Casuistic cases of parathyroid carcinoma with a verified mutation in the MEN1 gene
https://doi.org/10.14341/probl13176
Abstract
Parathyroid cancer (PTC) is usually sporadic; however, it could be presented as a component of hereditary syndromes. The prevalence of PTC among patients with primary hyperparathyroidism (PHPT) is about 1% cases. The lack of reliable preoperative predictors significantly complicates the diagnosis of PTC. The clinical course is non-specific and in most cases is determined by severe hypercalcemia. The final diagnosis can only be made on the basis of invasive histopathologic features, while an analysis immunohistochemical (IHC) one can be used only as an additional method. Given the rarity the diagnosis of MEN1-related PTC a challenge. We present two clinical cases of patients with PTC and a verified heterozygous mutation in the MEN1 gene. The described cases demonstrate the complexity of morphological diagnosis for PTC, the heterogeneity of clinical manifestations in patients with the MEN1 mutation, as well as the need for timely screening to identify other components of MEN1 syndrome and mutations of the MEN1 gene among first-line relatives.
About the Authors
S. V. Pylina
Endocrinology Research Center
Russian Federation
Competing Interests:
Russian Federation
Svetlana V. Pylina – MD.
11 Dm. Ulyanova street, 117036 Moscow
Competing Interests:
None
E. I. Kim
Endocrinology Research Center
Russian Federation
Competing Interests:
Russian Federation
Ekaterina I. Kim - MD.
Moscow
Competing Interests:
None
E. V. Bondarenko
Endocrinology Research Center
Russian Federation
Competing Interests:
Russian Federation
Ekaterina V. Bondarenko - MD, PhD.
Moscow
Competing Interests:
None
J. A. Krupinova
Endocrinology Research Center
Russian Federation
Competing Interests:
Russian Federation
Julia A. Krupinova - MD.
Moscow
Competing Interests:
None
A. K. Eremkina
Endocrinology Research Center
Russian Federation
Competing Interests:
Russian Federation
Anna K. Eremkina - MD, PhD.
Moscow
Competing Interests:
None
N. G. Mokrysheva
Endocrinology Research Center
Russian Federation
Competing Interests:
Russian Federation
Natalia G. Mokrysheva - MD, PhD, Professor.
Moscow
Competing Interests:
None
References
1. Fraser WD. Hyperparathyroidism. Lancet. 2009;374(9684):145-158. doi: https://doi.org/10.1016/S0140-6736(09)60507-9
2. Sainton P, Millot J. Malegne d’un adenoma parathyroidiene eosinophile. Au cours d’une de Recklinghausen. Ann Anat Pathol. 1933;(10):813-814.
3. Mamedova EO, Mokrysheva NG, Pigarova EA, et al. Molecular and genetic features of primary hyperparathyroidism in young patients. Problems of Endocrinology. 2016;62(2):4-11. (In Russ.). doi: https://doi.org/10.14341/probl20166224-11
4. Starker LF, Åkerström T, Long WD, et al. Frequent germ-line mutations of the MEN1, CASR, and HRPT2/CDC73 genes in young patients with clinically non-familial primary hyperparathyroidism. Horm Cancer. 2012;3(1-2):44-51. doi: https://doi.org/10.1007/s12672-011-0100-8
5. Goudet P, Murat A, Binquet C, et al. Risk factors and causes of death in MEN1 disease. A GTE (Groupe d’Etude des Tumeurs Endocrines) cohort study among 758 patients. World J Surg. 2010;34(2):249-255. doi: https://doi.org/10.1007/s00268-009-0290-1
6. Wassif WS, Moniz CF, Friedman E, et al. Familial isolated hyperparathyroidism: a distinct genetic entity with an increased risk of parathyroid cancer. J Clin Endocrinology Metab. 1993;77(6):1485-1489. doi: https://doi.org/10.1210/jcem.77.6.7903311
7. Simonds WF, Robbins CM, Agarwal SK, et al. Familial isolated hyperparathyroidism is rarely caused by germline mutation inHRPT2, the gene for the hyperparathyroidism-jaw tumor syndrome. J Clin Endocrinology Metab. 2004;89(1):96-102. doi: https://doi.org/10.1210/jc.2003-030675
8. Jenkins PJ, Satta MA, Simmgen M, et al. Metastatic parathyroid carcinoma in the MEN2A syndrome. Clin Endocrinol (Oxf). 1997;47(6):747-751.doi: https://doi.org/10.1046/j.1365-2265.1997.3421147.x
9. Alfaro JJ. MEN-2A syndrome and pulmonary metastasis. Postgrad Med J. 2002;78(915):51-52. doi: https://doi.org/10.1136/pmj.78.915.51
10. Posada-González M, Gómez-Ramírez J, Luque-Ramírez M, et al. Nonfunctional metastatic parathyroid carcinoma in the setting of multiple endocrine neoplasia type 2A syndrome. Surg Res Pract. 2014;2014(915):1-4. doi: https://doi.org/10.1155/2014/731481
11. Singh Ospina N, Sebo TJ, Thompson GB, et al. Prevalence of parathyroid carcinoma in 348 patients with multiple endocrine neoplasia type 1 — case report and review of the literature. Clin Endocrinol. 2015;84(2):244-249. doi: https://doi.org/10.1111/cen.12714
12. Frank-Raue K, Rondot S, Hoeppner W, et al. Coincidence of Multiple Endocrine Neoplasia Types 1 and 2: Mutations in the RET protooncogene and MEN1 tumor suppressor gene in a family presenting with recurrent primary hyperparathyroidism. J Clin Endocrinol Metab. 2005;90(7):4063-4067. doi: https://doi.org/10.1210/jc.2004-1759
13. Wu CW, Huang CI, Tsai ST, et al. Parathyroid carcinoma in a patient with non-secretory pituitary tumor: a variant of multiple endocrine neoplasia type-I? Eur J Surg Oncol. 1992;18:517-520.
14. Sato M, Miyauchi A, Namihira H, et al. A newly recognized germline mutation of MEN1 gene identified in a patient with parathyroid adenoma and carcinoma. Endocrine. 2000;12:223-226.
15. Dionisi S, Minisola S, Pepe J, et al. Concurrent parathyroid adenomas and carcinoma in the setting of multiple endocrine neoplasia type 1: presentation as hypercalcemic crisis. Mayo Clin Proc. 2022;77:866-869.
16. Agha A, Carpenter R, Bhattacharya S, et al. Parathyroid carcinoma in multiple endocrine neoplasia type 1 (MEN1) syndrome: two case reports of an unrecognised entity. J Endocrinol Invest. 2007;30:145-149. doi: https://doi.org/10.1007/bf03347413.
17. Shih RYW, Fackler S, Maturo S, et al. Parathyroid carcinoma in multiple endocrine neoplasia type 1 with a classic germline mutation. Endocr Pract. 2009;15:567-572. doi: https://doi.org/10.4158/ep09045.crr1.
18. Kalavalapalli S, Talapatra I, O’ Connell IPM. A complex case of Multiple Endocrine Neoplasia type 1 with Metastatic Parathyroid Carcinoma. Cent Eur J Med. 2010;5:53-58 doi: https://doi.org/10.2478/s11536-009-0116-4.
19. del Pozo C, García-Pascual L, Balsells M, et al. Parathyroid carcinoma in multiple endocrine neoplasia type 1. Case report and review of the literature. Hormones (Athens). 2011;10:326-331. doi: https://doi.org/10.14310/horm.2002.1325.
20. Juodelė L, Serapinas D, Sabaliauskas G, et al. Carcinoma of Two Parathyroid Glands Caused by a Novel MEN1 Gene Mutation — a Rare Feature of the MEN 1 Syndrome. Medicina. 2011;47:635-639. https://doi.org/10.3390/medicina47110092.
21. Lee KM, Kim EJ, Choi WS, et al. Intrathyroidal parathyroid carcinoma mimicking a thyroid nodule in a MEN type 1 patient. Journal of Clinical Ultrasound. 2014;42:212-214. doi: https://doi.org/10.1002/jcu.22090.
22. Singh Ospina N, Sebo TJ, Thompson GB, et al. Prevalence of parathyroid carcinoma in 348 patients with multiple endocrine neoplasia type 1 — case report and review of the literature. Clinical Endocrinology. 2015;84(2):244-9. doi: https://doi.org/10.1111/cen.12714
23. Christakis I, Busaidy NL, Cote GJ, et al. Parathyroid carcinoma and atypical parathyroid neoplasms in MEN1 patients; A clinico-pathologic challenge. The MD Anderson case series and review of the literature. International Journal of Surgery. 2016;31:10-16. doi: https://doi.org/10.1016/j.ijsu.2016.05.035.
24. Omi Y, Horiuchi K, Haniu K, et al. Parathyroid carcinoma occurred in two glands in multiple endocrine neoplasia 1: a report on a rare case. Endocr J. 2018;65:245-252. doi: https://doi.org/10.1507/endocrj.ej17-0409.
25. Cinque L, Sparaneo A, Cetani F, et al. Novel association of MEN1 gene mutations with parathyroid carcinoma. Oncol Lett. 2017;14:23-30. doi: https://doi.org/10.3892/ol.2017.6162.
26. Di Meo G, Sgaramella LI, Ferraro V, et al. Parathyroid carcinoma in multiple endocrine neoplasm type 1 syndrome: case report and systematic literature review. Clin Exp Med. 2018;18:585–593. doi: https://doi.org/10.1007/s10238-018-0512-7
27. Schantz A, Castleman B. Parathyroid carcinoma.A study of 70 cases. Cancer. 1973;31(3):600-605. doi: https://doi.org/10.1002/1097-0142(197303)31:3<600::AID-CNCR2820310316>3.0.CO;2-0
28. Sharretts JM, Kebebew E, Simonds WF. Parathyroid cancer. Semin Oncol. 2010;37(6):580-590. doi: https://doi.org/10.1053/j.seminoncol.2010.10.013
29. Kim J, Horowitz G, Hong M, et al. The dangers of parathyroid biopsy. J Otolaryngol - Head Neck Surg. 2017;46(1):4. doi: https://doi.org/10.1186/s40463-016-0178-7
30. Duan K, Mete O. Parathyroid carcinoma: diagnosis and clinical implications. Turkish J Pathol. 2015;46(1):4. doi: https://doi.org/10.5146/tjpath.2015.01316
31. O’Sullivan B, Brierley J, Byrd D, et al. The TNM classification of malignant tumours — towards common understanding and reasonable expectations. Lancet Oncol. 2017;18(7):849-851. doi: https://doi.org/10.1016/S1470-2045(17)30438-2
32. DeLellis RA. Parathyroid adenoma. In: Lloyd RV, Osamura RY, Kloppel G, Rosai J, editors. WHO classification of tumours of endocrine organs. Lyon: IARC; 2017. P. 153-158.
33. Tan M-H, Morrison C, Wang P, et al. Loss of Parafibromin Immunoreactivity Is a Distinguishing Feature of Parathyroid Carcinoma. Clin Cancer Res. 2004;10(19):6629-6637. doi: https://doi.org/10.1158/1078-0432.CCR-04-0493
34. Woodard GE, Lin L, Zhang J-H, et al. Parafibromin, product of the hyperparathyroidism-jaw tumor syndrome gene HRPT2, regulates cyclin D1/PRAD1 expression. Oncogene. 2005;24(7):1272-1276. doi: https://doi.org/10.1038/sj.onc.1208274
35. Mehta A, Patel D, Rosenberg A, et al. Hyperparathyroidism-jaw tumor syndrome: Results of operative management. Surgery. 2014;156(6):1315-1325. doi: https://doi.org/10.1016/j.surg.2014.08.004
36. Erickson LA, Mete O, Juhlin CC, et al. Overview of the 2022 WHO Classification of Parathyroid Tumors. Endocr Pathol. 2022;33(1):64-89. doi: https://doi.org/10.1007/s12022-022-09709-1
37. Pearce SHS, Trump D, Wooding C, et al. Loss of heterozygosity studies at the retinoblastoma and breast cancer susceptibility (BRCA2) loci in pituitary, parathyroid, pancreatic and carcinoid tumours. Clin Endocrinol (Oxf). 1996;45(2):195-200. doi: https://doi.org/10.1046/j.1365-2265.1996.d01-1561.x
38. Subramaniam P, Wilknson S, Shiepherd JJ. Inactivation of retinoblastoma gene in malignant parathyroid growths: a candidate genetic trigger? Aust N Z J Surg. 1995;65(10):714-716. doi: https://doi.org/10.1111/j.1445-2197.1995.tb00542.x
39. Erovic BM, Harris L, Jamali M, et al. Biomarkers of parathyroid carcinoma. Endocr Pathol. 2012;23(4):221-231. doi: https://doi.org/10.1007/s12022-012-9222-y
40. Hu L, Xie X. Parathyroid carcinoma with sarcomatoid differentiation: a case report and literature review. Diagn Pathol. 2020;15(1):142. doi: https://doi.org/10.1186/s13000-020-01060-5
41. Schaaf L, Pickel J, Zinner K, et al. Developing effective screening strategies in Multiple Endocrine Neoplasia Type 1 (MEN 1) on the basis of clinical and sequencing data of german patients with MEN 1. Exp Clin Endocrinol Diabetes. 2007;115(08):509-517. doi: https://doi.org/10.1055/s-2007-97016
42. Thakker RV, Newey PJ, Walls GV, et al. Clinical practice guidelines for Multiple Endocrine Neoplasia Type 1 (MEN1). J Clin Endocrinol Metab. 2012;97(9):2990-3011. doi: https://doi.org/10.1210/jc.2012-1230
43. Brown SJ, Riconda DL, Zheng F, et al. Features of Multiple Endocrine Neoplasia Type 1 and 2A in a patient with both RET and MEN1 germline mutations. J Endocr Soc. 2020;4(4):142. doi: https://doi.org/10.1210/jendso/bvaa020
44. Mastroianno S, Torlontano M, Scillitani A, et al. Coexistence of multiple endocrine neoplasia type 1 and type 2 in a large Italian family. Endocrine. 2011;40(3):481-485. doi: https://doi.org/10.1007/s12020-011-9501-2
45. Frank-Raue K, Rondot S, Hoeppner W, et al. Coincidence of Multiple Endocrine Neoplasia Types 1 and 2: Mutations in the RET protooncogene and MEN1 tumor suppressor gene in a family presenting with recurrent primary hyperparathyroidism. J Clin Endocrinol Metab. 2005;90(7):4063-4067. doi: https://doi.org/10.1210/jc.2004-1759
46. Goudet P, Murat A, Binquet C, et al. Risk factors and causes of death in MEN1 disease. A GTE (Groupe d’Etude des Tumeurs Endocrines) cohort study among 758 patients. World J of Surg. 2009;34(2):249-255. doi: https://doi.org/10.1007/s00268-009-0290-1
Supplementary files
|
|
1. Figure 1. PTG carcinoma (surgical material from 2017): A — tumor of a solid structure with invasive growth into adjacent tissues (×40); B — the presence of a single mitosis with an atypical form of division (×400); C, PTH expression; D - expression of chromogranin A. | |
| Subject | ||
| Type | Исследовательские инструменты | |
View
(1MB)
|
Indexing metadata ▾ | |
|
|
2. Figure 2. Histological examination of bronchoscopy: A — tumor growth of nest-trabecular structure from small relatively monomorphic cells with scanty light eosinophilic cytoplasm, rounded and oval hyperchromic nuclei. Hematoxylineosin stain (×100); B — positive reaction with an antibody to TTF-1 in a part of tumor cells. Immunohistochemical study (×100); B — Ki-67 proliferative activity index — 10%. Immunohistochemical study (×100); D — positive expression of PTH in tumor cells. Immunohistochemical study (×100). | |
| Subject | ||
| Type | Исследовательские инструменты | |
View
(1MB)
|
Indexing metadata ▾ | |
|
|
3. Figure 3. A — PTG carcinoma, stained with hematoxylin-eosin (×100); B — CD34 expression, vascular invasion (×100); C — PTH expression in the tumor outside the capsule; D — expression of Ki-67 2%. | |
| Subject | ||
| Type | Исследовательские инструменты | |
View
(1MB)
|
Indexing metadata ▾ | |
|
|
4. Figure 4. Staining for parafibromin: A, B — areas with positive staining of nuclei of different intensity and field of cytoplasmic reaction, ×400; C — pronounced nuclear expression in the parathyroid tissue surrounding the tumor, ×100. | |
| Subject | ||
| Type | Исследовательские инструменты | |
View
(1MB)
|
Indexing metadata ▾ | |
Review
For citations:
Pylina S.V., Kim E.I., Bondarenko E.V., Krupinova J.A., Eremkina A.K., Mokrysheva N.G. Casuistic cases of parathyroid carcinoma with a verified mutation in the MEN1 gene. Problems of Endocrinology. 2023;69(1):15-27. (In Russ.) https://doi.org/10.14341/probl13176
Views:
1854
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND 4.0).
Email this article 
.jpg){kind=logo}
