Objective: To investigate the clinicopathologic and molecular features of the rare cribriform morular variant of papillary thyroid carcinoma (CMV-PTC). Methods: The clinicopathologic data of 10 patients with CMV-PTC were retrospectively reviewed. Immunohistochemical (IHC) staining was done using LSAB method. DNA sequencing for APC were applied using Sanger method. BRAF V600E mutation was examined using ARMS method. The cytological, morphological, IHC and molecular features were analyzed. Results: All patients were female at an average age of 27 years old. The tumors were mostly located in the right lobe of thyroid. Fine needle aspiration cytology was performed in three patients; two were diagnosed as suspicious for PTC and one as PTC. Nine tumors presented as solitary nodule and two as multiple nodules in both lobes. Infiltration was demonstrated in three cases. The average size was 2.6 cm. The neoplastic cells were arranged in papillary, cribriform, solid and glandular patterns, with rare or without colloid inside the lumen. The number of morula varied, ranging from zero to many. The neoplastic cells were variably enlarged, showing round, oval or spindle shape. Nuclear irregularity was identified as irregular membrane, nuclear grooves or pseudoinclusion, but no typical ground glass feature. Peculiar nuclear clearing could be observed in the morular cells. IHC staining showed the neoplastic cells were negative for thyroglobulin and p63, but positive for TTF1, cytokeratin 19 and estrogen receptor. Diffuse staining with cytokeratin was seen in the neoplastic cells and the morula. Specific cytoplasmic and nuclear staining of β-catenin was seen in the neoplastic cells but not the morula. Ki-67 proliferation index was 1%-30%. No recurrence or metastasis was observed. One patient was demonstrated to harbor both somatic and germline mutations of the APC gene, who was found to have adenomatous polyposis and her mother died of colonic carcinoma. No BRAF V600E mutation was detected. Conclusions: CMV-PTC is rare and shows atypical cytological and clinicopathological features, and it is easily misdiagnosed.TG, TTF1, ER and β-catenin are specific IHC markers for CMV-PTC. The morula is negative for cytokeratin 19, in contrast to squamous metaplasia. Although CMV-PTC has indolent clinical behavior, a definite diagnosis is necessary to rule out the possibility of APC gene mutation and related extra-thyroidal neoplasm, such as FAP and Gardner syndrome.
目的： 探讨筛状桑葚型甲状腺乳头状癌(cribriform morular variant of papillary thyroid carcinoma，CMV-PTC)的细胞学特点、临床病理及分子生物学特征。 方法： 收集10例CMV-PTC患者存档资料，行细胞学、组织学观察及免疫组织化学(LASB法)染色。采用Sanger测序法检测其腺瘤性息肉病(adenomatous polyposis coli，APC)基因突变，采用突变扩增系统(ARMS)法检测BRAF V600E基因突变，分析其临床病理及分子生物学特征。 结果： 10例患者均为女性，平均年龄27岁。肿瘤主要位于甲状腺右叶。3例行术前甲状腺细针穿刺细胞检查，2例诊断为可疑甲状腺乳头状癌(PTC)，1例诊断为PTC。8例均为孤立性结节，2例为双叶多发结节，3例呈浸润性生长。平均直径2.6 cm。细胞学上缺乏炎性病变、坏死背景，肿瘤细胞特点为乳头状、筛状、实性、腺状排列，胶质稀少或缺无。PTC细胞核特点不典型，可见核内包涵体和核沟。桑葚体可有或无。组织形态学上复杂多变，肿瘤细胞特点与细胞学一致，细胞核多呈柱状或高细胞状，桑葚体细胞核多透明。免疫组织化学染色结果显示肿瘤细胞及桑葚体甲状腺球蛋白(TG)、p63阴性。甲状腺转录因子(TTF)1、雌激素受体(ER)、细胞角蛋白(CK)、CK19阳性表达于肿瘤细胞。β-catenin特异性阳性表达于肿瘤细胞质和细胞核。以上抗体桑葚体仅表达CK。Ki-67阳性指数1%～30%。随访未发现肿瘤复发和转移。APC基因检测发现1例结直肠癌相关性基因体细胞突变，该例血清学检查发现家族性腺瘤性息肉病(familial adenomatous polyposis，FAP)相关性胚系突变，肠镜证实多发性息肉病，其母亲死于肠癌。所有肿瘤均无BRAF V600E基因突变。 结论： CMV-PTC因罕见、细胞学、病理学及临床病理学特点不被熟知，容易漏诊、误诊或过诊。TG、TTF1、β-catenin、ER是诊断CMV-PTC较为特异的免疫组织化学指标。桑葚体不同于鳞状上皮化生，不表达p63和CK19，但表达CK。尽管肿瘤本身预后良好，但因其易伴发APC基因突变相关性肿瘤(如FAP、Gardner综合征)而须准确诊断。.
Keywords: Clinicopathological; Cribriform morular variant; Molecular feature; Papillary thyroid carcinoma; Thyroid neoplasms.