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

2. 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

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

4. Prevalence
Large population studies-Framingham study showed clinically significant nodules in 6.4% women and 1.5% men ages (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

5. 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

6. 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

7. Nodular Goiter

8. 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.

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

10. 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

11. Differentiation of Benign & Malign Lesions

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

13. 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”

14. FNA Simple, safe office procedure
Tissue sample obtained by 25 gauge needle
With experience adequate sample may be obtained in % 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

15. FNA Evaluation

17. FNA Evaluation

18. 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

19. 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

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 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

21. 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

23. 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

24. 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

26. 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

27. 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

29. THYROID CANCERS

30. 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  

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

32. 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

33. 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..

34. 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 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

35. 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.

36. 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%

37. 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.

38. 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

39. 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.

40. 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.

41. 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.

42. 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 .

43. 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

44. 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,

45. 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

46. Management of Thyroid Cancer
After recovery from surgery, liothyronine, 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.

47. 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 .

48. 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..

49. 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

50. 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.

51. 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.

52. 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

53. 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%

54. Thank You