Pulmonary neuroendocrine neoplasms with well differentiated morphology and high proliferative activity: illustrated by a case series and review of the literature

Hermans, B.; Derks, Jules L.; Moonen, Laura; Habraken, C.H.J.; Thüsen, Jan von der; Hillen, Lisa M.; Speel, Ernst J. M.; Dingemans, A-M.C.

doi:10.1016/j.lungcan.2020.10.015

Cited by 23 publications

(26 citation statements)

References 24 publications

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“…At the time of writing, there has been nearly a dozen recent publications, mostly small series, describing lung tumors with morphology of carcinoids but mitotic counts of >10 per 2 mm 2 . Such tumors also commonly exhibit elevated Ki67 rates, which may exceed 20–30% (see Hermans et al 21 and references therein). In most cases, mitotic counts and Ki67 exceed these thresholds only mildly, but a hot-spot Ki67 rates of up to ~60% has been reported.…”

Section: Carcinoidsmentioning

confidence: 94%

Lung neuroendocrine neoplasms: recent progress and persistent challenges

Rekhtman

2022

Modern Pathology

110

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This review summarizes key recent developments relevant to the pathologic diagnosis of lung neuroendocrine neoplasms, including carcinoids, small cell lung carcinoma (SCLC), and large cell neuroendocrine carcinoma (LCNEC). Covered are recent insights into the biological subtypes within each main tumor type, progress in pathological diagnosis and immunohistochemical markers, and persistent challenging areas. Highlighted topics include highly proliferative carcinoids and their distinction from small cell and large cell neuroendocrine carcinomas (NECs), the evolving role of Ki67, the update on the differential diagnosis of NEC to include thoracic SMARCA4-deficient undifferentiated tumors, the recent data on SCLC transcriptional subtypes with the emergence of POU2F3 as a novel marker for the diagnosis of SCLC with low/negative expression of standard neuroendocrine markers, and the update on the diagnosis of LCNEC, particularly in biopsies. There has been remarkable recent progress in the understanding of the genetic and expression-based profiles within each type of lung neuroendocrine neoplasm, and it is hoped that these insights will enable the development of novel diagnostic, prognostic, and predictive biomarkers to aid in the pathologic assessment of these tumors in the future.

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Section: Carcinoidsmentioning

confidence: 94%

Lung neuroendocrine neoplasms: recent progress and persistent challenges

Rekhtman

2022

Modern Pathology

110

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“…31,44,56,57 In addition, LCNEC with morphologic features resembling a carcinoid tumor but with an increased proliferation rate (>10 mitoses per 2 mm 2 ) has been identified. 30,[57][58][59][60] Molecular studies have revealed that these tumors are more likely to behave as carcinoids rather than "true" LCNEC, 58 although a separate AC-LCNEC cluster may exist. 61 Regarding outcome after surgery in carcinoids with increased proliferation rates, a relatively high frequency of distant disease relapse is reported and both a slightly longer and a comparable OS compared with LCNEC are reported.…”

Section: Q3 What Is the Value Of A Typical Or Atypical Carcinoid Diagnosis On A Biopsy Specimen In Local And Metastatic Disease?mentioning

confidence: 99%

“…13,67 Hence, a Ki-67 PI-based treatment strategy requires prospective validation and inclusion of additional markers previously correlated with treatment response in carcinoid, for example, SSTR2, of which expression has been correlated with response to PRRT, 68 and pRb and p53. 60 The WHO 2021 classification is based on morphologic evaluation of surgical resection specimens, separating high-grade NENs into LCNEC and SCLC. The need to separate LCNEC and SCLC however may be debated.…”

Section: Q3 What Is the Value Of A Typical Or Atypical Carcinoid Diagnosis On A Biopsy Specimen In Local And Metastatic Disease?mentioning

confidence: 99%

Clinical-Pathologic Challenges in the Classification of Pulmonary Neuroendocrine Neoplasms and Targets on the Horizon for Future Clinical Practice

Derks¹,

Rijnsburger²,

Hermans³

et al. 2021

Journal of Thoracic Oncology

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Diagnosing a pulmonary neuroendocrine neoplasm (NEN) may be difficult, challenging clinical decision making. In this review, the following key clinical and pathologic issues and informative molecular markers are being discussed: (1) What is the preferred outcome parameter for curatively resected low-grade NENs (carcinoid), for example, overall survival or recurrence-free interval? (2) Does the WHO classification combined with a Ki-67 proliferation index and molecular markers, such as OTP and CD44, offer improved prognostication in low-grade NENs? (3) What is the value of a typical versus atypical carcinoid diagnosis on a biopsy specimen in local and metastatic disease? Diagnosis is difficult in biopsy specimens and recent observations of an increased mitotic rate in metastatic carcinoid from typical to atypical and high-grade NEN can further complicate diagnosis. (4) What is the (ir)relevance of morphologically separating large cell neuroendocrine carcinoma (LCNEC) SCLC and the value of molecular markers (RB1 gene and pRb protein or transcription factors NEUROD1, ASCL1, POU2F3, or YAP1 [NAPY]) to predict systemic treatment outcome? (5) Are additional diagnostic criteria required to accurately separate LCNEC from NSCLC in biopsy specimens? Neuroendocrine morphology can be absent owing to limited sample size leading to missed LCNEC diagnoses. Evaluation of genomic studies on LCNEC and marker studies have identified that a combination of napsin A and neuroendocrine markers could be helpful. Hence, to improve clinical practice, we should consider to adjust our NEN classification incorporating prognostic and predictive markers applicable on biopsy specimens to inform a treatment outcome-driven classification.

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“…On the one side, a growing body of studies indicates that a subset of lung neuroendocrine tumors that are classified as pulmonary carcinoids based on mitotic index (therefore not above 10 mitotic figures in 2mm 2 ) have a significantly higher Ki-67 proliferation rate than the mean of overall carcinoid tumors [12,13]. These cases, although maintaining a well differentiated morphology, have Ki-67 proliferation index close to large-cell neuroendocrine carcinomas and display a more aggressive clinical behavior than those with lower proliferative rates, irrespective of the carcinoid histotype assessed by the WHO classification [14,15] (Fig. 1).…”

Section: The Grey Zone Between Thoracic Neuroendocrine Tumors and Neumentioning

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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Pulmonary neuroendocrine neoplasms with well differentiated morphology and high proliferative activity: illustrated by a case series and review of the literature

Cited by 23 publications

References 24 publications

Lung neuroendocrine neoplasms: recent progress and persistent challenges

Lung neuroendocrine neoplasms: recent progress and persistent challenges

Clinical-Pathologic Challenges in the Classification of Pulmonary Neuroendocrine Neoplasms and Targets on the Horizon for Future Clinical Practice

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

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