Goiter and Thyroid Cancer Hasan AYDIN, MD Yeditepe University Medical Faculty Department of Endocrinology and Metabolism

Definitions Goiter is a diffuse or nodular enlargement of the thyroid gland resulting from excessive replication of benign thyroid epithelial cells. A thyroid nodule is a discrete lesion within the thyroid gland that is palpably and/or ultrasonog- raphically distinct from the surrounding thyroid parenchyma Incidentalomas are non-palpable nodules incidentally discovered on USG or other radiological imaging performed for other reasons

Thyroid Structure Function - Diffuse - Euthyroid - Nodular - Hyperthyroid - Hypothyroid

Prevalence Large population studies-Framingham study showed clinically significant nodules in 6.4% women and 1.5% men 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 ultrasound Autopsy surveys show 37 to 57% of patients with thyroid nodules

Rate of Carcinoma in Thyroid Nodules Significant selection bias in surgical series USA: Pts with nodules were referred to surgery without biopsy and 6.5% of excised nodules were carcinomas Italy: 2327 pts with nodules were evaluated by FNA and of those 391 were selected for surgery. Carcinomas were found in 5% of total

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

Nodular Goiter

Pathogenesis Dyshormonogenesis or severe iodine deficiency Impaired hormone synthesis Secondarily and increase in TSH secretion. TSH induces diffuse thyroid hyperplasia, followed by focal hyperplasia with necrosis and hemorrhage, finally the development of new areas of focal hyperplasia. A clone of cells that may or may not be able to pick up iodine or synthesize thyroglobulin.

Presentation Asymptomatic Symptomatic Neck mass discovered by patient or physician Abnormal CXR Symptomatic Pressure symptoms Hoarseness Thyrotoxicosis

Suspicious Nodule or Goiter High suspicion Family history of medullary thyroid carcinoma Rapid tumor growth A nodule that is very firm or hard Fixation of the nodule to the adjacent structures Paralysis of the vocal cord Regional lymphadenopathy Distant metastasis Moderate suspicion Age of either<20 or >70 years Male sex History of head and neck irradiation A nodule >4 cm in diameter or partially cystic Symptoms of compression, including dysphagia, dysphonia, hoarseness, dyspnea, and cough

Differentiation of Benign & Malign Lesions

Evaluation TSH FT4, T3 Radionuclide Scan / RAIU US CT Scan (without contrast) FNA biopsy

FNA Evaluation Biopsy all accessible nodule(s) Biopsy suspicious nodule(s) cold on scan; firm by palpation; growing in size Results less reliable in large goiters Most common diagnosis is “colloid nodule”

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 nodules 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

FNA Evaluation

FNA Evaluation

FNA Results Malignant- pt needs to have surgical management Benign- observation with interval ultrasounds and clinical examinations Indeterminate- 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

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

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 low TSH levels Only slightly more than one-half of the excised malignant thyroid nodules appear cold because the scan is 2-D there is apposition of normal thyroid tissue next to abnormal tissue

Also although 80% of nodules greater than 2cm appear cold- smaller nodules can be indeterminate 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” Thyroid scintigraphy has fallen out of favor- definitely questions about how cost-effective it is for routine evaluation for patients with nodules

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

Ultrasound 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 components and up to 60-70% of all nodules 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 patients Many times the U/S findings differ from the physical exam, in one retrospective series up to 63% of the time

Ultrasound Ultrasonographic Cancer Risk Factors for a Thyroid Nodule hypoechogenicity, microcalcifications, irregular margins, increased nodular flow visualized by Doppler, the evidence of invasion or regional lymphadenopathy

Palpabl Thyroid Nodule Thyroid ultrasonography Algorithm Palpabl Thyroid Nodule TSH Low TSH Normal or High TSH Thyroid Scintigraphy Thyroid ultrasonography Hot Nodule Cold Nodule Follow-up FNAB High Risk Low risk Medium risk

THYROID CANCERS

Neoplasms of the Thyroid (from WHO Classification) II. Malignant Tumors     A. Differentiated 1. Papillary adenocarcinoma    a. Pure papillary adenocarcinoma    b.Mixed papillary and follicular ca    (variants including tall cell, follicular, oxyphyl, solid)  2. Follicular adenocarcinomas (variants: "malignant adenoma", Hurthle cell carcinoma or oxyphil carcinoma, clear-cell carcinoma, insular carcinoma B. Medullary carcinoma- (not a tumor of follicular cells) C. Undifferentiated         1. Small cell (to be differentiated from lymphoma)         2. Giant cell         3. Carcinosarcoma D. Miscellaneous         1. Lymphoma, sarcoma        2. Squamous cell epidermoid ca        3. Fibrosarcoma        4. Mucoepithelial ca.        5. Metastatic tumor I. Adenomas A. Follicular     1. Colloid variant     2. Embryonal     3. Fetal     4. Hurthle cell variant B. Papillary (probably malignant) C. Teratoma  

Thyroid Cancer Papillary (mixed papillary and follicular) 75% Follicular carcinoma 16% Medullary carcinoma 5% Undifferentiated carcinomas 3% Miscellaneous (lymphoma, fibrosarcoma, 1% squamous cell carcinoma, malignant hemangioendothelioma, teratomas, and metastatic carcinomas)

Papillary thyroid carcinoma Most often in the twenties to forties. Incidence rise: 1935 (1.3/100,000 for women and 0.2/100,000 for men) 1991 (5.8/100,000 for women and 2.5/100,000 for men) Cause: (1)R/T to children with head and neck benign disease between 1910 and 1960 (2) increased detection of small papillary cancers

Papillary Carcinoma Very slowly grow and remain confined to the thyroid gland and local lymph nodes for many years. In older patients, more aggressive and invade locally into muscles and trachea. In later stages, they can spread to the lung. Death is usually due to local disease, with invasion of deep tissues in the neck less commonly, death may be due to extensive pulmonary metastases..

Less Aggressive-Unpredictable Tm Behaviour Papillary Ca.-Prognostic factors Most Aggressive Primary Tm>4.5 cm Tm invasion into neck Aggressive Tm growth Anaplastic transformation Age ≥40 years Mediastinal LN Mx. Bone Mx. Large solitary pulm Mx. Distant Mx. With no 131I concentrate Less Aggressive-Unpredictable Tm Behaviour Primary Tm 1.5-4.5 cm Microscopic multicentric primary Tm. Bilat. Cervical LN Mx. Male gender Tm. Occuring after radiotx. Diffuse Pulm Mx. with 131I concentrate Lymphocytic infiltration of Tm Primary Tm < 1.5 cm Encapsulated Tm. Young patients Thyroglossal duct Tm. Least Aggressive

Follicular Carcinoma Characterized by the presence of small follicles, colloid formation is poor. Capsular or vascular invasion. More aggressive and local invasion of lymph nodes or by blood vessel invasion with distant metastases to bone or lung. Often retain the ability to concentrate radioactive iodine, to form thyroglobulin, and, rarely, to synthesize T3 and T4.

Follicular carcinoma More frequency than papillary cancer in iodine deficiency area. More frequently with increasing age Early hematogenous spread to lung, bone, brain, and liver (one fifth of patients ). Lymph node involvement :less than 1%

Follicular Carcinoma Rare ''functioning thyroid cancer'' is almost always a follicular carcinoma. More likely to respond to radioactive iodine therapy. In untreated patients, death is due to local extension or to distant bloodstream metastasis with extensive involvement of bone, lungs, and viscera.

Least AggressiveTm Behaviour Follicular Ca.-Prognostic factors Most Aggressive Primary Tm > 4 cm Tm invasion into neck Moderate to extensive vasc. and capsular invasion Oxyphilic Tm (Hurtle Cell) Age ≥40 years Male gender Anaplastic transformation Distant Mx. Least AggressiveTm Behaviour Medium sized or large Tm follicles Minimal capsular or vasc. Tm. invasion

Medullary Carcinoma a disease of the C cells (parafollicular cells) derived calcitonin, histaminase, prostaglandins, serotonin, other peptides more aggressive , but not undifferentiated thyroid cancer. locally into lymph nodes and into surrounding muscle and trachea. lymphatics and blood vessels and metastasize to lungs and viscera. Calcitonin and CEA clinically useful markers for diagnosis and follow-up.

Medullary Carcinoma About 80% are sporadic The remainder are familial: without associated endocrine disease (FMTC); MEN 2a medullary carcinoma, pheochromocytoma, and hyperparathyroidism; MEN 2B, medullary carcinoma, pheochromocytoma, and multiple mucosal neuromas; MEN 3 : with cutaneous lichen amyloidosis, a pruritic skin lesion located on the upper back.

Medullary Carcinoma Diagnosed by fine-needle aspiration biopsy or at surgery , it is essential that the patient be screened for the other endocrine abnormalities found in MEN 2. Screening : measurement of serum calcitonin after calcium infusion in patients who have demonstrated mutations in the ret proto-oncogene on DNA analysis, Calcium gluconate IV in a dose of 2 mg/kg over 1 minute, and blood for calcitonin determination is obtained at 1, 2, 3, and 5 minutes after the infusion. Peak values occur 1-2 minutes after injection.

Undifferentiated (Anaplastic) Carcinoma Small cell, giant cell, and spindle cell carcinomas. Usually occur in older patients with a long history of goiter in whom the gland suddenly -over weeks or months- begins to enlarge and produce pressure symptoms, dysphagia, or vocal cord paralysis. Death from massive local extension usually occurs within 6-36 months These tumors are very resistant to therapy .

Lymphoma Only type of rapidly growing thyroid cancer that is responsive to therapy As part of a generalized lymphoma or may be primary in the thyroid gland. Occasionally with long-standing Hashimoto's thyroiditis Characterized by lymphocyte invasion of thyroid follicles and blood vessel walls, which helps to differentiate thyroid lymphoma from chronic thyroiditis. If there is no systemic involvement, the tumor may respond dramatically to radiation therapy

Cancer metastatic to the thyroid Cancers of the breast and kidney, bronchogenic carcinoma, and malignant melanoma. The primary site of involvement is usually obvious, Occasionally , the diagnosis is made by needle biopsy or open biopsy of a rapidly enlarging cold thyroid nodule. The prognosis is that of the primary tumor,

Management of Thyroid Cancer Papillary and Follicular Carcinoma: Low-risk group under age 45 with primary lesions under 1 cm and no evidence of intra- or extraglandular spread. For these patients, lobectomy is adequate therapy All other patients high-risk, and for these total thyroidectomy and-if there is evidence of lymphatic spread -a modified neck dissection are indicated. Prophylactic neck dissection is not necessary. For the high-risk group, postoperative radioiodine ablation

Management of Thyroid Cancer After recovery from surgery, liothyronine, 50-100 g daily in divided doses for 4 weeks; The medication is then stopped for 2 weeks, The patient is placed on a low-iodine diet. At the end of the 2-week period, the serum thyroglobulin level is determined and the patient is scanned at 24 and 72 hours after a dose of 2-5 mCi of 131-I. If there is evidence of residual radioactive iodine uptake in the neck or elsewhere or if there is a rise in serum thyroglobulin greater than 10 ng/ml, radioactive iodine (131 Iodine) is effective treatment.

Management of Thyroid Cancer Follow-up at intervals of 6-12 months should include careful examination of the neck for recurrent masses. If a lump is noted, needle biopsy is indicated to confirm or rule out cancer. Serum TSH should be checked Serum Tg should be < 1 ng/ml .

Management of Thyroid Cancer Medullary Carcinoma: the marker for recurrent medullary cancer is serum calcitonin or CEA Family members of patients with a genetic ret oncogene mutation should be screened for the mutation. If a patient a persistently elevated serum calcitonin concentration after total thyroidectomy and regional node dissection, MRI of the neck and chest or selective venous catheterization and sampling for serum calcitonin may reveal the location of the metastases..

Management of Thyroid Cancer Metastatic foci may be revealed by PETscan, İndium-labeled somatostatin (octreotide), or sestamibi scan. If this fails to localize the lesion until the metastatic lesion shows itself as a palpable mass or a shadow on chest x-ray or MRI. Chemotherapy for meduIlary carcinoma has not been effective

Management of Thyroid Cancer Anaplastic Carcinoma: very poor prognosis. Isthmusectomy (to confirm the diagnosis and to prevent tracheal compression) and palliative x-ray therapy. Lymphomas are quite responsive to x-ray Giant cell, squamous cell, spindle cell, and anaplastic carcinomas are unresponsive. Chemotherapy is not very effective for anaplastic carcinomas. Doxorubicin is quite toxic; Side effects cardiotoxicity, myelosuppression, alopecia, GI symptoms.

Whole body scan rhTSH vs.thyroid hormone withdrawal rhTSH: stimulate 131I uptake without symptoms of hypothyroidism. Thyroid hormone withdrawal: for pts with likely residual disease.T4 switch to T3(rapidly cleared hormone) Tg measurements after rhTSH administration or when TSH level risen after thyroid hormone withdrawal.

Follow up Whole-body scan is negative and Tg level are low → repeat scan perform one year later→still negative →management with suppressive therapy and measurements of Tg every 6 to 12 months Scan negative, Tg-positive(>5 to 10 ng/mL) →radioiodine treatment. Lung metastasis: CXR,131I scan, spiral CT Bone metastasis: bone scintigraphy, CT, MRI

Prognosis of incurable DTC 85% of patients with DTC :disease-free after initial treatment 10–15% : recurrent disease 5%: distant metastases Distant metastases :lungs (50%), bones (25%), lungs and bones (20%) ,10-year-survival rates ranging from 25% to 42%

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