What clinicians are asking pathologists when dealing with lung neuroendocrine neoplasms?

https://doi.org/10.1053/j.semdp.2015.10.009Get rights and content

Abstract

Lung neuroendocrine tumors (NET) are currently classified in resection specimens according to four histological categories, namely typical carcinoid (TC), atypical carcinoid (AC), large-cell neuroendocrine carcinoma (LCNEC) and small cell carcinoma (SCC). Diagnostic criteria have remained unchanged in the 2015 WHO classification, which has ratified the wide acceptance and popularity of such terminology in the pathologists׳ and clinicians׳ community. A unifying umbrella of NE morphology and differentiation has been recognized in lung NET, which has pushed to enter an unique box of invasive tumors along with diffuse idiopathic pulmonary NE cell hyperplasia (DIPNECH) as a pre-invasive lesion with a potential toward the development of carcinoids. However, uncertainties remain in the terminology of lung NET upon small samples, where Ki-67 antigen could play some role to avoid misdiagnosing carcinoids as high-grade NE tumors. Epidemiologic, clinical and genetic traits support a biological three-tier over a pathology four-tier model, according to which TC are low malignancy tumors, AC intermediate malignancy tumors and LCNEC/SCC high malignancy tumors with no significant differences in survival among them. Inconsistencies in diagnostic reproducibility, troubles in the therapy of AC and LCNEC, and limitations to histology within the same tumor category argue in favor of a global re-thinking of lung NET where a grading system could play a role. This review outlines three main key questions in the field of lung NET: (A) unbiased diagnoses, (B) the role of Ki-67 and tumor grading, and (C) management of predictive markers. Answers are still inconclusive, thus additional research is required to improve our understanding on lung NET.

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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    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.

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