Thyroid cancer (TC) is the most common endocrine neoplasm. Approximately 12,000 new cases of thyroid carcinoma are diagnosed annually in the United States, and an estimated 1000 deaths are caused by this disease each year.1 Approximately 90% of thyroid carcinomas originating from the follicular epithelium are represented by well-differentiated tumors with papillary or follicular histotypes,2,3 and 3%–11% of all thyroid carcinomas are represented by medullary thyroid carcinoma (MTC).4–10

Hyperthyroidism, defined as hyperfunction of the thyroid gland, is diagnosed by clinical findings, laboratory findings, or both. Graves' disease is the most common form of hyperthyroidism, and a less common form of hyperthyroidism is uninodular or multinodular toxic goiter.1

The coexistence of hyperthyroidism and TC is extremely variable and may have distinct causes. The association of hyperthyroidism with differentiated TC has been extensively described, whereas its coexistence with MTC is very rare and usually diagnosed incidentally by histopathologic examination during or after surgery.1,6 Only a few cases have been reported in the English language literature through April 2011.4–7,1116 We describe a patient who had MTC together with subclinical hyperthyroidism incidentally detected by a high level of carcinoembryonic antigen (CEA).

Case Report

A 76-year-old man presented to us with a complaint of reflux. His medical history involved a high blood CEA level as well as weight loss and fatigue for 6 months. He was thought to have a gastrointestinal malignancy and therefore underwent panendoscopy, colonoscopy, and contrast-enhanced abdominal computed tomography (CT). No pathology was detected other than reflux esophagitis. Blood pressure was measured at 140/80 mmHg, and his pulse rate was 98 beats/min. He appeared cachectic. A 3- to 4-cm mass was detected in the left side of his neck by deep palpation during the physical examination. The laboratory examination revealed the following: thyroid-stimulating hormone  =  0.01 (0.2–4.2 µIU/mL), free triiodothyronine  =  3.3 (3.1–6.8 pmol/L), free thyroxine  =  18.2 (12–22 pmol/L), total thyroxine  =  107.1 (66–181 nmol/L), total triiodothyronine  =  1.43 (1.3–3.1 nmol/L), CEA  =  386 (0–5.2 ng/mL), and calcitonin  =  10.5 (<10 pg/mL). The patient had a normal serum calcium, parathormone, and 24-hour urinary excretion of metanephrines and vanillylmandelic acid. On ultrasonography, the right thyroid lobe appeared normal, whereas an approximately 6-cm nodule almost completely filled the left lobe together with a few 2- to 4-cm lymph nodes in the left cervical area. No pathology was detected in the surrenal glands with an abdominal CT. Marked contrast retention was observed in the left thyroid lobe and left cervical chain, suggesting malignancy with positron emission tomography–CT (PET-CT) (Fig. 1). The patient was given propylthiouracil for 3 weeks. Examination findings, thyroid function tests, PET-CT findings, and a high CEA level led to our initial diagnosis of MTC. MTC was suspected to be present during surgery because large, amphophilic cytoplasmic cells forming large clusters and separated from each other by fibrous bands with prominent boundaries were detected in frozen analysis of the left lobe. Bilateral total thyroidectomy plus left modified neck dissection was applied. A histopathologic examination showed a 5.5- × 3.5-cm partially encapsulated nodule in the left lobe with angiolymphatic and capsular invasion and positive amyloid deposits, which are histologic findings suggestive of MTC (Fig. 2). Two of the 10 lymph nodes removed were positive for MTC metastasis. Pathologic specimens stained strongly for CEA immunhistochemical stain (Fig. 3). CEA and calcitonin levels remained close to normal limits, and no relapse was observed radiologically (PET-CT) during the 17-month follow-up. No mutation of the RET proto-oncogene was detected in exons 10, 11, 13, 14, 15, and 16 in the patient's blood.

View Figure

• Download as Powerpoint
• Download Figure

View Figure

• Download as Powerpoint
• Download Figure

View Figure

• Download as Powerpoint
• Download Figure

Discussion

Jaquet first reported MTC as “malignant goiter with amyloid.”17 Hazard et al.18 provided a definitive histologic description in 1959, whereas Williams further stated that MTC originated from the calcitonin-secreting parafollicular C cells of the thyroid and may occur in sporadic (75%) or hereditary (25%) forms.3,5,10,19,20 The sporadic form usually presents with a palpable nodule or cervical lymphadenopathy, by which time basal calcitonin levels are almost always elevated.20 Hereditary MTC is associated with a germ line mutation in the RET proto-oncogene and occurs either as isolated familial MTC or as part of multiple endocrine neoplasia type 2.3,10,19 The patient in the present study had the sporadic form and it appeared as a palpable mass.

The frequency of thyroid malignancy in patients with hyperthyroidism varies from 0–21%.2,4,11,12 In a literature search that we conducted using PubMed and Google Scholar databases from 1982–2010, we retrospectively evaluated a total of 36 articles in which 23,080 patients were presented. We concluded from these studies that different histologic types of TC accompanied hyperthyroidism in 3.2% (737 cases) of all patients. Papillary carcinoma was the most frequently reported histologic type, followed by follicular thyroid carcinoma.4–7,11–16 The coexistence of MTC with hyperthyroidism is very rare. In addition, MTC accompanying hyperthyroidism was reported in a total of 20 patients in our literature search. We summarized the data of 15 patients of those presented in these studies in Table 1.4–7,11–16,21,22

Table 1 A summary of 15 cases of concomitant MTC in patients with hyperthyroidism reported in the English medical literature from 1980 to 2008

View Fullscreen

Studies in this field suggest that MTC comprises 3%–11% of all TC.3–10 Of the 737 TC cases we detected in our literature search, 20 (2.7%) were MTC. This study shows that hyperthyroidism does not cause a marked increase in any TC type.

MTC produces many tumor markers, including calcitonin, CEA, and chromogranin A. These markers can easily be detected with blood levels and immunohistochemical stains. Calcitonin is a hormone that is produced and secreted by thyroid C cells. Serum calcitonin levels are a highly sensitive tumor biomarker and considered to be 100% predictive of MTC when basal levels are >100 pg/mL or when stimulated levels with pentagastrin increase to >1000 pg/mL.16 Therefore, these levels are useful tools for preoperative diagnosis and postoperative surveillance of disease recurrence. As in our patient, several cases in which calcitonin levels did not or mildly increased have been reported in literature. At present, only six cases have been reported of negative calcitonin or a lack of elevated MTC.8–10,20,23 The demographic features of these patients are summarized in Table 2. The inability to monitor postoperative relapses by calcitonin levels in these cases causes difficulties in follow-up.

Table 2 A summary of the 6 cases with normal levels or lack of marked elevation of calcitonin in patients with MTC reported in the English medical literature from 2000 to 2010

View Fullscreen

CEA is a glycoprotein that was first detected by Gold et al in 1965 in colonic cancer tissue.24 CEA, mainly a tumor marker of gastrointestinal malignant diseases, is frequently used for follow-up of relapses and metastases. Tumors originating in the gastrointestinal system should be excluded first using endoscopy, colonoscopy, and CT in patients in whom high CEA levels are detected without any other clinical findings.25 However, one should keep in mind that CEA is not a marker for only the gastrointestinal system and levels may increase in the course of some benign diseases, including liver cirrhosis and inflammatory bowel diseases, as well as in some malignant diseases such as MTC. The literature contains a total of four MTC cases that were tested because of high CEA levels, as in our patient.23

CEA has been demonstrated to be a useful tumor marker in patients with MTC, and CEA levels are elevated in 50% of patients with MTC. A preoperative serum CEA level of >30 ng/mL is highly predictive of the inability to cure a patient with operative intervention. CEA levels of >100 ng/mL are highly associated with extensive lymph node involvement and distant metastasis.13 CEA is an important marker for follow-up of postoperative relapses in patients with close to normal or mildly elevated calcitonin levels.

18F-fluoro-2-deoxyglucose-positron emission tomography (18F-FDG-PET) is taken up by cells with a high glucose metabolism or during the synthesis of catecholamines. ¹⁸F-FDG-PET is used in the imaging of metastatic neuroendocrine tumors such as carcinoids and MTC. For MTC detection, ¹⁸F-FDG-PET provides a higher sensitivity (76%–96%) and specificity (79%–83%) compared with morphologic imaging methods and can be used postoperatively to detect apparently occult MTC, especially in the cervical and mediastinal regions. However, ¹⁸F-FDG-PET is generally not very useful in patients with mildly elevated calcitonin levels. Although the calcitonin level was slightly increased in the present case, successful outcomes were obtained with postoperative ¹⁸F-FDG-PET.

Consequently, in cases found to have high CEA levels in blood tests conducted for any reason, neuroendocrine tumors, such as MTC, should be investigated after exclusion of gastrointestinal malignancies because an increased CEA level may be the first and only finding of MTC.