Molecular strategies in the management of bronchopulmonary and thymic neuroendocrine neoplasms

Abstract

Thoracic NETs [bronchopulmonary NETs (BPNETs) and thymic NETs (TNET)] share a common anatomic primary location, likely a common cell of origin, the "Kulchitsky cell" and presumably, a common etiopathogenesis. Although they are similarly grouped into well-differentiated [typical carcinoids (TC) and atypical carcinoids (AC)] and poorly differentiated neoplasms and both express somatostatin receptors, they exhibit a wide variation in clinical behavior. TNETs are more aggressive, are frequently metastatic, and have a lower 5-year survival rate (~50% . ~80%) than BPNETs. They are typically symptomatic, most often secreting ACTH (40% of tumors) but both tumor groups share secretion of common biomarkers including chromogranin A and 5-HIAA. Consistently effective and accurate circulating biomarkers are, however, currently unavailable. Surgery is the primary therapeutic tool for both BPNET and TNETs but there remains little consensus about later interventions e.g., targeted therapy, or how these can be monitored. Genetic analyses have identified different topographies (e.g., significant alterations in chromatin and epigenetic remodeling in BPNETs versus frequent chromosomal abnormalities in TNETs) but there is an absence of clinically actionable mutations in both tumor groups. Liquid biopsies, tools that can measure neoplastic signatures in peripheral blood, can potentially be leveraged to detect disease early i.e., recurrence, predict tumors that may respond to specific therapies and serve as real-time monitors for treatment responses. Recent studies have identified that mRNA transcript analysis in blood effectively identifies both BPNET and TNETs. The clinical utility of this gene expression assay includes use as a diagnostic, confirmation of completeness of surgical resection and use as a molecular management tool to monitor efficacy of PRRT and other therapeutic strategies.

Molecular Pathology of Well-Differentiated Pulmonary and Thymic Neuroendocrine Tumors: What Do Pathologists Need to Know?

“…Recent studies have suggested that mRNA transcript analysis in blood can identify thymic neuroendocrine tumors Table 1 Modified proposal for a "morphomolecular grading system" of thymic neuroendocrine tumors ( Modified from Dinter et al [19]) NEC neuroendocrine carcinoma a Proposed morphomolecular thymic neuroendocrine tumor grade b Carcinoid morphology subtypes also include typical and atypical carcinoids as well as NET G3; the latter is similar to grade-discordant gastroenteropancreatic tract neuroendocrine tumors that are characterized by a well-differentiated (carcinoid) morphology and mitotic count like G2 tumors but increased Ki-67 index (> 20%) equivalent to G3 tumors [107] c Pos, expressed [5]. Three non-secretory atypical carcinoid tumors (i.e., no production of serotonin or ACTH) with low chromogranin A levels were found to have detectable expression of genes that have been linked to neuroendocrine tumor pathobiology in the circulating blood using the NETest [5,67]. However, these findings need to be validated in larger cohorts and their clinical utility in identifying progressive tumors, confirming complete tumor resection, and predicting treatment response has to be established.…”

“…Thymic neuroendocrine tumors represent less than 5% of all thymic and mediastinal neoplasms and 0.4% of all neuroendocrine tumors. In general, thymic neuroendocrine tumors behave more aggressively than pulmonary neuroendocrine tumors, they are frequently metastatic, and 5-year survival is not reached in approximately 50% [ 5 ]. Patients with these tumors are typically symptomatic, often secrete ectopic hormones (e.g., ACTH in 40% of tumors) and, like neuroendocrine tumors of the lung, secrete circulating biomarkers such as chromogranin A and 5-HIAA (metabolite of serotonin).…”

“…Recent studies have suggested that mRNA transcript analysis in blood can identify thymic neuroendocrine tumors [ 5 ]. Three non-secretory atypical carcinoid tumors (i.e., no production of serotonin or ACTH) with low chromogranin A levels were found to have detectable expression of genes that have been linked to neuroendocrine tumor pathobiology in the circulating blood using the NETest [ 5 , 67 ]. However, these findings need to be validated in larger cohorts and their clinical utility in identifying progressive tumors, confirming complete tumor resection, and predicting treatment response has to be established.…”

Endoscopic ultrasound ablation in a patient with multiple metastatic pancreatic tumors from adrenocorticotropic hormone‐producing thymic neuroendocrine neoplasm

“…The IHC staining helped to determine the primary tumor site. According to the literature, TTF‐1 is positive in IHC staining in 12% of patients with thymic NEN, PAX‐8 in 50%, and NKX6‐1 in 0% 5–7 . TTF‐1 is positive in 7% of patients with pancreatic NEN, PAX‐8 in 32%, and NKX6‐1 in 82% 6 .…”

Management recommendations for pancreatic manifestations of von Hippel–Lindau disease

“…The blood transcriptome-based marker NETest has been validated as a diagnostic and prognostic biomarker for neuroendocrine neoplasms in various scenarios. [28][29][30][31] However, in the context of VHL-related PNETs, there are not sufficient data to suggest its use at this time point.…”