Laryngeal Neuroendocrine Tumor With Elevated Serum Calcitonin: A Diagnostic and Therapeutic Challenge. Case Report and Review of Literature

Abstract

Introduction: Laryngeal neuroendocrine neoplasms (NENs) are a rare group of NENs of the neck, which commonly show immunostaining for calcitonin. Laryngeal NENs with calcitonin hypersecretion and lymph node metastases represent a diagnostic and therapeutic challenge, which should be included in the differential diagnosis of medullary thyroid carcinoma (MTC). We report a complex case of laryngeal NEN with calcitonin hypersecretion and a review of the literature. Case Presentation: A 59-year-old man presented with dysphagia, dyspnea, and lateral cervical mass; he was a smoker. At first imaging, a laryngeal lesion with lateral cervical lymphadenopathies was found, and it resulted as a moderately differentiated neuroendocrine tumor (G2), Ki67 = 5%, positive for calcitonin. Increased levels of serum calcitonin (50 pg/ml) were found. The patient started somatostatin analogs for lesions positivity to somatostatin receptor-based imaging. After 5 months, the disease progressed at 18F-fluorodeoxyglucose (18 F-FDG) PET-CT, and also new painful cutaneous lesions occurred. Considering high serum levels of calcitonin, differential diagnosis with MTC was required. Patient performed a thyroid color Doppler ultrasound, nodule fine needle aspiration, calcitonin dosage in fine needle washout fluid, and a calcium gluconate stimulation test. After multidisciplinary evaluation, we decided to perform a total thyroidectomy associated with lateral cervical lymphadenectomy and resection of skin metastases. No MTC was found. Two of the five resected lymph nodes, left upper parathyroid, and skin lesions were metastases of NEN G2, positive for calcitonin. After 2 months, new painful skin lesions occurred, and a target therapy with everolimus 10 mg/day was started. After 6 months of therapy, partial metabolic response with a reduction of 53.7% of radiotracer uptake at primary tumor was detected together with an improvement of patient's quality of life. Conclusions: The present case is the seventh described in the literature of laryngeal NEN associated with elevated serum calcitonin levels and the first case with parathyroid metastasis, suggesting the importance of a correct differential diagnosis between MTC and calcitonin-secreting laryngeal NEN, using an integrated approach of biochemistry and advanced imaging. This is also the first time that somatostatin analogs and then everolimus were used in this setting, resulting in clinical and partial metabolic response.

ENDOCRINE TUMOURS: Calcitonin in thyroid and extra-thyroid neuroendocrine neoplasms: the two-faced Janus

“…They are usually large cell neuroendocrine carcinomas and, like MTC, are often associated with stromal amyloid and TTF1 (albeit focal in laryngeal tumors) and calcitonin immunoreactivity (in 80% of cases) (41). Differential diagnosis between thyroid and laryngeal primary forms is thus based on the integration of clinical, biochemical and radiological data (42). Over 90% of laryngeal NENs arise near the aryepiglottic fold, arytenoid or false vocal cord, while thyroid NENs invade the subglottis or trachea, sparing the supraglottis.…”

Seltene Erkrankungen des Larynx, der Trachea und der Schilddrüse

“…Medullary thyroid carcinoma should be taken into consideration as differential diagnosis and excluded especially in cases of increased serum calcitonin levels that appear mainly in G2 NEC-L 218 . Further, NEC-L has to be delineated from laryngeal metastasis of a NEC of other origin (e. g. lung).…”

“…In sehr seltenen Fällen kann aufgrund einer tumorinduzierten Hormonüberproduktion ein paraneoplastisches Syndrom auftreten 216 . Besonders zu nennen ist die hohe Tendenz der NEC-L zur dermalen Metastasierung, die laut Literatur in bis zur 20% der Fälle auftritt 217 218 219 . Daher ist im Rahmen des Stagings die gründliche Inspektion der Haut zwingend erforderlich.…”

“…Das medulläre Schilddrüsenkarzinom sollte als Differenzialdiagnose in Betracht gezogen und insbesondere bei erhöhten Serumcalcitoninspiegeln, die v. a. beim G2 NEC-L auftreten können, ausgeschlossen werden 218 . Auch muss ein NEC-L von einer laryngealen Metastase eines NEC anderen Ursprungs (z.…”

“…NEC können verschiedene Hormone wie Serotonin, Calcitonin, Wachstumshormone, Insulin, Gastrin oder Glucagon sezernieren. Zur Beurteilung der Prognose des Patienten ist eine Expressionsanalyse von Ki 67 obligatorisch.Das medulläre Schilddrüsenkarzinom sollte als Differenzialdiagnose in Betracht gezogen und insbesondere bei erhöhten Serumcalcitoninspiegeln, die v. a. beim G2 NEC-L auftreten können, ausgeschlossen werden[218]. Auch muss ein NEC-L von einer laryngealen Metastase eines NEC anderen Ursprungs (z.…”