Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research.
NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital.
Am J Surg Pathol. 2019 Jan;43(1):35-46. doi: 10.1097/PAS.0000000000001017.
The gene CDC73 (previously known as HRPT2) encodes the protein parafibromin. Biallelic mutation of CDC73 is strongly associated with malignancy in parathyroid tumors. Heterozygous germline mutations cause hyperparathyroidism jaw tumor syndrome,which is associated with a high life-time risk of parathyroid carcinoma. Therefore loss of parafibromin expression by immunohistochemistry may triage genetic testing for hyperparathyroidism jaw tumor syndrome and be associated with malignant behavior in atypical parathyroid tumors. We share our experience that parafibromin-negative parathyroid tumors show distinctive morphology. We searched our institutional database for parathyroid tumors demonstrating complete loss of nuclear expression of parafibromin with internal positive controls. Forty-three parafibromin-negative tumors from 40 (5.1%) of 789 patients undergoing immunohistochemistry were identified. Thirty-three (77%) were external consultation cases; the estimated incidence in unselected tumors was 0.19%. Sixteen (37.2%) fulfilled World Health Organization 2017 criteria for parathyroid carcinoma and 63% had serum calcium greater than 3mmol/L. One of 27 (3.7%) noninvasive but parafibromin-negative tumors subsequently metastasized. Parafibromin-negative patients were younger (mean, 36 vs. 63 y; P<0.001) and had larger tumors (mean, 3.04 vs. 0.62 g; P<0.001). Not all patients had full testing, but 26 patients had pathogenic CDC73 mutation/deletions confirmed in tumor (n=23) and/or germline (n=16). Parafibromin-negative tumors demonstrated distinctive morphology including extensive sheet-like rather than acinar growth, eosinophilic cytoplasm, nuclear enlargement with distinctive coarse chromatin, perinuclear cytoplasmic clearing, a prominent arborizing vasculature, and, frequently, a thick capsule. Microcystic change was found in 21 (48.8%). In conclusion, there are previously unrecognized morphologic clues to parafibromin loss/CDC73 mutation in parathyroid tumors which, given the association with malignancy and syndromic disease, are important to recognize.
CDC73 基因（以前称为 HRPT2）编码 parafibromin 蛋白。CDC73 的双等位基因突变与甲状旁腺瘤的恶性密切相关。杂合性种系突变导致甲状旁腺功能亢进性颌骨肿瘤综合征，其终生甲状旁腺癌的风险较高。因此，免疫组化中 parafibromin 表达缺失可能会对甲状旁腺功能亢进性颌骨肿瘤综合征进行基因检测，并与非典型甲状旁腺瘤的恶性行为相关。我们分享了我们的经验，即 parafibromin 阴性甲状旁腺瘤具有独特的形态。我们在我们的机构数据库中搜索了甲状旁腺瘤，这些肿瘤显示 parafibromin 的核表达完全缺失，同时有内部阳性对照。在 789 例行免疫组化的患者中，我们发现了 43 例 parafibromin 阴性肿瘤，占 40 例（5.1%）。其中 33 例（77%）为外部咨询病例；在未选择的肿瘤中，估计发病率为 0.19%。16 例（37.2%）符合 2017 年世界卫生组织甲状旁腺癌标准，63%的患者血清钙>3mmol/L。1 例非侵袭性但 parafibromin 阴性的肿瘤随后发生转移。Parafibromin 阴性患者更年轻（平均 36 岁比 63 岁；P<0.001），肿瘤更大（平均 3.04 克比 0.62 克；P<0.001）。并非所有患者都进行了全面检测，但 26 例患者在肿瘤（n=23）和/或种系（n=16）中证实存在致病性 CDC73 突变/缺失。Parafibromin 阴性肿瘤表现出独特的形态，包括广泛的片状而不是腺泡样生长、嗜酸性细胞质、细胞核增大、具有独特的粗染色质、核周细胞质透明、突出的树枝状血管，以及经常出现厚包膜。21 例（48.8%）发现微囊性改变。总之，甲状旁腺瘤中存在以前未被认识到的与 parafibromin 缺失/CDC73 突变相关的形态学线索，鉴于其与恶性肿瘤和综合征性疾病的关联，这些线索非常重要。
