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Background: Recently, a 23-gene signature was developed to produce a melanoma diagnostic score capable of differentiating malignant and benign melanocytic lesions. The primary objective of this study was to independently assess the ability of the gene signature to differentiate melanoma from benign nevi in clinically relevant lesions., Methods: A set of 1400 melanocytic lesions was selected from samples prospectively submitted for gene expression testing at a clinical laboratory. Each sample was tested and subjected to an independent histopathologic evaluation by 3 experienced dermatopathologists. A primary diagnosis (benign or malignant) was assigned to each sample, and diagnostic concordance among the 3 dermatopathologists was required for inclusion in analyses. The sensitivity and specificity of the score in differentiating benign and malignant melanocytic lesions were calculated to assess the association between the score and the pathologic diagnosis., Results: The gene expression signature differentiated benign nevi from malignant melanoma with a sensitivity of 91.5% and a specificity of 92.5%., Conclusions: These results reflect the performance of the gene signature in a diverse array of samples encountered in routine clinical practice. Cancer 2017;123:617-628. © 2016 American Cancer Society., (© 2016 Myriad Genetics, Inc. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)

Background: Mycosis fungoides/Sézary syndrome (MF/SS) often requires multiple skin biopsies for definitive diagnosis. In vivo reflectance confocal microscopy (RCM) visualizes high-resolution cellular detail of the skin. The objective of this study is to evaluate the morphologic features of MF/SS using RCM and to correlate RCM features with histopathology and T-cell receptor (TCR) gene rearrangement studies., Methods: A cohort of patients with active/recurrent or suspicious MF/SS disease was prospectively recruited for RCM imaging and histopathologic/RCM images were evaluated. Statistical analyses were performed to identify unique RCM features and to correlate RCM features with histopathologic findings and TCR rearrangement studies., Results: Eighty-three lesions were evaluated. Correlation between RCM and histopathology was moderate for all relatable features (κ = 0.41, p<0.001), almost perfect for intraepidermal atypical lymphocytes [prevalence and bias-adjusted kappa (PABAK) = 0.90], and fair for Pautrier collections (κ = 0.32, p = 0.03). Lesions with Pautrier collections identified by RCM were significantly more likely to show TCR clonality (p = 0.04) and diagnostic features of MF/SS on histopathology (p = 0.03)., Conclusions: Our study captures morphologic RCM criteria for a variety of skin lesions. Pautrier collections visualized by RCM are associated with improved histopathologic diagnosis and detection of TCR gene clonality. Although further studies are needed to validate the diagnostic implications of RCM for MF/SS, our study highlights the potential utility of RCM., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Well-differentiated neuroendocrine tumors metastasize to the skin uncommonly, and only 35 cases are reported in the literature. In only five of these patients, cutaneous metastases were the presenting symptom of malignancy; herein, we report four such cases. Two patients were female and two male, aged 50-74 years (mean: 64.5 years), each with a solitary painless, slowly enlarging, non-ulcerated cutaneous nodule of 3-12 months duration (mean: 9 months). The lesions were on the scalp (n = 3) and trunk (n = 1), and ranged in greatest dimension from 0.5 to 2.5 cm. The distinction from other microscopically similar entities, and the interpretation of origination from gastrointestinal, pancreatic or respiratory system primaries, was made clinically, or was based on the morphological features and the immunohistochemical profile. One patient died of the disease progression after 36 months whereas two patients are alive with significant disease progression after 24 and 60 months. Metastatic neuroendocrine tumor should be considered in the differential diagnosis of cutaneous tumors with neuroendocrine morphology even in patients with no known history of visceral malignancy., Competing Interests: SOURCE OF FUNDING AND CONFLICTS OF INTEREST: The authors have no funding or conflicts of interest to declare., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Clear cell sarcoma (CCS) of tendons and aponeuroses, also known as melanoma of soft parts, represents an aggressive rare malignancy that is characterized by a nested or fascicular pattern of spindled cells and a pathognomonic reciprocal translocation, t(12;22)(q13;q12), that results in the fusion of EWSR1 and ATF1 genes. Numerous recent studies have recognized the importance of a cutaneous CCS variant that can mimic a broad spectrum of entities, including spindle cell melanoma, spindle cell squamous carcinoma, cutaneous leiomyosarcoma and atypical fibroxanthoma. We report a case of a 13-year-old boy with cutaneous CCS who presented with a few months history of an asymptomatic papule on the lower lip that was suggestive of a mucocele. Biopsy of the lesion showed a wedge shaped neoplasm arranged in nests and fascicles of epithelioid- to oval-shaped cells with pale cytoplasm, open chromatin and prominent nucleolus. The superficial component was closely opposed to the basal epithelium resembling the junctional nests of a melanocytic neoplasm. The process extended into and involved the striated muscle of the lip. The cells expressed S-100, CD99 and synaptophysin by immunohistochemistry, and there was focal HMB-45 and microphthalmia transcription factor (MiTF) positivity as well. Fluorescence in situ hybridization confirmed the presence of the t(12;22) (ESWR1-ATF1) translocation., (© 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.)

Background: Few data exist regarding techniques, indications, and outcomes for sentinel lymph node biopsy in pediatric patients with sarcomas and carcinomas., Methods: A retrospective 10-year review was conducted, with Institutional Review Board waiver, of the pathology, lymphoscintigraphy, and clinical records for all pediatric patients selected to undergo sentinel lymph node biopsy at a major cancer center., Results: Thirty-one sentinel lymph node biopsies were performed in 30 pediatric patients (median age, 12 years; range, 2-21 years). With the administration of technetium 99m sulfur colloid, sentinel lymph nodes were identified preoperatively in 30 of 31 cases, and intraoperatively in the remaining case. Radiotracer alone was used in 13 of 31 cases but was supplemented with isosulfan blue dye in the remaining 18 cases. There were no complications. Positive sentinel lymph nodes occurred in 1 of 9 patients with rhabdomyosarcoma and in 2 of 5 patients with breast cancer, and in both of these diseases the sentinel lymph node results helped guide treatment decisions. No other patients had positive sentinel lymph nodes, and among those with nonrhabdomyosarcoma soft-tissue sarcomas there were no lymph node basin recurrences despite a lack of lymph node basin irradiation or formal lymph node dissection. The median follow-up was 48 months (range, 0-111 months)., Conclusions: Sentinel lymph node biopsy for pediatric soft-tissue tumors can be performed safely, and the results can alter treatment decisions both for children with rhabdomyosarcoma and adolescents with breast cancer. In patients with nonrhabdomyosarcoma soft-tissue sarcoma, we observed no positive sentinel lymph nodes and no lymph node basin recurrences; these data should prompt the prospective study of sentinel lymph node biopsy as a modality that might help guide the administration or withholding of regional therapy among pediatric patients with nonrhabdomyosarcoma soft-tissue sarcoma.

Male breast cancer is a rare entity accounting for < 1% of all breast cancer cases in the United States, but with a rate that has been rising over the last 25 years. Nipple skin/subcutaneous tumors in men are even rarer. Likewise, true neuroendocrine carcinoma of the breast, defined as > 50% of tumor cells staining for either chromogranin or synaptophysin, is not a common entity, usually occurring in older women. We present the case of a 70-year-old man with a slowly growing nipple mass that had enlarged over the previous 1.5 years. The histology consisted of nests, trabeculae and sheets of basaloid cells with rare abortive gland formation and a pushing edge. The case was originally misdiagnosed as a Merkel cell carcinoma, based largely on histologic morphology. Strong staining for synaptophysin (in greater than 50% of cells), CD56, keratins AE1 : AE3 and Cam 5.2, as well as estrogen receptor and progesterone receptor was noted. Myoepithelial cells within in situ areas were identified using stains for calponin and 4A4, supporting a primary mammary duct origin. Additionally, a substantial portion of cells stained for Gross Cystic Disease Fluid Protein-15 (GCDFP-15), confirming some overlap with sweat duct differentiation. To the best of our knowledge, although reported in the male breast, no case of primary nipple neuroendocrine carcinoma in a male patient has been reported in the literature. The gender of the patient and association with the skin of the chest wall probably contributed to the original misdiagnosis of Merkel cell carcinoma in this patient.

Background: Immunohistochemical analysis of sentinel lymph nodes from patients with breast carcinoma and melanoma has been shown to increase the sensitivity for detecting lymph node metastases. To the authors' knowledge, this technique has not been described in patients with Merkel cell carcinoma., Methods: Lymphatic mapping and sentinel lymph node biopsy was performed on 26 patients with Merkel cell carcinoma between 1997 and 1999. All sentinel lymph nodes were analyzed with conventional hematoxylin and eosin (H&E) staining and then analyzed with immunohistochemical staining to evaluate whether this additional technique would increase the number of patients found to have lymph node metastasis., Results: The median age of the patients in the current study was 67 years and the median tumor size at the time of presentation was 2 cm. Lymph node metastases were identified in 5 of the 26 patients (19%). Three of these five lymph node positive patients were identified with H&E staining. The remaining two patients were identified only after immunohistochemical analysis. The median follow-up in this group of lymph node positive patients was 14 months, with 2 of the 5 lymph node positive patients developing a recurrence. The median follow-up in the 21 patients who were lymph node negative was 19 months, with only 1 patient having developed a recurrence at the time of last follow-up., Conclusions: Immunohistochemical analysis of sentinel lymph nodes from patients with Merkel cell carcinoma appears to increase the sensitivity of detecting clinically occult lymph node metastases., (Copyright 2001 American Cancer Society.)

The ultrastructural localization of an amorphous matrix to the interface between microvessel endothelium and tumor cells has been recently reported in a series of melanomas. Laminin expression as documented by immunohistochemistry was localized to microvessels in melanomas showing the amorphous matrix. In order to identify more precisely the type of laminin present in this amorphous material, immunostaining was carried out on cryostat sections from 16 human melanoma specimens. Four murine monoclonal antibodies directed against the alpha-3, beta-2, beta-3 and gamma-2 laminin chains were employed. In the melanomas studied, alpha3, beta3 and gamma2 laminin chains showed only minimal focal vascular positivity. In contrast, the beta2 (16/16 cases) laminin chain exhibited a consistent positivity in an angiocentric pattern about tumor microvessels. In all melanomas, some tumor cells seemed to spread along the abluminal surface of the small vessels, exhibiting a pericytic location, particularly along the intratumoral projections formed by the beta2 laminin chain. Given the role of laminin in migration and tumor progression, the results suggest a role of the beta2 laminin chain in melanoma spread, promoting tumor migration along the abluminal surface of vessel, a phenomenon which has been termed extra-vascular migratory metastasis.

Background: Melanoma in childhood is uncommon. Some believe that melanoma among children is associated with a better prognosis than among adults., Methods: The authors reviewed their institutional experience with melanoma in 40 patients younger than 18 years treated between 1950 and 1984. All slides were reviewed by a single dermatopathologist who was blinded to clinical outcomes. Long term follow-up was available for all but three patients., Results: There were 26 girls and 14 boys. The median age at diagnosis was 15 years (range, 3-17 years). Eleven patients (28%) were younger than 12 years. Fifteen patients (38%) had melanoma arise in a congenital nevus (2 had bathing trunk nevi. The most common site was the extremity (n = 23), followed by the trunk (n = 10) and the head and neck (n = 7). Seventeen patients (43%) initially were considered to have benign lesions, and 23 patients (57%) were diagnosed correctly with melanoma at initial presentation. Only 21 of 37 evaluable patients (57%) were alive at last follow-up with a median follow-up of 18 years (range, 2-48 years). Fifteen patients (41%) died of their disease, with a median survival of 12 months (range, 6-60 months). One patient died of breast carcinoma 14 years after treatment for melanoma. Disease free survival was 57% at 5 and 10 years. Of the 15 patients who died of disease, 12 were female (P = 0.09) and 10 had melanoma arising in a congenital nevus (P < 0.05). Five-year overall survival was 78% for patients who presented with localized disease (n = 23) and 30% for patients who presented with regional metastasis (n = 16, P < 0.001). There were no survivors among those who presented with systemic disease (n = 1)., Conclusions: Children with melanoma are at significant risk of dying of their disease. Survival is similar to that seen among adults and depends on stage at presentation. The survival advantage observed for adult females is not seen among children.

Lymphatic mapping allows the surgeon to identify and remove the first draining (sentinel) lymph node from a primary melanoma with minimal morbidity. The procedure facilitates accurate staging and identification of patients in need of additional therapy. We used lymphatic mapping and sentinel lymph node biopsy in two children with melanoma. Both patients had evidence of metastatic melanoma in their sentinel lymph nodes and underwent regional lymphadenectomy. Malignant melanoma and atypical pigmented lesions in children remain diagnostically challenging for the pathologist and clinician. Misdiagnoses occur, and the correct interpretation of a melanocytic tumor is too often made only after recurrence or metastasis has occurred. The use of lymphatic mapping facilitates accurate staging and identifies children in whom additional therapy may be indicated. In addition, it can assist in the assessment of the biologic potential of a difficult lesion.