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An algorithmic approach utilizing CK7, TTF1, beta-catenin, CDX2, and SSTR2A can help differentiate between gastrointestinal and pulmonary neuroendocrine carcinomas

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Abstract

Primary gastrointestinal neuroendocrine carcinoma (GI-NEC) cannot be distinguished morphologically from pulmonary neuroendocrine carcinoma (P-NEC). This can present a significant diagnostic challenge in cases where site of origin cannot be readily determined. To identify immunohistochemical (IHC) markers that can be used to reliably distinguish between GI-NECs and P-NECs, we constructed 3-mm tissue microarrays, one containing 13 GI-NECs and one containing 20 P-NECs. IHC was performed on both microarrays using 21 stains: AE1/AE3, CK7, CK20, synaptophysin, chromogranin, CD56, INSM1, SSTR2A, CDX2, SATB2, TTF1, Napsin A, PR, GATA3, PAX8, ISL1, beta-catenin, AFP, SMAD4, Rb, and p53. For GI-NEC, the most strongly expressed marker was synaptophysin (mean H-score 248), while AE1/AE3 was the most strongly expressed in P-NEC (mean H-score 230), which was stronger than in GI-NEC (p = 0.011). Other markers that were stronger overall in P-NEC than in GI-NEC included CK7 (p < 0.0001) and TTF1 (p < 0.0001). Markers that were stronger overall in GI-NEC than in P-NEC included SSTR2A (p = 0.0021), SATB2 (p = 0.018), CDX2 (p = 0.019), and beta-catenin (nuclear; p = 0.029). SMAD4, Rb, and p53 showed similar rates of abnormal protein expression. Based on these results, a stepwise algorithmic approach utilizing CK7, TTF1, beta-catenin, CDX2, and SSTR2A had a 91% overall accuracy in distinguishing these GI-NEC from P-NEC. This was tested on a second cohort of 10 metastatic GI-NEC and 10 metastatic P-NEC, with an accuracy in this cohort of 85% and an overall accuracy of 89% for the 53 cases tested. Our algorithm reasonably discriminates GI-NEC from P-NEC using currently available IHC stains.

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Acknowledgements

Teri Bowman, HT, ASCP assisted with immunohistochemical staining for this project.

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  1. Department of Pathology and Laboratory Medicine, Tufts Medical Center, Boston, MA, USA

    Sanhong Yu

  2. Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA

    Jason L. Hornick

  3. Department of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA, USA

    Raul S. Gonzalez

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Contributions

SY analyzed stains and data, devised the algorithm, and wrote the manuscript. JLH assisted in case selection, performed some tissue staining, and offered expert advice. RSG conceived the study, assisted in case selection, arranged tissue staining, and edited the manuscript.

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Correspondence to Raul S. Gonzalez.

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Yu, S., Hornick, J.L. & Gonzalez, R.S. An algorithmic approach utilizing CK7, TTF1, beta-catenin, CDX2, and SSTR2A can help differentiate between gastrointestinal and pulmonary neuroendocrine carcinomas. Virchows Arch 479, 481–491 (2021). https://doi.org/10.1007/s00428-021-03085-7

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