Case Report: Genetic Alterations Associated with the Progression of Carotid Paraganglioma

Paragangliomas (PGLs) are rare neuroendocrine tumors that can develop from any paraganglion across the body. The carotid body is the most often location of PGLs in the head and neck region. Carotid PGLs (CPGLs) are characterized by predominantly non-aggressive behavior; however, all tumors have the potential to metastasize. To date, molecular mechanisms of paraganglioma progression remain elusive. We report a case of a 38-year-old woman with metastatic CPGL manifesting as a recurrent tumor with lymph node metastasis. The tumor was fast-growing and had a high Ki-67 proliferation index. Immunohistochemical (IHC) examination and whole-exome sequencing were performed for both recurrent tumor and metastasis. A germline pathogenic splice acceptor variant in the SDHB gene was found in the patient. Immunoreactivity of the SDHB subunit was weak diffuse in both samples, indicating deficiency of the succinate dehydrogenase. Moreover, the recurrent tumor exhibited loss of heterozygosity (LOH) at the SDHB locus, that is according to Knudson’s "two-hit" hypothesis of cancer causation. We also identified a rare somatic promotor mutation in the TERT gene associated with the tumor progression. Obtained results confirmed the indicative role of the germline SDHB mutation for metastatic CPGLs, as well as the potential prognostic value of the TERT promoter mutation.

Assessment of Telomere Length and Molecular Characterization of TERT Gene Promoter in Periampullary Carcinomas

Genetic and epigenetic alterations of the telomere maintenance machinery like telomere length and telomerase reverse transcriptase (encoded by TERT gene) are reported in several human malignancies. However, there is limited knowledge on the status of the telomere machinery in periampullary carcinomas (PAC) that are rare and heterogeneous groups of cancers arising from different anatomic sites around the ampulla of Vater. In the current study, we investigated the relative telomere length (RTL) and the most frequent genetic and epigenetic alterations in the TERT promoter in PAC (n=20) and compared with tumor-adjacent nonpathological duodenum (NDu; n=16). We found shorter RTLs (1.27 vs 1.33, P=0.01) and lower TERT protein expression (p=0.04) in PAC tissues as compared to the NDu. Although we did not find any mutation at two reactivating hotspot mutation sites of the TERT promoter, we detected polymorphism in 55% (11/20) of the cases at rs2853669 (T>C). Also, we found a hypermethylated region in the TERT promoter of PACs consisting of four CpGs (cg10896616 with ∆β 7%; cg02545192 with ∆β 9%; cg03323598 with ∆β 19%; and cg07285213 with ∆β 15%). In conclusion, we identified shorter telomeres with DNA hypermethylation in the TERT promoter region and lower TERT protein expression in PAC tissues. Further studies with a larger sample size are necessary to substantiate these results.

Human TERT Promoter Mutations in Atypical and Anaplastic Meningiomas

Background: The role of telomerase reverse transcriptase (TERT) gene promoter mutations (pTERT) in atypical and anaplastic meningiomas remains controversial. This study aimed to evaluate their impact on the histologic diagnosis and prognosis in a retrospective series of 74 patients with atypical and anaplastic meningioma, including disease progression and relapse. A supplementary panel of 21 benign tumours was used as a control cohort. Materials and Methods: The mutation rate of the pTERT gene was assessed by Sanger sequencing. ATRX protein expression was detected by immunohistochemistry. The phenotypic and genotypic intra-tumour heterogeneity was studied in a sub-group of 12 cases using a Molecular Machines & Industries (MMI) CellCut laser microdissection (LMD) system. Results: pTERT mutations were detected in 12/74 (17.6%) malignant meningiomas. The mutation rate was significantly higher in anaplastic meningiomas (7/23, 30.4%) compared to atypical tumours (5/48, 10.4%) (p = 0.0443). In contrast, the mutation rate was < 5% in benign tumours. All pTERT mutant cases retained nuclear ATRX immunoreactivity. pTERT mutations were significantly associated with the histologic grade (p = 0.0443) and were adverse prognostic factors for anaplastic tumours (p = 0.06). Conclusion: We reported on the pTERT mutation spectrum in malignant meningiomas, supporting their use in the prognostic classification.

Malignant Sinonasal Tumors: Update on Histological and Clinical Management

Tumors of nasal cavity and paranasal sinuses (TuNSs) are rare and heterogeneous malignancies, presenting different histological features and clinical behavior. We reviewed the literature about etiology, biology, and clinical features of TuNSs to define pathologic features and possible treatment strategies. From a diagnostic point of view, it is mandatory to have high expertise and perform an immunohistochemical assessment to distinguish between different histotypes. Due to the extreme rarity of these neoplasms, there are no standard and evidence-based therapeutic strategies, lacking prospective and large clinical trials. In fact, most studies are retrospective analyses. Surgery represents the mainstay of treatment of TuNSs for small and localized tumors allowing complete tumor removal. Locally advanced lesions require more demolitive surgery that should be always followed by adjuvant radio- or chemo-radiotherapy. Recurrent/metastatic disease requires palliative chemo- and/or radiotherapy. Many studies emphasize the role of specific genes mutations in the development of TuNSs like mutations in the exons 4–9 of the TP53 gene, in the exon 9 of the PIK3CA gene and in the promoter of the TERT gene. In the near future, this genetic assessment will have new therapeutic implications. Future improvements in the understanding of the etiology, biology, and clinical features of TuNSs are warranted to improve their management.