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

Abstract

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.

Large Cell Neuroendocrine Carcinoma of the Lung: Current Understanding and Challenges

“…LCNEC appears as a high-grade malignant tumor with neuroendocrine morphology (organoid or trabecular patterns, rosette-like structures, or peripheral palisading), a non-small-cell cytology (with a cell size three times larger than lymphocytes diameter), abundant cytoplasm (often eosinophilic), prominent nucleoli and low nuclear-to-cytoplasmatic ratio, with frequent necrosis and a high mitotic rate, greater than 10 mitoses per 2 mm 2 (average 60–80 mitoses per 2 mm 2 ) [ 5 , 17 , 18 , 19 ].…”

ENETS standardized (synoptic) reporting for neuroendocrine tumour pathology

“…P53 and RB are thus incorporated as optional biomarkers as they emerge as helpful in the differential diagnosis of NET G3 versus NEC. The immunohistochemical staining patterns for these proteins reflect the underlying molecular changes that seem to be important in the clinical behaviour as NEC and also predicting therapy response as is suggested for tumours with RB mutations as often seen in small cell carcinoma 14 15 …”

Classifying Pulmonary and Urinary High-grade Neuroendocrine Carcinoma by CK7 Immunohistochemistry

“…37,47 To further differentiate the various subtypes of LCNEC, tumors were also tested by further genetic alterations of ASCL1, NOTCH, STK11, KEAP1, and KRAS. [35][36][37]47 Next-generation sequencing of type I LCNEC revealed frequent mutations in KRAS, STK11, or KEAP1, with high expression of ASCL1 and neuroendocrine markers. Type II LCNEC might be considered if the result showed a codeletion of Rb1 and TP53 with low expression of ASCL1 and high expression of NOTCH.…”

“…However, there is no gold standard for separating SmCC and LCNEC. Due to fuzzy boundaries and significant interobserver variabilities,35 the accuracy of cell size, cellular variants, nuclear-to-cytoplasm ratio, nucleoli, and chromatin morphology as advocated by morphologic methods36 for HGNEC was greatly challenged 37…”