Lauren Meldi Sholl

Comparative analysis of atypical Spitz tumors with heterozygous versus homozygous 9p21 deletions for clinical outcomes, histomorphology, BRAF mutation, and p16 expression

Studies have shown that atypical Spitz tumors (ASTs) with homozygous deletions in 9p21 have worse prognosis than those without this finding. Conversely, numerous studies have shown that a range of other copy number aberrations including isolated 6q23 or 3p21 loss may be seen in ASTs without conferring higher risk for aggressive behavior. We studied 31 cases of ASTs with heterozygous 9p21 loss and hypothesize that heterozygous 9p21 loss in ASTs does not confer an increased risk for aggressive behavior. We compared clinical, histopathologic, and immunohistochemical features of 31 ASTs with heterozygous 9p21 deletions with 30 ASTs with homozygous 9p21 deletions. No ASTs with heterozygous 9p21 deletions resulted in distant metastasis. Severe cytologic atypia, a predominance of epithelioid cytomorphology and increased dermal mitotic activity were more frequent in ASTs with homozygous deletions versus ASTs with heterozygous deletions (P=0.0003, 0.0004, and 0.042, respectively). Expression of p16 and mutated BRAFV600E proteins was also evaluated in 17 conventional (nonspitzoid) melanomas with homozygous 9p21 loss and the 2 groups of ASTs. Expression of p16 was retained in 67% of ASTs with heterozygous loss, whereas among ASTs with homozygous loss, 100% of cases had areas with complete loss of staining. Mutated BRAFV600E protein expression was detected in 53% of conventional melanomas, in none of the ASTs with heterozygous loss, and in 1 AST with homozygous loss (P=0.0007 between homozygous ASTs and the conventional melanomas). Coexisting BRAF mutation and 9p21 deletion was more common in conventional melanomas than in ASTs with heterozygous or homozygous 9p21 deletion. BRAF mutation was highly uncommon among the ASTs.

Strategies to regulate transcription factor–mediated gene positioning and interchromosomal clustering at the nuclear periphery

In yeast, transcription factors mediate gene positioning at the nuclear periphery and interchromosomal clustering. These phenomena are regulated by several different strategies that lead to dynamic changes in the spatial arrangement of genes over different time scales.

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.

Desmoplastic nevus of chronically sun-damaged skin: an entity to be distinguished from desmoplastic melanoma.

Abstract:Desmoplastic (sclerotic) nevus (DSN) can often be difficult to differentiate from desmoplastic melanoma (DM). This can be especially difficult when DSNs occur in a background of heavy solar elastosis. We have observed numerous examples of DSNs occurring in chronically sun-damaged (CSD) skin. In a subset of these cases, we have observed notable pleomorphism and nuclear atypia raising concern for the possibility of DM. In this study, we evaluated the clinical, histopathologic, and immunohistochemical findings in 23 cases of DSN occurring in CSD skin and compared them with 10 cases of DM. DSN on CSD skin is seen in adults (mean, 53.2 years) with a female predominance (70%) and upper (57%) and lower (17%) extremity anatomic locations. Most DSNs present as small flesh-colored macules or papules. Typical histologic features include symmetry, limited junctional growth, presence of a lentiginous component often with focal and limited pagetoid spread (extension across only a few rete ridges), and lack of deep extension. DSN and DM had a statistically significant difference in immunohistochemical staining for Melan-A and p75. Melan-A was positive in 18 of 20 DSNs and only 2 out of 10 DMs, whereas p75 was positive in all DMs (10/10) and was weakly positive in 11 of 20 DSN cases. We believe that our study offers some useful clinical, histologic, and immunohistochemical clues to help differentiate DSNs on CSD skin from DMs.

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.