36 Thyroid Ain.ppt - UK HealthCare CECentral · • Thyroid acropachy (similar to clubbing: rare) • Discriminate from: – Exogenous L-T4 – Toxic adenoma or multinodular goiter

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Thyroid Disease:Overview

Kenneth B. Ain, M.D.

Professor of Medicine

The Carmen L. Buck Chair of Oncology ResearchDirector, Thyroid Oncology Program

Div. of Endocrinology & Molecular MedicineDept. of Internal Medicine

University of Kentucky Medical Center&Veterans Affairs Medical Center, Lexington, KY

Thyroid Gland: In Situ

Copyright retained by Dr. Kenneth B. Ain


O

O

O

OH

I

I

I

I

N

deio

dina

se

5-d

T4 (Pro-Hormone) levothyroxine


O

O

O

OH

II

I

N

O

O

O

OH I

I

I

N

5'-d

-deiodinase

T3 (Active Hormone) triiodothyronine

reverse T3 (Inactive Metabolite)

Free T4

al T

4 T4 Bound to Serum Proteins

(TBG TBPA

Free T4

0 .03% of Total T4

Metabolically available to tissues.

Feedback regulation.


Tot

a (TBG, TBPA, Albumin, etc.)

99 . 97% of

Total T4


Regulates Gene Transcription

2


10

100

1000

Relationship Between TSH Levels and Free T4


Hyperthyroid

Free T4

0.01

0.1

1.0

Hypothyroid Euthyroid

Undetectable

Spencer CA, et al. J Clin Endocrinol Metab. 1990;70:453-460.

Normal

Causes of Hypothyroidism

• Primary– Destructive

• Hashimoto’s thyroiditis

• Post-131I therapy

• Post-thyroidectomy

R ibl

• Secondary• Pituitary tumor

• Pituitary granuloma


– Reversible• Endemic goiter:

– Iodine deficiency

– &/or natural goitrogens

• Iodine Excess

• Drugs: thioureas, lithium, etc.

– Congenital• Thyroid agenesis

• Ectopic thyroid

• Dyshormonogenesis

y g

• Pituitary apoplexy

• Tertiary• Hypothalamic disease

– Tumor

– Craniopharyngioma

Tiredness

Forgetfulness/Slower Thinking

Moodiness/ Irritability

DepressionPersistent Dry or Sore Throat

Hoarseness/Deepening of Voice

Enlarged Thyroid (Goiter)

Puffy Eyes

Clinical Features of Hypothyroidism


Inability to Concentrate

Thinning Hair/Hair Loss

Loss of Body Hair

Dry, Patchy Skin

Weight Gain

Cold Intolerance

Elevated Cholesterol

Family History of Thyroid Disease or Diabetes

Muscle Weakness/Cramps

Constipation

Infertility

Menstrual Irregularities/Heavy Period

Slower Heartbeat

Difficulty Swallowing

Persistent Dry or Sore Throat

Hypothyroidism and DepressionHave Many Common Features

Depression Hypothyroidism

• BradycardiaC

• Constipation• Appetite decrease


• Sleep decrease• Suicidal ideation

• Weight loss• Appetite increase/

decrease

Nemeroff CB, J Clin Psychiatry. 1989;50(suppl):13-20.

• Cardiac and lipidabnormalities

• Cold intolerance• Delayed reflexes

• Goiter• Hair and skin

changes

pp• Decreased concentration

• Decreased libido• Delusions

• Depressed mood• Diminished interest

• Sleep increase• Weight increase

• Fatigue

50

40

nts,

%

EuthyroidMild Thyroid FailureHypothyroid>35%

Many Patients With Hypothyroidism

Report No Symptoms


30

20

10

0

Par

ticip

an

0 1 2 3 4

Number of Symptoms

>25%

Canaris GJ, et al. Arch Intern Med. 2000;160:526-534.

Ladenson PW, et al. Arch Intern Med. 2000;160:1573-1575.

3

Special ConsiderationsNeed for Therapy With Other Populations

• Pregnant women– Thyroid failure may impede the intellectual development of the child

– Increased LT4 doses may be necessary

– TSH levels should be monitored each trimester

• Postpartum thyroiditisCan lead to symptomatic thyrotoxicosis and/or hypothyroidism


– Can lead to symptomatic thyrotoxicosis and/or hypothyroidism

– Reported prevalence varies from 2% to 21% (higher in type I DM)

– Has been associated with postpartum depression

– Can lead to chronic hypothyroidism

• Elderly Patients– Symptoms obscured by co-morbid conditions

– May worsen or be confused for dementia or psychiatric problems

Levothyroxine: Therapy of Hypothyroidism

• Pure levothyroxine is best– No role for thyroid extract

• Mixed bag of compounds

• Raw animal product

• Differing pharmacokinetics

N l f h i f

• Pharmacokinetics– Serum half-life: 7 days– GI absorption 81 (± 21)%– Time of oral absorp.: 2-4 hrs– Volume of distribution 12 liters

(13-14% body weight)


– No role for chronic use of T3/T4 mixtures

• Different pharmacokinetics

• Endogenous deiodinases

• No proven advantages

• Dose: individually titrate– Replacement: 1.6 mcg/kg/day

– Suppression: 2.0 mcg/kg/day

(13 14% body weight)– Time to steady-state:

6-8 weeks• Special considerations

– Cardiac disease• Treat underlying disease• May start with lower doses

– Elderly• Compliance issues paramount• May start with lower doses

Thyrotoxicosis (“Too much thyroid hormone”):

Causes

• Thyroid Stimulation

– Immunoglobulins [Graves’ Disease]

– HCG [Trophoblastic Tumors]

– TSH [TSH-secreting pituitary tumors]


• Intrinsic Thyroid Autonomy

– Toxic Adenoma

– Toxic Multinodular Goiter

• Thyrotoxicosis without Hyperthyroidism

– Inflammatory disease [Subacute thyroiditis, painless thyroiditis]

– Extrathyroidal Source [Hormone ingestion, Ectopic Tissue]

Cardiac symptoms common in Thyrotoxicosis

• Sinus Tachycardia: 40%

• Atrial Fibrillation: 20%


• Intra- or infranodal block: 5%

• Intraventricular conduction defect: 15%

• PVC’s, V Tach, PAT: rare

Graves’ Disease

• Key Features– Thyrotoxicosis

– Hyperplastic Goiter

– Ophthalmopathy

Other Autoimmune findings:


– Other Autoimmune findings:

• Localized dermatological myxedema

• Thyroid acropachy (similar to clubbing: rare)

• Discriminate from:– Exogenous L-T4

– Toxic adenoma or multinodular goiter

– Transient thyrotoxicosis from thyroiditis

– Abnormalities of thyroid hormone binding or resistance

Graves’ Ophthalmopathy

• Risks:– Cosmetic problem– Restriction of eye movement– Diplopia– Corneal ulceration– Optic nerve damage and blindness


• Evaluate:– Lids: retraction– Cornea: ulcer, keratitis– Proptosis: may need decompression surgery– Muscles: diplopia, may need surgery– Nerve: papilledema, field defect, loss of color vision & acuity

• Treatment:– Keratitis or chemosis: lubrication & protection– Rapidly worsening proptosis: systemic steroids, XRT– Severe proptosis &/or diplopia: orbital decompression surgery

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Treatment of Thyrotoxic Graves’ Disease

• Surgery (bilateral subtotal thyroidectomy)• Risk of surgery, anesthesia, recurrent laryngeal nerve damage,

permanent hypoparathyroidism, Scar• Requires careful preparation & beta-blockers

• Anti-thyroid Drugs: propylthiouracil (PTU) & methimazole (Tapazole)

– Uses:


Uses:• acute reduction in thyroid hormone; preparation for surgery or I-131• Primary therapy (remission <20%); Use in pregnancy

– Side Effects:• Minor: rash, urticaria, transient leukopenia• Major (rare): agranulocytosis, aplastic anemia, hepatitis, SLE-like

• Radioactive Iodine (131I):– Safe, administered orally, relatively inexpensive– No evidence for long-term adverse effects (aside from hypothyroidism)– Frequently 1st line therapy; can be used at any age

Other Causes of Thyrotoxicosis

• Toxic autonomous nodule (TSH receptor mutation)

– Tx: I-131 vs Surgery

• Toxic Multinodular Goiter– Tx: I-131 vs Surgery

Transient thyroiditis


• Transient thyroiditis– Tx: Beta-blockade & supportive care

• Exogenous Levothyroxine– Psychiatric counseling

• Pituitary Tumor (extremely rare)

– Inappropriate TSH, Evaluate with MRI, Often aggressive

– Tx: Surgery (if resectable), Gamma-knife, anti-thyroid Rx, octreotide

Post-Partum Thyroiditis

• Prevalence: approx 10% of pregnancies; <25% clinically obvious

• Presentation:– Onset of thyrotoxicosis: 1 - 6 months PP

– Onset of hypothyroidism: 4 - 12 months PP

– Some with thyrotoxicosis or hypothyroidism only


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:Overview of Diagnosis & Clinical

Management

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)


– 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.

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Presentations of Thyroid Cancer

• Thyroid noduleSolitary nodule

Dominant nodule of multinodular gland

• Cervical Node or Mass


• Distant metastases– Lung

– Bone

– Brain

• Incidental to Resection of Benign Thyroid Mass

Clinical vs. Occult Disease

• 5-60% (depending on method) of thyroid glands contain a microscopic (<1.0 cm) focus of papillary cancer


• Macroscopic (>1.0 cm) Nodules– Single: 10% malignant– Single Dominant in multinodular gland: 10% malignant– Palpable Nodule in irradiated gland: 30% malignant

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Evaluation of Thyroid Nodules

• Exam & History– Size, Location, Nodes– Is patient thyrotoxic?

• Yes: Get thyroid scan• NO: Do NOT do scan!!!


• Fine Needle Aspiration Biopsy– Requires some expertise– Specially trained Cytologist– Results (If Adequate Sample):

• Benign (95-98% accurate)• Malignant (definite)• Indeterminant/Suspicious

– Requires surgery to evaluate

The Management Team

• Surgeon: Thyroid Surgery is a specialtyThere are very few “THYROID SURGEONS”

• Pathologist: “Thyroid pathologist” is even rarerHave a very low threshold for getting 2nd opinions


Have a very low threshold for getting 2nd opinions

• Endocrinologist (Rarely oncologist)Life-long follow-up

Expertise in nuclear medicine & endocrinology

Primary Thyroid Cancer Surgery

Suspicious Unilateral Nodule (per cytology)

Ipsilateral Total Lobectomy with IsthmusectomyMinimal Initial Surgery

C l t T t l Th id t


Complete Total ThyroidectomyHistological or gross evidence of cancer during 1st surgeryPalpably abnormal contralateral lobe or XRT HxAt 2nd surgery (within 2 weeks) if cancer later confirmed

NEVER do nodulectomy or partial lobectomy

Primary Thyroid Cancer Surgery

Known Thyroid carcinoma (positive cytology or known metastases)

Total Thyroidectomy = minimum surgery(exception: primary unifocal non-metastatic papillary microcarcinoma)

Node Resection: Ipsilateral and Central Modified Neck Dissection vs


Node Resection: Ipsilateral and Central Modified Neck Dissection vsModified Central Neck Dissection vs Node Picking

Special cases:Medullary Thyroid carcinoma: Requires TOTAL thyroidectomy and

complete nodal resection

Anaplastic Thyroid cancer: Try for total thyroidectomy; the more resected the greater the chance of longer-term survival.

Types of Thyroid Carcinoma

• Papillary Carcinoma: 80%– Usual papillary 75%– Follicular variant 15%– Oxyphilic (Hürthle cell) 2%


– Diffuse sclerosing 3%– Columnar cell var. <1%– Tall cell variant 4%

• Follicular Carcinoma: 10%– Usual follicular 75%– Oxyphilic (Hürthle cell) 20%– Insular Carcinoma 5%

Types of Thyroid Carcinoma

• Medullary Carcinoma: <8%– Sporadic 80%– Inherited 20%

Isolated Medullary Ca


Isolated Medullary CaMEN2a: Medullary Ca, hyperparathyroid, pheoch.MEN2b: Medullary Ca, pheoch., neurogangliom.

• Anaplastic Carcinoma: <2%• Lymphoma: Exceedingly Rare• Angiomatoid neoplasms, mucoepidermoid Ca,

Malignant teratomas, paragangliomas, etc.

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Papillary Thyroid Cancer

• Most common type

• Makes up about 80% of all thyroid carcinomas in the United States


United States

• Females outnumber males 3:1– Highest incidence in women in midlife

– Most common type in children• More aggressive distant spread

• Assertive care critical

Follicular Thyroid Cancer

• Second most common type of thyroid cancer

• Solid invasive tumors, usually solitary and encapsulated


encapsulated

• Usually stays in the thyroid gland, but can spread to the bones, lungs, and central nervous system

• Usually does not spread to the lymph nodes

Follicular Thyroid Cancer

Hürthle Cell Cancer

• A variant of follicular cancer that tends to be aggressive

• Represents about 3% to 5% Hürthle Cell Tumor


• Represents about 3% to 5% of all types of thyroid cancer

• Infamous for losing iodine concentrating ability High power magnification

Anaplastic Thyroid Cancer

• Extremely aggressive and exceptionally virulent

• Composed wholly or in part of undifferentiated

ll


cells

Anaplastic Thyroid Carcinoma

• Rare: 1.6% of thyroid cancers (incidence = prevalence)

• Female to Male: 1.2 - 3.1 to 1


• Relentless and deadly clinical course

• Survival time: mean 2.5 - 7.4 months; median 4 - 12 months

• Tumors large & invasive, necrosis common, often distantly metastatic at presentation

Genesis of Anaplastic Thyroid Carcinoma

• Usually found in association with papillary or follicular cancers

• Often a history of long-standing goiter• Terminal dedifferentiation of pre-existing


Terminal dedifferentiation of pre existing papillary or follicular cancer– Loss or mutation of p53 gene– Other Oncogenes

• Ras• Nm23• C-myc

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Medullary Thyroid Cancer

• Tumor arising from the calcitonin-secreting C-cells of the thyroid gland

• Mortality rate of 10% to 20% t 10


at 10 years

Medullary (C-cell) Carcinoma

CadherinCysteine-

RichTM TK1 TK2

CODONS 609

Thyroid Parafollicular "C" CellTyrosine Kinase Receptor

Genetics of Medullary Thyroid Carcinom

Mutations611 618 620 634

CODON 768

CODON 918

RET Proto-Oncogene Genomic Organization

Normally expressed in C-cells, chromaffin& parathyroid cells

FMTC MEN 2A

FMTC MEN 2B

(80-90%)

(6-8%)

(Ex 11)

(Ex 10)

(5%)

(95%)

Mutations

Phenotype

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


Primary Thyroid LymphomaCharacteristics and Diagnosis

• Develops in the setting of pre-existing lymphocytic thyroiditis

• Often diagnosed because of airway obstruction


symptoms

• Tumors are firm, fleshy, and usually pale

• Best diagnosed by FNA biopsy with flow cytometry

• Responds well to chemotherapy and external beam radiotherapy (surgery not necessary)

Thyroid Cancer Cases Diagnosed in 2007

(N=34,000 )

Deaths by 2010(N=>2000)

Anaplastic 2%HürthlePapillary

Anaplastic 11%

Newly Detected and Fatal Cases of Thyroid Cancer


Papillary80%

Follicular12%

p4% Papillary

50%

Follicular27%

Hürthle12%

Modified from Robbins R, et al. Adv Intern Med. 2001;46:277-294.

Recurrence and Death After Diagnosis of Thyroid Cancer

30

40

Recurrence

Death


0

10

20

0 10 20 30 40 50

Years After Diagnosis

Mazzaferri EL, et al. Am J Med. 1994;97:418-428.

N=1355

Differentiated Thyroid Cancer: Functional Features

• Iodine Uptake and Organification

• Thyroglobulin production

• Response to Thyrotropin


p y p

• Slow Growth (TSH-dependent)

• Low Distant Metastatic Potential

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Traditional Therapy

• Total thyroidectomy and node resection

• Radioiodine scanning and treatment

• Suppression of TSH with levothyroxine


pp y


Thyroglobulin: tumor marker

• Specific marker for thyroid follicular cell neoplasms• Expression often independent of NIS expression

– Elevated in dedifferentiated tumors despite lack of iodide transport

• Most sensitive when stimulated by TSH


Most sensitive when stimulated by TSH (hypothyroid)

• ≈ 1/3rd patients have TG-Abs, invalidates assay

• RT-PCR of peripheral blood for TG mRNA: clinical utility pending

Iodide Uptake and Retention

• Functional Na+/ I- symporter (NIS)– TSH-responsive expression– Accounts for iodide uptake

• Organification permits retention– Thyroid peroxidase involved


Thyroid peroxidase involved– Full mechanism not fully elucidated

• Tumoricidal Activity Requires:– Sufficient radiation delivered at effective dose rate (≥80 Gy

at ≥0.6 Gy/hr)– Tumor geometry to absorb dose

Augmentation of 131I Effectiveness

• Uptake– TSH stimulation– Stable iodide depletion

• Iodide Retention


– Lithium carbonate– Hypothyroidism

• Magnitude of Dose: limited only by toxicity– Dosimetry (200 REM red marrow limited)

External Beam Radiotherapy

• Purpose– Local control of tumor: critical sites– “Clean-up” after surgery– Debulk tumor prior to surgical resection– Palliation (bone mets painful sites)


Palliation (bone mets, painful sites)

• Method– High dose, hyperfractionation– Chemoradiosensitization: unproven, higher morbidity

Documents

36 Thyroid Ain.ppt - UK HealthCare CECentral · • Thyroid acropachy (similar to clubbing: rare) • Discriminate from: – Exogenous L-T4 – Toxic adenoma or multinodular goiter