia was developed according to the following histological parameters: nest cohesion, melanocytic hyperplasia, nuclear features, and pagetoid spread. Lesions were scored according to the number of criteria as mild (1-2), moderate (3-4) and severe (5-8). Nineteen PAM lesions showed mild (n = 8), moderate (n = 4), and severe (n = 7) atypia. The remaining PAM lesions were without atypia. IJCN cases showed architectural disorder only. Neither architectural disorder nor cytological atypia were found in the CN. There were no recurrences in the IJCN and PAM lesions without and with mild atypia, while two PAM with moderate and two with severe atypia recurred. Three cases (two of which had a history of recurrent PAM with severe atypia) progressed to MM. The criteria for evaluation of atypia were found to be significantly associated with the clinical outcome (p < 0.0001). The standardised histological scoring protocol of MCL is reliable, and may reduce the risk of confusing a benign MCL, such as IJCN, with one that is potentially preneoplastic. It may also prove useful in predicting which PAM lesions will progress to MM.

Epidemiology of conjunctival melanocytic neoplasms

Abstract Purpose To summarise the epidemiology of conjunctival melanocytic neoplasms. Methods Review of population‐based data on 85 patients with primary conjunctival melanoma (CM) and recently published literature. Results CM accounts for 5‐7% of ocular melanoma in Europe. Its age‐adjusted incidence has increased 2‐fold in North Europe (Finland, from 0.40 to 0.80/million) and North America (USA, from 0.27 to 0.54) during the last 25 y. In both regions, age‐adjusted incidence is higher in men. Different rates between regions result from differences in registries, ethnicity and solar radiation. Age‐adjusted incidence of CM is 3‐fold in non‐Hispanic Caucasians and 2‐fold in Hispanics relative to Asians, African Americans and American Indians; among non‐Hispanic Caucasians it increases 2.5‐fold from 48 deg. (e.g. Paris) to 21 deg. (e.g. Mecca) of latitude. CM is rare below 30 y of age (age‐specific incidence, 0.06) but increases steadily thereafter (0.48, 1.05 and 1.57 for 30‐49, 50‐70 and &gt;70 y, respectively). Median age at diagnosis is 58‐60 y. Most CM arise in limbal (57‐64%) followed by bulbar (12‐13%), palpebral (7‐9%) and caruncular (3%) conjunctiva. Tumor‐specific 5‐and 10‐y mortality estimates are 14‐20% and 29‐38%, respectively. Non‐limbal location, increasing tumor thickness and local recurrence are consistently associated with higher mortality. Clinically detectable primary acquired melanosis (PAM) and nevus precede or accompany CM in 57‐61% and 7‐23% of patients, respectively. Median age at diagnosis of PAM is 56 y. The risk of malignant change is not precisely known and depends heavily on subtype of PAM, ranging from 10 to 90%. Conclusion Recent studies provide epidemiological data on CM which are remarkably consistent. The epidemiology of conjunctival nevi and PAM is less precisely known.

Conjunctival melanoma : the Curie experience

Abstract Purpose To evaluate the treatment of conjunctival melanoma at the Institut Curie in term of local recurrences, ocular preservation, distant metastasis and survival Methods Retrospective study of patients with conjunctival melanoma treated for their first tumoral localisation between January 2000 and December 2005. The clinical records, histologic features, ocular treatments were rewiewed. The rate of local recurrences, ocular preservation, regional and distant metastasis, and survival were recorded. Results During the study period, 91 patients were referred for conjunctival melanoma. 67 of them were treated for a first occurrence of malignant melanoma (38 women and 29 men). The mean age was 62 years (25 – 90). 32/67 patients (47 %) presented a primary acquired melanosis (PAM). Most cases (55 patients) were treated by surgical excision and adjunctive radiotherapy (Iodine plaque, protonbeam or external beam irradiation), 5 cases were treated by surgery alone, and the last 6 by surgery and adjunctive cryotherapy or adjunctive topical chemotherapy. 3 patients were lost of follow‐up. With a mean follow‐up of 52 months (15‐101months) 20/64 patients developped at least one local recurrence (between 1 and 7 recurrences). 16 of them presented a PAM. An enucleation was finally necessary for 1 patient and an exenteration for 2 patients. 7 patients developped metastatic disease (all but one presented a PAM) and 6 of them died. Conclusion Local recurrences, metastatic disease and tumor related death appear to occur at higher frequency when melanoma is associated with PAM. This risk must be taken into account in the therapeutic approach of conjunctival melanoma.

Topisches Mitomycin C als Therapie konjunktivaler Tumore

Surgical excision with tumour free margins is the gold standard for squamous cell and melanocytic tumours of the conjunctiva. In cases of diffuse and extensive tumours a complete surgical excision is sometimes not possible. Therefore, alternative or adjuvant therapies are required. Topical chemotherapy with mitomycin C (MMC) is increasingly finding use in clinical practice. MMC has several advantages such as good tolerability and mild side effects. Present studies have shown that mitomycin C is a good option in squamous cell neoplasia of the conjunctiva. However, further multi-centre studies and long-term follow-up are needed.The results in treating melanocytic tumours of the conjunctiva with MMC are less convincing. MMC seems to be an option for the treatment of primary acquired melanosis (PAM); but, if the tumour is suspicious for melanoma primary chemotherapy with MMC is obsolete. In these cases MMC can only be used as an adjuvant therapy, otherwise tumour control is not assured. However, prospective randomized controlled trials are necessary for a final evaluation of MMC therapy in melanocytic tumours of the conjunctiva.

Primary acquired melanosis with atypia treated with mitomycin C

The authors report the case of a 56-year-old Caucasian man who was found to have prominent melanotic conjunctival pigmentation inferotemporally in his right eye. Histopathologic evaluation disclosed malignant melanoma of the conjunctiva arising within primary acquired melanosis (PAM) associated with melanocytic atypia. The patient was treated by incisional conjunctival biopsy followed by two cycles of mitomycin C 0.04% eye drops and supplemental double-freeze thaw cryotherapy to residual foci of PAM. By 1 year following this treatment, there was no clinically apparent residual conjunctival melanosis, and visual acuity remained stable at 20/30.

Resolution of primary acquired melanosis with atypia after minimal mitomycin C treatment

The most effective dose of mitomycin C (MMC) in the treatment of primary acquired melanosis (PAM) with atypia of the conjunctiva and cornea has yet to be established. This case report describes successful treatment of PAM with atypia with a single four day cycle of 0.02% MMC.

Complications of management in primary acquired melanosis with atypia

The management of conjunctival primary acquired melanosis (PAM) with atypia is in flux. Lesions are treated with biopsy, excision, adjunctive cryotherapy, or topical mitomycin.1 Acceptable, usually minimal, complications have been...

Primary Acquired Melanosis of the Conjunctiva: Risks for Progression to Melanoma in 311 Eyes: The 2006 Lorenz E. Zimmerman Lecture

To evaluate the clinical features and risks for transformation of conjunctival primary acquired melanosis (PAM) into melanoma. Noncomparative case series. Three hundred eleven eyes with conjunctival PAM without melanoma at initial examination from a single-center tertiary referral center. Retrospective chart review with evaluation of the clinical features of PAM at initial presentation and follow-up. Times to PAM enlargement, recurrence, and transformation into melanoma were assessed using Kaplan-Meier estimates. Risk factors for these outcomes were analyzed using Cox proportional hazards regressions. Primary acquired melanosis enlargement, recurrence, and transformation into melanoma. Mean patient age at diagnosis of PAM was 56 years (range, 15-90), 62% were female, and 96% were Caucasian. The conjunctival quadrant(s) affected by PAM were temporal (57%), inferior (45%), nasal (42%), and superior (37%). The anatomic location(s) of PAM included bulbar conjunctiva (91%), limbal conjunctiva (55%), cornea (23%), forniceal conjunctiva (13%), palpebral conjunctiva (12%), and caruncle (11%). Primary acquired melanosis extended for a mean of 3 clock hours (range, 1-12). Initial management included observation (n = 194 eyes [62%]), biopsy combined with cryotherapy (n = 107 eyes [34%]), and topical chemotherapy and/or cryotherapy without biopsy (n = 10 [4%]). Of PAM that was observed, Kaplan-Meier estimates at 10 years revealed PAM enlargement in 35% and transformation into melanoma in 12%. Of those that underwent incisional or excisional biopsy, 10-year estimates of PAM recurrence and transformation into melanoma were 58% and 11%, respectively. Progression to melanoma occurred in 0% of cases of PAM without atypia, 0% of cases of PAM with mild atypia, and 13% of cases of PAM with severe atypia. Of the 9 patients with PAM who developed melanoma, none have developed systemic metastasis. Multivariable analysis revealed that the most significant factor for both PAM recurrence and progression to melanoma was extent of PAM in clock hours. Primary acquired melanosis without atypia or with mild atypia shows 0% progression to melanoma, whereas PAM with severe atypia shows progression to melanoma in 13%. The greater the extent of PAM in clock hours, the greater the risk for transformation to melanoma.

Conjunctival melanoma &amp; histone deacetylase inhibitors

Abstract Purpose: Conjunctival melanoma is a rare disease with a poor prognosis. Malignant conjunctival melanoma or primary acquired melanosis (PAM) with atypia are usually treated by surgical excision and cryotherapy. Topical mitomycin C (MMC) is also increasingly used for treating PAM with atypia. Histone deacetylase (HDAC) inhibitors can modify tumour growth and induce tumour cell death, and may be useful adjuvants for treating conjunctival melanoma. We examined the effects of HDAC inhibitors (sodium butyrate ‐ SB , Trichostatin A ‐ TSA) and MMC on the growth and survival of human conjunctival melanoma cells. Methods: Two conjunctival melanoma cell lines (CRMM‐1 &amp; CRMM‐2), and primary human melanocytes and fibroblasts, were treated with SB (0‐8mM), TSA (0‐1uM), and MMC (0‐20ug/ml) for up to 72 hrs. Viability was assessed using MTT assays and cell counts. Inverted and fluorescence microscopy was used to assess morphology and cell death (DNA stains). Results: HDACs and MMC significantly decreased cell growth and viability in a concentration and time dependent manner for both conjunctival melanoma cell lines. Low concentration HDACs (&lt;2mM SB; &lt;0.1uM TSA) reduced melanoma cell growth, associated with morphological differentiation, particularly in CRMM‐1 cells. Melanocytes and fibroblasts remained viable with HDACs, although at maximal doses used (SB 8mM, TSA 1uM), some cell death was seen. At 48 hrs, MMC &gt;5ug/ml killed &gt;80% of CRMM‐1 &amp; CRMM‐2 cells. Conclusions: These observations suggest that HDACs do not affect melanocyte and fibroblast viability at doses which can inhibit growth and survival of conjunctival melanoma cells. As such, these compounds may be useful for controlling conjunctival melanoma growth, alone or combined with topical agents such as MMC.

Low-risk and High-risk Histologic Features in Conjunctival Primary Acquired Melanosis With Atypia: Clinicopathologic Analysis of 29 Cases

The current World Health Organization classification of conjunctival melanocytic proliferations divides them into conjunctival nevi and invasive melanoma but, in contrast to other anatomic sites, does not recognize melanoma in situ. All atypical intraepithelial conjunctival proliferations are included in a heterogeneous category designated as primary acquired melanosis (PAM) with atypia. We performed clinicopathologic analysis of 29 cases of PAM with atypia. On the basis of histologic features and frequency of association with invasive melanoma and metastases, we were able to divide our cases into 2 histologic groups. The low-risk group (13 cases) included lesions composed of small to medium size melanocytes with high nuclear to cytoplasmic ratio and small to medium size hyperchromatic nuclei devoid of nucleoli showing predominantly single cell lentiginous growth pattern. Invasive melanoma occurred in only 2 cases from this group. None of these lesions metastasized. The second, high-risk group (16 cases), showed increased frequency of association with invasive melanoma (15/16 cases, 94%) and metastases (4/16 cases, 25%). These lesions were more heterogeneous architecturally but were all composed of melanocytes showing various degrees of epithelioid features such as abundant cytoplasm, vesicular nuclei, or prominent nucleoli. In 4 cases discrete areas showing high-risk and low-risk features were identified. All 4 lesions were associated with invasion. Our findings offer a practical approach for prognostically useful subclassification of PAM with atypia, which emphasizes cytologic features of intraepithelial conjunctival melanocytic proliferation.

INV 18 Conjunctival primary acquired melanosis (PAM) and melanoma

INV 18 Conjunctival primary acquired melanosis (PAM) and melanoma

A Non-Invasive Pigmented Nodule Arising Within Primary Acquired Melanosis—an Unusual Phenomenon

We report a case of a raised pigmented nodule that arose within conjunctival primary acquired melanosis (PAM). This nodule showed no histological features of invasive disease.

Role of topical chemotherapy for primary acquired melanosis and malignant melanoma of the conjunctiva and cornea: review of the evidence and recommendations for treatment

Surgical excision with cryotherapy is a well-established treatment option for malignant melanoma or primary acquired melanosis (PAM) with atypia of the conjunctiva and cornea. Topical chemotherapeutic agents such as mitomycin C (MMC) however, are increasingly finding use in clinical practice. A search was performed of Medline and Pubmed databases for English language articles from 1980 to the present in this field. Relevant studies were reviewed with regards to treatment regimen, rates of recurrence and metastasis, side effect profile and length of follow up. A total of 22 and 16 unique cases of biopsy proven PAM with atypia and malignant melanoma, respectively, treated with topical MMC were identified. Topical MMC was well tolerated and shows considerable promise, particularly in the treatment of diffuse PAM with atypia. However, long-term data are lacking and further studies are required.

Primary acquired melanosis of the conjunctiva

Background Primary acquired melanosis (PAM) presents as a unilateral patchy area of conjunctival pigmentation mostly found in middle-aged or elderly white patients. Because PAM has the potential of becoming malignant, it is important to recognize PAM and to rule out other causes of pigmented lesions. The presence or absence of atypia is helpful in determining the potential for malignancy, because PAM without atypia is usually benign, whereas PAM with atypia may convert into a conjunctival melanoma. If atypia is present, the presence or absence of epithelioid cells and the pattern of intraepithelial growth are the main factors in determining the likelihood of neoplastic transformation. However, atypia can only be determined with histopathologic examination. Therefore, a biopsy is usually recommended. Case report A 72-year-old white man presented for his annual examination with no visual complaints. His ocular history was remarkable for early cataracts and for a choroidal nevus. Slit lamp examination found a large dark area of elevated conjunctival pigmentation at the medial canthus that extended onto the superior bulbar conjunctiva and superior palpebral conjunctiva in the left eye. No conjunctival pigmentation had been noted previously. Results of a biopsy indicated primary acquired melanosis with atypia. The lesion was surgically excised, and the conjunctiva was reconstructed with an amniotic membrane graft. The patient was subsequently treated with topical 5-fluorouracil chemotherapy. There have been no signs of recurrence to date after his treatment. Conclusion Because of the potential for malignancy, biopsies of all cases of primary acquired melanosis are indicated. If atypia is present, treatment options include local excision, cryotherapy, and topical chemotherapy.