Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
Mod Pathol. 2021 Sep;34(9):1696-1703. doi: 10.1038/s41379-021-00822-w. Epub 2021 May 16.
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.
钙化性巢状间质-上皮性肿瘤（CNSET）是一种罕见的肝脏肿瘤，发生于儿童和年轻成人。文献中报道的病例数<40 例，其发病机制和生物学行为尚不确定。在此，我们研究了 8 例 CNSET 的临床病理和分子遗传学特征。6 例患者（75%）为女性，发病时的中位年龄为 22.5 岁（范围 14-34 岁）。肿瘤的中位大小为 14cm（范围 2.7-18cm）。所有肿瘤均有纤维基质，其中包含上皮样至梭形肿瘤细胞的类器官巢，胞质呈中度嗜酸性，细胞核呈卵圆形或泡状。5 例肿瘤有钙化，1 例有血管淋巴管侵犯。所有肿瘤均未见坏死。免疫组化显示，5 例中有 5 例检测到核β-连环蛋白表达，7 例中有 5 例检测到 WT-1 核弥漫至灶状阳性。肝细胞标志物（HepPar-1、精氨酸酶-1 和白蛋白原位杂交）和神经内分泌标志物（突触素、嗜铬粒蛋白和 INSM1）均为阴性。下一代测序显示 7 例测序肿瘤均存在 CTNNB1 改变。Sanger 测序显示 6 例测序肿瘤均存在 TERT 启动子突变。7 例患者可获得临床随访（中位随访时间 4.4 年；范围 1.2-6.2 年）：4 例（57%）发生转移性疾病；所有 4 例均发生肺转移，其中 2 例还有腹部转移。所有 4 例发生转移的患者其肝内肿瘤仍持续存在或复发。3 例有转移的患者在最近的随访中仍患有疾病，1 例死于疾病。另外 3 例可获得随访的患者未发生转移或复发。1 例接受新辅助化疗的肿瘤未见反应，另 1 例肿瘤纤维化达 90%；后者患者在 6.2 年的随访中仍无疾病。我们的研究表明，所有测序肿瘤均存在 TERT 启动子突变和 CTNNB1 改变，提示 CNSET 可能比之前报道的更具侵袭性。
