SAT556 An Unusual Case of Papillary Thyroid Carcinoma With Biallelic MEN1 Variants In a Patient With MEN1
Authors: Chuki Elias , Raffeld Mark , Klubo-Gwiezdzinska Joanna , Gubbi Sriram , Jha Smita 
Published: October 2023

Disclosure: E. Chuki: None. M. Raffeld: None. J. Klubo-Gwiezdzinska: None. S. Gubbi: None. S. Jha: None.

Introduction: Multiple endocrine neoplasia (MEN1) syndrome is caused by germline variants in MEN1. Papillary Thyroid Cancer (PTC) is not regarded as a canonical MEN1-related endocrine tumor. Pathogenic variants in MEN1 are rare in PTC. Herein, we report an MEN1 patient with biallelic loss of MEN1 in PTC.Clinical case: A 59-year-old Hispanic female presented with asymptomatic hypercalcemia due to primary hyperparathyroidism [serum calcium: 13.9 mg/dl (8.4-10.2), PTH: 314 pg/ml (15-65) and 25 hydroxy vitamin D: 15 ng/ml (33 – 100)]. Physical examination was unrevealing for any neck mass or lymph nodes. Kidney function was normal with no history of or imaging evidence of kidney stones or calculi. Bone densitometry revealed osteoporosis [lowest T-score of -2.7 in spine]. Germline genetic testing was performed given large size of the parathyroid tumor and biochemical presentation suspicious for parathyroid cancer. A pathogenic MEN1 p.Ile54Serfs*65 was identified. A neck sonogram and 99-technetium sestamibi scan showed a 4.1 cm left parathyroid adenoma and incidental 3.5 cm, heterogeneous right thyroid lobe nodule having smooth margins without microcalcifications, and no cervical lymphadenopathy. Thyroid function studies were normal. Fine needle aspiration of right thyroid nodule revealed epithelial neoplasia containing many atypical cells with enlarged nuclei, nuclear grooves, fine chromatin, and moderate amounts of granular to oxyphilic cytoplasm. Patient underwent left inferior parathyroidectomy and right thyroid lobectomy. Histology was consistent with parathyroid adenoma and a hyperplastic adenomatous thyroid nodule with a 1.1 cm focus of classic PTC with minor follicular and oncocytic components, limited to the thyroid with clear margins and no lymphovascular invasion (pT1bNxMx). Genetic sequencing of the PTC (TSO500 gene panel) revealed two pathogenic frameshift variants in MEN1 p.I54fs*65 and p.D33fs*82 at variant allele frequency (VAF) of 53% and 42% respectively, TERT promoter (TERTp) variant [C228T (c.-124C&gt;T)] at VAF of 44.8% and an NRAS p.Q61K variant at VAF of 39%. The two MEN1 variants were in trans to each other on opposite alleles, suggestive of a second-hit leading to a loss of biallelic function of MEN1.Conclusion: PTC in MEN1 has been rarely reported in the literature [1]. However, per our knowledge, this is the first report of a PTC with second-hit in the MEN1 gene. Somatic MEN1 pathogenic variants have been reported in occasional cases of thyroid oncocytic tumors and NRAS is more frequently associated with follicular or oncocytic thyroid tumors. Thus, whether this tumor should be regarded as a rare manifestation of the MEN1 syndrome is unclear. The histopathologic and molecular characteristics of thyroid tumors in MEN1 warrant further investigation.

Reference: 1. Desai et al. Ann Surg Oncol 2001;8(4):342-6.

Presentation Date: Saturday, June 17, 2023