Nooshin ahmadi fellowship of endocrinology

1. Nooshinahmadifellowship of endocrinology Parathyroid carcinoma in familial hyperparathyroidism syndromes

2. Problem list • A37 y/o woman with hyperparathyroidism and parathyroid adenoma • A 40 y old man with symptomatic hyperparathyroidism and parathyroid adenoma and recurrence of hypercalcemia 2 years after first surgery diagnosed as parathyroid carcinoma with negative MENIN • A 26 y/o woman with manifestation of hyperparathyroidism

3. Hereditary Hyperparathyroidism Syndromes.Journalof Clinical Densitometry: Assessment of Skeletal Health, 2013 Familial hyperparathyroidism includes a group of disorders in which primary hyperparathyroidism (PHPT) is inherited ,usually as an autosomal dominant trait. These include: • Multiple endocrine neoplasia type 1 (MEN1), • MEN2A, • MEN4, • Familial hypocalciurichypercalcemia (FHH), • neonatal severe hyperparathyroidism (NSHPT), • autosomal dominant moderate hyperparathyroidism (ADMH), • hyperparathyroidism-jaw tumor syndrome (HPT-JT), • familial isolated hyperparathyroidism(FIHPT)

4. MEN1 • PHPT is the most common endocrine component of MEN1, occurring in 90% of individuals aged between 20 and 25 yrand showing penetrance of 100% within 50 yr. Patients usually exhibit a multiglandularparathyroid disease with enlargement of all the parathyroid glands, each considered as a monoclonal lesion. The growth of the glands is asynchronous and asymmetric • The MEN1 gene was identified in 1997 and is the only gene known to be associated with this syndrome. Hereditary Hyperparathyroidism Syndromes.Journal of Clinical Densitometry: Assessment of Skeletal Health, 2013

5. MEN2A In MEN2A, PHPT occurs in 20-30% of cases. It is usually mild and asymptomatic, except for 15% of subjects presenting with hypercalciuria and renal calculi. The average age of onset of PHPT is 38 yr, many years after the diagnosis of MTC.Inmost individuals with MEN2A, parathyroid adenoma or hyperplasia are diagnosed many years after thyroidectomy, rarely hyperparathyroidism is diagnosed at the time of thyroidectomy Hereditary Hyperparathyroidism Syndromes.Journal of Clinical Densitometry: Assessment of Skeletal Health, 2013

6. MEN4 • MEN4 IS very rare • Characterized by the occurrence of parathyroid and anterior pituitary tumors in association with tumors of adrenal , kidney and reproductive organs • MEN1- and RET-negative patients, showing a MEN-like phenotype, were analyzed for CDKN1B mutations;

7. Familial hypocalciurichypercalcemia(FHH) • benign rare condition • Affected patients exhibit hypocalciuria(urinary calcium/creatinine ratio typically !0.01) • inactivation of CaSR protein in renal tubules • FHH patients do not usually develop symptoms, being often identified by chance.

8. HPT-JT • Hpt-jt is a syndrome of hpt, jaw tumors and renal lesions. Transmission is autosomal dominant. • The most common and sometime the only feature is HPT. • the HPT typically involves one parathyroid gland at a time, and there is a uniquely high malignant potential in the parathyroid tumors,15% of patients have parathyroid cancer. • The associated jaw tumors (in 25%)are ossifying or cementifying fibromas, unlike the jaw tumor of HPT. they are not osteoclast rich or influenced by the parathyroid status. • The associated renal lesion (in 5%) are multiple renal cyst , hamartomas or wilms tumor. Uterine tumors are common and can impair fertility Williams text book of endocrinology 13 edition

9. Hyperparathyroidism jaw tumour syndrome: a pictoralreview, Insights Imaging (2016) Individuals with HPT-JT typically present with jaw and teeth deformities secondary to ossifying fibromas of the maxilla and mandible. These produce a hard, deforming jaw swelling, which can cause early tooth displacement. Alternatively, they may present with symptoms and signs of hypercalcaemia secondary to hyperparathyroidism due to an underlying parathyroid adenoma or carcinoma. A few patients will also be detected incidentally with a high serum calcium on blood biochemistry that subsequently prompts further investigation

10. To date, less than 300 cases from approximately 100 families have been reported. HPT-JT syndrome was first described in 1990 but the genetic marker has been identified only in 2002 for these reasons, its real incidence is still unknown and might be underestimated.

12. Hereditary hyperparathyroidism—a consensus report of the European Society of Endocrine Surgeons (ESES) Langenbecks Arch Surg (2015

13. familial isolated hyperparathyroidism(FIHPT) patients were required to have hypercalcaemia with a non-suppressed parathyroid hormone (PTH) AND • history of the same in one or more first degree relative(s), • histopathological evidence from surgery of parathyroid adenoma, carcinoma, or hyperplasiain the patient or relative. • MEN1, MEN2A, FHH and HPT-JT phenotypes had been excluded in known affected family members by clinical, biochemical, and radiological investigation

15. To date, more than 100 FIHPT families have been described, but most kindreds have an unknown genetic background). In these patients,the following germline mutations of the following genes have been identified:the MEN1 gene in 20-23%the CaSRgene in 14-18%less frequently the HRPT2 gene Hereditary Hyperparathyroidism Syndromes Journal of Clinical Densitometry: Assessment of Skeletal Health, vol. 16, no. 1, 69e74, 2013

16. Genetic testing in familial isolated hyperparathyroidism: unexpected results and their implications. Warner J et al. J Med Genet. 2004 • in 22 unrelated subjects with FIHP phenotypes, MEN1, CASR, and HRPT2 genotyping the authors found 5 (23 %) with MEN1 mutations, 4 (18 %) with CASR, and none with an HRPT2 mutation. • Of the subjects with CASR mutations, none was of the typical FBHH phenotype • MEN 1and CaSRmutations are more likely in younger patients with multiglandular disease, • whereas HRPT2 mutations should be considered in those families with parathyroid carcinomas or cystic parathyroid tumors

17. Familial isolated hyperparathyroidism:a distinct genetic entity with an increased risk of parathyroid cancer.journal of clinical endocrinology and metabolism1993 • we tested 19 members of a large, well characterized family with FIHP in which the disease is transmitted through 4 generations, examination of four affected subjects19 genotyping MEN1region • In this family, FIHP appears to be a distinct genetic entityunlinked to the MEN1 region or the MEN2A and PTH genes. • a clinically discrete syndrome with a more aggressive course of parathyroid disease compared with MENI • one individual developed a double adenoma upon recurrence of primary hyperparathyroidism, another developed recurrent parathyroid carcinoma, and four affected members died before the age of 40 yr. • It is suggestive of an increased risk of malignant parathyroid disease in families with FIHP.

18. Familial Isolated Hyperparathyroidism Is Rarely Caused by Germline Mutation in HRPT2, the Gene for the Hyperparathyroidism-Jaw Tumor Syndrome The Journal of Clinical Endocrinology & Metabolism 2004 We investigated 32 families with FIHP to determine the frequency of occult mutation in HRPT2, the gene causing HPT-JT. Among the 32 FIHP families, only a single one was found to have a mutation in HRPT2. The FIHP kindred with HRPT2 mutation has four known affected members with HPT, including two with a lipomaand the proband with parathyroid cancer these results indicate that an unexpectedly large fraction of FIHP has currently unrecognized causes

19. Genetic basis of familial isolated hyperparathyroidism: a case series and a narrative review of the literature, J Bone Miner Metab2014. we report a case series of FIHP in a four generation Greek family, with no identifiable gene mutations. a total of 95 families in which FIHP has been detected; member genomes were analyzed for mutations

20. Genetic basis of familial isolated hyperparathyroidism: a case series and a narrative review of the literature, J Bone Miner Metab2014 • The age of FIHP onset is usually between 20 and 25 years, 30 years earlier than sporadic cases. • Patients with FIHP more frequently present with severe hypercalcemiaor hypercalcemic crisis compared with MEN 1 patients.

21. Update on parathyroid carcinoma. J Endocrinol Invest 2016 Parathyroid carcinoma Parathyroid carcinoma is commonly a sporadic disease, but familialcases may occur ,particularly in: • HPT-JT. • PC is also part of familial isolated hyperparathyroidism (FIHP), • rarely MEN1and MEN2Asyndrome .

22. Surveillance for Early Detection of Aggressive Parathyroid Disease: Carcinoma and Atypical Adenoma in Familial Isolated Hyperparathyroidism Associated With a Germline HRPT2 Mutation Germline HRPT2 mutations importance • Germline HRPT2 mutations have also been described in a small minority of kindreds with familial isolated hyperparathyroidism • HRPT2 mutations seem to be associated with aggressive parathyroid disease. HPTJT carries a substantially increased risk of parathyroid carcinoma (∼15% versus <1% in sporadic PHP). • Moreover, inactivating mutations in HRPT2 have been identified in the large majority of sporadic parathyroid carcinomas, • suggesting a crucial role for loss of parafibrominfunction in parathyroid carcinogenesis

23. HRPT2 IMPORTANCE The association of mutations in this gene with FIHP and parathyroid carcinoma underscore the need to closely monitor at-risk individuals in such kindreds. The identification of an HRPT2 loss-of-function mutation in the proband was of clinical significance in that it allowed genetic evaluation of siblings, one advantage being that mutation-negative individuals no longer required close biochemical monitoring. These findings strongly support the consideration of biochemical screeningand/or genetic screening for HRPT2 mutations in individuals in the setting of a family history of parathyroid carcinoma or an atypical parathyroid tumor,whetheror not other features of HPT-JT are present.

24. Surveillance for Early Detection of Aggressive Parathyroid Disease: Carcinoma and Atypical Adenoma in Familial IsolatedHyperparathyroidism Associated With a Germline HRPT2 Mutation When should we suspect HRPT2 germ line mutation in familial hyperparathyroidism reinforce the concept that HRPT2 germlinemutation should be suspected when parathyroid carcinoma or atypical adenomas occur in familial hyperparathyroidism

25. TREATMENT of FIHP? Parathyroid surgery is the treatment of choice for FIPH,particularlywhen complications of the disease have been observed.Surgical procedure differs from that followed in sporadic forms of PHT and even among the familial forms per se. In case of FIHPT, since it may be either caused by single adenoma, or asymmetric multiple gland disease, bilateral neck exploration with visualization of all four parathyroid glands is the approach most likely to provide the most long-term cure. Genetic basis of familial isolated hyperparathyroidism: a case series and a narrative review of the literature, J Bone Miner Metab2014

26. Hereditary hyperparathyroidism—a consensus report of the European Society of Endocrine Surgeons (ESES) Langenbecks Arch Surg (2015) FIHPT linked to mutations in the MEN1 gene, or the HRPT2 gene should be treated similar as in MEN1 and HPT-JT, respectively, since the patient may be from a kindred with absent or low penetrance of other associated tumour types In case of HPT-JT syndrome, when preoperative localization is negative, a bilateral neck exploration is recommended,withsubtotal parathyroidectomy or total parathyroidectomy(with or more frequently without autotransplantation). In the presence of concordant imaging suggestive of single-gland involvement, a focused approach with selective parathyroidectomymay be performed). In case of suspicion of parathyroid carcinoma,(typically large, gray-white, locally invasive parathyroid) an en bloc resection including the ipsilateral thyroid lobe and adjacent soft tissues with a view to avoiding fragmentation of the tumouris recommended.

27. FIHP with MEN1 mutation It has been proposed that the initial surgical procedure in patients with FIHP withMEN1 mutations is either subtotal parathyroidectomy, leaving a remnant of 20–30 mg of one of the glands, or total parathyroidectomy with heterotopic auto-transplantation of resected parathyroid tissue]. In patients with mutations of the MEN1 gene, a less than total parathyroidectomy is associated with unacceptably high frequency of persistent and recurrent hyperparathyroidism . Genetic basis of familial isolated hyperparathyroidism: a case series and a narrative review of the literature, J Bone Miner Metab2014

28. FIHP with HRPT2 mutation • The treatment of choice in patients with HRPT2-related FIHP is still controversial. • It has been suggested that the resection of all grossly enlarged parathyroid glands in the absence of any suspicion of parathyroid cancer is the optimal therapeutic approach • On the other hand, given the high rate of recurrence or persistence, the morbidity of a second operation and the risk of parathyroid carcinoma, some authors suggest ipsilateralhemithyroidectomy and total parathyroidectomy • Genetic basis of familial isolated hyperparathyroidism: a case series and a narrative review of the literature, J Bone Miner Metab2014

29. Intra operative pTH • The intraoperative PTH assay is likely to be helpful to assure adequate resection. it has become routine in surgery for sporadic primary HPT • The Miami criteria advocate a 50% or more drop in PTH from the highest preincisionor preexcisionlevel at 10 min • there can be a significant false-positive rate ( [50% drop in PTH when resection of parathyroid tissue is inadequate) in patients with multiglandular disease (up to 50%) • small false-negative rate using rapid PTH assays

30. Update on parathyroid carcinoma. J Endocrinol Invest 2016Parathyroid carcinoma: a 22-year experience. Head Neck204 Importance of parathyroid carcinoma follow up PC has a recurrence rate of >50 %. Most recurrences occur within 2–3 years after initial surgery, with a local recurrence rate between 33 and 82 % within 5 years .

31. Follow up of proband parathyroid carcinoma in FIHP We arbitrarily planned semiannual follow-up evaluations for the proband after his initial surgery. Surveillance for Early Detection of Aggressive Parathyroid Disease: Carcinoma and Atypical Adenoma in Familial Isolated Hyperparathyroidism Associated With a GermlineHRPT2 Mutation

32. Follow up of HRPT2 mutation-positive siblings in FIHP Monitor asymptomatic, normocalcemic, mutation-positive siblings of the proband using calcium and PTH measurements every 6 months Surveillance for Early Detection of Aggressive Parathyroid Disease: Carcinoma and Atypical Adenoma in Familial Isolated Hyperparathyroidism Associated With a GermlineHRPT2 Mutation

33. CLINICAL CASE SEMINAR Diagnosis of Parathyroid Tumors in Familial Isolated Hyperparathyroidism with HRPT2 Mutation: Implications for Cancer Surveillance The Journal of Clinical Endocrinology & Metabolism2006

34. Follow up Our experience with this particular kindred suggests that there may be occurrence of parathyroid tumor without a hypercalcemicharbinger. PTH levels may provide added sensitivity in screening, but even so, longitudinal surveillance by serum biochemistry may not always be enough, as was the case in the recurrence among patients Adding neck ultrasonography to periodic screening with serum calcium and PTH assays may occasionally lead to even earlier disease detection, although the actual clinical benefit added by ultrasonography remains uncertain and should be examined in other kindreds

35. prognosis • The prognosis of PC is quite variable. Patients with complete resection of the tumor at initial surgery carry the best prognosis. • The mean time to recurrence is usually 3 years. Once the tumor recurs, a complete cure is unlike, although prolonged survival is still common with palliative surgery. A 5- and 10-year survival rate of 78.3 and 49 %, respectively, has been reported . • Negative prognostic factors for survival were higher calcium level at recurrence, numbers of neck recurrences, the use of several calcium-lowering medications, simple parathyroidectomyas initial surgery, presence of lymph nodes or distant metastases, and nonfunctioning PC. In addition, patients whose tumor carries a CDC73 mutation, and/o loss of parafibromin or CASR expression have a worse survival rate.