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Calcifying nested stromal–epithelial tumor: a clinicopathologic and molecular genetic study of eight cases highlighting metastatic potential and recurrent CTNNB1 and TERT promoter alterations

Abstract

Calcifying nested stromal–epithelial tumor (CNSET) is a rare hepatic tumor that occurs in children and young adults. With <40 cases in the literature, the mechanism for tumorigenesis and the biological behavior of CNSET remain uncertain. Here, we studied the clinicopathologic and molecular genetic features of eight CNSETs. Six patients (75%) were female, and the median age at presentation was 22.5 years (range 14–34 years). The median tumor size was 14 cm (range 2.7–18 cm). All tumors had fibrous stroma that contained organoid nests of epithelioid to spindled tumor cells with moderate amounts of palely eosinophilic cytoplasm and ovoid, vesicular nuclei. Five tumors showed calcifications, and one showed lymphovascular invasion. Necrosis was absent in all. Immunohistochemistry demonstrated nuclear β-catenin expression in five of five tested tumors and focal to diffuse nuclear WT-1 positivity in five of seven. Hepatocellular markers (HepPar-1, arginase-1, and albumin in situ hybridization) and neuroendocrine markers (synaptophysin, chromogranin, and INSM1) were uniformly negative. Next-generation sequencing demonstrated CTNNB1 alterations in all seven sequenced tumors. Sanger sequencing demonstrated TERT promoter mutations in all six sequenced tumors. Clinical follow-up was available for seven patients (median duration 4.4 years; range 1.2–6.2 years): four (57%) developed metastatic disease; all four developed lung metastases; and two also had abdominal metastases. All four patients with metastatic disease also had persistent or recurrent liver tumors. Three patients with metastases were alive with disease at the most recent follow-up and one died of disease. The other three patients with available follow-up did not develop metastasis or recurrence. One tumor treated with neoadjuvant chemotherapy showed no response, and another showed 90% tumor fibrosis; the latter patient remained disease-free at 6.2 years of follow-up. Our series demonstrates the presence of TERT promoter mutations and CTNNB1 alterations in all sequenced tumors and suggests that CNSET might perhaps be more aggressive than previously reported.

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Fig. 1: Low-magnification view of calcifying nested stromal–epithelial tumor.
Fig. 2: Cytomorphology of calcifying nested stromal–epithelial tumor.
Fig. 3: Bone formation was present in five of eight tumors in this series.
Fig. 4: Ductular proliferation in calcifying nested stromal–epithelial tumor.
Fig. 5: Clear cell features.
Fig. 6: Pseudo-glandular architecture.
Fig. 7: Immunohistochemistry of calcifying nested stromal–epithelial tumor.

Data availability

The data generated and/or analyzed for this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank the following pathologists and clinicians who kindly provided case material and clinical follow-up information when available: Prof. A.P. Dei Tos (Padova, Italy), Dr. N. Donner (Amsterdam, The Netherlands), Dr. W.R. Jeck (Durham, NC), Dr. P. Puspanathan (Alor Setar, Malaysia), Dr. J.E. Rostedt (Tacoma, WA), Dr. C.D. Savci Heijink (Amsterdam, The Netherlands), Dr. S.A. Whitworth (Denver, CO), and Dr. X. Zhang (Cleveland, OH).

Funding

No external funding was used for this project, which was supported through intradepartmental funds.

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D.J.P., C.D.M.F., and L.Z. conceived of and designed this study. All authors (D.J.P., F.D., X.Z., R.K., O.B., C.D.M.F., and L.Z.) performed data acquisition, analysis, and/or interpretation. D.J.P., C.D.M.F., and L.Z. wrote the manuscript. All authors revised the manuscript, and all authors read and approved the final manuscript.

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Correspondence to Lei Zhao.

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The authors declare no competing interests.

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This retrospective study was approved by the Institutional Review Board of Mass General Brigham (protocol #2019P002519). No human subjects were recruited for the study.

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Papke Jr., D.J., Dong, F., Zhang, X. et al. Calcifying nested stromal–epithelial tumor: a clinicopathologic and molecular genetic study of eight cases highlighting metastatic potential and recurrent CTNNB1 and TERT promoter alterations. Mod Pathol (2021). https://doi.org/10.1038/s41379-021-00822-w

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