The Work-up of a Thyroid Nodule: A Case Presentation and Discussion Junko Ozao PGY-3 Mount Sinai General Surgery

1. The Work-up of a Thyroid Nodule: A Case Presentation and DiscussionJunko OzaoPGY-3Mount Sinai General Surgery

2. CC: thyroid nodule on PET scan HPI: A.P. is a 52 y.o. F s/p sigmoid resection for a 4.9 cm mod-differentiated adenoca c 2/14 lymph nodes positive on 5/6/2005 (T3bN1Mx). In preparation for surgery, the pt underwent a PET scan, where an increased uptake in her thyroid was noted. Pt denies pain, trouble breathing, hoarseness or dysphagia. No hx of radiation exposure. Med and Surg Hx: hysterectomy 2000 for fibroids. Meds: none All: none Fam Hx: mother with hypothyroidism

3. P.E.- 2cm firm nodule in right mid-pole of thyroid, no LAD Labs: TSH: 2.24 (0.35-5.5) PTH 42(10-65) Ultrasound:2.4x1.6x1.3cm nodule on R lobe with calcifications seen, smaller 0.5x0.3x0.5cm nodule in R superior pole; left lobe unremarkable Thyroid scan: non-diagnostic FNA: papillary thyroid cancer

4. Uncomplicated total thyroidectomy was performed on 6/5/2005 Pathology-1.7cm papillary thyroid carcinoma, uninvolved tissue Hashimoto’s thyroiditis, 2 lymph nodes negative for tumor Currently undergoing chemo for sigmoid ca Possibility and timing of iodine ablation being discussed with oncology

5. Work-up of a Thyroid Nodule Prevalence and risk factors H&P Labs Imaging Modalities Biopsy Management Controversial topics

6. Prevalence Large population studies-Framingham study showed clinically significant nodules in 6.4% women and 1.5% men¹ ages 30-59 (total 4.2%) but thought to be significantly understated Ultrasounds- 20% to 76% of females had at least one thyroid nodule on ultrasound² Autopsy surveys show 37 to 57% of patients with thyroid nodules³ ¹ Vander JB, et al. The significance of nontoxic thyroid nodules. Final report of a 15 year study of the incidence of thyroid malignancy. Ann Intern Med 1968;69:537. ²Belfiore et al. High frequency of cancer in cold thyroid nodules occuring at a young age. Acta Endocrinol 1989;121:197 ³ Rice CO et al. Incidence of nodules in the thyroid. Arch Surg 1932;24:505. Mortensen JD, Woolner LB, Bennett, WA. Gross and microscopic findings in clinically normal thyroid glands. J Clin Endocrinol Metab 1955; 15:1220

7. Risk Factors of nodules and of carcinoma Increased risk of nodules with age Increased risk of carcinoma in adults over 60 and under 30 Solitary palpable nodules are about 4x more prevalent in women than in men However, among pts with nodules- rate of carcinoma 2x as high in men as in women (8% vs. 4%) Wong CKM, et al. Thyroid nodules: Rational management. World J Surg 2000;24:934-941 Mazzaferri EL. Management of a solitary thyroid nodule. NEJM 1993;328:553-559

8. Nodules are very common– estimates of 9 million adults in the US have a thyroid nodule New nodules appear at a rate of 0.8%/yr Thyroid cancer is rare 4/100,000 per year-12,000 new cases/yr in US 1% of all malignancies 0.5% of all cancer deaths-1,000/yr Up to 35% of thyroids at autopsy contain clinically silent carcinoma Wong CKM, et al. Thyroid nodules: Rational management. World J Surg 2000;24:934-941 Mazzaferri EL. Management of a solitary thyroid nodule. NEJM 1993;328:553-559

9. Exposure to radiation, especially in childhood is associated with increased prevalence of thyroid nodules and malignancy¹-2%/yr increased risk with peak incidence 15-20 years Presence of a nodule in a child is 2x as likely to be carcinoma Two large series 20-27% of patients with prior radiation exposure had thyroid nodularity and 30 to 33% of the nodules were carcinomas² Prior family history of thyroid cancer ¹Schneider AB et al. Radiation-induced tumors of the head and neck following childhood irradiation.J Clin Endocrinol Metab. 1985;61(3):547-50. ²Favus MJ et al. Thyroid cancer occurring as a late consequence of head and neck irradiation. Evaluation of 1056 patients. N Engl J of Med 1976;294:1019; Cerletty JM et al. Radiation-related thyroid carcinoma. Arch Surg 1978;113:1072.

10. Rate of Carcinoma in Thyroid Nodules Significant selection bias in surgical series North Carolina study in a community hospital pts with nodules were referred to surgery without biopsy and 6.5% of excised nodules were carcinomas¹ Catania, Italy 2327 pts with nodules were evaled by FNA and of those 391 were selected for surgery. Carcinomas were found in 28 which was 5% of total² ¹Werk EE, Vernon BM, Gonzalez, JJ. Cancer in thyroid nodules. A community hospital survey. Arch Intern Med 1984; 144:474. ²Belfiore et al. High frequency of cancer in cold thyroid nodules occuring at a young age. Acta Endocrinol 1989;121:197

11. Causes of Thyroid Nodules Benign- >90% Multinodular goiter (colloid adenoma) Hashimoto’s (chronic lymphocytic) thyroiditis Cysts: colloid, simple, or hemorrhagic-7-14% can be malignant- most commonly papillary ca with a cystic component with most increased size 2-4cm Follicular Adenoma Macrofollicular adenoma Microfollicular or cellular Hurthle-cell (oxyphil cell) adenomas- macro or microfollicular Malignant -about 6% Papillary Follicular Minimally or widely invasive Oxyphilic type Medullary Anaplastic Primary thyroid lymphoma Metastatic carcinoma

12. Toxic Multinodular Goiter

13. Papillary Carcinoma

14. Work-up of a Thyroid Nodule Prevalence and risk factors H&P Labs Imaging Modalities Biopsy Management Controversial topics

15. H&P Age and gender Recent history of hoarseness, dysphagia or dyspnea Sxs of hypothyroidism or hyperthyroidism Family h/o thyroid or endocrine disease h/o prior radiation exposure, especially early in life

16. Thorough history of other endocrine disorders-MEN type II– and other malignant syndromes ---familial adenomatous polyposis, Gardner’s syndrome Palpate thyroid – determine size and consistency of thyroid nodule(s), shape, location and mobility Examine for cervical LAD Hard, fixed, irregular-shaped nodules and LAD are suggestive of malignancy

17. Work-up of a Thyroid Nodule Prevalence and risk factors H&P Labs Imaging Modalities Biopsy Management Controversial topics

18. Laboratory Thyroid function tests- should be assessed Calcitonin if suspect medullary thyroid disease Most thyroid nodules are euthyroid However, if TSH is low, the possibility of a hot nodule is increased- may want to consider thyroid scintigraphy TSH is high suggestive of Hashimoto’s thyroiditis- may want to ultrasound to see if nodularity is lymphocytic infiltrate vs. TSH induced hyperplasia vs. thyroid tumor Still should fully evaluate a nodule- may have co-existence of malignancy and thyroiditis

19. Work-up of a Thyroid Nodule Prevalence and risk factors H&P Labs Imaging Modalities Biopsy Management Controversial topics

20. Imaging- Thyroid Scintigraphy Utilizes iodine or technetium-99m pertechnate- more is taken up and organified by functional tissue Non-functioning thyroid nodule is cold and mandates further work-up by FNA The scan is often used in working up nodules in patients with high TSH levels but has many problems Nelson et al. showed that only slightly more than one-half of their excised malignant thyroid nodules appeared cold¹ because the scan is 2-D there is apposition of normal thyroid tissue next to abnormal tissue ¹Nelson RL et al. Rectilinear thyroid scanning as a predictor of malignancy. Ann of Intern Med 1978;88:41.

21. Also although 80% of nodules greater than 2cm appear cold- smaller nodules can be indeterminate¹ Malignancy has been shown to occur 15-20% of “cold” nodules and, additionally, in 5-9% of nodules with uptake that is “warm” or “hot”² This is not very sensitive or specific for malignancy– thus, warm or hot nodules still mandate a continued aggressive approach to work-up- may not really change management Traditionally hot nodules rx’ed in past with radioactive iodine or taken to surgery Thyroid scintigraphy has fallen out of favor- definitely questions about how cost-effective it is for routine evaluation for patients with nodules ¹Nelson RL et al. Rectilinear thyroid scanning as a predictor of malignancy. Ann of Intern Med 1978;88:41. ²Price DC et al. Radioisotopic evaluation of the thyroid and the parathyroid. Radiol Clin North Am 31:967-989. 1993.

22. Ultrasound Provides considerable anatomic information but no functional information Determine the volume of a nodule, multicentricity and whether it is cystic or solid- often performed before FNA Extremely useful in also following patients being managed conservatively for possible increasing size of lesion Unable, however, to accurately predict the diagnosis of solid nodules

23. Cystic lesion are reassuring but only 1-5% of total thyroid nodules In addition, as many as 25% of well-differentiated thyroid cancers had cystic components¹ and up to 60-70% of all nodules² Physician can correlate the nuclear medicine and u/s finding and determine the function of the particular nodule Additional nodules can be found 20-48% of patients² Many times the u/s findings differ from the physical exam, in one retrospective series up to 63% of the time³ ¹Burch HB et al. Evaluation and management of the solid thyroid nodule. Endocrinol Metab Clin North Am 24:663-710 ²Tan GH et al. Thyroid incidentalomas: management approaches to non-palpable nodules discovered incidentally on thryoid imaging. Ann Intern Med 1997;126:226. ³Marqusee E et al. Usefulness of ultrasonography in the management of nodular disease. Ann Intern Med 1997;126:226.

24. Work-up of a Thyroid Nodule Prevalence and risk factors H&P Labs Imaging Modalities Biopsy Management Controversial topics

25. FNA Simple, safe office procedure Tissue sample obtained by 25 gauge needle With experience adequate sample may be obtained in 90 -97% of aspirates of solid nodules¹,² False negative rate (FNA benign but nodule turn out malignant) is 0-5% usually due to sampling error False positive rates (malignant but turns out benign) <5% due to focal hyperplasia in a macrofollicular adenoma or cellular atypia in a degenerating adenoma ¹Gershengorn et al. FNA cytology in the preoperative diagnosis of thyroid nodules. Ann Intern Medicine 1977;87:265. ²Hall TL et al. Sources of diagnostic error in error in FNA of the thyroid. Cancer 1989;63:718.

27. La Rosa et al. series of 5605 FNA procedures false negatives in 2.3% and false positives in 1.1%. Overall accuracy exceeds 95%.¹ Euthyroid patients should be evaluated with FNA as first step per endocrine– often surgeons will send for u/s first to find out if cystic or solid Results- benign (70%), malignant (5%), indeterminate (10%), nondiagnostic (15%) ¹La Rosa GL et al. Evaluation of the fine needle aspiration biopsy in the preoperative selection of cold nodules. Cancer 1991;90:967.

28. Work-up of a Thyroid Nodule Prevalence and risk factors H&P Labs Imaging Modalities Biopsy Management Controversial topics

29. FNA results Malignant- pt needs to have surgical management Benign- observation with interval ultrasounds and clinical examinations Inderminate- radioisotope scan- perform suppression scan and if cold proceed to surgical management- if hot nodule consider observation Non diagnostic- repeat FNA or U/S guided FNA

30. Wong CKM, et al. Thyroid nodules: Rational management. World J Surg 24(2000):934-941.

31. Work-up of a Thyroid Nodule Prevalence and risk factors H&P Labs Imaging Modalities Biopsy Management Controversial topics

32. U/S-guided FNA

33. Often used after FNA comes back non-diagnostic rather than repeating another FNA Inadequate sampling cited as most common reason for false negative rates Repeat FNA with u/s can decrease nondiagnostic smears from 15% to 3%¹,² May be particularly valuable for smaller nodules <1.5cm Also very useful in complex cysts-can see the needle sample the solid component of the cyst Probably will have a more prominent role ¹Carmeci C et al. Ultrasound-guided fine-needle aspiration biopsy of thyroid masses. Thyroid. 1998;8:284-239. ²Danese D et al. Diagnostic accuracy of conventional versus sonography-guided fine-needle aspiration biopsy of thyroid nodules. Thyroid. 1998;8:15-21.

34. Routine Calcitonin Screening Calcitonin screening is advocated in several reports to identify those with medullary cancer Italian report- 10,864 patients screened after 1991, 44 (0.4%) had an elevated calcitonin and ALL had medullary cancer¹ 59% of these patients maintained a full remission of cancer as compared to 2.7% of patients who were not screened² French study only 41% of their patients with elevated calcitonin had MTC Some false positives as high as 59% -so routine screening remains controversial ¹Elisei et al. Impact of routine measurement of serum calcitonin on the diagnosis and outcome of medullary and thyroid cancer: experience in 10,864 patients with nodular thyroid disorders. J of Endocrinol Metab 2004;89:163. ²Niccoli P et al. Interest of routine measurement of serum calcitonin: study in a large series of thyroidectomized patients. J Clin Endocrinol MEtab 1997;82:338.

35. PET Scans and the Thyroid Nodule

36. History 56 year old female with a history of papillary thyroid carcinoma, status post thyroidectomy with rising thyroglobulin level and negative I-131 scan. Nuclear Medicine In this particular case, a small normal appearing jugulodigastric lymph node was found to have FDG uptake and was subsequently resected and found to be positive for recurrent papillary carcinoma. Courtesy of Todd Blodgett, MD, University of Pittsburgh Medical Center

37. PET scan-reflects glucose metabolism of tissues in vivo Consensus considers faint homogenous uptake of FDG by thyroid tissue to be physiologic¹ Cohen et al. found 102/4250 (2.3%) thyroid incidentalomas² Cytology only available in 15 pts– but 47% were carcinoma 40% nodular hyperplasia and 1 thyroiditis/1 atypical cells ¹McDougall IR et al. Positron emission tomography of the thyroid, with an emphasis on thyroid cancer. Nucl Med Commun 22:485-492. ²Cohen MS et al. Risk of malignancy in thyroid incidentalomas identified by fluorodeoxyglucose- positron emission tomogrpahy. Surgery 130:941-946.

38. Adler et al. showed by pooling data that if a peak standard uptake value (SUV)>8 used that successfully able to indentify 7/7 thyroid cancers and 31/33 of benign lesions¹ Others studies show that papillary and follicular carcinoma have significantly different SUV values compared to benign nodules² Other studies show that regardless of SUV- malignancy rates are high in positive PET scans³ However, still not known if PET scans can reliably distinguish between benign and malignant disease ¹Adler LP et al. Positron emission tomography of thyroid masses. Thyroid 3:957-963. ²Sasaki M et al. An evaluation of FDG-PET in the detection and differentiation of thyroid tumors. Nucl Commun 18:957-963. ³Kim TY. 18F-fluorodeoxyglucose uptake in thyroid from positron emission tomogram (PET) for evaluation in cancer patients: high prevalence of malignancy in thyroid PET incidentaloma. Laryngoscope. 2005;115(6):1074-8. 

39. “Never advance anything that cannot be proved in a simple and decisive fashion. Worship the spirit of criticism. If reduced to itself, it is not an awakener of ideas or a stimulant to great things, but, without it, everything is fallible; it always has the last word.” -Louis Pasteur 1888 on the opening of the Pasteur Institute (Paris, France)