TERT and TERT promoter in melanocytic neoplasms: Current concepts in pathogenesis, diagnosis, and prognosis

Background and objectiveLocated on chromosome locus 5p15.33, telomerase reverse transcriptase (TERT or hTERT) encodes the catalytic subunit of telomerase which permits lengthening and preservation of telomeres following mitosis. Mutations in TERT promoter (TERT‐p) upregulate expression of TERT, allowing survival of malignant cells and tumor progression in wide variety of malignancies including melanoma. The objective of this review is to examine the roles of TERT and TERT‐p in the pathogenesis, diagnosis, and prognostication of cutaneous melanoma.MethodsAll studies of TERT or TERT‐p in cutaneous melanocytic neoplasms with the following inclusion criteria were reviewed: publication date between 2010 and 2019, English language, and series of ≥3 cases were reviewed for evidence supporting the role of TERT in pathogenesis, diagnosis, and prognosis. Studies with <3 cases or focused primarily on mucosal or uveal melanocytic tumors were excluded.Results and conclusionTERT‐p mutations are frequent in chronic and non‐chronic sun damage melanoma and correlate with adverse prognosis, inform pathogenesis, and may provide diagnostic support. While TERT‐p mutations are uncommon in acral melanoma, TERT copy number gains and gene amplification predict reduced survival. Among atypical spitzoid neoplasms, TERT‐p mutations identify biologically aggressive tumors and support the diagnosis of spitzoid melanoma. TERT‐p methylation may have prognostic value in pediatric conventional melanoma and drive tumorigenesis in melanoma arising within congenital nevi. Finally, TERT‐p mutations may aid in the differentiation of recurrent nevi from recurrent melanoma.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156143/2/cup13691.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156143/1/cup13691_am.pd

A pediatric case of pigmented epithelioid melanocytoma with chromosomal copy number alterations in 15q and 17q and a novel NTRK3‐SCAPER gene fusion

Pigmented epithelioid melanocytoma (PEM) represents a group of rare, heavily pigmented melanocytic tumors encompassing lesions previously designated as “animal‐type melanomas” and “epithelioid blue nevi.” Despite the association of multiple such tumors in the setting of Carney complex, most cases of PEM occur spontaneously as solitary neoplasms in otherwise healthy patients. PEM may arise in both children and adults, and has a known propensity to spread to the regional lymph nodes. Despite this latter finding, recurrence at the biopsy site or spread beyond the lymph node basin is exceptionally uncommon. Although the molecular basis for PEM continues to be characterized, findings to date suggest that this category of melanocytic neoplasia has genetic alterations distinct from those seen in common nevi, dysplastic nevi, Spitz nevi, and melanoma. Herein, we present an in‐depth clinical, histopathologic, and molecular analysis of a case of PEM occurring on the scalp of a young African American girl found to have a novel NTRK3‐SCAPER gene fusion.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152480/1/cup13566.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/152480/2/cup13566_am.pd

A pediatric case of pigmented epithelioid melanocytoma with chromosomal copy number alterations in 15q and 17q and a novel NTRK3‐SCAPER gene fusion

Pigmented epithelioid melanocytoma (PEM) represents a group of rare, heavily pigmented melanocytic tumors encompassing lesions previously designated as “animal‐type melanomas” and “epithelioid blue nevi.” Despite the association of multiple such tumors in the setting of Carney complex, most cases of PEM occur spontaneously as solitary neoplasms in otherwise healthy patients. PEM may arise in both children and adults, and has a known propensity to spread to the regional lymph nodes. Despite this latter finding, recurrence at the biopsy site or spread beyond the lymph node basin is exceptionally uncommon. Although the molecular basis for PEM continues to be characterized, findings to date suggest that this category of melanocytic neoplasia has genetic alterations distinct from those seen in common nevi, dysplastic nevi, Spitz nevi, and melanoma. Herein, we present an in‐depth clinical, histopathologic, and molecular analysis of a case of PEM occurring on the scalp of a young African American girl found to have a novel NTRK3‐SCAPER gene fusion.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152480/1/cup13566.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/152480/2/cup13566_am.pd

KRAS mutation in secondary malignant histiocytosis arising from low grade follicular lymphoma

Abstract Background Transformation of follicular lymphoma most typically occurs as diffuse large B-cell lymphoma, however other forms of transformation such as classic Hodgkin lymphoma and lymphoblastic transformation can occur. Secondary malignant histiocytosis also represents a rare form of transformation, which is thought to occur due to a process of transdifferentiation whereby the lymphoma cells exhibit lineage plasticity and lose all evidence of B-cell phenotype and instead acquire the phenotype of a histiocytic neoplasm. Little is known about the underlying genetic alterations that occur during this unusual process. Comparative genetic analysis of pre- and post-transformation/transdifferentiation would be one tool by which we could better understand how this phenomenon occurs. Case presentation Here we report the clinical, immunophenotypic and genetic features of a rare case of secondary malignant histiocytosis, Langerhans cell-type (Langerhans cell sarcoma) arising from a previous low grade follicular lymphoma. FISH analysis confirmed the presence of IgH/BCL2 rearrangement in both the low grade follicular lymphoma (FL) and transformed Langerhans cells sarcoma (LCS) samples, demonstrating a clonal relationship. Comparative whole exome sequencing was then performed, which identified a KRAS p.G13D mutation in the LCS that was not present in the FL. Conclusions This report highlights genetic alterations, in particular an acquired somatic KRAS mutation, that may occur during transdifferentiation, with additional significance of KRAS mutation as a possible therapeutic target in cases which otherwise would have limited treatment options.https://deepblue.lib.umich.edu/bitstream/2027.42/145736/1/13000_2018_Article_758.pd

Comprehensive histopathological comparison of epidermotropic/dermal metastatic melanoma and primary nodular melanoma

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141829/1/his13384.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141829/2/his13384_am.pd

Appropriate use criteria in dermatopathology: Initial recommendations from the American Society of Dermatopathology

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/145218/1/cup13142.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/145218/2/cup13142_am.pd

Molecular testing for melanocytic tumors: a practical update

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/171197/1/his14570.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/171197/2/his14570_am.pd

Primary cutaneous cribriform carcinoma: report of six cases with clinicopathologic data and immunohistochemical profile

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111956/1/cup12469.pd

Acrokeratosis paraneoplastica (Bazex syndrome): Report of a case associated with small cell lung carcinoma and review of the literature

Acrokeratosis paraneoplastic (Bazex syndrome) is a rare, but distinctive paraneoplastic dermatosis characterized by erythematosquamous lesions located at the acral sites and is most commonly associated with carcinomas of the upper aerodigestive tract. We report a 58-year-old female with a history of a pigmented rash on her extremities, thick keratotic plaques on her hands, and brittle nails. Chest imaging revealed a right upper lobe mass that was proven to be small cell lung carcinoma. While Bazex syndrome has been described in the dermatology literature, it is also important for the radiologist to be aware of this entity and its common presentations

Significance of epidermal mitoses in challenging melanocytic proliferations

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135988/1/cup12855.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135988/2/cup12855_am.pd