Duodenal gangliocytic paraganglioma, a rare entity among GEP-NET: a case report with immunohistochemical and molecular study

Gastroenteropancreatic neuroendocrine tumors are the most incident neuroendocrine tumors. In the new WHO classification (2010) the embryological derivation of each neoplastic entity is one of the most important parameters. Gangliocytic Paraganglioma is a tumor originating in the hindgut, a rare neoplasm, generally affecting the second portion of the duodenum, the majority of which are benign. Cases of gangliocytic paraganglioma with local metastasis or local recurrence have also been reported. We describe a GP in a 48-year-old caucasian male with an unusual site (4th portion of duodenum) and an interesting immunohistochemical and molecular pattern. In particular, we examined the expression of some neuroendocrine markers and a marker of neuronal differentiation, NeuroD1, whose expression can help to better understand the nature of this neoplasia. VIRTUAL SLIDES: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/372095916109680

Molecular characterization of a bladder pleomorphic rhabdomyosarcoma in an adult patient

Pleomorphic rhabdomyosarcoma (PRMS) is a rare but highly aggressive soft tissue tumor, accounting for 3% of soft tissue sarcomas. PRMS is the most frequent subtype of RMS in adulthood and it is mainly located in the large muscles of the extremities, particularly the lower limbs and the trunk, more rarely in other locations especially in the bladder. At our knowledge, only six cases of adult pleomorphic rhabdomyosarcoma of the bladder have been reported in the literature. In this study, we report a case of PRMS of bladder with a very poor prognosis. In fact, the patient died a month after surgery. The tumor was characterized by poorly differentiated, medium-sized sometimes rhabdoid cells, mixed with large-sized and pleomorphic elements with evident anisonucleosis, and with large areas of necrosis. We used an extensive immunohistochemical panel to exclude other tumors much more frequently reported at this site. The positivity for myogenic markers such as actin, desmin, myogenin and MyoD1 allowed the correct diagnosis. Furthermore, since preliminary studies highlighted a series of specific molecular alterations in PMRS cell lines, we analyzed a panel of specific mutations and gene rearrangements by RT-PCR and FISH methods. We showed a copy gains of CCND1 and MALT genes in our samples, suggesting an accurate molecular characterization of PRMS to establish a better management of patients and new therapeutic opportunities

COX-2 expression positively correlates with PD-L1 expression in human melanoma cells.

Abstract BACKGROUND: The resistance to PD-1/PD-L1 inhibitors for the treatment of melanoma have prompted investigators to implement novel clinical trials which combine immunotherapy with different treatment modalities. Moreover is also important to investigate the mechanisms which regulate the dynamic expression of PD-L1 on tumor cells and PD-1 on T cells in order to identify predictive biomarkers of response. COX-2 is currently investigated as a major player of tumor progression in several type of malignancies including melanoma. In the present study we investigated the potential relationship between COX-2 and PD-L1 expression in melanoma. METHODS: Tumor samples obtained from primary melanoma lesions and not matched lymph node metastases were analyzed for both PD-L1 and COX-2 expression by IHC analysis. Status of BRAF and NRAS mutations was analyzed by sequencing and PCR. Co-localization of PD-L1 and COX-2 expression was analyzed by double fluorescence staining. Lastly the BRAFV600E A375 and NRASQ61R SK-MEL-2 melanoma cell lines were used to evaluate the effect of COX-2 inhibition by celecoxib on expression of PD-L1 in vitro. RESULTS: BRAFV600E/V600K and NRASQ61R/Q61L were detected in 57.8 and 8.9% of the metastatic lesions, and in 65.9 and 6.8% of the primary tumors, respectively. PD-L1 and COX-2 expression were heterogeneously expressed in both primary melanoma lesions and not matched lymph node metastases. A significantly lower number of PD-L1 negative lesions was found in primary tumors as compared to not matched metastatic lesions (P = 0.002). COX-2 expression significantly correlated with PD-L1 expression in both primary (P = 0.001) and not matched metastatic (P = 0.048) lesions. Furthermore, in melanoma tumors, cancer cells expressing a higher levels of COX-2 also co-expressed a higher level of PD-L1. Lastly, inhibition of COX-2 activity by celecoxib down-regulated the expression of PD-L1 in both BRAFV600E A375 and NRASQ61R SK-MEL-2 melanoma cell lines. CONCLUSIONS: COX-2 expression correlates with and modulates PD-L1 expression in melanoma cells. These findings have clinical relevance since they provide a rationale to implement novel clinical trials to test COX-2 inhibition as a potential treatment to prevent melanoma progression and immune evasion as well as to enhance the anti-tumor activity of PD-1/PD-L1 based immunotherapy for the treatment of melanoma patients with or without BRAF/NRAS mutations

Variability in Immunohistochemical Detection of Programmed Death Ligand 1 (PD-L1) in Cancer Tissue Types

In normal cell physiology, programmed death 1 (PD-1) and its ligand, PD-L1, play an immunoregulatory role in T-cell activation, tolerance, and immune-mediated tissue damage. The PD-1/PD-L1 pathway also plays a critical role in immune escape of tumor cells and has been demonstrated to correlate with a poor prognosis of patients with several types of cancer. However, recent reports have revealed that the immunohistochemical (IHC) expression of the PD-L1 in tumor cells is not uniform for the use of different antibodies clones, with variable specificity, often doubtful topographical localization, and with a score not uniquely defined. The purpose of this study was to analyze the IHC expression of PD-L1 on a large series of several human tumors to correctly define its staining in different tumor tissues

PD-L1 Immunohistochemical Detection in Tumor Cells and Tumor Microenvironment: Main Considerations on the Use of Tissue Micro Arrays

PD-1/PD-L1 (programmed death 1/programmed death ligand 1) pathway plays a critical role in immune escape of tumor cells. Recent studies have described that PD-L1 is heterogeneously expressed in various types of cancer, although its prognostic/predictive value is still uncertain. These problems are partly due to a not well defined operating protocol for its detection by immunohistochemistry, but also because most of the studies conducted on large case series were made by Tissue Micro Array (TMA). We are going to discuss this latter point, to highlight that TMA must be set up in an appropriate manner, especially for some markers, such as PD-L1, which, besides being poorly expressed in tumor cells, can be expressed by cells of the tumor microenvironment

LncRNA <i>HOTAIR</i> in Tumor Microenvironment: What Role?

lncRNAs participate in many cellular processes, including regulation of gene expression at the transcriptional and post-transcriptional levels. In addition, many lncRNAs can contribute to the development of different human diseases including cancer. The tumor microenvironment (TME) plays an important role during tumor growth and metastatic progression, and most of these lncRNAs have a key function in TME intracellular signaling. Among the numerous identified lncRNAs, several experimental evidences have shown the fundamental role of the lncRNA HOTAIR in carcinogenesis, also highlighting its use as a circulating biomarker. In this review we described the contribution of HOTAIR in the TME modulation, highlighting its relation with cellular and non-cellular components during tumor evolution and progression

Resistance to anti-PD-1-based immunotherapy in basal cell carcinoma: a case report and review of the literature

Abstract Background Immunotherapy with immune checkpoint inhibitors has radically changed the management of a broad spectrum of tumors. In contrast, only very limited information is available about the efficacy of these therapies in non-melanoma skin cancers, especially in basal cell carcinoma. The latter malignancy is often associated with both an impairment of the host immune response and a high mutation burden, suggesting that immune checkpoint inhibitor-based immunotherapy may be effective in the treatment of this tumor. Case presentation A 78-year-old woman was diagnosed with a metastatic non-small-cell-lung-cancer. Following the lack of response to two lines of systemic chemotherapy, she was treated with the anti-PD-1 monoclonal antibody nivolumab, obtaining a prolonged stable disease. Under nivolumab treatment, the patient developed a basal cell carcinoma of the nose. The latter was surgically resected. Immunohistochemical staining of tumor tissue showed a PD-L1 expression < 1% and lack of human leukocyte antigen class I subunit (i.e. heavy and light chain) expression on tumor cells. In addition, a limited number of T cells (CD3+) was present in the tumor microenvironment, with a higher number of regulatory T cells (Foxp3+) and macrophages (Cd11b+) as compared to a low infiltration of activated cytotoxic T cells (CD8+/ Granzyme B+). Two months following the surgical removal of the tumor, while still on nivolumab treatment, the patient relapsed with a basal cell carcinoma in the same anatomic site of the previous surgical excision. The tumor displayed the same pathological characteristics. Conclusion Preclinical lines of evidence suggest a potential role of immune checkpoint inhibitors for basal cell carcinoma treatment. However, limited clinical data is available. In the patient we have described administration of the immune checkpoint inhibitor nivolumab for the treatment of a responsive non-small cell carcinoma was associated with the development and relapse of a basal cell carcinoma tumor. This association is likely to reflect the resistance of basal cell carcinoma cells to anti-PD-1 based immunotherapy because of a “cold” tumor microenvironment characterized by lack of human leukocyte antigen class I expression, low PD-L1 expression and high number of immune regulatory cells