OVARIAN GRANULOSA CELL TUMOR IN A PATIENT WITH A PATHOGENIC VARIANT IN THE CDC73 GENE (HYPERPARATHYROIDISM-JAW TUMOR SYNDROME) MD 1

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1 AACE Clinical Case Reports Rapid Electronic Articles in Press Rapid Electronic Articles in Press are preprinted manuscripts that have been reviewed and accepted for publication, but have yet to be edited, typeset and finalized. This version of the manuscript will be replaced with the final, published version after it has been published in the print edition of the journal. The final, published version may differ from this proof. Case Report ACCR OVARIAN GRANULOSA CELL TUMOR IN A PATIENT WITH A PATHOGENIC VARIANT IN THE CDC73 GENE (HYPERPARATHYROIDISM-JAW TUMOR SYNDROME) Rowella Licup Sirbiladze MD 1, Denise Uyar MD 2, Jennifer L. Geurts MS 3, Joseph L. Shaker MD 1 From: 1 Division of Endocrinology, Metabolism and Clinical Nutrition, Medical College of Wisconsin, Milwaukee, WI; 2 Division of Gynecologic Oncology, Medical College of Wisconsin, Milwaukee, WI 3 Department of Surgery, Medical College of Wisconsin, Milwaukee, WI Running title: Ovarian GCT in HPTJT Syndrome Correspondence should be addressed to: Joseph L. Shaker MD W129 N 7155 Northfield Drive Building A, Suite 203 Menomonee Falls, WI Joseph.Shaker@gmail.com

2 Abstract: Objective: To report a patient with the hyperparathyroidism-jaw tumor syndrome (HPT-JT) who was found to have a rare ovarian tumor (granulosa cell tumor -GCT). HPT-JT is caused by pathogenic variants in the CDC73 gene and results in PHPT, benign fibro-osseous jaw tumors, benign or malignant renal tumors and cysts, and benign or malignant uterine tumors. We believe this is the first reported case of HPT-JT and GCT. Methods: The patient is 31 year-old woman with abdominal pain who was found to have adult GCT. Her history was significant for a single gland parathyroidectomy at age 23 for PHPT. Her mother also had PHPT with 1-gland removal as well as history of renal cysts. Because of the personal and familial history of PHPT, she underwent germline sequencing of genes associated with PHPT including CASR, CDC73, CDKN1B, MEN1 and RET. Results: Genetic testing revealed a CDC73 gene pathogenic variant (c.687_688dupag) which creates a premature translational stop signal causing loss-of-function. Conclusions: We report a case of ovarian granulosa cell tumor in a young patient with primary hyperparathyroidism and CDC73 gene mutation. Ovarian granulosa cell tumor may be another CDC73-related tumor.

3 Abbreviations: HPT-JT = hyperparathyroidism-jaw tumor syndrome; GCT = granulosa cell tumor; PHPT = primary hyperparathyroidism; MRI = magnetic resonance imaging; PTH = parathyroid hormone; IHC = immunohistochemistry. Introduction Hyperparathyroidism-Jaw Tumor syndrome is one of the familial syndromes of primary hyperparathyroidism (PHPT). It is caused by germline pathogenic variants involving the tumor suppressor gene CDC73 which codes for the protein parafibromin. It is inherited in an autosomal dominant fashion. HPT-JT was first described by Jackson et al in 1990 although he first studied this kindred in 1958 (1,2). About 80% of patients with HPT-JT develop PHPT from a parathyroid adenoma (3), although % of PHPT cases are caused by parathyroid carcinoma (4,5). Approximately 25-50% of affected individuals may also have benign fibro-osseous jaw tumors (4). Benign or malignant tumors involving the kidneys and the uterus can also be present (3). We report a case of HPT- JT observed with an ovarian GCT, a rare ovarian tumor. Case Report A 31 year-old Caucasian woman presented to her gynecologist due to a 3 month history of progressive abdominal pain. Her physical examination was normal. A pelvic

4 ultrasound revealed a 3 cm heterogenous right ovarian cyst. A pelvic MRI demonstrated a 3.5 x 2.8 x 3.8 cm rim-enhancing solid structure in the right ovary. She underwent a laparoscopic right salpingo-oophorectomy. Pathology revealed GCT (Figure 1). Her medical history was significant for PHPT diagnosed at age 23. Preoperatively, she had a serum calcium of 10.8 mg/dl ( mg/dl), ionized calcium of 1.48 mmol/l ( mmol/l), serum intact parathyroid hormone (PTH) of 107 pg/ml (15-72 pg/ml), and a 24-hour urinary calcium of 275 mg ( mg/24 hour). She underwent 1-gland parathyroidectomy (920 mg hypercellular left superior gland consistent with an adenoma) and has remained normocalcemic. Current biochemical evaluation including calcium, creatinine, phosphorus, PTH, 25-hydroxy-vitamin D and 24-hour urinary calcium were normal. The family history was significant for PHPT (single gland) and renal cysts in her mother. Because of her personal and familial history of PHPT, she was referred for genetic evaluation. A three-generation family history pedigree was obtained and is shown in Figure 2. She is of European mixed ancestry with no known Ashkenazi Jewish heritage. There is no personal or family history of pancreatic, pituitary, jaw, or uterine tumors, pheochromocytoma, paraganglioma, medullary thyroid cancer, hamartomatous gastrointestinal polyps, enchondromas or hemangiomas.

5 She underwent a next-generation sequencing panel for genes associated with hyperparathyroidism including CASR, CDC73, CDKN1B, MEN1, and RET. A previously described ( CDC73 gene pathogenic variant was found, specifically c.687_688dupag, which inserts 2 nucleotides in exon 7 of the CDC73 mrna causing a frameshift at codon 230. This creates a premature translational stop signal (p.val230glufs*28) expected to result in an absent or disrupted protein product. Other germline tumor predisposition genes analyzed (ALK, APC, ATM, BAP1, BARD1, BRCA1, BRCA2, BRIP1, BMPR1A, CDH1, CDK4, CDKN2A, CHEK2, DICER1, EPCAM, EZH2, GPC3, GREM1, HRAS, KIF1B, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, NF1, NF2, PALB2, PHOX2B, PMS2, POLD1, POLE, POT1, PRKAR1A, PTCH1, PTCH2, PTEN, RAD50, RAD51C, RAD51D, RB1, SMAD4, SMARCA4, SMARCB1, SMARCE1, STK11, SUFU, TP53, TSC1, TSC2, VHL) did not demonstrate any pathogenic variants. Immunohistochemistry (IHC) analysis for parafibromin was performed using clone 2H1 from Santa Cruz Biotechnology at a dilution of 1:50 and incubation of 30 minutes with the Dako Autostainer Plus platform on our patient s normal ovarian tissue and granulosa cell tumor. In our patient, parafibromin staining was detected in both the normal ovarian tissue and the tumor.

6 Discussion Familial forms of PHPT are unusual, comprising 2-5% of PHPT cases (5). Genes associated with familial hyperparathyroidism include MEN1, RET, CASR, CDKN1B, GNA11, AP2S1, and CDC73 (5). Pathogenic variants in these genes may result in other tumors or cause familial isolated hyperparathyroidism. In a study of 86 patients under the age of 45 with apparently non-syndromic, non-familial PHPT, 9.3% had germline alterations in the MEN1, CASR, or CDC73 genes (6). HPT-JT is a relatively recently described disease entity. In 1958, Jackson reported PHPT from parathyroid adenomas in two generations of the same family and concluded there was autosomal dominant inheritance (2). Rosen and Palmer, in 1981, reported five patients with skeletal fibro-osseous tumors in the setting of PHPT and posed the question whether this represents a syndrome with familial and genetic implications (7). It was in 1990 when Jackson et al postulated that HPT-JT is a clinically and genetically distinct syndrome (1). They reinvestigated the same family from Multiple ossifying jaw tumors were found in affected members from the first and third generations. Ultimately, HRPT2, now known as CDC73, was discovered to be the gene involved in HPT-JT and was mapped to the long arm of chromosome 1 (1q21-q31) in 1995 (8). The CDC73 gene is a tumor suppressor gene located on chromosome 1q31.2 that encodes parafibromin. Parathyroid Involvement

7 PHPT, the hallmark of HPT-JT, is seen in 80% of patients by age 40 (3). The average age of onset of PHPT is not clearly defined. It is usually noted in late adolescence or early adulthood (9), but it has been reported in patients younger than 10 years old (10). Median ages of years have been reported (10). PHPT is most commonly caused by a single benign parathyroid adenoma with a notably high incidence of cystic changes on histopathology (11,12). A second parathyroid adenoma may present synchronously or metachronously months to decades after the first tumor (12). Familial cystic parathyroid adenomatosis has also been used to refer to these recurring parathyroid adenomas with cystic changes (12). Parathyroid carcinoma causing PHPT in HPT-JT has been reported in % of cases (4,5). Nonfunctioning parathyroid carcinomas have also been reported (13). As stated above, parafibromin is the protein encoded by the putative tumor suppressor gene CDC73. A relationship between loss of nuclear expression of parafibromin with HPT-JT and parathyroid carcinoma has been reported (14). Mutations predicted to inactivate parafibromin were first detected in the germline of patients with HPT-JT. Gill et al (15) previously performed immunohistochemistry (IHC) on 115 parathyroid tissues and concluded that the complete absence of nuclear staining for parafibromin is highly predictive of parathyroid carcinoma or an HPT-JT related tumor. Jaw Tumors

8 Ossifying fibromas of the mandible or maxilla occur in 25-50% of cases (4). Some of these fibromas are visible or palpable while others are only detected on dental x-rays. These are aggressive tumors and may progressively enlarge if left untreated. They are histologically distinct from osteitis fibrosa cystica which is the classical bone lesion of severe PHPT. They also do not regress with the resolution of the hyperparathyroidism after parathyroidectomy (4). Renal Tumors Renal lesions noted in HPT-JT include Wilms tumors, renal hamartomas, renal carcinomas, and renal parenchymal cysts (3,16). Loss of heterozygosity in chromosome 1q was seen in these renal hamartomas, representing a new phenotypic variant of HPT- JT (16). About 16% of patients with HPT-JT have renal abnormalities, with multiple renal cysts comprising more than 75% of these lesions (4). Uterine tumors Bradley et al studied 15 affected women from 9 kindreds with HPT-JT (17). Uterine tumors occurred in about 75% of women affected with HPT-JT (17). These affected women experienced menorrhagia eventually requiring hysterectomy. More than 85% of these uterine tumors are benign and consisted of adenomyosis, adenofibromas, leiomyomas and endometrial hyperplasia. Adenosarcoma was also reported in two of the 15 women. These women, who often had multiple miscarriages, were found to have

9 significantly decreased fecundity thought to contribute to the rarity of large HPT-JT kindreds. Other Tumors Other tumors have been reported with HPT-JT which include Hurthle cell thyroid adenomas, papillary thyroid carcinomas, pancreatic adenocarcinomas, colon carcinoma, prostate carcinoma, breast cancer, lipomas and testicular mixed germ cell tumors (4). However, colorectal, prostate, breast and pancreatic cancers may be no more prevalent in HPT-JT patients than in the general population (4). HPT-JT and Ovarian GCT Our patient was found to have a frameshift pathogenic variant at exon 7 of the CDC73 gene. HPT-JT is very likely in the setting of her personal and familial history of PHPT as well as renal cysts in her mother. In addition, she has been diagnosed with an ovarian granulosa cell tumor. GCTs are rare ovarian malignancies, accounting for less than 5% of all ovarian tumors. They usually occur in a younger age group who present with abdominal pain or distention. Somatic mutation in the FOXL2 gene, which encodes for the transcription factor required for normal development of the granulosa cell, is seen in 97% of adult GCT (18). Genetic syndromes associated with GCT include Peutz Jeghers (STK11) and Ollier Disease/Maffucci syndrome (somatic mutations of IDH1 or IDH2) (19).

10 In our patient, the presence of parafibromin expression could suggest the ovarian tumor is unrelated to the CDC73 gene pathogenic variant. We believe the chance occurrence of this rare ovarian tumor in a patient with a rare syndrome such as HPT-JT is unlikely. Further, some HPT-JT related tumors can exhibit parafibromin staining. Indeed, Gill et al (15) found parafibromin staining in 1 of 4 CDC73 related parathyroid adenomas. An additional possibility is that a truncated, non-functional protein was detected by the IHC parafibromin staining. Interestingly, a possible role of parafibromin down regulation in promoting malignant transformation of ovarian epithelial cells has been postulated (20).. In summary, we report a case of ovarian granulosa cell tumor in a young patient with primary hyperparathyroidism and CDC73 gene mutation. Ovarian granulosa cell tumor may be another CDC73-related tumor.

11 References: 1. Jackson CE, Norum RA, Boyd SB et al. Hereditary hyperparathyroidism and multiple ossifying jaw fibromas: a clinically and genetically distinct syndrome. Surgery 1990;108: Jackson CE. Hereditary hyperparathyroidism associated with recurrent pancreatitis. Ann Int Med 1958;49: Carpten JD, Robbins CM, Villablanca A et al. HRPT2, encoding parafibromin, is mutated in the hyperparathyroidism-jaw tumor (HPT-JT) syndrome. Nature Genet 2002; 32: Bradley KJ, Thakker RV. The hyperparathyroidism-jaw tumour (HPT-JT) syndrome. Clin Cases Miner Bone Metab 2006;3: Li Y, Simonds WF. Endocrine neoplasms in familial syndromes of hyperparathyroidism. Endocrine-Related Cancer 2016;23, R229 R Starker LF, Akerstrom 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: Rosen IB, Palmer JA. Fibroosseous tumors of the facial skeleton in associated with primary hyperparathyroidism: An endocrine syndrome or coincidence? Am J Surg 1981;142: Szabo J, Heath B, Hill WM et al. Hereditary hyperparathyroidism-jaw tumor syndrome: The endocrine tumor gene HRPT2 maps to chromosome 1q21-q31. Am J Hum Genet 1995;56:

12 9. Frank-Raue K, Haag C, Schulze E et al. CDC73-related hereditary hyperparathyroidism: five new mutations and the clinical spectrum. Euro J Endocrine 2011;165: Simonds WF, James-Newton LA, Agarwal SK et al. Familial isolated hyperparathyroidism: clinical and genetic characteristics of 36 kindreds. Medicine 2002;81: Chen JD, Morrison C, Zhang C et al. Hyperparathroidism-jaw tumour syndrome. J Int Med 2003;253: Malette LE, Malini S, Rappaport MP et al. Familial cystic parathyroid adenomatosis. Ann Int Med 1987;107: Guarnieri V, Scillitani A, Muscarella LA et al. Diagnosis of parathyroid tumors in familial isolated hyperparathyroidism with HRPT2 mutation: Implications for cancer surveillance. J Clin Endocrinol Metab 2006;91: Cetani F, Banti C, Pardi E, et al. CDC73 mutational status and loss of parafibromin in the outcome of parathyroid cancer. Endocr Connect 2013;2: Gill AJ, Clarkson A, Gimm O, et al. Loss of nuclear expression of parafibromin distinguishes parathyroid carcinomas and hyperparathyroidism-jaw tumor (HPT-JT) syndrome-related adenomas from sporadic parathyroid adenomas and hyperplasias. Am J Surg Pathol. 2006;30: Teh BT, Farnebo F, Kristoffersson U et al. Autosomal dominant primary hyperparathyroidism and jaw tumor syndrome associated with renal hamartomaas and

13 cystic kidney disease: Linkage to 1q21-q32 and loss of the wild type allele in renal hamartomas. J Clin Endocrinol Metab 1996;81: Bradley KJ, Hobbs MR, Buley ID et al. Uterine tumours are a phenotypic manifestation of the hyperparathyroidism-jaw tumour syndrome. J Int Med 2005;257: Shah SP, Kobel M, Senz J, et al. Mutation of FOXL2 in granulosa-cell tumors of the ovary. N Engl J Med 2009;360: Jamieson S, Fuller PJ. Molecular pathogenesis of granulosa cell tumors of the ovary. Endocr Rev 2012;33: Shen D, Liu X, Ynag, X, et al. The roles of parafibromin expression in ovarian epithelial carcinomas: a marker for differentiation and prognosis and a target for gene therapy. Tumor Biol 2016;37;

14 Figure Legends Figure 1 Pathology Revealing Ovarian Granulosa Cell Tumor H&E Stain showing nests and single file cords of cells which display elongated, ovoid nuclei with nuclear grooves and occasional small nucleoli. Figure 2 Pedigree

15 Figure 1

16 Colon cancer Prostate cancer Pancreatic cancer Gastric cancer Breast cancer PHPT Renal Cysts Breast cancer Calcium normal Calcium normal KEY =Primary Hyperparathyroidism (PHPT) =Cancer/Tumor Calcium normal PTH normal PHPT Ovarian granulosa cell tumor Figure 2