Extracutaneous Melanomas Research Articles

Oncoviruses and melanomas: A retrospective study and literature review.

The role of human oncoviruses in melanoma has been poorly investigated. The aim of this study was to investigate the association between oncoviruses and melanomas searching for human papillomavirus (HPV), Epstein Barr virus (EBV), and human herpesvirus 8DNA in melanoma specimens. Formalin-fixed and paraffin-embedded tissue specimens of cutaneous, mucosal, and ocular melanomas (OM) were selected from the Pathology Departments of the Galliera Hospital (Genoa) and the University Hospitals of Turin and Cagliari. Cutaneous and mucosal nevi have been collected as controls. The oncoviruses search has been performed with different polymerase chain reaction reagent kits.Fifty-four melanomas (25 mucosal, 12 ocular, and 17 cutaneous) and 26 nevi (15 cutaneous and 11 mucosal) specimens were selected. The detection rate for one of the investigated oncoviruses was 17% in mucosal, 20% in ocular, and 0% in cutaneous melanomas (CMs). Despite the differences between groups seeming remarkable, there was no statistical significance (p > 0.5). Our data do not support a primary role of oncoviruses in melanoma carcinogenesis; however, the finding of HPV and EBV DNA in a considerable fraction of mucosal and OMs suggests that these viruses may act as cofactors in the development of extra-CMs.

Magnetic Resonance Imaging findings in Primary Extracutaneous Melanoma from a Tertiary Cancer Care Centre: A Retrospective Cohort Study

Introduction: Extracutaneous melanomas are rare, aggressive type of tumour, clinically and biologically distinct from their cutaneous counterpart. The two large broad categories of the extracutaneous melanomas are ocular and mucosal subtypes. Melanomas are classically hyperintense on T1 weighted images and hypointense on T2 weighted images due to the paramagnetic effects of melanin and presence of paramagnetic elements. Aim: To describe the Magnetic Resonance Imaging (MRI) findings in primary extracutaneous melanomas at various anatomic sites. Materials and Methods: This was a retrospective study in which 13 cases of primary extracutaneous melanomas were identified from Picture Archiving and Communication System (PACS) archive over a period of eight years (January 2013 - December 2020). Location and morphology of the tumour, signal intensity characteristics in T1 weighted, T2 weighted (hyperintense/ isointense/hypointense to adjacent muscle) and Diffusion Weighted Imaging (DWI) (presence or absence of diffusion restriction) were analysed. Results: The ocular melanomas (n=2) were seen as well-defined small intraocular mass attached to the choroid. The mucosal melanomas of the nasal cavity (n=2), rectum (n=4), vagina (n=3) and cervix (n=2) presented as large intraluminal polypoidal masses. Three categories of MRI appearances emerged in this study. Majority of the cases (n=8) showed hyperintense signals in T1- weighted images and hypointense signals in T2 weighted images (category 1). Diffusion restriction was seen in all cases (n=13) with low Apparent Diffusion Coefficient (ADC) values which ranged from 439-966 mm/sec with an average value of 755 mm/ sec. Conclusion: T1 and T2 shortening are typical of melanoma, the absence of these does not exclude the diagnosis. Although diffusion restriction and low ADC values help in the diagnosis of these tumours, they do not tend to play a specific role in the diagnosis.

Malignant Melanoma: Skin Cancer-Diagnosis, Prevention, and Treatment.

Melanoma is a skin cancer caused by a malignancy of melanocytes. Incidence of melanoma is rapidly increasing worldwide, which results in public health problems. Primary extracutaneous melanomas can be ocular, gastrointestinal, mucosal, leptomeningeal, genitourinary, and lymphatic. The relationship between exposure to ultraviolet (UV) light and development of melanoma is intensively acute and complex, and intermittent sun exposure greatly increases the risk of melanoma. It is the fifth most common type of cancer in men number and the sixth most common in women. The diagnosis of melanoma is made through clinical assessment of the pigmented by health care professionals. Architectural features of malignant melanoma including asymmetry, confluence of growth, marked cellularity, and poor circumscription. The cytological feature of malignant melanoma include an irregular and thick nuclear membrane and prominent nucleoli. The preventive measures include reducing exposure to UV light and the sun. The early detection of skin cancer greatly reduces both short- and long-term morbidity and mortality. The treatment and follow-up with the doctor for melanoma patients may differ because of the stage of the tumor and the primary lesion. The typical therapy for malignant melanoma is surgical excision, immunotherapy such as interleukin 2 (IL-2), gene therapy, and biochemotherapy.

Urogenitalis lokalizációjú mucosamelanoma primer és áttétes esetei klinikánkon

Both primary and metastatic cases of mucosal melanoma in urogenital localization are rare tumors. Only 4-5% of all primary melanomas do not arise from the skin. Extracutaneous melanomas have a complex clinical presentation, but these aggressive tumors have a poor prognosis. In our department, we found 7 patients with malignant melanoma of the genitourinary tract in the past few years. The 7 cases were: primary amelanotic melanoma of the female urethra, a primary melanoma of the bladder, two primary melanomas of the penis, a metastatic melanoma of the urethra and another to the testis and a metastatic melanoma of the bladder with melanuria. We retrospectively analyzed the available data to describe the presentation, management, and clinical outcome of the patients. In the three inoperative cases, palliative, urologic surgical procedures and systemic antitumor therapy were performed. Two of the four primary urogenital tumors were localized to the penis. In one case, local recurrence developed after surgical treatment, but with a radical, repeated surgery, the patient has been asymptomatic for a year and a half. In the other, neglected case, the penis melanoma spread through the urethra and the inguinal lymph nodes two years after radical surgery and inguinal block dissection. In the female primary urethral melanoma case, the first histological study reported a primary mesenchymal tumor, and the recurrent tumor that occurred one and a half years later showed melanoma diagnosis. Radical surgery performed because of urethral involvement resulted in a 5-year asymptomatic state, followed by local recurrence and distant metastasis. In the fourth case of a primary bladder melanoma, the rapid progression of the disease and the BRAF positivity of the tumor suggested that not the firstly diagnosed bladder melanoma was the primary tumor. The occurrence of urinary tract melanoma is very rare and its discovery happens often in a disseminated state, so the expected prognosis of the cases is also poor. The most important factors for increasing therapeutic efficacy are early diagnosis and radical surgical intervention. Tumors appearing in different localizations require different urological surgical approaches. The literature recommendations for treatment are not uniform. Their prognosis is worse compared to the cutaneous melanoma, which may be due to clinical and pathological diagnostic difficulties. The latest targeted and immunotherapeutic agents can significantly improve the survival of metastatic patients. Orv Hetil. 2019; 160(10): 378-385.

Clinicopathological study of malignant melanoma in a regional cancer center.

: Malignant melanoma is a tumor of melanocytic origin. Although uncommon in India as compared with the west, its prevalence is increasing. To document the pattern of clinicopathological features of malignant melanoma cases attending in a regional cancer center in eastern India. The present study was a retrospective study of 182 cases diagnosed histopathologically as malignant melanoma during 2011-2016. Out of the total cases, 170 (93.4%) were cutaneous and 12 (6.6%) were noncutaneous melanoma. The most common age group was sixth decade with a male predominance. Conventional melanotic melanomas were 176 (96.70%), and only 6 cases (3.30%) were amelanotic melanoma. Among noncutaneous melanomas, 6 were in anorectum, 2 in conjunctiva, and 1 case each in nasal cavity, palate, gingivo-buccal sulcus, and vagina. The acrallentigenous type was the most common variety, and the mixed epithelioid and spindle cell type was the most common histopathological pattern. Clark's level III was the most common level of invasion. The lower extremity is the most common site for melanoma, whereas extracutaneous melanomas are exceedingly rare and aggressive neoplasms. Melanoma can metastasize to regional lymph nodes, however, visceral metastasis to liver can also occur. In the absence of pigment in amelanotic melanoma, immunohistochemical markers such as HMB 45 can be used for definitive diagnosis.

Advances in the Treatment of Advanced Extracutaneous Melanomas and Nonmelanoma Skin Cancers.

Cutaneous malignancies make up the greatest proportion of all human cancers and include melanomas as well as nonmelanoma skin cancers (NMSCs) such as basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), as well as less common Merkel cell carcinoma (MCC), cutaneous lymphomas, cutaneous adnexal tumors, Kaposi sarcomas, and other sarcomas. Each of these NMSCs differ significantly in biology, clinical behavior, and optimal treatment recommendations from each other and from cutaneous melanoma. Similarly, less common extracutaneous melanomas, such as mucosal (MMs) and uveal (UMs), are unique biologic and clinical entities that require distinct diagnostic and management considerations. In this review, we summarize recent advances in biology and treatment of extracutaneous melanomas and NMSCs, including MMs, UMs, cSCC, BCC, and MCC.

Advances in the Treatment of Advanced Extracutaneous Melanomas and Nonmelanoma Skin Cancers

Cutaneous malignancies make up the greatest proportion of all human cancers and include melanomas as well as nonmelanoma skin cancers (NMSCs) such as basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), as well as less common Merkel cell carcinoma (MCC), cutaneous lymphomas, cutaneous adnexal tumors, Kaposi sarcomas, and other sarcomas. Each of these NMSCs differ significantly in biology, clinical behavior, and optimal treatment recommendations from each other and from cutaneous melanoma. Similarly, less common extracutaneous melanomas, such as mucosal (MMs) and uveal (UMs), are unique biologic and clinical entities that require distinct diagnostic and management considerations. In this review, we summarize recent advances in biology and treatment of extracutaneous melanomas and NMSCs, including MMs, UMs, cSCC, BCC, and MCC.

Two Cases of Primary Extracutaneous Melanoma: Primary Gastric Melanoma and Primary Melanoma of the Lung

Primary extracutaneous melanoma is an exceedingly rare occurrence, and primary extracutaneous melanomas arising in tissues thought to be devoid of melanocytes are even rarer. The paper that follows describes two such cases, one case of primary gastric melanoma and one case of primary melanoma of the lung. Both cases were treated solely with surgical excision of the lesion, and the patients have experience no recurrent disease. Novel approaches to treat extracutaneous melanomas are also discussed.

Primary anal malignant melanoma: a case report

Primary anal malignant melanoma is an uncommon and aggressive disease. In many cases, the disease is undetected or mistaken for a benign polyp or haemorrhoids until it reaches an advanced stage. Extracutaneous melanomas require special consideration due to their late diagnosis and consequently poor prognosis. Extracutaneous melanomas are considered to be biologically more aggressive than their cutaneous counterparts. Surgical excision remains the cornerstone of therapy. This case is reported because of the rarity of the disease in anal canal found in an 80 year old female who was managed with wide local excision of the growth.

Epidemiology and survival outcomes of ocular and mucosal melanomas: A population‐based analysis

Extracutaneous melanomas are poorly characterized tumors that include ocular (OM), mucosal (MM) and leptomeningeal melanomas, often lacking standardized staging and treatment guidelines. We analyzed cases of cutaneous melanoma (CM, N = 219,890), OM (N = 7,069) and MM (N = 2,755) of different anatomical origins, diagnosed between 1988 and 2010, recorded in the Surveillance Epidemiology and End Results (SEER) database. Relative survival was studied in patients grouped by summary stage classification (localized, regional or distant disease) and in multivariate models adjusting for varying distribution of baseline factors. Unlike in CM, the incidence rate in MM increased exponentially with age. Five-year relative survival was significantly worse for OM (78%) and for most mucosal sites (aggregate 34%, range 3-69%) compared with CM (89%). The differences between primary sites were particularly pronounced in localized disease, with a hazard ratio of 5.7 for OM, 4.3-9.0 for external genital or oral cavity MM and 19.8-90.4 for other mucosal locations. Melanomas of the pharynx, gastrointestinal, urinary tract and vagina had poor outcomes regardless of clinical stage. In contrast to CM, there was no evidence of improved survival in OM and MM during the study period. A substantial proportion of patients with operable OM or MM underwent radical organ resections (13-88% depending on site and stage) or perioperative radiotherapy (0-66%). In conclusion, extracutaneous melanomas have a markedly worse survival than CM and aggressive locoregional management appears to be insufficient for their control. Because of poor outcomes in MM, studies of systemic therapy are warranted regardless of the extent of disease at presentation.

Extracutaneous melanomas and the risk of second primary melanocytic malignancy in the Canadian population

Extracutaneous melanomas and the risk of second primary melanocytic malignancy in the Canadian population

DNA from BK Virus and JC Virus and from KI, WU, and MC Polyomaviruses as Well as from Simian Virus 40 Is Not Detected in Non-UV-Light-Associated Primary Malignant Melanomas of Mucous Membranes

The single most important causative factor for malignant melanomas of the skin is UV radiation. However, this is not true for melanomas on body surfaces sheltered from the sun; thus, it is important to seek new causative factors of melanoma genesis. Human papillomaviruses and gammaherpesviruses are associated with human skin cancer; for example, human papillomavirus types 5 and 8 are associated with epidermodysplasia verruciformis, and human herpesvirus 8 is associated with Kaposi's sarcoma. Recently, a newly described human polyomavirus, Merkel cell polyomavirus (MCPyV), has been associated with Merkel cell carcinoma, an unusual form of neurotropic skin cancer. Moreover, melanocytes are of neuroepithelial origin. This background impelled us to investigate if human polyomavirus DNA could play a role in the development of extracutaneous melanomas. Sixty-four extracutaneous melanomas were initially collected and dissected. Of these, 38 could be successfully used for further testing for the presence of the five human polyomaviruses known so far-BK virus (BKV), JC virus (JCV), KI polyomavirus (KIPyV), WU polyomavirus (WUPyV), and MCPyV-and of simian virus 40 (SV40). No polyomavirus DNA could be detected in any of the samples tested by use of a nested PCR detecting BKV, JCV, and SV40; a newly designed PCR detecting KIPyV and WUPyV; or a newly designed PCR for MCPyV. We conclude that since no human polyomavirus DNA was detected in primary malignant melanomas on non-sun-exposed body surfaces, these polyomaviruses presumably are not major factors for the development of extracutaneous melanomas.

Short German guidelines: Malignant melanoma

Malignant melanoma is a malignant tu-mor which arises from melanocytic cellsand primarily involves the skin. For thebalance of these guidelines, the termsmalignant melanoma and melanoma willbe used interchangeably, because thereare no benign melanomas. Melanomascan also arise in the eye (conjunctiva anduvea), meninges and on various mucosalsurfaces. While melanomas are usuallyheavily pigmented, there are also amela-notic tumors. Even small tumors have atendency towards metastasis and thus arelatively unfavorable prognosis. Melan-omas account for 90% of the deaths as-sociated with cutaneous tumors. The incidence of melanoma is increasingworldwide in white populations, especi-ally where fair-skinned peoples receiveexcessive sun exposure. In central Europethe incidence is 10 – 12 / 100,000yearly; in the USA, 10-25 / 100,000yearly; and in Australia the highest inci-dence, 50-60 / 100,000 yearly. In indivi-duals with more pigmentation (Asians,Africans) melanomas are uncommonand almost always found on either acralor mucosal surface. Individuals withlarge numbers of melanocytic nevi andthose with melanoma precursors (dyspla-stic nevi, congenital nevi) are at greaterrisk. The inheritance of melanoma is po-lygenic; 5-10% of melanomas appear inmelanoma-prone families. In addition tothese genetic and constitutional factors,the most important exogenous factor isexposure to UV irradiation. The relativeroles of toxic substances, medicationsand hormones (pregnancy, oral contra-ceptives) are controversial. The immunestatus of the patient plays a major role indetermining the course of melanoma, asnumerous examples of spontaneous re-gression or of rapid progression in im-munosuppressed individuals bear testi-mony.A number of different types of melano-mas can be identified clinically and hi-stologically. Some tumors either repre-sent mixed forms or are not classifiable.Examples of special forms are amelanoticmelanomas, mucosal melanomas, andother extracutaneous melanomas, whichtogether account for about 5% of allmelanomas.

Extracutaneous Melanomas Can Be Easily Missed

Extracutaneous Melanomas Can Be Easily Missed

Extracutaneous Malignant Melanomas

Extracutaneous malignant melanomas are rare tumors with vexing clinical presentation and grim prognosis. Only 4%–5% of all primary melanomas do not arise from the skin. These tumors are almost uniformly fatal, even in 2006. Although a fairly good number of these lesions were reported in the literature, the lack of a side-by-side analysis of these studies has resulted in tentative conclusions that merely offer a first glimpse at the clinicopathologic diversity of these lesions. To remedy this issue, this article took an aim at presenting a literature review concerning extracutaneous malignant melanomas. It also reports several cases of extracutaneous melanomas, which I came across in my 15 years of surgical and molecular pathology practice. The study raises several notions. Extracutaneous malignant melanomas are rare but extremely aggressive lesions with a grim outcome. They include ocular, metastatic, anorectal, mucosal, nail beds, conjunctival, vaginal, urogenital, orbital, esophageal, and leptomeningial malignant melanomas. The development of these lesions lacks an association with sun damage, family history, or precursor nevi. These lesions cause considerable diagnostic consternation and their distinction from other types of tumors (such as undifferentiated carcinomas, high-grade sarcomas, and lymphomas) is critical both from a diagnostic and prognostic point of view. In the proper clinical, histological, and cytological context, immunopositivity for S100 protein, HMB45, and vimentin allows the distinction of these malignant melanomas from other histologically similar malignancies. To conclude, extracutaneous melanoma should be considered while undifferentiated neoplasms, especially those displaying prominent eosinophilic nucleoli, and the coexistence of epithelioid and spindle cells. Special staining and immunohistochemistry should be resorted to establish the diagnosis.

The association between large congenital melanocytic naevi and cutaneous melanoma: preliminary findings from an Internet-based registry of 379 patients

There is ample evidence in the literature to support the fact that there is an increased risk of the development of melanoma in individuals with a large congenital melanocytic naevus (LCMN). The published melanoma risk estimates, by and large, do not distinguish between cutaneous and extracutaneous melanomas. It is currently not known to what extent each contributes to the overall cited melanoma risk estimates. In order to obtain a better understanding of the association between LCMN and cutaneous melanoma arising within an LCMN, we report the preliminary findings of a cross-sectional study of 379 patients, with a median age of 3 years, from the first self-referred, Internet-based registry of patients with LCMN. To date, no cutaneous melanoma has been reported; possible reasons for this finding are discussed. Further research is required to clarify the risk of the development of cutaneous melanoma separate from non-cutaneous melanoma and to identify subgroups of patients with LCMN at highest risk for the development of melanoma. This information will help to formulate appropriate decisions concerning the management of patients with LCMN.

Primary malignant melanoma of the vulvaAn aggressive tumor for modeling the genesis of Non-UV light-associated melanomas

Malignant melanomas appear in such sun-shielded areas as the vulva, challenging conventional knowledge that they are associated with UV radiation. Based on 1 442 patients with vulvar melanomas the tumors’ epidemiology, clinical manifestations, histopathology, molecular genetics, treatment strategies, and prognosis were surveyed. Despite their sun-shielded location and rare incidence, vulvar melanomas were, on average, more dense than melanomas on the body surface and nearly the density of melanomas in chronically sun-exposed skin of the head and neck. Vulvar melanomas differed markedly from cutaneous melanomas, as evidenced by histopathological lesions and molecular genetics. Most melanomas were located on the glabrous skin as opposed to the hairy skin within the vulva and differed significantly in biological properties. The prognosis for the patients was poor, and in the 11 largest studies of surgical strategies, none offered a significant survival advantage. Tumor thickness and ulceration were usually significant predictors of (poor) prognosis in multivariate analyses along with macroscopic amelanosis, angioinvasion or DNA non-diploidy in some reports. Clear-cut biological differences between vulvar and cutaneous melanomas and between melanomas within different vulvar sites provide new paths for extensive research on melanomagenesis and for potential therapies. Additionally, studies of vulvar and other extracutaneous melanomas should characterize subgroups of cutaneous melanomas and identify their cause(s), which are apparently not linked to UV radiation.

Large congenital melanocytic nevi and the risk for development of malignant melanoma and neurocutaneous melanocytosis.

To determine the risk for developing malignant melanoma and neurocutaneous melanocytosis (NCM) in patients with large congenital melanocytic nevi. Follow-up data suitable for calculations were available on 160 patients in the New York University Registry of Large Congenital Melanocytic Nevi who had been free of known melanomas or NCM when entered into the Registry. The cumulative 5-year life-table risks for developing melanoma and NCM were calculated. The relative risk for developing melanoma, using a control general population reference group, was determined. The 160 patients (median age at entry: 14 months) were followed prospectively for an average of 5.5 years. Three extracutaneous melanomas developed: 2 were in the central nervous system (CNS) and 1 was retroperitoneal. The 5-year cumulative life-table risk for developing melanoma was 2.3% (95% confidence interval [CI]:.8-6.6) and the relative risk was 101 (95% CI: 21-296). No melanoma occurred within a large congenital melanocytic nevus. Four patients developed manifest NCM, 2 with CNS melanomas. The 5-year cumulative life-table risk for developing NCM was 2.5% (95% CI:.8-7.2). Ten patients were excluded from the calculations because of preexisting disease on entry into the Registry: 5 with manifest NCM and 5 with melanomas (3 in large congenital melanocytic nevi, 1 in nonnevus skin, and 1 unknown primary). Patients with large congenital melanocytic nevi are at increased risk for developing melanomas. There is also a significant increased risk for developing NCM. The high incidence of CNS involvement may influence decisions concerning treatment of the large congenital melanocytic nevi.

Cutaneous melanoma risk and phenotypic changes in large congenital nevi: A follow-up study of 46 patients

Background: Large congenital melanocytic nevi may undergo malignant transformation. Few prospective studies have evaluated the incidence of melanoma in large congenital nevi or have described how their phenotypic characteristics change over time. Objective: We attempted to ascertain the incidence of cutaneous melanoma in a cohort of patients with large congenital nevi and to evaluate the frequency and nature of several morphologic changes over time. Methods: Forty-six patients with large congenital nevi were prospectively followed up in our Pigmented Lesion Group. Large congenital nevi were defined as those occurring at birth and comprising 5% body surface area or greater in infants, children, and preadolescents and more than 20 cm in adolescents and adults. Information was obtained on location, satellitosis, changes in color and nodularity, and incidence of melanoma. The most atypical histologic findings from those who underwent biopsy were also noted. Standardized morbidity ratios (SMR) and 5-year cumulative risk were calculated and presented with corresponding 95% confidence intervals (CI). Results: Twenty-four male and 22 female patients (age range, 7 days to 36.7 years; mean, 8.4 years) with large congenital nevi were followed up prospectively for a total of 335 person-years (range, 0.17 to 17.5 person-years; mean, 7.3 person-years). Two patients (4.3%) experienced 3 cutaneous melanomas that originated in their primary congenital nevi. We found one case of neurocutaneous melanosis. No satellite, extremity, or extracutaneous melanomas were detected. The majority of nevi in our cohort were located on the posterior trunk, were accompanied by multiple satellite congenital nevi, and became lighter over time. In the 27 patients who underwent biopsies, the most atypical histologic findings included melanoma, atypical melanocytic dysplasia, neurocristic dysplasia, atypical neural crest hamartomas, atypical spindle cell tumors, and congenital nevi with dysplasia. The SMR comparing observed-to-expected melanoma incidence was 148 (95% CI 18, 535; P = .0002) indicating a substantially increased risk of melanoma in patients with large congenital nevi. The cumulative 5-year risk of cutaneous melanoma was 5.7% (95% CI 0%, 13.5%). Conclusion: Our findings are consistent with the previously observed increased risk for the occurrence of cutaneous melanoma in patients with large congenital nevi. Although the number of patients with melanoma in this study is small, our observations and those of previous studies suggest that location and age correlates with melanoma risk. The majority of large congenital nevi are located on the trunk and may undergo several clinical changes as these patients age. Additional prospective studies are needed to gain more insight into the natural history and optimal management of large congenital nevi. (J Am Acad Dermatol 1998;39:923-32.)

Neurocutaneous Melanosis

A case of neurocutaneous melanosis with malignant leptomeningeal melanoma is reported in a 50-year-old white woman. The case is exceptional as regards the late onset of symptoms and death. Although the association of extracutaneous melanomas with cutaneous pigmented lesions is rare, dermatologists must be aware of their presence.