Christina Y. Lee

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.

Multiple Cutaneous Melanomas and Clinically Atypical Moles in a Patient With a Novel Germline BAP1 Mutation

IMPORTANCE Several kindreds having germline BAP1 mutations with a propensity for uveal and cutaneous melanomas and other internal malignancies have been described in an autosomal dominant tumor predisposition syndrome. However, clinically atypical moles have not been previously recognized as a component of this syndrome, to our knowledge. We describe the first kindred to date with a germline mutation in BAP1 associated with multiple cutaneous melanomas and classic dysplastic nevus syndrome. OBSERVATIONS We describe a 53-year-old man who was initially seen in 2003 with dysplastic nevus syndrome, multiple atypical melanocytic proliferations showing loss of immunostaining for BAP1, and 7 cutaneous melanomas. Germline testing was performed in the proband, his 16-year-old son, and his 13-year-old daughter, revealing a germline mutation in the BAP1 gene (c.592G>T, p.Glu198X) in the proband and in his 16-year-old son. CDKN2A and CDK4 genes were wild type. No members of this kindred reported a history of uveal melanoma. CONCLUSIONS AND RELEVANCE To our knowledge, this is the first report of a patient with multiple melanomas, dysplastic nevus syndrome, and an inactivating germline BAP1 mutation. The coexistence of dysplastic nevus syndrome and a BAP1 germline mutation extends the spectrum of the BAP1 tumor predisposition syndrome and may confer a greater risk for cutaneous melanomas.

Atypical Spitzoid Neoplasms in Childhood: A Molecular and Outcome Study

Abstract: 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.

Molecular techniques for predicting behaviour in melanocytic neoplasms.

Molecular tools are rapidly emerging as novel tools for clinicians caring for cancer patients. Roles for these assays in melanocytic neoplasms include diagnosis for histologically ambiguous tumors, prognosis for conventional melanoma, and theragnosis for advanced disease. The introduction of these molecular strategies is timely, as different therapeutic options are rapidly developing to treat melanoma. With the development of new and effective therapeutic options, it is more critical than ever to improve the discrimination between patients with aggressive disease and those with more indolent tumours. In this review, we will evaluate the traditional staging of melanoma and what are the likely greatest opportunities for improvement with molecular strategies. We will explore a number of molecular assays that are now commercially available for the assessment of melanocytic neoplasms, which include techniques such as fluorescence in situ hybridisation, comparative genomic hybridisation, mRNA expression profiling and next generation sequencing, and discuss the optimal utilisation of each of these assays.

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.

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

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.

Combined cutaneous tumors with a melanoma component: A clinical, histologic, and molecular study

BACKGROUND The histogenesis and clinical behavior of combined cutaneous tumors (CCTs) in which the mesenchymal component consists of melanoma remain unclear. OBJECTIVE We sought to characterize the clinical, histologic, and molecular findings in CCTs with an epithelial and a melanoma component. METHODS We retrospectively reviewed the records from 2 institutions for CCTs. Fluorescence in situ hybridization was performed to assess chromosomal copy number alterations in both components. RESULTS Sixteen CCTs were included. The most common subtype was the squamomelanocytic tumor (11), followed by the basomelanocytic tumor (3) and the trichoblastomelanoma (2). CCTs were more common in men (87%), on the head and neck (57%), and had extensive solar elastosis (81%). The median follow-up was 25 months (range, 8-167 months). One case had an adverse outcome. Fluorescence in situ hybridization revealed chromosomal alterations in approximately 55% of the cases. Five cases showed chromosomal gains only in the melanocytic component. One case showed 11q13 gains in both the epithelial and melanocytic components. LIMITATIONS Our study is retrospective and the sample is small. CONCLUSIONS The low incidence of adverse outcomes suggests that CCT may be more indolent than noncombined tumors. 11q13 amplification in both components supports the theory of dual differentiation from a common progenitor cell.

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.

Immunohistochemical and molecular analysis of spitzoid neoplasms with pulverocyte subclones

Clonal naevi are characterized by a focal proliferation of pigmented melanocytes in an otherwise banal naevus. These subclones are often composed of aggregates of larger, epithelioid melanocytes with nuclear atypia and dusty‐grey cytoplasmic pigmentation, which are referred to as ‘pulverocytes’, and this finding may lead to a misdiagnosis of malignant melanoma (MM).