What clinicians are asking pathologists when dealing with lung neuroendocrine neoplasms?
Section snippets
Approaching lung NET
The new 2015 WHO classification on lung neuroendocrine tumors (NET)1 has substantially confirmed the four widely agreed upon histological variants crystallized in the two previous editions of 19992 and 2004,3 namely typical carcinoid (TC), atypical carcinoid (AC), large-cell neuroendocrine carcinoma (LCNEC), and small cell carcinoma (SCC). Remarkably, in this 2015 edition, these tumors have been pushed to enter a unique box of NE proliferations by moving LCNEC from the all-inclusive chapter of
Designing the article
A review of papers reported on the issue of lung NET with special reference to diagnosis, Ki-67, grading and predictive markers was performed until July 2015, taking advantage of a list of key questions for either subject. We limited our bibliography research to the English literature, apart from some historical papers published in other languages. Only full papers of peer-reviewed journals were considered. Research terms included carcinoid, typical, atypical, small cell, large cell, LCNEC,
Diagnosing lung NET
Diagnosis still remains the first but no longer the only task clinicians are requiring to pathologists whenever facing lung NET. Some entities proposed over time in the field of lung NET may be considered milestones with direct and continuing integration to the current terminology, while other terms or taxonomy schemes are only a historical inheritance (at least according to recent guidelines4 and WHO classification).1 Diagnostic criteria for SCC—as we still know and currently rely on—date
Unraveling Ki-67 and tumor grading
As outlined above, current criteria for lung NET basically include mitosis count and necrosis,12 while tumor architecture, cell atypia, vascular invasion, lymph node metastases, or immunohistochemistry profile do not play any role in this separation.14, 17 However, some controversies still persist in their diagnostic reproducibility, so that searching for additional criteria more related to behavioral traits is clinically warranted.
Ki-67 antigen has been largely studied in lung NET,12, 25, 29,
Predicting in NET
According to recent guidelines, no molecular tests should currently be routinely carried out in lung NET, unless specifically required by study protocols (Level of Evidence 4; Grade of Recommendation C).4 However, an increasing body of knowledge is accumulating in lung NET about biomarkers with predictive value, which could modify the therapy of these tumors in near future. This holds true especially for TC and AC where treatment, when non directly surgical (as mainly happens), relies on
Conclusion
Lung NET comprise a quite heterogeneous cluster of human malignancies with profound differences in the epidemiologic, genetic, pathologic and behavioral characteristics, which can cause a conundrum to the biological understanding of these lesions. Through an enlightened re-thinking of lung NET, pathologists should provide clinicians with better diagnostic refining of the diverse categories of lung NET with closer adherence to the clinical reality by means of an innovative concept of tumor
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Cited by (29)
Prognostic implications of synaptophysin, CD56, thyroid transcription factor-1, and Ki-67 in pulmonary high-grade neuroendocrine carcinomas
2024, Annals of Diagnostic PathologyUSP7 inhibitors, downregulating CCDC6, sensitize lung neuroendocrine cancer cells to PARP-inhibitor drugs
2017, Lung CancerCitation Excerpt :Lung neuroendocrine tumors (L-NETs), that comprise 20–25% of all lung tumors, include both the high grade small cell lung cancers (SCLC) and large cell neuroendocrine carcinomas (LCNEC), the intermediate grade atypical carcinoids (AC) and the low grade typical carcinoids (TC) [1], accordingly to the last World Health Organization (WHO) classification [2].
The Use of Immunohistochemistry Improves the Diagnosis of Small Cell Lung Cancer and Its Differential Diagnosis. An International Reproducibility Study in a Demanding Set of Cases
2017, Journal of Thoracic OncologyCitation Excerpt :In our study the significant increase in the percentage of the diagnostic score in 70% or more of the cases with use of IHC in the second level demonstrates a gain in diagnostic confidence by the pathologist, although it should be noted that the diagnostic difficulty of the specimens in the study set may indicate a level of bias when compared with standard cases. A strategy for IHC in the diagnosis of SCLC could therefore contain a two-tiered approach, as illustrated in Table 4.5,15–42 First, a pro-SCLC panel consisting of one or more of the following may be used: CD56, low-molecular-weight CK (e.g., CK 7, CK8, or CK18), TTF1, MIB1, and perhaps p16.
Pulmonary Large Cell Neuroendocrine Carcinoma
2022, Pathology and Oncology ResearchNew Prognostic Frontiers for Lung Neuroendocrine Tumors
2022, Research Square
This work was supported by Lega Italiana per la Lotta contro i Tumori (LILT), Sezione di Milano, Milan, Italy. The Funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript, which are responsibilities of the Authors only. This work is dedicated to the memory of Carlotta, an extraordinarily lively girl who untimely died of cancer in the prime of life.