Malignant melanoma of sun-protected sites: a review of clinical, histological, and molecular features.

In most cases of cutaneous melanoma, ultraviolet (UV) radiation is recognized as a prominent risk factor. Less is known regarding the mechanisms of mutagenesis for melanoma arising in sun-protected sites, such as acral and mucosal melanoma. Acral and mucosal melanoma share many common features, including a late age of onset, a broad radial growth phase with prominent lentiginous growth, the presence of field cancerization cells, and, in most cases, lack of a precursor nevus. In addition to early chromosomal instability, many of the same genes are also involved in these two distinct melanoma subtypes. To better understand non-UV-mediated pathogenesis in melanoma, we conducted a joint literature review of clinical, histological, and molecular features in acral and mucosal melanoma. We also reviewed the current literature regarding aberrations in KIT, PDGFRA, TERT, and other commonly involved genes. By comparing common features of these two subtypes, we suggest potential mechanisms underlying acral and/or mucosal melanoma and offer direction for future investigations.

A clinical, histologic, and follow-up study of genital melanosis in men and women.

BACKGROUND: Genital melanosis may clinically mimic melanoma. Little is known about the potential risk for genital and nongenital melanoma in these patients. OBJECTIVE: In this retrospective cohort study, we analyzed clinical and histologic data from patients with genital melanosis to better characterize these lesions and the risk they confer for genital and nongenital melanoma. METHODS: In all, 41 patients were identified for a retrospective chart review and histologic analysis. RESULTS: Genital melanosis can clinically mimic melanoma but the typical age of onset is younger than for genital melanoma. A majority of lesions were found to stabilize or regress over time. Five patients were found to have a history of melanoma, only 1 of which was in the genital region. Lesions from these patients were more likely to show melanocytes with suprabasal movement (P = .0101) and to have a higher melanocyte count (P < .0462). LIMITATIONS: We present a relatively small cohort of patients with an average follow-up of only 30.5 months. CONCLUSION: Patients with genital melanosis, and in particular those with any level of histologic atypia in the genital melanosis lesion, may require careful total body skin examinations for the possibility of melanoma in any body site.

Atypical Spitzoid Neoplasms in Childhood: A Molecular and Outcome Study.

The natural history of atypical Spitz neoplasms remains poorly understood, resulting in significant patient and clinician anxiety. We sought to better characterize outcomes that correlated with molecular features by performing a prospective cohort study of pediatric atypical spitzoid neoplasms in which fluorescence in situ hybridization studies were obtained for diagnosis. Cases with sufficient tissue underwent additional retrospective assessment for translocations in ALK, NTRK1, BRAF, RET, and ROS1. Among 246 total patients assessed, 13% had a positive fluorescence in situ hybridization result. Follow-up data was available in 85 patients. Two patients had a recurrence of whom 1 had distant metastasis. Both patients had homozygous deletions in 9p21. Homozygous deletions in 9p21 significantly correlated with recurrence of disease (P = 0.027). Fifteen (36%) of 42 cases were found to have a kinase fusion protein. However, the presence of kinase fusions was nonprognostic of recurrence (P > 0.99). This study was limited by the availability and length of follow-up data and the number of adverse outcomes. The majority of atypical spitzoid neoplasms in childhood have indolent behavior. Although the subgroup of patients with homozygous deletions in 9p21 is at higher risk for aggressive clinical behavior, their prognosis seems considerably better than similarly staged conventional melanoma.

Evaluation of dermoscopic features for distinguishing melanoma from special site nevi of the breast.

BACKGROUND: Nevi of special sites display aberrant clinical and histologic features that can be difficult to distinguish from melanoma, leading to unnecessarily high rates of excision with poor cosmetic or functional results. Dermoscopy can improve clinical assessment of melanocytic lesions by visualizing morphologic structures beyond the epidermis. OBJECTIVE: We sought to assess the value of specific dermoscopic features for diagnosing melanocytic neoplasms arising on the breast area in females. METHODS: In this retrospective cohort study, we collected clinical and dermoscopic information for 104 nevi and 13 melanomas removed from the breast, chest, and areola, and evaluated the diagnostic performance of each dermoscopic feature. RESULTS: Melanomas from the breast area were larger (P = .0175) than nevi and occurred in older women (P = .0117). Irregular blotches, nonuniform radial streaks, blue-gray veil, and regression were highly specific for melanoma, whereas atypical network and irregular dots and globules had low to moderate specificity. LIMITATIONS: This study was retrospective with a small sample size. CONCLUSION: Compared to melanocytic neoplasms from other sites, atypical network and irregular dots and globules were poor indicators for breast melanoma. Irregular blotches, nonuniform radial streaks, blue-gray veil, and regression were highly specific and should heighten clinical suspicion for melanoma arising on the breast.

A comparative study of proliferative activity and tumor stage of pregnancy-associated melanoma (PAM) and non-PAM in gestational age women.

BACKGROUND: The influence of pregnancy on the development, progression, and prognosis of melanoma is controversial. OBJECTIVE: We sought to compare clinical characteristics, histologic features, and proliferative activity in pregnancy-associated melanoma (PAM) and melanoma in nonpregnant women of reproductive age (non-PAM). METHODS: In this retrospective cohort study, we reviewed medical records and pathology reports from women given a diagnosis of melanoma between 2006 and 2015. We also examined tumor proliferation rates using mitotic count and 2 immunohistochemical markers of proliferation, phosphohistone H3 and Ki-67. RESULTS: In 50 PAM and 122 non-PAM cases, a diagnosis of melanoma in situ was associated with PAM. Among invasive melanomas, there was no difference in proliferative activity between groups. Pregnancy status was also not associated with age at diagnosis, tumor site, Breslow depth, Clark level, ulceration, or overall stage. LIMITATIONS: This was a retrospective study with a small sample size of mostly patients with early-stage melanoma. CONCLUSIONS: In our study of primarily early-stage melanoma, pregnancy did not have a significant impact on tumor proliferation. Particularly for patients given a diagnosis of stage I melanoma who are undergoing close surveillance, a history of PAM should not outweigh traditional factors, such as advanced maternal age, in planning future pregnancies.

The utility of dermoscopy-guided histologic sectioning for the diagnosis of melanocytic lesions: A case-control study.

BACKGROUND: Dermoscopy allows for visualization of morphologic structures beyond the epidermis, including features that may indicate early malignant transformation. However, dermoscopic features are rarely considered during routine histologic sectioning, and areas of clinical concern may be missed during microscopic evaluation. OBJECTIVE: We assessed the diagnostic impact of a dermoscopy-guided micropunch score for the evaluation of melanocytic lesions. METHODS: In this case-control study, we evaluated 150 scored melanocytic lesions. Original tissue specimens were reprocessed to create a control group, in which a new score was introduced elsewhere in the lesion to guide an alternative plane of section. Slides were reviewed in a randomized, double-blinded manner to assess histologic features and render a diagnosis. Dermoscopy was also reviewed. RESULTS: The proportion of cases with a higher grade in the original, dermoscopy-guided section was statistically significant. Four invasive melanomas were exclusively identified using the scoring protocol. The presence of regression structures, negative pigment network, radial streaming or pseudopods, and irregular blotches were highly specific for a higher diagnostic grade. LIMITATIONS: This study is retrospective and reprocessing tissue does not perfectly mimic routine sectioning. CONCLUSION: Dermoscopy can identify important, histologically high-grade areas, and this information can be used to optimize the sectioning of melanocytic neoplasms.

Immunosuppression is an independent prognostic factor associated with aggressive tumor behavior in cutaneous melanoma.

BACKGROUND: A number of factors other than those identified by the American Joint Committee on Cancer (AJCC) may have prognostic significance in the evaluation of melanoma. OBJECTIVE: We sought to evaluate commonly recorded clinical features potentially associated with aggressive melanoma. METHODS: We conducted a retrospective case-control study. We included patients given a diagnosis of cutaneous melanoma with at least 5 years of follow-up or documented metastases. Patients were divided into nonaggressive and aggressive groups. Univariate and multivariate statistical analyses were performed to evaluate the association of multiple clinical and histologic parameters and metastases. RESULTS: We included 141 patients. Significant prognostic factors in univariate analysis associated with nonaggressive disease included history of dysplastic nevus syndrome and ABCDE criteria. Significant factors in univariate analysis associated with aggressive disease included age and immunosuppression. Only age and immunosuppression remained significant in multivariate analysis when controlled across statistically significant histologic variables from AJCC. LIMITATIONS: The study is retrospective and has a small sample size. CONCLUSION: Older patients and those with a history of immunosuppression may be at higher risk for aggressive disease and should be closely monitored after an initial diagnosis of melanoma.

Morphologic clues and utility of fluorescence in situ hybridization for the diagnosis of nevoid melanoma.

BACKGROUND: Nevoid melanomas include melanomas with a low power silhouette similar to melanocytic nevi. However, at higher power magnification, nevoid melanoma may have severe nuclear atypia and dermal mitoses. METHODS: We performed a clinical, pathological and molecular study on a series of 58 examples of nevoid melanoma, excluding cases with spitzoid morphology. RESULTS: We identified distinct morphologic patterns: 'classic' nevoid melanoma, superficial spreading melanomas with nevoid invasive melanoma, lentigo maligna with nevoid invasive melanoma and deep penetrating nevus-like nevoid melanoma. Fluorescence in situ hybridization (FISH) was positive in 74% of cases. Copy number gains in 8q24 were common in amelanotic nevoid melanoma. The median follow-up was 28 months (range 140). At last follow-up, 37 patients had no evidence of disease, 3 were alive with metastases and 6 died from metastatic melanoma. Of these six patients who died, four had a sentinel lymph node biopsy (SLNB) performed, which was negative in all four. CONCLUSIONS: We describe distinct clues to the diagnosis of nevoid melanoma including occult intraepidermal atypia, and expansile nesting resulting in asymmetric silhouette or dermal papillae expansion. We also describe that nevoid melanoma have infrequent SLNB involvement in aggressive cases, and have frequent 8q24 gains rather than 9p21 deletions. Our results suggest that nevoid melanoma are distinct from spitzoid melanomas and should be distinguished.

Treatment of traumatic hypertrophic scars and keloids: a systematic review of randomized control trials.

Exaggerated healing and remodeling after skin injury may cause hypertrophic and keloidal scars, which are associated with functional and quality of life impairment. There is limited guidance available regarding the relative effectiveness of therapies for hypertrophic scars and keloids. In this review, we aim to compare the effectiveness of treatments for hypertrophic scars and keloids. MEDLINE, Embase, Scopus, and the Cochrane Collaboration database were searched from inception to March 2019 for randomized control trials of treatments for hypertrophic and keloid scars that included 20 or more patients. Outcomes evaluated included the standardized mean reduction in scarring and adverse events. The type of scar and the demographic features were analyzed for their effect on clinical outcome. Based on 25 included clinical trials, intralesional injection (64.1% [95% CI 60.8-67.5%]) may be more effective than physical (29.9% [95% CI 28.9-30.9%]) or topical treatments (34% [95% CI 31.8-36.8%]). Combination of 5-fluorouracil and triamcinolone (9:1 dilution) appeared superior among intralesional treatments for keloids. Ablative laser and pulsed-dye laser were the most useful laser treatments. Regression modeling showed laser treatment response was linked to Fitzpatrick skin type (p = 0.002). Adverse events were uncommon for all treatments and mostly transient. Intralesional treatments for keloid and hypertrophic scars may be the most reliable treatment option to improve pathologic scars, while laser treatment may have specific benefits for Fitzpatrick skin types I-III over types IV-VI. Management of pathological scars is an area of critical need, where appropriate treatment can have a significant impact on quality of life.

Paediatric melanoma: clinical update, genetic basis, and advances in diagnosis.

Paediatric melanoma is rare and challenging to diagnose. The three subtypes are Spitzoid melanoma, melanoma arising in a congenital melanocytic nevus, and conventional (also known as adult-type) melanoma. Spitzoid melanomas have characteristic histopathological and genomic aberrations. Despite frequent involvement of the sentinel lymph nodes, most cases have an uneventful clinical course. Among congenital nevi, the risk of melanoma varies by projected size in adulthood, with the greatest risk in large or giant nevi. The clinical course is generally aggressive and accounts for most melanoma-related deaths in childhood. In conventional melanoma, superficial spreading and nodular melanoma account for most cases, with risk factors and presentation largely similar to adult disease. In this Review, we discuss advances in histological diagnosis using adjunctive molecular assays, and summarise the genetic basis of paediatric melanoma.

Distinct Patterns of Acral Melanoma Based on Site and Relative Sun Exposure.

Acral melanoma is distinct from melanoma of other cutaneous sites, yet there is considerable variation within this category. To better define this variation, we assessed melanomas occurring on dorsal (n = 21), volar (n = 9), and subungual/interdigital (n = 13) acral skin as well as acral nevi (n = 24) for clinical, histologic, and molecular features. Melanomas on dorsal acral surfaces demonstrated clear differences compared with volar and subungual/interdigital melanomas. The latter two groups exhibited significantly less frequent BRAF mutations (P = 0.01), were significantly less likely to have the superficial spreading histologic subtype (P = 0.01), occurred in older patients (P = 0.05), and had more frequent involvement in non-Caucasians (P = 0.01). These differences can be explained by differing levels of UV exposure. Subungual/interdigital melanomas had the most diverse group of oncogenic mutations including PIK3CA (2/13), STK11 (2/13), EGFR (1/13), FGFR3 (1/13), and PTPN11 (1/13). In addition, subungual/interdigital melanomas had a significantly higher frequency of copy number aberrations (67%) than other subgroups (P = 0.02), particularly in CDK4 and cyclin D1, and were less likely to have BRAF mutations or a superficial spreading histologic subtype (P = 0.05) compared with volar acral melanomas. Although based on a limited sample size, differences between volar and subungual/interdigital melanomas in our study may be the result of differing levels of UV exposure.

A Comparison of Morphologic and Molecular Features of BRAF, ALK, and NTRK1 Fusion Spitzoid Neoplasms.

Recent studies have identified translocations involving the kinase domains of ALK, NTRK1, BRAF, RET, and ROS in spitzoid neoplasms. Subsequent studies have also characterized morphologic features corresponding to ALK and NTRK1 translocations. In this study, we sought to further compare morphologic features across a range of 49 genetically defined spitzoid neoplasms with ALK, NTRK1, BRAF, or RET fusions to determine discriminating features. We also compared them with a group of 22 spitzoid neoplasms, which were confirmed to be negative for fusions in ALK, NTRK1, BRAF, and RET. Features with the highest discriminatory value included diameter of the lesion, dermal architecture, and certain cytomorphologic features. Specifically, cases with a large diameter (≥9 mm) and wedge-shaped, plexiform dermal architecture of nests of large, spindle-shaped cells were most likely to have an ALK fusion. NTRK1-fused cases were most likely of the fusions to have Kamino bodies and were typically arranged in smaller nests with smaller predominantly spindle-shaped cells, occasionally forming rosettes. BRAF fusion cases were the only fusion subtype to have a predominance of epithelioid cells, were less organized in nests, and commonly had a sheet-like growth pattern or dysplastic Spitz architecture. BRAF fusion cases were most likely to have high-grade nuclear atypia, to be diagnosed as spitzoid melanoma, to have a positive result by melanoma fluorescence in situ hybridization assay, and to develop copy number gains in the kinase domain of the fusion protein. On the basis of experience from this cohort, BRAF-fused cases appear most likely to progress to melanoma.

Nonoverlapping Clinical and Mutational Patterns in Melanomas from the Female Genital Tract and Atypical Genital Nevi.

Genital melanomas (GM) are the second most common cancer of the female external genitalia and may be confused with atypical genital nevi (AGN), which exhibit atypical histological features but have benign behavior. In this study, we compared the clinical, histological, and molecular features of 19 GM and 25 AGN. We described chromosomal copy number aberrations and the mutational status of 50 oncogenes and tumor suppressor genes in both groups. Our study showed that a pigmented lesion occurring in mucosal tissue, particularly in postmenopausal women, was more likely to be a melanoma than a nevus. GM had high levels of chromosomal instability, with many copy number aberrations. Furthermore, we found a completely nonoverlapping pattern of oncogenic mutations when comparing GM and AGN. In GM, we report somatic mutations in KIT and TP53. Conversely, AGN had frequent BRAF V600E mutations, which were not seen in any of the GM. Our results show that GM and AGN have distinct clinical and molecular changes and that GM have a different mutational pattern compared with AGN.