Clinical implications of mismatch repair deficiency screening in patients with mixed neuroendocrine non-neuroendocrine neoplasms (MiNEN)

Lou, Lei; Lv, Fengzhu; Wu, Xin; Li, Yuehong; Zhang, Xianghong

doi:10.1016/j.ejso.2020.08.022

Cited by 13 publications

(15 citation statements)

References 34 publications

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“…Although it is difficult to simply extrapolate this data to Em-NEC, because of organ-specific tumor size and growth speed, their report supports the clinical significance of MSI-H/dMMR detection in patients with Em-NEC. 15 Among the patients with MSI-H/dMMR solid tumors, Lynch syndrome (LS) has been identified in 16.3%. 16 The present case does not meet the revised Amsterdam II criteria or LS genetic testing criteria on the basis of individual/family history.…”

Section: Discussionmentioning

confidence: 99%

Mixed large and small cell neuroendocrine carcinoma and endometrioid carcinoma of the endometrium with high microsatellite instability: A case report and literature review

Inoue

Kai

Sato

et al. 2021

SAGE Open Medical Case Reports

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A 65-year-old, gravida 3, para 2 Japanese woman was referred to our hospital for symptomatic thickening of the endometrial lining. Endocervical and endometrial cytology revealed an adenocarcinoma. The endometrial biopsy specimen was mixed, with a glandular part diagnosed as endometrioid carcinoma and a solid part diagnosed as high-grade mixed large and small cell neuroendocrine carcinoma (L/SCNEC). She underwent extra-fascial hysterectomy with bilateral salpingo-oophorectomy, complete pelvic and para-aortic lymphadenectomy, and omentectomy (FIGO IIIB, pT3b pN0 M0). She currently has no deleterious germline mutation, but high tumor mutation burden and high microsatellite instability (MSI) were identified. She underwent six cycles of platinum-based frontline chemotherapy and achieved complete remission. Immune checkpoint blockade therapy is a promising second-line therapy for MSI-high solid tumors. However, the MSI or mismatch repair (MMR) status of endometrial L/SCNEC remains unclear in the literature. Universal screening for MSI/MMR status is needed, particularly for a rare and aggressive disease.

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Section: Discussionmentioning

confidence: 99%

Mixed large and small cell neuroendocrine carcinoma and endometrioid carcinoma of the endometrium with high microsatellite instability: A case report and literature review

Inoue

Kai

Sato

et al. 2021

SAGE Open Medical Case Reports

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“…33,34 The most important neuroendocrine neoplasms known to harbor MSI/dMMR are represented by NEC, and only a few studies have linked this genetic alteration to well-differentiated NET. 6,9 More importantly, only one recent study has indicated MiNEN as a potential tumor setting harboring MSI, 13 but no specific data have been provided regarding MiNEN where the neuroendocrine counterpart is represented by a well-differentiated (non-NEC) NET. Our report highlights the need for MSI/dMMR testing in all intestinal MiNEN, not only for NEC mixed with other entities but also for mixed NET.…”

Section: Discussionmentioning

confidence: 99%

“…[10][11][12] Some preliminary reports have indicated that MSI/dMMR can also be found in neuroendocrine tumors (NETs)/NECs of the intestinal tract, opening new horizons for immunotherapeutic strategies for this kind of tumors. 13,14 To the best of our knowledge, no extensive molecular data have been reported in the literature regarding MSI/ dMMR intestinal MiNEN. Here, we provide the clinical, pathologic, and molecular report of a 73-year-old man presenting with a MSI/dMMR intestinal MiNEN, composed of well-differentiated G3 NET and colloid adenocarcinoma, also tracing its clonal evolution.…”

mentioning

confidence: 99%

Molecular Analysis of an Intestinal Neuroendocrine/Non-neuroendocrine Neoplasm (MiNEN) Reveals MLH1 Methylation-driven Microsatellite Instability and a Monoclonal Origin: Diagnostic and Clinical Implications

Sciammarella¹,

Bencivenga

Mafficini

et al. 2021

Applied Immunohistochemistry &Amp; Molecular Morphology

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Mixed neuroendocrine/non-neuroendocrine neoplasms (MiNEN) are rare mixed epithelial neoplasms in which a neuroendocrine component is combined with a non-neuroendocrine component. Here, we provide the clinical, pathologic, and molecular report of a 73-year-old-man presenting with an intestinal MiNEN. The lesion was composed of a well-differentiated G3 neuroendocrine tumor and a colloid adenocarcinoma. The molecular characterization was performed using a multigene nextgeneration sequencing panel. The neoplasm displayed microsatellite instability due to MLH1 promoter methylation. The extended molecular profile documented the same mutations affecting ARID1A, ASXL1, BLM, and RNF43 genes in both components, indicating a monoclonal origin of the tumor. Regarding component-specific gene mutations, BRCA2 was specifically altered in the neuroendocrine area. It may represent a new actionable target for precision oncology in MiNEN, but the lack of its alteration in the colloid component calls for further considerations on intratumor heterogeneity. The most important finding with potential immediate implications regards the presence of microsatellite instability: it indicates that this molecular alteration should become part of the diagnostic algorithm for these rare neoplasms.

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“…To date, the definition of MiNEN also excludes nonneuroendocrine neoplasms in which scattered tumor cells express neuroendocrine markers without the presence of neuroendocrine morphology (Table 1 ). Since neuroendocrine markers can be positive in many nonneuroendocrine tumors, including poorly differentiated adenocarcinomas, performing IHC alone may lead to an overdiagnosis of MiNEN[ 19 - 21 ]. Therefore, it is highly recommended to avoid the application of neuroendocrine markers to tumors that do not have a morphological neuroendocrine component to overcome this difficulty.…”

Section: Diagnosis Of Minenmentioning

confidence: 99%

“…Another finding supporting a common carcinogenic pathway is that a proportion of either PDNEC or MiNEN of the stomach and colorectum has increased methylation with a mismatch repair-deficient phenotype[ 41 - 44 ]. Since these tumors had less aggressive behavior, similar to sporadic colon adenocarcinoma in the elderly, it is proposed that mismatch repair deficiency could be a pathway between PDNEC/MiNEN and adenocarcinoma[ 21 , 25 ]. In addition, the neuroendocrine component of PDNEC carries mutations specific to the organ from which it originates and is similar to adenocarcinoma in localization; meanwhile, these alterations are different from a common neuroendocrine alteration.…”

Section: Pathogenesis Of Minenmentioning

confidence: 99%

Mixed neuroendocrine–nonneuroendocrine neoplasms of the gastrointestinal system: An update

Elpek¹

2022

WJG

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Mixed neuroendocrine-nonneuroendocrine neoplasms (MiNENs) of the digestive tract are a rare heterogeneous group of tumors that present many challenges in terms of diagnosis and treatment. Over the years, the diagnostic criteria, classification, and clinical behavior of these tumors have been the subjects of ongoing debate, and the various changes in their nomenclature have strengthened the challenges associated with MiNENs. This review is performed to provide an understanding of the key factors involved in the evolution of the designation of these tumors as MiNEN, highlight the current diagnostic criteria, summarize the latest data on pathogenesis and provide information on available treatments. Moreover, this work seeks to increase the awareness about these rare neoplasms by presenting the clinicopathological features and prognostic factors that play important roles in their behavior and discussing their different regions of origin in the gastrointestinal system (GIS). Currently, the MiNEN category also includes tumors in the GIS with a nonneuroendocrine component and epithelial tumors other than adenocarcinoma, depending on the organ of origin. Diagnosis is based on the presence of both morphological components in more than 30% of the tumor. However, this value needs to be reconfirmed with further studies and may be a limiting factor in the diagnosis of MiNEN by biopsy. Furthermore, available clinicopathological data suggest that the inclusion of amphicrine tumors in the definition of MiNEN is not supportive and warrants further investigation. The diagnosis of these tumors is not solely based on immunohistochemical findings. They are not hybrid tumors and both components can act independently; thus, careful grading of each component separately is required. In addition to parameters such as the metastatic state of the tumor at the time of diagnosis and the feasibility of surgical resection, the aggressive potential of both components has paramount importance in the choice of treatment. Regardless of the organ of origin within the GIS, almost MiNENs are tumors with poor prognosis and are frequently encountered in the elderly and men. They are most frequently reported in the colorectum, where data from molecular studies indicate a monoclonal origin; however, further studies are required to provide additional support for this origin.

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Clinical implications of mismatch repair deficiency screening in patients with mixed neuroendocrine non-neuroendocrine neoplasms (MiNEN)

Cited by 13 publications

References 34 publications

Mixed large and small cell neuroendocrine carcinoma and endometrioid carcinoma of the endometrium with high microsatellite instability: A case report and literature review

Mixed large and small cell neuroendocrine carcinoma and endometrioid carcinoma of the endometrium with high microsatellite instability: A case report and literature review

Molecular Analysis of an Intestinal Neuroendocrine/Non-neuroendocrine Neoplasm (MiNEN) Reveals MLH1 Methylation-driven Microsatellite Instability and a Monoclonal Origin: Diagnostic and Clinical Implications

Mixed neuroendocrine–nonneuroendocrine neoplasms of the gastrointestinal system: An update

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