Overview of Thyroid Nodules and Their Management Matthew D. Ringel, M.D. Professor of Medicine Divisions of Endocrinology and Oncology, The Ohio State University Co-Director, Thyroid Cancer Unit Arthur G. James Comprehensive Cancer Center UCSF Head and Neck Course; 2010 Evaluation and Management of Thyroid Nodules Prevalence of Thyroid Nodules Evaluation of Thyroid Nodules Clinical Evaluation Laboratory and Radiographic Analysis Fine Needle Aspiration Management of Thyroid Nodules New Developments Example Case Prevalence of Thyroid Nodules Increasing with Age More Common in Women Than Men Palpation 1.5% of Men and 6.4% of Women (30-59 years) in Framingham, MA Ultrasound 30-50% of patients in several series. Usually Multiple Thyroid Nodule detection: U/S versus Exam 55% of nodules > 1.5 cm not palpable. Schneider et al JCEM 1997;82:4020. The chance of thyroid nodule on ultrasound, surgery, or autopsy < age 40: age -10 = % chance age 40-60: age -15 = % chance >age 60: age -20 =% chance (above is based on NEJM 1993:328:553. More simply: chance is almost equal to age) 1
New Standards of Care: U/S in nodular thyroid disease Ultrasound Findings Exam Findings Uninodular Multinodular No Nodules Uninodular 40% 44% 16% Goiter 21% 52% 27% Multinodular 8% 80% 12% Marquisee et al. Ann Int Med 2000;133:696 U/S in nodular thyroid disease Marquisee et al. Ann Int Med 2000;133:696 Cancer found in 7% of solitary nodules, and 9% of MNG. In 1/3 of patients diagnosed with cancer, the malignant nodule was not palpable. Uncertain if long-term outcome affected by early detection; but probably beneficial. U/S should be seriously considered for all patients with suspected nodules. Frequency of Cancer in Nodules and as a Function of US Characteristics 1985 patients with 3483 Nodules FNA if nodule was >1.0 cm in at least two dimensions 14.8% chance of cancer 46% multifocal 72% occurred in the largest nodule Gender (male>female), Ultrasound defined nodule composition (solid vs cystic; hypoechoic vs others, and calcifications (especially punctate) predicted malignancy. Size did not predict malignancy Frates M, et al. J Clin Endocrinol Metab: 2006: 91: 3411-3417 Thyroid Nodules: Reasons to Evaluate Thyroid Cancer Need to be certain whether or not nodules are malignant for proper therapy. Hyperthyroidism Need to treat hyperthyroidism to avoid cardiac, bone or other complications. TSH <0.1 mu/l is action value Local Symptoms If large enough, multinodular goiters can compress the trachea or esophagus 2
Thyroid Nodules: Step 1: Clinical Evaluation Clinical History: High Risk of Cancer Head/Neck Irradiation Family History (Medullary) Dysphonia Rapid Growth Associated Neck Masses 71% of Patients with one or more of these positive had thyroid cancer Laboratory Evaluation Obtain Serum TSH in all patients with thyroid nodules If TSH is low.measure free T4 and T3 May be an autonomous nodule or toxic MNG May also be consistent with a cold nodule in the context of hyperthyroidism High TSH would suggest Hashimoto s or other forms of thyroiditis. Thyroid Ab may be useful Hamming, et al. Arch Intern Med. 1990;150:113-116 Initial Radiographic Evaluation: Thyroid Ultrasound If TSH is normal or Elevated, thyroid ultrasound is the next step Often Identifies multiple nodules Can allow for nodule characterization that can help stratify for FNA Irregular Margins, Calcifications; Intranodular hypervascularity Can be used to improve accuracy of FNA At Our Institution, nearly all FNAs are performed with ultrasound guidance. Cytopathology of Thyroid Nodules Fine Needle Aspiration: Clinical Utility Easy to perform, cost effective, and well-tolerated Accurately identifies papillary carcinoma in most cases accurate for benign diagnoses False positive rate of 1%, False Negative rate (benign FNA with final malignant pathology in the same nodule) 5% 1 1. Grant CS, et al. Surgery. 1989;106:980-986. 3
Cytopathology of Thyroid Nodules Fine Needle Aspiration: Limitations Insufficient or indeterminate in 21-31% of cases 1,2 Requires skill and expert pathology for accuracy Unable to distinguish follicular carcinoma from adenoma May be difficult in predominantly cystic lesions 1. Gharib H. Thyroid Today. 1997;XX(1). 2. Burch HB, et al. Acta Cytologica. 1996;40:1176-1183. Cytopathology of Thyroid Nodules Bethesda Classification Insufficient Benign (~1% malignant) Atypical/Follicular Lesion of Undetermined Significance (AFLUS) (5-20% malignant) Follicular Neoplasm (20-30% malignant) Suspicious for Malignancy (~70% malignant) Malignant (>90% malignant) Baloch Z, et al; 2008; Cytojournal 7;5-6. FNA Results: Benign Conditions FNA Results: Papillary Thyroid Cancer Colloid Nodule: Bland nuclei Similar size, more colloid-less cells Hashimoto s: Hurthle Cells Lymphocytes, giant cells PTC: Nuclear Crowding, Hi N/C ratio, intranuclear Inclusions, Nuclear Grooves, More cells-less colloid 4
Improving Accuracy of FNA using Molecular Testing Approach 1: Isolated DNA and RNA from Needle Hubs or an additional pass Amplify known oncogenes Highly specific for papillary thyroid cancer BRAF and RET/PTC Less specific for FTC vs FA RAS abd PPARg/PAX8 Will miss about 1/3 of thyroid cancers with no known mutation Approach 2: Amplify a panel of markers identified in non-biased analyses May be more sensitive Likely to be more expensive Applying Oncogene Testing to A/FLUS Cytologies Ohori, et al (Cancer Cytopathol; 2010; 17-23) 513 A/FLUS cytologies (14-27% of cases depending on cytopathologist) 455 had adequate nucleic acid preparation All analyzed for mutations in BRAF, RAS oncogenes, and for RET/PTC and PPARg/PAX8 rearrangements 117 went to operating room 20 were papillary cancer: mutations found in 12 cases; including FVPTC 79 non-neoplastic: 0 mutations found 18 follicular adenomas: 0 mutations found 0 FTCs in the cohort Oncogene and Molecular Testing for FTC Oncogene testing is less accurate due to lower sensitivity and also lower specificity Less tumors have an identifiable mutation Some abnormalities are found in Follicular Adenomas Global Analysis or other panels will likely be needed to reduce to reduce the number of surgeries for benign disease from 70% to the 5% accepted for benign FNA cytology results Large multicenter trials are ongoing Other Thyroid Imaging CT or MRI of Neck Useful for evaluation of local compressive symptoms Tracheal Compression Esophageal Compression Not Useful for evaluation of intrathyroidal nodules Insensitive 5
Nuclear Medicine Thyroid Imaging Thyroid Scanning Performed to Evaluate Nodule Function Technetium-99 versus Iodine Approx. 5% of nodules that trap Tech-99 are cold on iodine scan Patient Convenience Measurement of Uptake (Iodine Only) Most Useful in Patients with Hyperthyroidism Solitary Autonomous Nodules Solitary Autonomous ( Hot ) Nodules Definition: Causing Suppression of Remaining Gland Very Low Risk of Malignancy FNA generally not required Treatment: Radioiodine or Surgical lobectomy if TSH <0.1 mu/l Caused by activating mutations of the TSH receptor or downstream signaling molecules 6
Evaluation and Management of Thyroid Nodules Prevalence of Thyroid Nodules Evaluation of Thyroid Nodules Clinical Evaluation Laboratory and Radiographic Analysis Fine Needle Aspiration Management of Thyroid Nodules New Developments Example Case Indications for Treating Patients with Thyroid Nodules Hyperthyroidism Suppressed TSH Level (<0.1 mu/l) Indicates Hyperthyroidism, even if Free T4 and T3 are normal. Increased incidence of Atrial Fibrillation, Cardiac Death, and Osteoporosis (Post Menopausal Women) FNA Diagnostic/Suspicious for PTC or Follicular Neoplasm Nodule Growth or Local Compression Potential Therapies for Thyroid Nodules Surgery hemithyroidectomy (risk recurrence in MNG) subtotal or total thyroidectomy (100% hypothyroidism) L-thyroxine (cost, iatrogenic TSH suppression) Considered for nodular disease in hypothyroid and euthyroid patients I-131 (hypothyroidism, radiation risk) Considered for nodular disease in hyperthyroid and euthyroid patients New Alternatives: Ethanol Injection and Laser Ablation Management of Thyroid Nodules Multinodular Goiter FNA of Dominant Cold Nodules Carries Same Risk of Cancer as Solitary Cold Nodule 1 If none is dominant, usually FNA the largest Surgery indicated for concerning FNA, Local Compressive Symptoms Radioiodine if hyperthyroid, iodine uptake is high or if poor surgical risk 1. Belfiore, et al. Am. J. Med. 1992;93:363-369 7
I-131 in Non-toxic Goiter 34 patients with diffuse goiter and compressive or cosmetic symptoms. Median 600 MBq (16.2 mci) therapy and 36 months follow-up. Goiter reduced 36% after 3 months, and 72% after 3 years. 36% became hypothyroid by 3 years. Bonnema et al. Eur J Endocrinol 2004;150:439 I-131 for Large Compressive MNG Euthyroid and hyperthyroid patients given 100 uci/g thyroid tissue retained activity at 24 hrs no exacerbation of compressive symptoms thyroid volume reduced 34-40%, max. tracheal deviation reduced 20%, & narrowest tracheal lumen increased 36% at 1 yr. dyspnea & stridor improved in 8/12, dysphagia in 7/8, SVC obstruction in 1/1, & elevated venous pressure in 1/1. 14% hypothyroidism after 2 years Huysmans, et al. Ann Intern Med 1994;121:757. de Klerk, et al. J Nucl Med 1997;38:372 Surgery for Multinodular Goiter Subtotal Thyroidectomy Recurrence rates : 10-20% at 10 years, ~45% at 30 years. (e.g. 10+%/decade). Maurer et al. J Nucl Med 1999;40:1313 Thus, total thyroidectomy by experienced surgeon for any patients with bilateral nodules or bilaterally enlarged thyroid is the treatment of choice. No prospective data demonstrates that TSH suppression decreases goiter or nodule recurrence rate after subtotal Thyroidectomy Except in Radiated Population. Mandel, et al. Ann Intern Med 1993;119;492. Maurer et al. J Nucl Med 1999;40:1313 Complications of Total Thyroidectomy Total Thyroidectomy: Laryngeal nerve injury: 3% Hypoparathyroidism 2.6% Subtotal Thyroidectomy: Laryngeal Nerve Injury: 1.9% Hypoparathyroidism: 0.2% Udelsman et al. World J Surg 20:88;1996. Higher rates with re-operation. Maurer et al. J Nucl Med 1999;40:1313 Surgeons performing >100 thyroidectomies had a 4 fold lower complication rate than those performing < 10 cases annually. Sosa et al. Ann Surg 228:320;1998 8
Management of Thyroid Nodules Solitary Autonomous Nodules Treatment for patients with TSH <0.1 mu/l Radioactive Iodine Therapy No Surgical Risk Nodule May Remain Incidence of Hypothyroidism Hemithyroidectomy Surgical Risk Nodule is Gone Low Incidence of Hypothyroidism Outcome of I-131 for Solitary Hot Nodules 346 Patients treated between 1975 and 1995 Incidence of Hypothyroidism 7.6% at 1 year; 28% at 5 years; 46% at 10 Years; 60% at 20 years (no new patients after 15 years). Older age and higher iodine uptake associated with more hypothyroidism Hyperthyroidism Controlled with one dose (~30 mci) in 94% of patients Ceccareli, et al. Clin Endocrinol (2005) 62;331-335 Management of Benign Euthyroid Nodules Natural History Kuma, et al. 1 9-11 follow-up by ultrasound and FNA, no treatment. All patients had benign initial FNA Classification (n) No Change Smaller/Disappeared Larger Single Nodule (86) 34% 43% 23% Multiple Nodules (14) 36% 43% 21% Cysts (34) 21% 27% 0% Repeat FNA on all enlarging nodules, 92% with same diagnosis, 99% remained benign Kuma K, et al. World J Surg. 1994;18:495-499 Rationale: Thyroxine Suppression Reduction in circulating TSH concentrations will shrink or inhibit growth of thyroid nodules May help distinguish benign from malignant nodules Side-effects of Thyroxine are small Problems: Not all nodules are alike and may respond differently Well differentiated cancers express TSH-receptors Long-term therapy may have significant side-effects, particularly as patients age 9
Side-effects Thyroxine Suppression Bone Loss Postmenopausal Women, but not men or premenopausal women 1 Arrhythmia Atrial Fibrillation Cardiac Hypertrophy Not shown in all studies, may be improved by beta blockers. 1. Uzzan B, et al. J Clin Endocrinol Metab. 1996;81:4278-4289. Papini, et al. Thyroxine Suppression 5 year randomized placebo-controlled solid benign colloid nodules FNA repeated at end of the study, US yearly 85 patients enrolled in the study. FNA at end of study was benign for all patients Papini E, et al. J Clin Endocrinol Metab. 1998;83:780-783. Thyroxine Suppression Thyroxine Suppression: Meta-Analysis Papini, et al. Mean nodule size increased in placebo group, unchanged in treatment group if TSH was >0.1 mu/l, and reduced if TSH was suppressed New nodules were found more frequently in the placebo group (28.5% vs 7.5%) Concluded that L-T4 reduced nodule size in a subset of patients, and that it more consistently reduced the appearance of new nodules Papini E, et al. J Clin Endocrinol Metab. 1998;83:780-783. Castro, et al J Clin Endocrinol Metab (2002) 87:4154-41594159 10
Thyroid FNA: Key Points Management of Thyroid Nodules Accurate for Benign Lesions Accurate for PTC Unable to distinguish benign Follicular Adenomas from Carcinomas ~30,000 surgeries in US per year for benign follicular adenomas! TSH suppression is probably not warranted based on modest benefit. Molecular Testing is Being Used now to improve diagnosis and potentially to guide surgical approaches Euthyroid/Hypothyroid FNA (US) TSH Benign A/FLUS Follicular Cancer Monitor by US +/- L-T4 Re-FNA Molecular Testing +/- scan Thyroidectomy Hyperthyroid I-131 scan and uptake Cold Nodule Hot Nodule/ Toxic MNG 131-I/ ATDs Surgery 11