Successful Treatment of Metastatic Primary Cutaneous Adnexal Carcinoma With a PD-1 Inhibitor.

SUMMARY: Standard of care treatment for metastatic cutaneous adnexal carcinomas is not well established. In this case report, we highlight the successful use of anti-programmed cell death protein 1 (anti-PD-1) therapy in treating a patient with low tumor mutation burden, microsatellite stable, high programmed death-ligand 1 (PD-L1) gene expression, metastatic primary cutaneous adnexal carcinoma with significant radiographic, and circulating tumor DNA response with durable benefit. Immune checkpoint inhibitors hold promise as a future treatment option in rare instances of metastatic disease from primary skin adnexal carcinoma. Further studies are needed to identify better immune checkpoint inhibitor predictive biomarkers for rare, advanced-stage non-melanoma skin cancers.

Single-cell RNA sequencing of neurofibromas reveals a tumor microenvironment favorable for neural regeneration and immune suppression in a neurofibromatosis type 1 porcine model.

Neurofibromatosis Type 1 (NF1) is one of the most common genetically inherited disorders that affects 1 in 3000 children annually. Clinical manifestations vary widely but nearly always include the development of cutaneous, plexiform and diffuse neurofibromas that are managed over many years. Recent single-cell transcriptomics profiling efforts of neurofibromas have begun to reveal cell signaling processes. However, the cell signaling networks in mature, non-cutaneous neurofibromas remain unexplored. Here, we present insights into the cellular composition and signaling within mature neurofibromas, contrasting with normal adjacent tissue, in a porcine model of NF1 using single-cell RNA sequencing (scRNA-seq) analysis and histopathological characterization. These neurofibromas exhibited classic diffuse-type histologic morphology and expected patterns of S100, SOX10, GFAP, and CD34 immunohistochemistry. The porcine mature neurofibromas closely resemble human neurofibromas histologically and contain all known cellular components of their human counterparts. The scRNA-seq confirmed the presence of all expected cell types within these neurofibromas and identified novel populations of fibroblasts and immune cells, which may contribute to the tumor microenvironment by suppressing inflammation, promoting M2 macrophage polarization, increasing fibrosis, and driving the proliferation of Schwann cells. Notably, we identified tumor-associated IDO1 +/CD274+ (PD-L1) + dendritic cells, which represent the first such observation in any NF1 animal model and suggest the role of the upregulation of immune checkpoints in mature neurofibromas. Finally, we observed that cell types in the tumor microenvironment are poised to promote immune evasion, extracellular matrix reconstruction, and nerve regeneration.

Expression of Insulinoma-Associated Protein 1 (INSM1) and Orthopedia Homeobox (OTP) in Tumors with Neuroendocrine Differentiation at Rare Sites.

Insulinoma-associated protein 1 (INSM1) and orthopedia homeobox (OTP) are transcription factors that play a critical role in neuroendocrine (NE) and neuroepithelial cell development. INSM1 has been identified in multiple tumors of NE or neuroepithelial origin, whereas OTP expression has been mainly studied in NE tumors of pulmonary origin. Expression of OTP appears to correlate with poorer prognosis in pulmonary carcinoids; however, its expression patterns in other NE/neuroepithelial tumors need further investigation. Here, we assessed the diagnostic utility of INSM1 and OTP in tumors with NE differentiation at relatively uncommon sites including prostate, breast, and tumors of gynecologic origin. Thirty-two formalin-fixed, paraffin-embedded cases were used to construct a tissue microarray. Immunohistochemistry for INSM1 and OTP was performed and scored semi-quantitatively. INSM1 was diffusely expressed in 60% of gynecologic tumors, 71.4% of mammary carcinoma, and 25% of prostate adenocarcinoma with NE differentiation. Diffuse expression of OTP was detected in 50% of prostate adenocarcinoma with NE differentiation and 100% neuroendocrine carcinoma of the ovary. Immunostain for achaete-scute homolog 1, chromogranin, synaptophysin, and CD56 supported the NE and/or neuroepithelial differentiation of the tumors. In summary, INSM1 is expressed in most of the tumors with NE and neuroepithelial differentiation in this study, confirming the diagnostic utility of INSM1 as a novel and sensitive marker of NE/neuroepithelial differentiation. The expression of OTP in some NE tumors outside of lung expands the spectrum of tumors that may express this biomarker and should be considered when working up a NE tumor of unknown primary site.

Implementation and Clinical Utility of an Integrated Academic-Community Regional Molecular Tumor Board.

PURPOSE: Precision oncology develops and implements evidence-based personalized therapies that are based on specific genetic targets within each tumor. However, a major challenge that remains is the provision of a standardized, up-to-date, and evidenced-based precision medicine initiative across a geographic region. MATERIALS AND METHODS: We developed a statewide molecular tumor board that integrates academic and community oncology practices. The Precision Medicine Molecular Tumor Board (PMMTB) has three components: a biweekly Web-based teleconference tumor board meeting provided as a free clinical service, an observational research registry, and a monthly journal club to establish and revise evidence-based guidelines for off-label therapies. The PMMTB allows for flexible and rapid implementation of treatment, uniformity in practice, and the ability to track outcomes. RESULTS: We describe the implementation of the PMMTB and its first year of activity. Seventy-seven patient cases were presented, 48 were enrolled in a registry, and 38 had recommendations and clinical follow-up. The 38 subjects had diverse solid tumors (lung, 45%; GI, 21%; breast, 13%; other, 21%). Of these subjects, targeted therapy was recommended for 32 (84%). Clinical trials were identified for 24 subjects (63%), and nontrial targeted medicines for 16 (42%). Nine subjects (28%) received recommended therapy with a response rate of 17% (one of six) and a clinical benefit rate (partial response + stable disease) of 38% (three of eight). Although clinical trials often were identified, patients rarely enrolled. CONCLUSION: The PMMTB provides a model for a regional molecular tumor board with clinical utility. This work highlights the need for outcome registries and improved access to clinical trials to pragmatically implement precision oncology.

Merkel Cell Carcinoma Analysis of Outcomes: A 30-Year Experience.

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy with poor prognosis. Limited data exists to guide treatment decisions. Here we report on our institutional experience and outcomes treating patients with MCC. METHODS: A database search (1984-2014) of patients treated at the University of Wisconsin Hospital and Clinics was used to identify patients with histologically confirmed MCC. Patient, tumor, and treatment characteristics were examined via review of medical records. Statistical analyses were performed to assess outcomes and associated prognostic factors. RESULTS: A total of 87 patients with MCC were identified with a median follow-up of 17 months (mean: 38, range: 0-210 months). Two and five-year overall survival rates were 53.9% and 32.8%, respectively. Recurrence was documented in 31.0% of patients (85.2% locoregional, 48.1% distant and 33.3% both). Patients with a history of immunosuppression exhibited significantly worse survival (hazard ratio, 2.01; 95% CI, 1.1-3.7) when compared to immune-competent individuals. The head and neck region was the most common location of primary lesion (N=49) followed by the extremities (N=31). Upper extremity primaries predicted significantly better overall survival (hazard ratio, 0.48; 95% CI, 0.23-0.99) while lower extremity primaries did not have significantly better results (hazard ratio, 0.5; 95% CI, 0.21-1.2) in comparison to head and neck site of primary. Nodal involvement (hazard ratio, 2.95; 95% CI, 1.5-5.79) was also a negative prognostic factor associated with poor overall survival when compared with clinically node negative patients. Primary tumor size > 2 cm (hazard ratio, 1.76; 95% CI, 0.91-3.4) was not associated with survival. CONCLUSIONS: This study highlights the role of various factors in determining prognosis of Merkel cell carcinoma; history of immunosuppression, nodal involvement, and head/neck primary predicted worse overall survival. These findings suggest that improvements in both distant and locoregionally directed therapies might play an important role in control of MCC and identify areas for future study.