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Diagnosis and Discussion: Case 1172

Final Diagnosis

Well-differentiated parathyroid carcinoma.

Discussion

Parathyroid carcinoma represents less than 1% of human malignancy and of causes of primary hyperparathyroidism. 1 When it does occur, presentation with hypercalcemia and elevated serum PTH is typical; another common presentation is that of a suspicious thyroid nodule, subsequently found to be associated with hypercalcemia. Parathyroid carcinoma even more rarely occurs wherever ectopic parathyroid tissue may be present, such as the mediastinum. 2

With rare exceptions (known metastasis, vocal cord paralysis) the diagnosis of carcinoma is not suspected preoperatively. However, the intraoperative finding of unexpectedly difficult surgical resection (due to tumor infiltration or tissue response) is highly suspicious and should alert the interpreting pathologist to an elevated risk of malignancy. Finally, many cases are only recognized at the time of histopathologic examination. 3

The diagnosis of parathyroid carcinoma may be challenging both because of its rarity in comparison to the much more common parathyroid hyperplasias and adenomata, and the lack of reliable features of malignancy in a significant proportion of cases. Parathyroids are unencapsulated and carcinoma arising from them often does not develop a true continuous capsule through which invasion may be identified; the present case is an exception.

Increased mitotic activity and necrosis may be caused by trauma or surgical manipulation; intratumoral band-like fibrosis, a common feature in parathyroid carcinoma, also occurs in large or longstanding benign parathyroid lesions. Scattered nuclear atypia is common in many benign endocrine lesions, including those of the parathyroid, and conversely parathyroid carcinoma may be cytologically bland. Frank infiltrative growth, perineural invasion and distant metastasis are unambiguously malignant features, but these are not typically present in cases where malignancy was not already suspected. In one series of 51 parathyroid nodules with atypical features such as increased mitotic activity and intratumoral fibrosis but no definitive evidence of malignancy, none of the patients developed recurrence. 4

True extratumoral vascular invasion is a useful feature as long as stringent criteria are applied to avoid overdiagnosis of artefactual tumor displacement. Definitive vascular invasion usually requires clear-cut extension of tumor cells through the vascular wall into the lumen, or evidence of in vivo reaction with tumor-related fibrin complexes or thrombi. In this case, the presence of even one focus of vascular invasion with fibrin and vascular endothelium apposed to tumor is the strongest argument in favor of malignancy. The presence of vascular invasion is known to independently increase the risk of recurrence. 5

Parathyroid carcinoma may occur in the context of familial syndromes, most notably hyperparathyroidism-jaw tumor syndrome (HPTJT). HTPJT is caused by pathogenic germline mutations in CDC73, which encodes parafibromin. The lifetime risk of parathyroid carcinoma in individuals with HTPJT is quoted as 15%, although this is based on a small number of individuals. 6 Somatic mutations in CDC73 also occur in a significant subset of parathyroid carcinoma and are associated with a higher risk of recurrence, but detection by parafibromin immunohistochemistry is known to be technically difficult. 7 In this case, parafibromin staining was absent, but insufficient expression in the on-slide control impaired interpretation. Subsequent genetic testing did not uncover a germline mutation in the patient, whether in CDC73 or other potentially implicated genes such as MEN1. 8

Parathyroid carcinoma, including recurrent disease, is managed by surgery. Long-term surveillance is achieved by monitoring serum calcium and PTH. Extended surveillance is necessary as the cumulative incidence of disease recurrence continues to increase even after 10 years of follow-up. 9

References

  1. Givi B, Shah JP. Parathyroid Carcinoma. Clinical Oncology. 2010;22(6):498-507. doi:10.1016/j.clon.2010.04.007
  2. Bao Y, Kang G, Wu X, Li J, Huang Y, Wang Y. Mediastinal parathyroid carcinoma: a case report and review of the literature. BMC Endocr Disord. 2023;23(1):130. doi:10.1186/s12902-023-01363-w
  3. Akirov A, Asa SL, Larouche V, et al. The Clinicopathological Spectrum of Parathyroid Carcinoma. Front Endocrinol (Lausanne). 2019;10:731. doi:10.3389/fendo.2019.00731
  4. McCoy KL, Seethala RR, Armstrong MJ, et al. The clinical importance of parathyroid atypia: is long-term surveillance necessary?. Surgery. 2015;158(4):929–935; discussion 935–936. doi:10.1016/j.surg.2015.06.022
  5. Ryhänen EM, Leijon H, Metso S, et al. A nationwide study on parathyroid carcinoma. Acta Oncol. 2017;56(7):991-1003. doi:10.1080/0284186X.2017.1306103
  6. Carpten J, Robbins C, Villablanca A, et al. HRPT2, encoding parafibromin, is mutated in hyperparathyroidism–jaw tumor syndrome. Nat Genet. 2002;32(4):676-680. doi:10.1038/ng1048
  7. Gill AJ, Lim G, Cheung VKY, et al. Parafibromin-deficient (HPT-JT Type, CDC73 Mutated) Parathyroid Tumors Demonstrate Distinctive Morphologic Features. Am J Surg Pathol. 2019;43(1):35-46. doi:10.1097/PAS.0000000000001017
  8. Yip L, Seethala RR, Nikiforova MN, et al. Loss of heterozygosity of selected tumor suppressor genes in parathyroid carcinoma. Surgery. 2008;144(6):949–955; discussion 954–955. doi:10.1016/j.surg.2008.08.030
  9. Asare EA, Silva-Figueroa A, Hess KR, et al. Risk of Distant Metastasis in Parathyroid Carcinoma and Its Effect on Survival: A Retrospective Review from a High-Volume Center. Ann Surg Oncol. 2019;26(11):3593-3599. doi:10.1245/s10434-019-07451-3