NTRK and ALK rearrangements in malignant pleural mesothelioma, pulmonary neuroendocrine tumours and non-small cell lung cancer

Leal, José Luis; Peters, Geoffrey; Szaumkessel, Marcin; Leong, Trishe; Asadi, Khashayar; Rivalland, Gareth; Do, Hongdo; Senko, Clare; Mitchell, Paul; Quing, Chai Zi; Dobrovic, Alexander; Thapa, Bibhusal; John, Thomas

doi:10.1016/j.lungcan.2020.05.019

Cited by 22 publications

(15 citation statements)

References 40 publications

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“…Molecular alterations that are typical of non-small cell lung cancer, including those that are targets for biologic therapy, are infrequent in pulmonary neuroendocrine tumors. ALK or NTRK fusions are very rarely detected in pulmonary carcinoids, with only single cases reported [38,39], including cases with well-differentiated morphology but high proliferative rate [40].…”

Section: Genomic Profiling Of Pulmonary Neuroendocrine Tumors (Carcinmentioning

confidence: 99%

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

et al. 2021

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Thoracic (pulmonary and thymic) neuroendocrine tumors are well-differentiated epithelial neuroendocrine neoplasms that are classified into typical and atypical carcinoid tumors based on mitotic index cut offs and presence or absence of necrosis. This classification scheme is of great prognostic value but designed for surgical specimens, only. Deep molecular characterization of thoracic neuroendocrine tumors highlighted their difference with neuroendocrine carcinomas. Neuroendocrine tumors of the lung are characterized by a low mutational burden, and a high prevalence of mutations in chromatin remodeling and histone modification-related genes, whereas mutations in genes frequently altered in neuroendocrine carcinomas are rare. Molecular profiling divided thymic neuroendocrine tumors into three clusters with distinct clinical outcomes and characterized by a different average of copy number instability. Moreover, integrated histopathological, molecular and clinical evidence supports the existence of a grey zone category between neuroendocrine tumors (carcinoid tumors) and neuroendocrine carcinomas. Indeed, cases with well differentiated morphology but mitotic/Ki-67 indexes close to neuroendocrine carcinomas have been increasingly recognized. These are characterized by specific molecular profiles and have an aggressive clinical behavior. Finally, thoracic neuroendocrine tumors may arise in the background of genetic susceptibility, being MEN1 syndrome the well-defined familial form. However, pathologists should be aware of rarer germline variants that are associated with the concurrence of neuroendocrine tumors of the lung or their precursors (such as DIPNECH) with other neoplasms, including but not limited to breast carcinomas. Therefore, genetic counseling for all young patients with thoracic neuroendocrine neoplasia and/or any patient with pathological evidence of neuroendocrine cell hyperplasia-to-neoplasia progression sequence or multifocal disease should be considered.

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Section: Genomic Profiling Of Pulmonary Neuroendocrine Tumors (Carcinmentioning

confidence: 99%

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

et al. 2021

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“…In a comparative study in genic reorganization of neurotrophic tropomyosin receptor kinase (NTRK) and anaplastic lymphoma kinase (ALK), it was observed that NTRK is specific to malignant pleural mesothelioma while ALK as single arrangement was identified in intermediate-grade NETs (58)(59)(60)(61). The pathway Kelch-like Ech-associated protein 1/nuclear factor erythroid 2-related factor 2 (KEAP1/NRF2) was investigated due to its implication in cancer cell survival and treatment resistance.…”

Section: Biological Landscape Of Lung Neuroendocrine Tumors (Lnets)mentioning

confidence: 99%

Lung neuroendocrine tumors: A systematic literature review (Review)

et al. 2021

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Neuroendocrine tumors (NETs) can have multiple localizations in the human body however, most often, it appears in the in thorax at tracheobronchial tree and the thymus. NETs are a group of tumors with heterogenous malignancy that evolve from neuroendocrine cells, with the lung being the second target organ after the gastrointestinal tract. These rare tumors are usually asymptomatic and non-functional with little information regarding incidence in the specialty literature. The main purpose of this review, was the analysis of the available literature in all aspects while mainly focusing on molecular diagnosis data and secondly, by using this molecular landscape to establish a differentiation of lung neuroendocrine tumors (LNETs). By analyzing the literature, new data were revealed regarding histological evaluation, genetic aberrations, prognosis depending on the type of LNET and therapeutic options that derive from these. Efficient management of these tumors is essential in the handling of symptoms and increase in life expectancy, especially in patients with functional tumors. Histological differentiation of LNETs is important in establishing proper therapeutic options and prognosis. Combined types of LNETs remain a controversial topic of discussion regarding diagnosis and treatment, a topic on which further studies are required in order to improve diagnosis in this group of tumors with heterogenous malignancy. Contents1. Introduction 2. Materials and methods 3. Epidemiology 4. Classification 5. Precursor lesions 6. Clinical features 7. Tumor staging 8. Biological landscape of lung neuroendocrine tumors (LNETs) 9. Radiological diagnosis 10. Surgical treatment 11. Advanced LNETs therapy 12. Conclusions

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“…On the other hand, in children and young adults, rare cases of peritoneal mesotheliomas unrelated to asbestos exposure harboring recurrent gene fusions in ALK , 11–14 NTRK 14 and EWSR1/FUS::ATF1 15–17 have been reported. EWSR1::YY1 fusion was reported only in 2 cases of peritoneal mesothelioma, both in males in their sixties 18 .…”

Section: Discussionmentioning

confidence: 99%

“…[4][5][6][7][8] Additionally, genetic alterations in Hippo pathway genes [neurofibromatosis type 2/merlin (NF2), LATS1/2, RASSF1, SAV1], as well as SETD2, SETDB1, DDX3X, DDX51, TP53, CDKN2A, were also reported in a subset of malignant mesotheliomas. [4][5][6]9,10 Rare cases of peritoneal mesotheliomas, typically in children or young adults, harboring recurrent gene fusions in ALK [11][12][13][14] and EWSR1/FUS::ATF1 [15][16][17] have been reported without associated asbestos exposure. Moreover, an EWSR1::YY1 fusion was reported in a single case study of 2 patients with peritoneal mesothelioma.…”

Section: Introductionmentioning

confidence: 99%

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EWSR1::YY1 fusion positive peritoneal epithelioid mesothelioma harbors mesothelioma epigenetic signature: Report of 3 cases in support of an emerging entity

Dermawan

Torrence

Lee

et al. 2022

Genes Chromosomes & Cancer

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Mesothelioma is a rare, aggressive malignant neoplasm of mesothelial origin. A small subset of peritoneal mesothelioma is driven by recurrent gene fusions, mostly EWSR1/FUS::ATF1 fusions, with predilection for young adults. To date, only two cases of mesothelioma harboring EWSR1::YY1 fusions have been described. We present three additional cases of EWSR1::YY1‐fused peritoneal mesotheliomas, two localized and one diffuse, all occurring in the peritoneum of middle‐aged adults (2 females and 1 male), and discovered incidentally by imaging or during surgery performed for unrelated reasons. None presented with symptoms or had a known history of asbestos exposure. All three cases were cellular epithelioid neoplasms with heterogeneous architectural patterns comprising mostly solid nests and sheets with variably papillary and trabecular areas against collagenous stroma. Cytologically, the cells were monomorphic, polygonal, epithelioid cells with dense eosinophilic cytoplasm and centrally located nuclei. Overt mitotic activity or tumor necrosis was absent. All cases showed strong diffuse immunoreactivity for pancytokeratin, CK7, and nuclear WT1, patchy to negative calretinin, retained BAP1 expression, and were negative for Ber‐EP4 and MOC31. RNA‐sequencing confirmed in‐frame gene fusion transcripts involving EWSR1 exon 7/8 and YY1 exon 2/3. By unsupervised clustering analysis, the methylation profiles of EWSR1::YY1‐fused mesotheliomas clustered similarly with EWSR1/FUS::ATF1‐fused mesotheliomas and conventional mesotheliomas, suggesting a mesothelioma epigenetic signature. All three patients underwent surgical resection or cytoreductive surgery of the masses. On follow‐up imaging, no recurrence or progression of disease was identified. Our findings suggest that EWSR1::YY1‐fusion defines a small subset of peritoneal epithelioid mesothelioma in middle‐aged adults without history of asbestos exposure.

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NTRK and ALK rearrangements in malignant pleural mesothelioma, pulmonary neuroendocrine tumours and non-small cell lung cancer

Cited by 22 publications

References 40 publications

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

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

Lung neuroendocrine tumors: A systematic literature review (Review)

EWSR1::YY1 fusion positive peritoneal epithelioid mesothelioma harbors mesothelioma epigenetic signature: Report of 3 cases in support of an emerging entity

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