Thyroid hormone inactivation in gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GISTs) are resistant to traditional chemotherapy but are responsive to the tyrosine kinase inhibitors imatinib and sunitinib. The use of these agents has improved the outcome for patients but is associated with adverse effects, including hypothyroidism. Multiple mechanisms of this effect have been proposed, including decreased iodine organification and glandular capillary regression. Here we report the finding of consumptive hypothyroidism caused by marked overexpression of the thyroid hormone-inactivating enzyme type 3 iodothyronine deiodinase (D3) within the tumor. Affected patients warrant increased monitoring and may require supernormal thyroid hormone supplementation.

Malignant struma ovarii.

BACKGROUND: A 25-year-old woman presented to her gynecologist with pelvic pain. Pelvic ultrasonography showed a 9 cm left ovarian mass. The patient underwent left oophorectomy, omental biopsy, and lymph node sampling. The ovarian mass proved to be a struma ovarii with numerous microscopic foci of papillary thyroid carcinoma. The patient had no symptoms of hyperthyroidism, and her thyroid function and serum thyroglobulin levels were normal. INVESTIGATIONS: Investigations included a pelvic ultrasound scan, histological examination of the ovarian mass and omental nodules, and lymph node sampling. DIAGNOSIS: Malignant struma ovarii. MANAGEMENT: The patient was referred to an endocrinology clinic for further investigations. Serum levels of TSH, thyroglobulin and thyroglobulin antibodies were measured. In addition, the patient underwent thyroid ultrasonography, which showed a 1 cm nodule that proved benign on biopsy. She was treated with thyroxine to reduce TSH secretion. Follow-up pelvic ultrasonography 1 year later showed no evidence of recurrent disease, and her serum thyroglobulin levels remained normal.

Hypothyroidism after sunitinib treatment for patients with gastrointestinal stromal tumors.

BACKGROUND: Sunitinib malate is an oral tyrosine kinase inhibitor recently approved for the treatment of gastrointestinal stromal tumors and renal cell carcinoma. Because the ret proto-oncogene is also inhibited by this agent, clinical evaluation of thyroid function was performed. OBJECTIVE: To describe the prevalence and clinical presentation of thyroid dysfunction related to sunitinib therapy. DESIGN: Prospective, observational cohort study. SETTING: Tertiary care hospital. PATIENTS: 42 patients treated for a median of 37 weeks (range, 10 to 167 weeks). MEASUREMENTS: Following analysis of serial thyroid-stimulating hormone (TSH) measurements collected prospectively during a clinical trial of sunitinib, the authors determined the proportion of patients with thyroid dysfunction. RESULTS: Abnormal serum TSH concentrations were documented in 26 of 42 patients (62%): 15 (36%) developed persistent, primary hypothyroidism; 4 (10%) developed isolated TSH suppression; and 7 (17%) experienced transient, mild TSH elevations. The risk for hypothyroidism increased with the duration of sunitinib therapy. Six of 15 (40%) hypothyroid patients had suppressed TSH concentrations before developing hypothyroidism, suggesting thyroiditis. Two hypothyroid patients evaluated with thyroid ultrasonography had no visualized thyroid tissue despite normal baseline thyroid function. LIMITATIONS: The exploratory nature of this study precluded more frequent biochemical and sonographic analysis that may better define the mechanism of sunitinib-associated thyroid dysfunction. CONCLUSION: Hypothyroidism is a frequent complication of sunitinib therapy. Regular surveillance of thyroid function is warranted in patients receiving the drug. Although the mechanism by which this complication occurs is unknown, the observations of preceding TSH suppression and subsequent absence of visualized thyroid tissue in some patients suggest that sunitinib may induce a destructive thyroiditis through follicular cell apoptosis. This provides a rationale for further investigation of sunitinib treatment in patients with advanced thyroid cancer.

Thyroid hormone early adjustment in pregnancy (the THERAPY) trial.

BACKGROUND: Thyroid hormone requirement increases 20-40% during gestation. Women with treated hypothyroidism must increase their l-T(4) in pregnancy to prevent maternal hypothyroidism, although how this should be accomplished is unclear. METHODS: We prospectively enrolled 60 women with treated hypothyroidism seeking pregnancy. Once pregnant, women were randomized to increase l-T(4) by either two tablets/wk (group A) or three tablets/wk (group B). Thyroid function was tested biweekly through midpregnancy and at 30 wk gestation. Levothyroxine was adjusted to maintain goal TSH concentrations. The primary objective was to assess efficacy in preventing maternal hypothyroidism and the safety of this intervention. RESULTS: Forty-eight women completed the protocol. Increasing the l-T(4) dose once pregnant (regardless of study arm) prevented TSH elevation over 5.0 mIU/liter throughout the first trimester and replicated physiological changes of pregnancy. The early l-T(4) increase caused TSH suppression below 0.5 mIU/liter in eight of 25 women in group A compared with 15 of 23 women in group B (P < 0.01). This risk was significantly increased in athyreotic patients [odds ratio (OR) = 3.3; 95% confidence interval (CI) = 1.1-11.1], those with prepregnancy TSH less than 1.5 mIU/liter (OR = 4.6; 1.3-16.2), and those receiving prepregnancy l-T(4) doses of 100 microg/d or more (OR = 7.2; 1.7-30.6). However, if a trimester-specific TSH lower reference range of 0.1 mIU/liter was used, only two patients (8%) in group A required dose reduction. TSH testing every 4 wk identifies 92% of abnormal values. CONCLUSIONS: A two-tablet increase in l-T(4) initiated at confirmation of pregnancy significantly reduces the risk of maternal hypothyroidism during the first trimester and mimics normal physiology. Monitoring TSH every 4 wk through midgestation is recommended.

Long-term assessment of a multidisciplinary approach to thyroid nodule diagnostic evaluation.

BACKGROUND: The diagnostic evaluation of patients with thyroid nodules is imprecise. Despite the benefits of fine-needle aspiration (FNA), most patients who are referred for surgery because of abnormal cytology prove to have benign disease. Recent technologic and procedural advances suggest that this shortcoming can be mitigated, although few data confirm this benefit in unselected patients. METHODS: A total of 2587 sequential patients were evaluated by thyroid ultrasound and were offered ultrasound-guided FNA (UG-FNA) of all thyroid nodules that measured > or =1 cm during a 10-year period. Results of aspiration cytology were correlated with histologic findings. The prevalence of thyroid cancer in all patients and in those who underwent surgery was determined. Surgical risk was calculated. RESULTS: Tumors that measured > or =1 cm were present in 14% of patients: Forty-three percent of patients had tumors that measured <2 cm in greatest dimension, and 93% had American Joint Committee on Cancer stage I or II disease. The cytologic diagnoses 'positive for malignancy' and 'no malignant cells' were 97% predictive and 99.7% predictive, respectively. Repeat FNA of initial insufficient aspirates, as well as more detailed classification of inconclusive aspirates, improved preoperative assessment of cancer risk and reduced surgical intervention. Fifty-six percent of patients who were referred for surgery because of abnormal cytology had cancer compared with from 10% to 45% of patients historically. An analysis of operative complications from a subset of 296 patients demonstrated a 1% risk of permanent surgical complications. CONCLUSIONS: The current findings demonstrated the benefits of UG-FNA and of a more detailed classification of inconclusive aspirates in the preoperative risk assessment of thyroid nodules, supporting adherence to recently published guidelines.