A case of struma carcinoid and Graves disease

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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 A case of struma carcinoid and Graves disease ACCR Asha K. Pathak, MD 1 ; Gregory M. Cheeney, MD 2 ; Mara H. Rendi, MD, PhD 2 ; Renata R. Urban, MD 3 ; Richard A. Failor, MD 1 ; Alan Chait, MD 1 From: University of Washington, Seattle, Washington, USA; 1 Department of Medicine, Division of Metabolism, Endocrinology, and Nutrition; 2 Department of Pathology; 3 Department of Obstetrics and Gynecology, Division of Gynecologic Oncology Corresponding Author and Address: Alan Chait, MD University of Washington, Division of Metabolism, Endocrinology and Nutrition 1959 NE Pacific St., Box Seattle, WA achait@uw.edu

2 Abstract Objective: We describe a case of coexisting Graves disease and struma carcinoid in a woman with an ovarian mass and history of hyperthyroidism. Methods: Patient history, presentation, diagnostic studies, and treatment are described. Results: A 59 year old female with an antecedent history of hyperthyroidism was scheduled for resection of a 4.1 cm left ovarian mass. Pre-operative labs demonstrated TSH <0.007, free T pg/ml ( pg/ml), and free T ng/dl ( ng/dl). Radioactive iodine uptake (RAIU) was 0 % in the neck at both 4 and 24 hours. A functioning strumal tumor was suspected. In preparation for surgery, propranolol 40 mg three times a day was initiated. Pathology of the left ovary was consistent with struma carcinoid. Hyperthryoidism persisted on post-op follow up. Repeat RAIU with scan at 6 months post-op demonstrated 4- and 24-hour uptake in the neck of 10.4% (4-20%) and 23.6% (10-30%), with diffuse, minimally inhomogeneous uptake in the thyroid lobes bilaterally and uptake visualized in the pyramidal lobe. There was no uptake outside the neck on whole body imaging. Thyroid stimulating immunoglobulin level was 329% (<= 122%). Taken together these findings were consistent with Graves disease. The patient was treated with radioactive iodine ablation (16.02 mci). Six weeks post-ablation she developed hypothyroidism (TSH ), and levothyroxine was initiated. Conclusion: To our knowledge this is the first reported case of Graves disease co-existing with struma carcinoid. Graves disease may be diagnosed after resection of strumal tumors in patients with persistent or recurrent hyperthyroidism.

3 Abbreviations: RAIU = Radioactive iodine uptake; TSH = Thyroid stimulating hormone. Case Report Introduction Struma ovarii are monodermal teratomas containing a predominance of thyroid tissue (1-3). When both thyroid and carcinoid components are identified within the ovary, the tumor is described as struma carcinoid (1-3). Patients with struma carcinoid may present with a pelvic mass or, less commonly, with carcinoid syndrome or hyperthyroidism (3,4). Hyperthyroidism has been described in less than 10% of cases, similar to that reported with struma ovarii (1-3). Hyperthyroidism may be related to autonomous function of thyroid tissue in the ovary, or responsiveness of this tissue to circulating TSH receptor antibodies, as has been described in patients with Graves disease and struma ovarii (2,5-7). Additionally, excess thyroid hormone production by the thyroid gland may occur in the setting of both functioning and nonfunctioning struma ovarii (8,9). We present a case of struma carcinoid coexisting with Graves disease, which to our knowledge has not previously been reported. Case Description A 59 year old female was undergoing pre-operative evaluation for pelvic surgery to remove a 4.1 cm left ovarian mass associated with abdominal pain. She was referred to endocrinology clinic because of an antecedent history of thyroid nodules and hyperthyroidism. Her previous medical history was significant for chronic anxiety, nephrolithiasis, and fibromyalgia. Her medications included sertraline, amitriptyline, alprazolam, and cyclobenzaprine. She had never taken thyroid medications, undergone thyroid uptake

4 and scan or biopsy, or been exposed to significant radiation. There was no family history of thyroid disease. Review of systems was positive for heat intolerance, anxiety, hand tremor, and postmenopausal hot flashes. There were no features concerning for carcinoid syndrome. Serum CA-125 was 31.5 U/mL (0-35 U/mL). Thyroid ultrasound identified a heterogeneous, nodular gland with a dominant solid right mid lobe nodule measuring 1.0 x 1.1 x 1.5 cm. Physical examination demonstrated a nontender thyroid gland normal in size, a palpable right thyroid nodule, and bilateral hand tremor. Laboratory studies demonstrated TSH <0.007 μiu/ml ( μiu/ml), free T pg/ml ( pg/ml), and free T ng/dl ( ng/dl). Radioactive iodine uptake (RAIU) was 0% in the neck at both 4 and 24 hours. Unfortunately, concurrent abdominal and pelvic scans were not obtained to evaluate for extra-cervical concentration of radioactive iodine. However, based on lack of uptake in the neck, a functioning strumal tumor was suspected. In preparation for surgery, propranolol 40 mg three times a day was initiated. Intraoperatively, a smooth mass was identified emanating from the left ovary, interpreted on frozen section as a low grade epithelial neoplasm. Bilateral salpingo-oophorectomy, total hysterectomy, lymph node dissection, and omental biopsy were performed. On pathology, the left ovary was found to contain a 4.0 cm teratoma with components of thyroid tissue and low grade neuroendocrine neoplasm, consistent with struma carcinoid (Figure 1). Nuclei were relatively uniform, and mitotic rate was low. Immunohistochemistry in the carcinoid component was positive for chromogranin (1+; 5-24% of cells) and synaptophysin (3+; >75% of cells) (2). Staining in the thyroid component was positive for TTF-1 and thyroglobulin (2). Incidental cervical intermediate grade squamous intraepithelial neoplasia (CIN 2) was noted. Remaining tissues and peritoneal wash were negative for malignant cells or neoplasm. The patient was seen in clinic 2 weeks post-operatively, at which time she was feeling well. TSH was

5 0.024 μiu/ml and serum chromogranin A level was 123 ng/ml (<93). At 6 weeks post-op TSH was μiu/ml, free T4 1.0 ng/dl and total T3 113 ng/dl ( ng/dl). Five months post-op her TSH remained suppressed at μiu/ml, with elevated free T4 1.7 ng/dl and total T3 202 ng/dl. She described heat intolerance, fatigue, and anxiety. Blood count and electrolyte values were within normal limits. On physical examination her thyroid gland was near upper limit of normal in size, and repeat thyroid ultrasound demonstrated bilateral subcentimeter nodules with otherwise normal thyroid echogenicity, vascularity, and lymph node morphology. Repeat RAIU and scan at 6 months post-op (Figure 2) demonstrated 4- and 24-hour uptake in the neck of 10.4% (4-20%) and 23.6% (10-30%), with diffuse, minimally inhomogeneous uptake in the thyroid lobes bilaterally. Uptake was also visualized in the pyramidal lobe. There was no uptake outside the neck on whole body imaging. Thyroid stimulating immunoglobulin level was 329% (<= 122%). Taken together these findings were consistent with Graves disease, and the patient was treated with radioactive iodine ablation (16.02 mci). Six weeks postablation TSH was μiu/ml, with free T ng/dl and total T ng/dl. Levothyroxine was initiated. The patient continues to be followed, 1.5 years after initial evaluation, and is doing well. Discussion We present a case of concurrent struma carcinoid and Graves disease in a 59 year old woman presenting with hyperthyroidism and an ovarian mass. Fewer than 20 cases of coexisting Graves disease and struma ovarii have been described (5,6). To our knowledge, this is the first report of coexisting Graves disease and struma carcinoid. Hyperthyroidism in the setting of an ovarian mass may be related to excess thyroid hormone production by the thyroid gland and/or thyroid tissue within the ovary (8). RAIU and scans are useful in localizing site of thyroid hormone production, both during initial evaluation and investigation of recurrent or persistent hyperthyroidism. Extracervical scans can help identify an ectopic focus of thyroid hormone

6 production in cases of hyperthyroidism with diminished uptake in the neck. Several reports have described diagnosis of struma ovarii in the setting of recurrent or persistent hyperthyroidism after treatment for Graves disease or toxic adenoma based on abdominopelvic radioactive iodine concentration (5-9). In the present case, while abdominopelvic scans were not obtained after the first 123 I adminstration pre-operatively, a strumal tumor was suspected as the source of excess thyroid hormone, given 0% uptake in the neck and presence of an ovarian mass. Our patient demonstrated persistent hyperthyroidism after resection of struma carcinoid, leading to subsequent diagnosis of Graves disease based on laboratory evaluation and findings on the second RAIU and accompanying scans. Pathologic evaluation of the struma carcinoid in this case demonstrated a thyroid component with benign features and normal morphology, and no high-grade features within the carcinoid component. However cancer may be identified in either component of these tumors, originating within the ovary or metastatic from a primary site (2,3,10). Thyroid tissue demonstrating typical appearance and contained within the ovary is usually benign (2). Spread within the peritoneum identified at surgery, known as peritoneal strumosis, is also usually benign, although patients should continue to be followed, as recurrence would instead suggest a diagnosis of minimal deviation follicular thyroid-type carcinoma (2). Rare cases of thyroid-type carcinoma originating in strumal tumors have been described, and may metastasize; additionally, thyroid cancer can metastasize to the ovary (2,11,12). Carcinoid within the ovary is subtyped histologically as insular, trabecular, or mucinous, and more than one subtype may be present (2,3,8). Atypical features or primary carcinoma with or without metastasis may be found, and carcinoid may also metastasize to the ovary from a primary site (10,11,13).

7 In summary, we describe a case of persistent hyperthyroidism after resection of struma carcinoid in a 59 year old woman, leading to diagnosis of Graves disease. To our knowledge this is the first reported case of co-existing struma carcinoid and Graves disease, and emphasizes the importance of monitoring thyroid function after resection of ovarian tumors containing thyroid tissue. Figure 1. Ovarian mass pathology specimen. Photomicrographs and inserts at 200X magnification. Staining performed with hematoxylin and eosin, and as otherwise described. A-C. Neuroendocrine component (ovarian carcinoid), low-grade neoplasm. Neuroendocrine cells with uniform nuclei and low mitotic rate demonstrate solid (A), insular (B), and trabecular (C) patterns, with staining positive for chromogranin (part B inset) and synaptophysin (part C inset). D. Thyroid component (struma ovarii), benign. Thyroid tissue within the ovarian mass demonstrates normal colloid follicles, with staining positive for TTF-1 (inset) and thyroglobulin (not shown). Taken together, these findings are consistent with struma carcinoid.

8

9 Figure 2. Thyroid and whole body uptake and scan 6 months after struma carcinoid resection. A. Cervical scan. The thyroid gland demonstrates diffusely increased, minimally inhomogeneous 123 I uptake bilaterally and in the pyramidal lobe. RAO: right anterior oblique. LAO: left anterior oblique. B. Whole body 123 I scan (anterior, left; posterior, right). Physiologic uptake is demonstrated in the neck, with expected concentration in the gastrointestintal tract and bladder. No pathologic uptake is seen in the abdomen or pelvis. A. B.

10 References 1. Clement PB and Young RH, eds. Atlas of Gynecologic Pathology. 3rd ed. London, UK: Saunders Elsevier, Roth LM, Talerman A. The enigma of struma ovarii. Pathology. 2007;39: Mutter GL and Prat JD, eds. Pathology of the Female Reproductive Tract. 3rd ed. Edinburgh, UK: Churchill Livingstone, Gorin I, Sastre-Garau X. Struma carcinoid of the ovary. J Clin Oncol. 2008;26: Sitasuwan T, Hanamornroongruang S, Peerapatdit T, Thongtang N. Coexistence of Graves disease and unilateral functioning struma ovarii: a case report. BMC Endocr Disord. 2015;15: Anastasilakis AD, Ruggeri RM, Polyzos SA, et al. Coexistence of Graves disease, papillary thyroid cancer and unilateral benign struma ovarii: case report and review of the literature. Metabolism. 2013:62: Teale E, Gouldesbrough DR, Peacey SR. Graves disease and coexisting struma ovarii: struma expression of thyrotropin receptors and the presence of thyrotropin receptor stimulating antibodies. Thyroid. 2006;16: Mimura Y, Kishida M, Masuyama H, et al. Coexistence of Graves disease and struma ovarii: case report and literature review. Endocr J. 2001;48: Ciccarelli A, Valdes-Socin H, Parma J et al. Thyrotoxic adenoma followed by atypical hyperthyroidism due to struma ovarii: clinical and genetic studies. Eur J Endocr. 2004;150: Lenicek T, Tomas D, Soljacić-Vranes H, et al. Struma carcinoid of the ovary: report of two cases. Acta Clin Croat. 2012;51: Robboy SJ, Scully RE. Strumal carcinoid of the ovary: An analysis of 50 cases of a distinctive tumor composed of thyroid tissue and carcinoid. Cancer. 1980;46:

11 12. Armes JE, Ostor AG. A case of malignant struma carcinoid. Gynecol Oncol. 1993;51: Baker PM, Oliva E, Young RH, Talerman A, Scully RE. Ovarian mucinous carcinomas including some with a carcinomatous component. Am J Surg Pathol. 2001;25:

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