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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
- Diffuse
- Nodular
Function
- Euthyroid
- 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
– Neck mass discovered by patient or
physician
– Abnormal CXR
• Symptomatic
• Pressure symptoms
• Hoarseness
• Thyrotoxicosis
Suspicious Nodule or Goiter
• High suspicion
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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
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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
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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 favordefinitely 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
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hypoechogenicity,
microcalcifications,
irregular margins,
increased nodular flow visualized by Doppler,
the evidence of invasion or regional lymphadenopathy
Algorithm
Palpabl Thyroid Nodule
TSH
Low TSH
Normal or High TSH
Thyroid ultrasonography
Thyroid Scintigraphy
Hot Nodule
High Risk
FNAB
Follow-up
Cold Nodule
Low risk
FNAB
Follow-up
Medium risk
THYROID CANCERS
Neoplasms of the Thyroid
(from WHO Classification)
I. Adenomas
A. Follicular
1. Colloid variant
2. Embryonal
3. Fetal
4. Hurthle cell variant
B. Papillary (probably
malignant)
C. Teratoma
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
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..
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
Least Aggressive
•Lymphocytic infiltration of
Tm
•Primary Tm < 1.5 cm
•Encapsulated Tm.
•Young patients
•Thyroglossal duct Tm.
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.
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 monthsbegins 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, İndiumlabeled 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 xray 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-yearsurvival rates ranging from 25% to 42%
Thank You