ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2019) 64 036 | DOI: 10.1530/endoabs.64.036

Medullary thyroid carcinoma in two patients with neurofibromatosis type 1

Pollet Emily 1, Martens Broes2, Van Haecke Helena1, Sajevets Tatjana3 & Van den Bruel Annick4

1Medical student, KU Leuven, Leuven, Belgium; 2Department of Internal Medicine, UZ Brussel, Jette, Belgium; 3Department of Endocrinology, AZ West, Veurne, Belgium; 4Department of Endocrinology, AZ Sint Jan Brugge-Oostende, Brugge, Belgium.

Introduction: Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disorder characterised by the appearance of multiple, mostly benign, tumours throughout the skin and central nervous system. Furthermore, NF1 is associated with a number of (pre)malignant tumours including pheochromocytoma, glioma, invasive breast cancer and (pre)malignant peripheral nerve sheath tumours (1). Approximately 1:2500 to 1:3500 individuals are affected.

Medullary thyroid carcinomas (MTCs) are rare tumours, accounting for less than 2 percent of all thyroid cancers (incidence around 0.2/100 000 py (2)). Although the coexistence of NF1 and MTC has only rarely been described, a possible role for the NF1 gene mutation is suggested in the pathogenesis of MTC.

Clinical cases: (1) A 45-year old women attended the obesity clinic. Her clinical exam was remarkable for multiple café-au-laits spots and cutaneous neurofibroma’s. Her family history included similar skin lesions in her father and two brothers, one brother had suffered from a brain tumour at age 9. NF1 had been diagnosed based on Ferner’s criteria. On clinical examination a left sided thyroid nodule was noticed. Neck ultrasound showed a 2.5 cm hypoechoic hypervascular nodule in the left thyroid lobe and an ipsilateral suspicious lymph node in level 3. Fine needle aspiration and a high serum calcitonin concentration (518 pg/ml, normal value 0–15 pg/ml) were diagnostic of MTC. 24 hour urinary catecholamines and (nor) metanefrines were normal. A total thyroidectomy with central and left lateral lymph node dissection was performed. Pathological examination confirmed the diagnosis of MTC (T1N0). The postoperative calcitonin was undetectable.

(2) A 81-year old woman presented with weight loss, dysphagia and high CEA. Multiple facial cutaneous neurofibromas had been present since age 17, her father had had similar skin nodules but none of her 7 siblings had. Neck palpation revealed a 3 cm left sided thyroid nodule. Neck ultrasound showed a highly suspicious hypoechoic thyroid nodule with microcalcifications and irregular margins, a contralateral suspicious lymph node in level 6 and an ipsilateral pathologic lymph node in level 3. Serum calcitonin was high (1.721 pg/ml). 24 hour urinary catecholamines and (nor) metanefrines were normal. A total thyroidectomy with central and left lateral lymph node dissection was performed. Anatomopathology confirmed MTC (pT2N1). Postoperative calcitonin level was 29.7 pg/ml consistent with minimal residual disease.

Conclusion: NF1 can be considered as a tumour predisposition syndrome caused by constitutional mutations in the NF1 gene. This hereditary disorder is proven to be associated with a higher incidence of several malignancies (1). Up until now, MTC has not been proven to be one of them. Nevertheless the presence of NF1 in 2 patients of a consecutive series of 19 MTC in a single centre (2002–2018) is striking. NF1 is the commonest ‘RASopathy’, a group of syndromes caused by hyperactivation of the RAS/MAPK pathway (neurofibromin downregulates RAS, defective neurofibromin causes RAS activation) (3). Besides the genomic landscape of MTC has been deciphered and 20% of sporadic MTC harbour H or K-RAS mutations (whereas 50% of sporadic MTC harbour somatic RET mutations) (4). These molecular findings, the co-occurrence of NF1 and MTC in our two cases and (at least) 5 other cases in the literature warrant research into a possible association.

References: 1. Beert E et al. Atypical neurofibromas in neurofibromatosis type 1 are premalignant tumors. Genes Chromosomes Cancer 2011.

2. Mathiesen JS et al. Incidence and prevalence of sporadic and hereditary MTC in Denmark 1960-2014: a nationwide study. Endocrin Connect 2018.

3. Simanshu DK et al. RAS Proteins and Their Regulators in Human Disease. Cell 2017.

4. Ji et al. Identification of Driving ALK Fusion Genes and Genomic Landscape of Medullary Thyroid Cancer. PLOS Genetics 2015.

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