Pulmonary large cell neuroendocrine carcinoma with adenocarcinoma-like features: napsin A expression and genomic alterations

Abstract

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a highly aggressive malignancy, which was recently found to comprise three major genomic subsets: small cell carcinoma-like, non-small cell carcinoma (predominantly adenocarcinoma)-like and carcinoid-like. To further characterize adenocarcinoma-like subset, here we analyzed the expression of exocrine marker napsin A, along with TTF-1, in a large series of LCNECs (n=112), and performed detailed clinicopathologic and genomic analysis of napsin A-positive cases. For comparison, we analyzed napsin A expression in other lung neuroendocrine neoplasms (177 carcinoids, 37 small cell carcinomas) and lung adenocarcinomas (n=60). We found that napsin A was expressed in 15% of LCNEC (17/112), whereas all carcinoids and small cell carcinomas were consistently negative. Napsin A reactivity in LCNEC was focal in 12/17 cases, and weak or moderate in intensity in all cases, which was significantly lower in the extent and intensity than seen in adenocarcinomas (p<0.0001). The combination of TTF-1-diffuse/napsin A-negative or focal was typical of LCNEC but was rare in adenocarcinoma, and could thus serve as a helpful diagnostic clue. The diagnosis of napsin A-positive LCNECs was confirmed by classic morphology, diffuse labeling for at least one neuroendocrine marker, most consistently synaptophysin, and the lack of distinct adenocarcinoma component. Genomic analysis of 14 napsin A-positive LCNECs revealed the presence of mutations typical of lung adenocarcinoma (KRAS and/or STK11) in 11 cases. In conclusion, LCNECs are unique among lung neuroendocrine neoplasms in that some of these tumors exhibit low-level expression of exocrine marker napsin A, and harbor genomic alterations typical of adenocarcinoma. Despite the apparent close biological relationship, designation of adeno-like LCNEC as a separate entity from adenocarcinoma is supported by their distinctive morphology, typically diffuse expression of neuroendocrine marker(s) and aggressive behavior. Further studies are warranted to assess the clinical utility and optimal method of identifying adenocarcinoma-like and other subsets of LCNEC in routine practice.

Best Practices Recommendations for Diagnostic Immunohistochemistry in Lung Cancer

“…In TTF1-positive nonsmall cell tumors, napsin A may play a role in classification of NE tumors, as it may be positive in a subset of large cell NE carcinomas (LCNECs), which are molecularly similar to adenocarcinoma, helping to separate them from high-grade NE tumors such as small cell carcinoma, which are typically napsin A-negative. 7,8 The use of surfactant protein A is discouraged, as its performance is inferior. 9,10 As a marker of squamous cell carcinoma, p63 was more frequently used in IHC analysis before introduction of the p40 antibody.…”

Is the sum of positive neuroendocrine immunohistochemical stains useful for diagnosis of large cell neuroendocrine carcinoma (LCNEC) on biopsy specimens?

“…In the differential diagnosis of LCNEC versus SCLC, staining of RB1 IHC is indicative of a non‐SCLC‐like tumour . Finally, napsin‐A is proposed as a marker to differentiate the TTF1‐positive molecular LCNEC‐NSCLC subtype from adenocarcinoma, as only few show focal staining for napsin‐A while all adenocarcinomas show (strong) staining for both markers …”

“…4 Finally, napsin-A is proposed as a marker to differentiate the TTF1-positive molecular LCNEC-NSCLC subtype from adenocarcinoma, as only few show focal staining for napsin-A while all adenocarcinomas show (strong) staining for both markers. 36 Our study was restricted by the limited number of paired biopsy-resection specimens evaluated by the panel of pathologists. Nevertheless, the described diagnostic issues in this study reflect the daily clinical practice closely.…”

A practical guide for ancillary studies in pulmonary cytologic specimens

“…8,14 Although napsin A expression is not seen in TCs, ACs, or SCC, it can be expressed in a subset of LCNEC at a lower level than adenocarcinoma; it was shown that these LCNECs harboured mutations typical of lung adenocarcinoma. 38 Of note, 5% to 10% of SCCs and LCNECs may lack expression of all 3 neuroendocrine markers. 34 The proliferation index is high (40% to 80%), and necrosis may be present.…”