Appreciation for genomic and immune heterogeneity in cancer has grown though the relationship of these factors to treatment response has not been thoroughly elucidated. To better understand this, we studied a large cohort of melanoma patients treated with targeted therapy or immune checkpoint blockade (n = 60). Heterogeneity in therapeutic responses via radiologic assessment was observed in the majority of patients. Synchronous melanoma metastases were analyzed via deep genomic and immune profiling, and revealed substantial genomic and immune heterogeneity in all patients studied, with considerable diversity in T cell frequency, and few shared T cell clones (<8% on average) across the cohort. Variables related to treatment response were identified via these approaches and through novel radiomic assessment. These data yield insight into differential therapeutic responses to targeted therapy and immune checkpoint blockade in melanoma, and have key translational implications in the age of precision medicine.

Sentinel lymph node evaluation is a critical component of melanoma staging, and lymph node status provides one of the most powerful predictors of melanoma recurrence and survival. One of the well-known diagnostic pitfalls in melanoma sentinel lymph node evaluation is the presence of nodal melanocytic nevi, which has been demonstrated in up to 26% of lymphadenectomy specimens and specifically in melanoma patients. Melanocytic markers enhance the sensitivity of melanoma detection in sentinel lymph nodes. However, established markers such as anti-melan-A/MART1, S100 protein and SOX10 antibodies cannot discriminate melanoma metastasis from nodal nevi. Recent studies have demonstrated strong expression of neural stem/progenitor cell markers nestin and SOX2 in melanoma. In this study, we tested the diagnostic utility of nestin and SOX2 in differentiating metastatic melanomas from nodal nevi. Twenty-three lymph nodes with metastatic melanomas and 17 with nodal nevi were examined. Of the 23 metastatic melanomas, 18 showed diffuse and strong (3 þ ) nestin, 4 showed rare cells with strong (3 þ ) nestin, and one showed diffuse but faint (1 þ ) nestin staining. Nuclear SOX2 was positive in 13 metastatic melanomas. In contrast, 15 nodal nevi showed no nestin, and 2 showed rare cells with very faint (o1 þ ) nestin staining. SOX2 was negative in 13 nodal nevi. Overall, nestin was strongly expressed in metastatic melanomas (n ¼ 22/23; 96%), but not in nodal melanocytic nevi (n ¼ 15/17; 88%; Po0.0001). SOX2 was also expressed in metastatic melanomas (n ¼ 13/23; 57%) but not in the majority of nodal melanocytic nevi (n ¼ 13/16; 81%; P ¼ 0.02). In one lymph node harboring metastatic melan-A-negative desmoplastic melanoma, nestin and SOX2 strongly highlighted the infiltrating tumor cells, suggesting the potential clinical value of these two markers in desmoplastic melanoma lymph node biopsies. This study provides evidence that nestin and SOX2 can effectively differentiate nodal melanocytic nevi from metastatic melanomas and serve as powerful diagnostic adjuncts in melanoma staging. Modern Pathology (2013) 26, 44-53; doi:10.1038/modpathol.2012; published online 17 August 2012Keywords: metastatic melanomas; nestin; nodal melanocytic nevi; SOX2 Malignant melanoma is a malignant tumor of melanocytes that accounts for less than 10% of all skin cancer diagnoses but the majority of skin cancerrelated deaths. 1 For patients diagnosed with malignant melanoma, sentinel lymph node biopsy is an essential component of tumor staging, and lymph node status provides one of the most powerful predictors of melanoma recurrence and survival. [2][3][4] When melanoma metastasizes, a regional lymph node is the most common site, and tumor burden can range from rare tumor cells to complete effacement of lymph nodes. The presence of either micro-or macrometastasis in a single lymph node changes melanoma staging from stage I to stage III. 5 In addition, a single positive lymph node signifies a decrease in 10-year survival from 95% (stage IA) to 68% (stage II...

Gnathodiaphyseal dysplasia (GDD; OMIM #166260) is an ultra-rare autosomal dominant disorder caused by heterozygous mutation in the anoctamin 5 (ANO5) gene and features fibro-osseous lesions of the jawbones, bone fragility with recurrent fractures, and bowing/sclerosis of tubular bones. The physiologic role of ANO5 is unknown. We report a 5-year-old boy with a seemingly atypical and especially severe presentation of GDD and unique ANO5 mutation. Severe osteopenia was associated with prenatal femoral fractures, recurrent postnatal fractures, and progressive bilateral enlargement of his maxilla and mandible beginning at ~2months-of-age that interfered with feeding and speech and required four debulking operations. Histopathological analysis revealed benign fibro-osseous lesions resembling cemento-ossifying fibromas of the jaw without psammomatoid bodies. A novel, de novo, heterozygous, missense mutation was identified in exon 15 of ANO5 (c.1553G>A; p.Gly518Glu). Our findings broaden the phenotypic and molecular spectra of GDD. Fractures early in life with progressive facial swelling are key features. We assessed his response to a total of 7 pamidronate infusions commencing at age 15months. Additional reports must further elucidate the phenotype, explore any genotype-phenotype correlation, and evaluate treatments.

ABHD5, PGRMC1 and SQS are novel markers for sebaceous carcinoma and can reliably distinguish sebaceous neoplasms from non-sebaceous tumors, specifically BCC with clear cell features.

The malignant peripheral nerve sheath tumor is a relatively uncommon type of soft tissue sarcoma arising from a peripheral nerve or extraneural soft tissues and showing nerve sheath differentiation. The diagnosis of malignant peripheral nerve sheath tumor is one of the most challenging tasks in surgical pathology because of its uncommon type (5-10% soft tissue sarcomas), morphologic resemblance to other spindle cell neoplasms and lack of sensitive and specific immunohistochemical markers. The pathologic diagnosis is more straightforward in the clinical setting of neurofibromatosis-1, but problems are mainly centered on the non-neurofibromatosis-1 malignant peripheral nerve sheath tumors. To date, S100 protein is the most widely applied marker in the case of a suspected malignant peripheral nerve sheath tumor, yet its suboptimal sensitivity and its expression in other spindle cell neoplasms, including spindle cell melanoma, clear-cell sarcoma, leiomyosarcoma and monophasic synovial sarcoma, add to the diagnostic conundrum. Growth-associated protein 43 (GAP43), a membrane-associated phosphoprotein expressed in neuronal growth cones and Schwann cell precursors during neural development and axonal regeneration, was applied to a set of nerve sheath and non-nerve sheath spindle cell neoplasms. The findings in this study indicate that GAP43 is expressed in malignant peripheral nerve sheath tumors (n ¼ 18/21; 86%) and demonstrates a sensitivity superior to S100 protein (n ¼ 13/21; 62%). GAP43 is also positive in neurofibromas (n ¼ 17/18; 94%), schwannomas (n ¼ 11/12; 92%) and desmoplastic melanomas (n ¼ 7/10; 70%). In contrast, it is negative in the non-desmoplastic spindle cell melanomas (n ¼ 20/22; 91%). Of the other non-neural soft tissue sarcomas, GAP43 is non-reactive in most leiomyosarcomas (n ¼ 14/16; 88%) and clear-cell sarcomas (n ¼ 8/8), and only focally positive in monophasic synovial sarcomas (n ¼ 3/7; 43%). GAP43 is seemingly a highly sensitive marker for peripheral nerve sheath tumors and may serve as a useful diagnostic adjunct in the diagnosis of malignant peripheral nerve sheath tumor from other spindle cell neoplasms, including spindle cell melanoma.