Introduction: Medullary thyroid cancer (MTC) is a rare tumor of neuroendocrine origin that co-secretes various peptides leading to diarrhea and vasodilation. Ectopic Cushing syndrome due to production of adrenocorticotropic or corticotrophin-releasing hormone is a well-recognized but uncommon paraneoplastic manifestation of advanced MTC. We report an extremely rare presentation of eosinophilia in a patient with MTC that correlated with disease progression. Case: A 58-year-old woman with sporadic metastatic MTC harboring somatic RET M918T mutation developed metastatic disease to the liver, lung and bones 2 years after surgery for locally advanced disease. Calcitonin (Ctn) was 123 pg/ml and CEA was 2575 ng/ml. At that time, leukocytosis [WBC 30.8 K/ul (4-11k/ul)] and eosinophilia [eosinophil count 16.01 k/ul (0.04-0.40 k/ul)] were noted. She was asymptomatic. Extensive evaluation of hypereosinophilia ruled out hematological or infectious causes. The patient initiated vandetanib with a partial response (PR) with decrease in lung and liver metastases and a significant improvement of the paraneoplastic eosinophilia [eosinophil count 2.39 k/ul] after 10 weeks of treatment. After a year on treatment, there was progressive disease (PD) with increasing hilar and abdominal lymphadenopathy associated with increased eosinophilia of 4.34 K/ul. Vandetanib was discontinued. She was enrolled on a clinical trial with a highly potent and selective RET inhibitor. The patient achieved PR to study drug by the 2nd month on treatment and durable response for 30 months. The eosinophil count normalized [0.32 k/ul] 4 weeks after starting the new treatment. She developed PD in liver metastases associated with recurrent leukocytosis (WBC 58.6 K/ul) and eosinophilia of 28.13 K/ul. Ctn was 1646 pg/ml. CEA was 8722 ng/ml. Her bone marrow biopsy showed marked eosinophilia, focal MTC metastatic infiltrate, no increased blasts, and was negative for the BCR-ABL1 translocation and the FIP1L1-PDGFRA fusion. She was switched to a different RET Inhibitor but passed away 1 month after starting the new protocol. Discussion: Paraneoplastic eosinophilia should be considered after excluding other causes (e.g. infections, allergy, collagen, vascular or malignant hematopoietic diseases). Thyroid tumors producing colony-stimulating factors, associated with neutrophilia and/or eosinophilia have been described almost exclusively in patients with anaplastic thyroid cancer. This patient had a poorly differentiated MTC as evidenced by the disproportionally high CEA relative to Ctn. The course of the eosinophilia paralleled the clinical behavior of her disease. To our knowledge, this is only the 2nd report of eosinophil trends corresponding with MTC disease course, consistent with a paraneoplastic process. Conclusion: PNE is very rare in MTC and its presence suggests a poor prognosis.
Background: In 40% of pheochromocytoma/paraganglioma (PPGL) cases a causal germline mutation in a well-defined gene can be identified. The remainder are sporadic. The most common hereditary syndromes are NF1, MEN2 and VHL. Paragangliomas usually produce exclusively norepinephrine (NE) and are more likely to metastasize than adrenal tumors. Exclusively NE producing adrenal tumors are extremely rare and almost always associated with VHL or SDH syndromes (1). Clinical Case: A 45-year-old South Asian woman with a 5-year history of HTN controlled on losartan presented emergently complaining of chest pressure. Cardiovascular workup was unrevealing. CT chest showed an incidental 3.2 x 2.4 cm lipid-poor left adrenal adenoma. No further follow-up done at that time. Two years later she presented with recurring episodes of chest pressure and uncontrolled HTN on amlodipine, metoprolol and losartan. She denied panic attacks, diaphoresis and other symptoms of anxiety. She denied personal and familial history of clinical features seen in NF1, MEN 2, VHL or SDH. Plasma metanephrines were 26 (<=57 pg/mL) and free normetanephrine 902 (<=148 pg/mL). 24-hour urine metanephrine was 178 (58-203 mcg/24h), normetanephrine 2422 (88-649 mcg/24h) and total metanephrine 2600 (182-739 mcg/24h) confirming the diagnosis of a solely NE secreting PPGL. MRI abdomen showed a well-circumscribed 3.3 cm lipid-poor left adrenal mass. MIBG scan and SPECT CT showed a focal area of intense radiotracer uptake corresponding to a 3.2 x 2.5 cm mass within the left adrenal gland. No extra-adrenal activity was demonstrated. Alpha blockade was started with doxazosin and the patient asked to salt/fluid load. She underwent left adrenalectomy. Pathology revealed a 5 x 2.5 x1.1 cm intra-adrenal pheochromocytoma; Chromogranin (+), synaptophysin (-), MIB1 low reactivity < 5%, S100 positive in sustentacular cells, keratin (-), EMA (-), Inhibin (-). Genetic testing for VHL, SDHD, SDHB, SDHC and MAX has been ordered per guidelines. One month post-operatively the patient had no symptoms of adrenergic overactivity and normal plasma metanephrine levels. Clinical Lessons: This rare case of norepinephrine-only secreting pheochromocytoma is made even more unusual by absence of features of autosomal dominant hereditary syndromes. This may be sporadic or present a novel VHL, SDHD, SDHB, SDHC or MAX germline mutation (2). 1. Eisenhofer, G., et al., Distinct gene expression profiles in norepinephrine- and epinephrine-producing hereditary and sporadic pheochromocytomas: activation of hypoxia-driven angiogenic pathways in von Hippel–Lindau syndrome. 2004. 11(4): p. 897. 2. Ercolino, T., et al., Uncommon clinical presentations of pheochromocytoma and paraganglioma in two different patients affected by two distinct novel VHL germline mutations. Clinical Endocrinology, 2008. 68(5): p. 762-768.
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