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Review
. 2025 Jun;117(3):220-242.
doi: 10.32074/1591-951X-N1102. Epub 2025 Jun 27.

Clinical needs and pathology's answers in neuroendocrine neoplasms of the lung

Giuseppe Pelosi #  1   2 , Alice Laffi #  3 , Mauro Papotti  4 , Sylvie Lantuejoul  5 , Jean-Yves Scoazec  6 , Maria Gemelli  7 , Riccardo Ricotta  7 , Sergio Harari  8   9 , Eleonora Duregon  4 , Riccardo Papa  2 , Angelica Sonzogni  10 , Fabrizio Bianchi  11 , Antonino Bruno  12   13 , Barbara Bassani  12 , Silvia Uccella  14   15 , Carlo Carnaghi  16 , Alexia Francesca Bertuzzi  3
Affiliations
Review

Clinical needs and pathology's answers in neuroendocrine neoplasms of the lung

Giuseppe Pelosi et al. Pathologica. 2025 Jun.

Abstract

Lung neuroendocrine neoplasms (NENs) make up a variegated ensemble of malignancies encompassing typical carcinoid (TC) and atypical carcinoid (AC). These are low to intermediate grade neuroendocrine tumors (NETs), and large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC), which are full-fledged high-grade neuroendocrine carcinomas (NECs) showing similar clinical outcomes. Through a peer interaction between oncologist and pathologist, we herein constructed a practical approach based on questioning and answering regarding 8 practical issues aimed to provide shared solutions for clinical decision-making. These issues were itemized as sequential steps guided by clinical reasoning and concerned differential diagnosis, combined subtypes, primary and metastatic tumors, small diagnostic material, predictive biomarkers, tumor staging and, lastly, standardizing terminology. This study takes advantage of the close interaction between oncologists and pathologists as a tool to better delineate the decision-making on lung NENs.

Keywords: diagnosis; lung; neuroendocrine neoplasms; oncology; pathology.

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Conflict of interest statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Figures

Figure 1.
Figure 1.
Histologic features of pulmonary neuroendocrine tumors. A spindle cell-shaped typical carcinoid (TC) features elongated tumor cells disposed in intertwining fascicles mimicking a mesenchymal neoplasm, with no necrosis or recognizable mitotic figures (A). Another TC example shows polygonal cells organized in trabecular and lobular structures of epithelial appearance, again with no necrosis or recognizable mitotic figures (B). INSM1 immunohistochemistry is shown to decorate tumor cell nuclei (B, inset). A case of atypical carcinoid (AC) presents with a solid histologic appearance, but superimposable cytologic characteristics (C), along with immunohistochemical membrane reactivity for somatostatin receptor type 2A (C, inset). Punctate necrosis is a histologic hallmark, which is diagnostic of AC (D). The new category of carcinoid tumor with elevated mitotic count and/or Ki-67 proliferation index exhibits increased mitotic activity (highlighted by yellow arrows) (E), punctate necrosis (F) and increased Ki-67 labeling index (G). Pictures taken at 20X or 40X magnification.
Figure 2.
Figure 2.
Histologic features of pulmonary neuroendocrine carcinomas. A large cell neuroendocrine carcinoma (LCNEC) is composed by organoid aggregates of tumor cells with peripheral palisading and abundant necrosis (A), with common TTF1 expression (A, inset). Tumor cells present with coarse nuclear chromatin and plentiful mitoses (B). Small cell lung carcinoma (SCLC) is characterized by small-sized tumor cells with extensive geographic-type necrosis (C) and faint immunohistochemical decoration for chromogranin A (C, inset). This case presents with variable immunoreactivity for the ASCL1 gene product (D). For comparison, another morphologically similar SCLC case expressed POU2F3 rather than ASCL1 (E). Pictures taken at 20X or 40X magnification.
See this image and copyright information in PMC

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