Thyroid Disease: Thyroid Gland: in Situ Overview

Thyroid Disease: Thyroid Gland: In Situ Overview

Kenneth B. Ain, M.D.

Professor of Medicine The Carmen L. Buck Chair of Oncology Research Director, Thyroid Oncology Program Div. of Endocrinology & Molecular Medicine Dept. of Internal Medicine University of Kentucky Medical Center &Veterans Affairs Medical Center, Lexington, KY Copyright retained by Dr. Kenneth B. Ain

T4 (Pro-Hormone) levothyroxine

OH I

I I N O

O O e s a in I d o i 5 e - d d '- e i 5 o d i n a s e OH OH I I I N O I N O

O O O O I I T3 (Active Hormone) reverse T3 (Inactive Metabolite) triiodothyronine

Free T4 0 . 03% of Total T4 Free T4 Metabolically available to tissues.

Feedback regulation.

T4 Bound to Serum Proteins

l T4 (TBG, TBPA , a Albumin, etc.) Tot

99 . 97% of Total T4 Regulates Gene Transcription

1 Relationship Between TSH Levels

and Free T4

1000

100

1.0 Normal

0.1

0.01 Undetectable

Hypothyroid Euthyroid Hyperthyroid

Free T4

Copyright retained by Dr. Kenneth B. Ain Copyright retained by Dr. Kenneth B. Ain Spencer CA, et al. J Clin Endocrinol Metab. 1990;70:453-460.

Causes of Hypothyroidism Clinical Features of Hypothyroidism

• Primary Tiredness – Destructive Puffy Eyes Enlarged Thyroid (Goiter) • Hashimoto’s thyroiditis • Secondary Forgetfulness/Slower Thinking •Post-131I therapy Moodiness/ Irritability Hoarseness/ • Pituitary tumor Deepening of Voice • Post-thyroidectomy Depression •Pituitaryyg granuloma – RiblReversible Persistent Dry or Sore Throat • Pituitary apoplexy Inability to Concentrate • Endemic goiter: Thinning Hair/Hair Loss Difficulty Swallowing – Iodine deficiency Loss of Body Hair Slower Heartbeat – &/or natural goitrogens Dry, Patchy Skin Menstrual Irregularities/ • Iodine Excess • Tertiary Heavy Period • Drugs: thioureas, lithium, etc. • Hypothalamic disease Weight Gain Infertility – Congenital – Tumor Cold Intolerance – Craniopharyngioma • Thyroid agenesis Elevated Cholesterol Constipation • Ectopic thyroid Muscle Weakness/ Family History of Thyroid Cramps • Dyshormonogenesis Disease or Diabetes Copyright retained by Dr. Kenneth B. Ain Copyright retained by Dr. Kenneth B. Ain

Hypothyroidism and Depression Many Patients With Hypothyroidism Have Many Common Features Report No Symptoms

Depression Hypothyroidism 50 Euthyroid Mild Thyroid Failure • Constipation 40 >35% •Appetite decrease • Bradycardia ts, % Hypothyroid n • Cardiac and lipid 30 • Decreased concentration >25% • Sleep decrease • Decreased libido abnormalities • Suicidal ideation • Delusions • Cold intolerance 20 •Weight loss • Depressed mood • Delayed reflexes

• Appetite increase/ Participa • Diminished interest •Goiter 10 decrease • Sleep increase • Hair and skin • Weight increase changes 0 • Fatigue 01234 Number of Symptoms Canaris GJ, et al. Arch Intern Med. 2000;160:526-534. Nemeroff CB, J Clin Psychiatry. 1989;50(suppl):13-20. Copyright retained by Dr. Kenneth B. Ain Copyright retained by Dr. Kenneth B. Ain Ladenson PW, et al. Arch Intern Med. 2000;160:1573-1575.

2 Special Considerations Levothyroxine: Therapy of Need for Therapy With Other Populations Hypothyroidism

• Pregnant women • Pure levothyroxine is best • Pharmacokinetics – Thyroid failure may impede the intellectual development of the child – No role for thyroid extract – Serum half-life: 7 days – Increased LT doses may be necessary 4 • Mixed bag of compounds – GI absorption 81 (± 21)% – TSH levels should be monitored each trimester • Raw animal product – Time of oral absorp.: 2-4 hrs • Postpartum thyroiditis • Differing pharmacokinetics – Volume of distribution 12 liters – Can lead to symptomatic thyrotoxicosis and/or hypothyroidism – NlfhiNo role for chronic use o f (13-14% body weight) – Reported prevalence varies from 2% to 21% (higher in type I DM) T3/T4 mixtures – Time to steady-state: – Has been associated with postpartum depression • Different pharmacokinetics 6-8 weeks – Can lead to chronic hypothyroidism • Endogenous deiodinases • Special considerations • Elderly Patients • No proven advantages – Cardiac disease • Treat underlying disease – Symptoms obscured by co-morbid conditions • Dose: individually titrate • May start with lower doses – May worsen or be confused for dementia or psychiatric problems – Replacement: 1.6 mcg/kg/day – Elderly – Suppression: 2.0 mcg/kg/day • Compliance issues paramount • May start with lower doses

Thyrotoxicosis (“Too much thyroid hormone”): Cardiac symptoms common in Causes Thyrotoxicosis

• Thyroid Stimulation – Immunoglobulins [Graves’ Disease] • Sinus Tachycardia: 40% – HCG [Trophoblastic Tumors] – TSH [TSH-secreting pituitary tumors] • Atrial Fibrillation: 20% • Intrinsic Thyroid Autonomy – Toxic Adenoma • Intra- or infranodal block: 5% – Toxic Multinodular Goiter • Intraventricular conduction defect: 15% • Thyrotoxicosis without Hyperthyroidism – Inflammatory disease [Subacute thyroiditis, painless thyroiditis] • PVC’s, V Tach, PAT: rare – Extrathyroidal Source [Hormone ingestion, Ectopic Tissue]

Graves’ Disease Graves’ Ophthalmopathy

• Risks: • Key Features – Cosmetic problem – Thyrotoxicosis – Restriction of eye movement – Hyperplastic Goiter – Diplopia – Corneal ulceration – Ophthalmopathy – Optic nerve damage and blindness – Other Autoimmune findings: • Evaluate: • Localized dermatological myxedema – Lids: retraction • Thyroid acropachy (similar to clubbing: rare) – Cornea: ulcer, keratitis • Discriminate from: – Proptosis: may need decompression surgery – Muscles: diplopia, may need surgery – Exogenous L-T4 – Nerve: papilledema, field defect, loss of color vision & acuity – Toxic adenoma or multinodular goiter • Treatment: – Transient thyrotoxicosis from thyroiditis – Keratitis or chemosis: lubrication & protection – Rapidly worsening proptosis: systemic steroids, XRT – Abnormalities of thyroid hormone binding or resistance – Severe proptosis &/or diplopia: orbital decompression surgery

3 Treatment of Thyrotoxic Graves’ Disease Other Causes of Thyrotoxicosis

• Surgery (bilateral subtotal thyroidectomy) • Toxic autonomous nodule (TSH receptor mutation) • Risk of surgery, anesthesia, recurrent laryngeal nerve damage, – Tx: I-131 vs Surgery permanent hypoparathyroidism, Scar • Requires careful preparation & beta-blockers • Toxic Multinodular Goiter • Anti-thyroid Drugs: propylthiouracil (PTU) & methimazole (Tapazole) – Tx: I-131 vs Surgery – Uses: • acute reduction in thyroid hormone; preparation for surgery or I-131 • Transient thyroiditis • Primary therapy (remission <20%); Use in pregnancy – Tx: Beta-blockade & supportive care – Side Effects: • Exogenous Levothyroxine • Minor: rash, urticaria, transient leukopenia – Psychiatric counseling • Major (rare): agranulocytosis, aplastic anemia, hepatitis, SLE-like • Radioactive Iodine (131I): • Pituitary Tumor (extremely rare) – Safe, administered orally, relatively inexpensive – Inappropriate TSH, Evaluate with MRI, Often aggressive – No evidence for long-term adverse effects (aside from hypothyroidism) – Tx: Surgery (if resectable), Gamma-knife, anti-thyroid Rx, – Frequently 1st line therapy; can be used at any age octreotide Copyright retained by Dr. Kenneth B. Ain Copyright retained by Dr. Kenneth B. Ain

Post-Partum Thyroiditis : • Prevalence: approx 10% of pregnancies; <25% clinically obvious Thyroid Cancer • Presentation: Overview of Diagnosis & Clinical – Onset of thyrotoxicosis: 1 - 6 months PP Management – Onset of hypothyroidism: 4 - 12 months PP – Some with thyrotoxicosis or hypothyroidism only • Associations: – Type I Diabetes Mellitus: 25% PPT – Possible associations with miscarriage – Post-partum Depression: hypothyroid phase – TPO-Abs: + Abs have 33% PPT • Screening: – All patients with Type I Diabetes Mellitus – Patients with positive antibodies

Thyroid Cancer Statistics: 2007

• Incidence around 34,000 U.S. cases – 75% Female/25% Male – 1.6% of cancers of all ages – 3. 8% of cancers in children (0-19 yrs) • Mortality: 1,530 in U.S. – 58% Female/42% Male • Prevalence: > 450,000 cases in U.S.

4 Presentations of Thyroid Cancer Clinical vs. Occult Disease

• Thyroid nodule Solitary nodule • 5-60% (depending on method) of thyroid glands Dominant nodule of multinodular gland contain a microscopic (<1.0 cm) focus of papillary • Cervical Node or Mass cancer • Distant metastases • Macroscopic (>1.0 cm) Nodules – Lung – Single: 10% malignant – Bone – Single Dominant in multinodular gland: 10% malignant –Brain – Palpable Nodule in irradiated gland: 30% malignant • Incidental to Resection of Benign Thyroid Mass

5 Evaluation of Thyroid Nodules The Management Team

•Exam & History • Surgeon: Thyroid Surgery is a specialty – Size, Location, Nodes There are very few “THYROID SURGEONS” – Is patient thyrotoxic? • Yes: Get thyroid scan • Pathologist: “Thyroid pathologist” is even rarer • NO: Do NOT do scan!!! • Fine Needle Aspiration Biopsy Have a very low threshold for getting 2nd opinions – Requires some expertise • Endocrinologist (Rarely oncologist) – Specially trained Cytologist – Results (If Adequate Sample): Life-long follow-up • Benign (95-98% accurate) Expertise in nuclear medicine & endocrinology • Malignant (definite) • Indeterminant/Suspicious – Requires surgery to evaluate

Primary Thyroid Cancer Surgery Primary Thyroid Cancer Surgery

Suspicious Unilateral Nodule (per cytology) Known Thyroid carcinoma (positive cytology or known metastases) Ipsilateral Total Lobectomy with Isthmusectomy Total Thyroidectomy = minimum surgery (exception: primary unifocal non-metastatic papillary microcarcinoma) Minimal Initial Surgery Node Resection: Ipsilateral and Central Modified Neck Dissection vs CltTtlThidtComplete Total Thyroidectomy Modified Central Neck Dissection vs Node Picking Histological or gross evidence of cancer during 1st surgery Palpably abnormal contralateral lobe or XRT Hx Special cases: At 2nd surgery (within 2 weeks) if cancer later confirmed Medullary Thyroid carcinoma: Requires TOTAL thyroidectomy and complete nodal resection NEVER do nodulectomy or partial lobectomy Anaplastic Thyroid cancer: Try for total thyroidectomy; the more resected the greater the chance of longer-term survival.

Types of Thyroid Carcinoma Types of Thyroid Carcinoma

• Papillary Carcinoma: 80% • Medullary Carcinoma: <8% – Usual papillary 75% – Sporadic 80% – Follicular variant 15% – Inherited 20% – Oxyphilic (Hürthle cell) 2% Isolated Medullary Ca – Diffuse sclerosing 3% MEN2a: Medullary Ca, hyperparathyroid, pheoch. – Columnar cell var. <1% MEN2b: Medullary Ca, pheoch., neurogangliom. – Tall cell variant 4% • Anaplastic Carcinoma: <2% • Follicular Carcinoma: 10% • Lymphoma: Exceedingly Rare – Usual follicular 75% • Angiomatoid neoplasms, mucoepidermoid Ca, – Oxyphilic (Hürthle cell) 20% Malignant teratomas, paragangliomas, etc. – Insular Carcinoma 5%

6 Papillary Thyroid Cancer Follicular Thyroid Cancer

• Most common type • Second most common • Makes up about 80% of all type of thyroid cancer thyroid carcinomas in the • Solid invasive tumors, usually solitary and United States encapsulated • Females outnumber males 3:1 • Usually stays in the thyroid gland, but can – Highest incidence in women in midlife spread to the bones, – Most common type in children lungs, and central nervous • More aggressive distant spread system Follicular Thyroid Cancer • Assertive care critical • Usually does not spread to the lymph nodes

Hürthle Cell Cancer Anaplastic Thyroid Cancer

• A variant of follicular • Extremely aggressive and cancer that tends to be exceptionally virulent aggressive • Composed wholly or in Hürthle Cell Tumor part of undifferentiated • Represents about 3% to 5% cells of all types of thyroid cancer • Infamous for losing iodine

concentrating ability High power magnification

Anaplastic Thyroid Carcinoma Genesis of Anaplastic Thyroid Carcinoma

• Usually found in association with papillary or • Rare: 1.6% of thyroid cancers (incidence = follicular cancers prevalence) • Often a history of long-standing goiter • Female to Male: 1.2 - 3.1 to 1 • Terminal dedifferentiation of pre-existing • Relentless and deadly clinical course papillary or follicular cancer • Survival time: mean 2.5 - 7.4 months; median – Loss or mutation of p53 gene 4 - 12 months – Other Oncogenes • Tumors large & invasive, necrosis common, •Ras •Nm23 often distantly metastatic at presentation •C-myc

7 Medullary Thyroid Cancer Genetics of Medullary Thyroid Carcinom

Thyroid Parafollicular "C" Cell Tyrosine Kinase Receptor

• Tumor arising from the Cysteine- Cadherin TM TK1 TK2 calcitonin-secreting C-cells Rich of the thyroid gland • Mortality rate of 10% to 20% CODONS Mutations 609 at10t 10 years (5%) 611 618 Normally expressed CODON RET Proto-Oncogene (6-8%) 620 CODON in C-cells, chromaffin (80-90%) 634 768 (95%) 918 Medullary (C-cell) Genomic Organization & parathyroid cells Carcinoma

(Ex 10) FMTC FMTC MEN 2B Phenotype (Ex 11) MEN 2A

Adapted from: Wohllk et. al. Endocrinol Metab Clin N Am 25(1): 1-25, 1996

Primary Thyroid Lymphoma Newly Detected and Fatal Cases of Characteristics and Diagnosis Thyroid Cancer

Thyroid Cancer Cases Deaths by 2010 • Develops in the setting of pre-existing Diagnosed in 2007 (N=>2000) lymphocytic thyroiditis (N=34,000 ) Anaplastic 11% • Often diagnosed because of airway obstruction Hürthle Anaplastic 2% Papillary symptoms 4% Follicular Hürthle 50% • Tumors are firm, fleshy, and usually pale 12% 12% • Best diagnosed by FNA biopsy with flow cytometry • Responds well to chemotherapy and external Follicular beam radiotherapy (surgery not necessary) 27% Papillary 80% Copyright retained by Dr. Kenneth B. Ain Copyright retained by Dr. Kenneth B. Ain Modified from Robbins R, et al. Adv Intern Med. 2001;46:277-294.

Recurrence and Death After Diagnosis of Differentiated Thyroid Cancer: Functional Features Thyroid Cancer

Recurrence Death • Iodine Uptake and Organification 40 • Thyroglobulin production 30 •Resppyponse to Thyrotropin

20 • Slow Growth (TSH-dependent) • Low Distant Metastatic Potential 10

0 0 1020304050 Years After Diagnosis N=1355

Copyright retained by Dr. Kenneth B. Ain Mazzaferri EL, et al. Am J Med. 1994;97:418-428. Copyright retained by Dr. Kenneth B. Ain

8 Traditional Therapy

• Total thyroidectomy and node resection • Radioiodine scanning and treatment •Suppression of TSH with levoth yroxine

Thyroglobulin: tumor marker Iodide Uptake and Retention

- • Specific marker for thyroid follicular cell neoplasms • Functional Na+/ I symporter (NIS) • Expression often independent of NIS expression – TSH-responsive expression – Elevated in dedifferentiated tumors despite lack of iodide – Accounts for iodide uptake transport • Organification permits retention • Most sensitive when stimulated by TSH – Thyroid peroxidase involved (hypothyroid) – Full mechanism not fully elucidated • ≈ 1/3rd patients have TG-Abs, invalidates assay • Tumoricidal Activity Requires: • RT-PCR of peripheral blood for TG mRNA: clinical – Sufficient radiation delivered at effective dose rate (≥80 Gy utility pending at ≥0.6 Gy/hr) – Tumor geometry to absorb dose

Augmentation of 131I External Beam Effectiveness Radiotherapy

• Uptake • Purpose – TSH stimulation – Local control of tumor: critical sites – Stable iodide depletion – “Clean-up” after surgery – Debulk tumor prior to surgical resection • Iodide Retention – Palliation (bone mets , painful sites) – Lithium carbonate • Method – Hypothyroidism – High dose, hyperfractionation • Magnitude of Dose: limited only by toxicity – Chemoradiosensitization: unproven, higher morbidity – Dosimetry (200 REM red marrow limited)