Sapna M. Amin

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.

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.

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.

Primary cutaneous mammary analog secretory carcinoma with ETV6-NTRK3 translocation

Abstract:Mammary analog secretory carcinoma (MASC) is a recently described tumor of the salivary glands named for its morphological and molecular similarity to secretory carcinoma of the breast. Many primary carcinomas arising from the adnexal glands also share similar morphology to those arising from the breast. Brandt et al first described primary cutaneous MASC in 2009 and since then only 2 other cases have been reported. Herein, we describe a long-standing mass on the arm of an otherwise healthy 40-year-old female. Histologic examination revealed a circumscribed but unencapsulated, nodular tumor composed of bland epithelial cells arranged in solid and microcystic growth patterns. The cells showed vacuolated cytoplasm and round to oval nuclei with vesicular chromatin. Intraluminal homogenous eosinophilic secretions were present. Mitotic figures were not identified. The tumor cells stained positive for CK8/18, CK7, and S100 but were negative for other markers performed, including estrogen receptor, progesterone receptor, HER2/neu, paired box 8 (PAX8), and thyroid transcription factor 1 (TTF1). As the patient clinically had no other masses or known carcinomas, a diagnosis of primary cutaneous MASC was rendered. The ETV6-NTRK3 fusion transcript was subsequently detected by reverse transcriptase polymerase chain reaction amplification, further supporting the diagnosis. We present this case to review the histologic features of MASC and highlight the importance of recognizing this lesion not only as a possible cutaneous metastasis but also as a primary cutaneous tumor.

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.

Epidermal necrosis with multinucleated keratinocytes: a possible diagnostic clue for dermatitis artefacta in children.

Editor Dermatitis artefacta (DA) is a rare disorder, characterized by self-inflicted cutaneous lesions. DA typically occurs in adolescents and young adults, often with a history of psychiatric disorders. Histopathology is often non-specific, although epidermal necrosis is common. Herein, we describe three adolescents with clinical findings suggestive of DA and multinucleated keratinocytes in their biopsies. A 13-year-old female with attention deficit hyperactivity disorder presented with a 3-month-history of multiple tender erythematous well-defined round patches and erosions located on the right thigh (Fig. 1a). One month after onset, the patient was changed from dexmethylphenidate to lisdexamfetamine, but the lesions persisted. A 15-year-old female presented with an intermittent eruption that started on the arms and spread to the legs, cheeks and neck. The lesions started with tender well-demarcated erythematous plaques and evolved into hyperpigmented patches (Fig. 1b–c). Her family history was significant for bipolar disorder and DA in a sibling. During a 2-year period, new lesions continued to develop. A 12-year-old female presented with an 8-month history of bullae on the arms and sharply demarcated, deeply erythematous plaques with multiple shapes and polygonal borders. Outbreaks lasted 2 weeks and extended to the face and limbs. The patient reported bullying at school due to the lesions and was allowed to remain home during flares. She had been treated with multiple topical medications without improvement. In all patients, laboratory studies were within normal limits. All patients and their caregivers denied skin manipulation. Skin biopsies from active lesions of each patient showed epidermal necrosis and syncytial keratinocytes in the epidermis, with some of these cells harbouring up to 20 nuclei (Fig. 2a–b) and showing a morula-like appearance (Fig. 2c), reminiscent of multinucleated cells seen viral infections. However, other cytopathic changes were not identified. Additional biopsies showed foci of subepidermal bullae without immune deposits (Fig. 2b). No history of herpetic infections, medication changes or drug allergies were reported. Based on the geographic clinical appearance, psychiatric histories in patients 1-2, psychological stressors at school in patient 3, histological epidermal necrosis and lack of infectious or autoimmune aetiologies, all patients were diagnosed with DA. Multinucleated cells are often encountered in skin biopsies and can be mesenchymal or epithelial. Histiocytic multinucleated giant cells are most frequently seen, usually related to infection, inflammatory or reparative conditions. Multinucleated epithelial cells (MEC), also called syncytial keratinocytes, are less frequent, and may be seen in viral infections (Herpesviridae, measles, monkeypox) epidermal tumours, (trichoepitheliomas, basal cell carcinomas) and inflammatory disorders. In these conditions, MEC display 2–3 nuclei per cell. In our series, all biopsies displayed epidermal necrosis and MEC with a myriad of nuclei. DA is a self-inflicted dermatosis presenting with lesions in areas which the patient can reach, and demonstrate geometric or bizarre configurations. Methods implicated in DA include cutting, stabbing, thermal burns and aerosol sprays. Deodorant spray has recently been implicated in four cases of bullous DA in teenagers. While all four cases showed epidermal necrosis, two showed numerous MEC, similar to ours. In summary, the diagnosis of DA is challenging, especially in the paediatric population given the denial from patients and

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.

CD8+ mycosis fungoides clinically masquerading as alopecia areata

A 33‐year‐old female with a 7‐year history of CD8‐positive hypopigmented mycosis fungoides (MF) involving the trunk and extremities presented with a large well‐defined alopecic patch on her frontal scalp. Clinically, this area resembled alopecia areata (AA) and was without hypopigmentation or erythema. A scalp biopsy revealed a non‐scarring inflammatory alopecia and a superficial band‐like atypical lymphoid infiltrate with prominent epidermotropism. Atypical, predominately CD8‐positive lymphocytes were seen surrounding and infiltrating the bulb portion of several hair follicles. Treatments for her MF lesions have included topical bexarotene, topical corticosteroids and phototherapy. Her alopecia has been treated with high potency topical corticosteroids and multiple intralesional triamcinolone injections with very minimal hair regrowth to date. Alopecia due to cutaneous lymphoma is an uncommon phenomenon but can occur in erythrodermic MF or Sezary syndrome. AA‐like changes have most often been reported in conventional patch/plaque stage MF and folliculotropic MF. In these cases, the atypical lymphoid infiltrate is comprised predominately of CD4‐positive lymphocytes. This is a rare report of a CD8‐positive MF causing AA‐like changes. This case highlights the importance of a scalp biopsy in patients with a history of cutaneous lymphoma presenting with alopecia in order to evaluate the nature of their hair loss.

Eruptive keratoacanthomatous atypical squamous proliferations (KASPs) arising in skin graft sites

Keratoacanthomas (KAs) and squamous cell carcinomas (SCCs) are common epidermal neoplasms, particularly in sun-exposed areas of fair-skinned individuals. Although surgical excision is the standard of care, eruptive KAs and SCCs provide a therapeutic challenge. We present an unusual case of a patient who developed eruptive low-grade keratoacanthomatous atypical squamous proliferations (KASPs) in split-thickness skin graft (STSG) donor and recipient sites after SCC excision.