1. Thyroid Nodules & Cancer
Ronen Gurfinkel, PGY4
February 8, 2012

2. Objectives
To review the presentation, investigation and treatment of thyroid nodules
To review most recent clinical practice guidelines for thyroid nodules
American Thyroid Association (ATA) Guidelines 2009

3. Background Thyroid nodule Incidentaloma
Discrete lesion within the thyroid gland
Radiologically distinct from surrounding thyroid parenchyma
Incidentaloma
Nonpalpable nodules detected on ultrasound or other imaging study
Have same risk of malignancy as palpable nodules of same size

4. Epidemiology Thyroid nodules are very common
Palpable nodules
5% of women
1% of men
Ultrasound series
19-67%
Autopsy series
37-57%
The prevalence of nodules increases with age
Prevalence in women times higher than men

5. Epidemiology Prevalence of thyroid nodule by age Age (years) Women (%)
18-25
7.6
4.5
26-30
10.5
6.9
31-35
12.6
8.4
36-40
16.7
9.6
41-45
19.0
11.9
45-50
21.2
13.5
51-55
24.5
15.2
56-65
26.9
17.5

6. Thyroid Nodules
Why do we care?
Cosmetic

7. Thyroid Nodules

8. Thyroid Nodules
Why do we care?
Cosmetic
Obstruction

9. Thyroid Nodules
This young woman had a rapidly growing left thyroid nodule that compressed her trachea and displaced it to the opposite side.  She also had mild dysphagia.  She had a left hemithyroidectomy.

10. Thyroid Nodules
Why do we care?
Cosmetic
Obstruction
Thyroid cancer

11. Thyroid Cancer
Thyroid cancer occurs in 5-15% of thyroid nodules, and rate depends on risk factors
Types of thyroid cancer
Differentiated
Papillary
Follicular
Medullary
Anaplastic
Incidence of thyroid cancer is increasing
1973: 3.6 per 100,000
2009: 8.7 per 100,000
Rise in incidence mostly attributed to papillary thyroid cancer and tumours < 2cm in size

12. Thyroid Cancer Risk factors Age Sex History of thyroid irradiation
Thyroid nodules in children are twice as likely to be malignant
In adults, higher rate of malignancy if age > 60
Sex
Malignancy rate 2x higher in men as compared to women (8% versus 4%)
History of thyroid irradiation
~25% have thyroid nodules
~33% have of nodules are malignant
No evidence that radiation-associated thyroid cancers are more aggressive than other thyroid cancers

13. Thyroid Cancer Risk factors Size > 4cm
Family history of multiple endocrine neoplasia type 2 (MEN2) or medullary thyroid cancer (MTC)
Growing nodule
Firm or hard nodule consistency
Fixed nodule
Cervical lymphadenopathy
Persistent hoarseness, dysphonia, dysphagia, dyspnea

14. Thyroid Nodules - Causes
BENIGN (95%)
MALIGNANT (5%)
Multinodular (sporadic) goitre
Papillary carcinoma
Hashimoto’s (chronic lymphocytic thyroiditis)
Follicular carcinoma
Cysts: colloid, simple, or hemorrhagic
Minimally or widely invasive
Follicular adenomas
Hurthle-cell (oxyphilic) type
Macrofollicular adenomas
Medullary carcinoma
Microfollicular or cellular adenomas
Anaplastic carcinoma
Hurthle-cell (oxyphil-cell) adenomas
Primary thyroid lymphoma
Macro- or microfollicular patterns
Metastatic carcinoma (breast, renal cell, lung, others)

15. Thyroid Cancer

16. Thyroid Cancer Prognosis Papillary thyroid carcinoma
30-year survival 95%
Follicular thyroid carcinoma
30-year survival 85%
Medullary thyroid carcinoma
10-year survival 65%
Anaplastic thyroid carcinoma
5-year survival 5%
Median survival is 8.1 months

17. Presentation How do patients with thyroid nodules present?
Nodule noted by patient
Nodule noted on routine physical
Nodule discovered incidentally on imaging
Carotid doppler U/S
Neck CT
18FDG-PET scan
Etc
Obstructive symptoms

18. Evaluation Who should be evaluated? Nodules > 1cm
Occasionally, nodules < 1cm
Diffuse or focal uptake on 18FDG-PET scan

19. Evaluation History & Physical TSH Ultrasound
Fine-needle aspiration (FNA)

20. Evaluation Complete history Symptoms of hyperthyroidism
Risk factors for malignancy
Childhood head and neck irradiation
Exposure to ionizing radiation from fallout in childhood or adolescence
Family history of thyroid carcinoma or thyroid cancer syndrome in first-degree relative
Rapid growth
Hoarseness, dysphagia, stridor

21. Evaluation Physical examination Thyroid gland
Size of gland, goitre
Does this Patient Have a Goiter? – JAMA 1995
“Goiter ruled out”: normal size on palpation, not visible with neck extended
“Goiter ruled in”: large goiter on palpation or lateral prominence > 2 mm
“Inconclusive”: all other findings
Nodule number, size, consistency, mobility
Adjacent cervical lymph nodes
Pemberton’s sign

22. Lateral Thyroid Prominence

23. A, Enlarged left lobe of the thyroid.
A, Enlarged left lobe of the thyroid. B, Marked facial plethora after elevation of both of the patient’s arms.
Jukić T , Kusić Z JCEM 2010;95:
©2010 by Endocrine Society

24. Investigations Laboratory tests Serum TSH Serum thyroglobulin (Tg)
Serum calcitonin

25. Investigations Laboratory tests Serum TSH Serum thyroglobulin (Tg)
If low  radionuclide thyroid scan
Either 123I or 99mTc pertechnetate
Otherwise  Further evaluation for possible FNA
TSH level correlates to risk of thyroid cancer
Serum thyroglobulin (Tg)
Serum calcitonin

26. Prevalence of thyroid cancer (%)
Thyroid Cancer and TSH
TSH (mU/L)
Prevalence of thyroid cancer (%)
< 0.4
2.8%
0.4 – 0.9
3.7%
1.0 – 1.7
8.4%
1.8 – 5.5
12.3%
> 5.5
29.7%

27. Investigations Laboratory tests Serum TSH Serum thyroglobulin (Tg)
Can be elevated in most thyroid diseases
Insensitive and nonspecific test for thyroid cancer
Not recommended as part of the initial evaluation
Serum calcitonin

28. Investigations Laboratory tests Serum TSH Serum thyroglobulin (Tg)
Serum calcitonin
Evaluated in prospective, nonrandomized studies
Screening with calcitonin may detect MTC at an earlier stage (likely present if level > 100 pg/mL)
But also detects C-cell hyperplasia and micromedullary carcinoma (clinical significance uncertain)
Cannot recommend either for or against routine measurement

29. Investigations Ultrasound Should be performed in all patients with:
Suspected thyroid nodule
Nodular goitre
Nodule found on other imaging modality

30. Thyroid Cancer and Ultrasound
High Risk Features
Low Risk Features
Hypoechoic
Increased central vascularity
Incomplete halo
Microcalcifications
Irregular borders
Taller than wide (transverse view)
Suspicious lymph nodes
Hyperechoic
Peripheral vascularity
Complete Halo
Comet-tail
Large, coarse calcifications

31. Central Vascularity

32. Microcalcifications

33. Irregular Borders

34. Taller Than Wide

35. Comet-tail Artifact

36. Investigations Radionuclide scan
If TSH low, 123I or 99mTc pertechnetate should be obtained
Hyperfunctioning (hot) nodules are rarely malignant

37. Investigations Fine-needle aspiration (FNA)
Most accurate and cost effective method for evaluating thyroid nodules
Sensitivity 76-98%, specificity %
Prior to FNA, only 15% of resected nodules were malignant
With FNA, malignancy rate of resected nodules > 50%
False positive and non-diagnostic cytology rates lowered with US guidance
Non-palpable
Posterior location
Predominantly cystic

38. Figure 7a.  Parallel positioning of the fine-gauge needle for thyroid nodule biopsy.
Figure 7a.  Parallel positioning of the fine-gauge needle for thyroid nodule biopsy. This positioning helps maximize the number of needle-generated reflected echoes perpendicular to the sound wave and is preferred by many operators. (a) Diagram shows insertion of the needle in a plane parallel to that of scanning. (b) US image, obtained with the transducer and needle positioned as in a, depicts the entire length of the needle (arrows) within the nodule.
Kim M J et al. Radiographics 2008;28:
©2008 by Radiological Society of North America

39. Figure 7b.  Parallel positioning of the fine-gauge needle for thyroid nodule biopsy.
Figure 7b.  Parallel positioning of the fine-gauge needle for thyroid nodule biopsy. This positioning helps maximize the number of needle-generated reflected echoes perpendicular to the sound wave and is preferred by many operators. (a) Diagram shows insertion of the needle in a plane parallel to that of scanning. (b) US image, obtained with the transducer and needle positioned as in a, depicts the entire length of the needle (arrows) within the nodule.
Kim M J et al. Radiographics 2008;28:
©2008 by Radiological Society of North America

40. Figure 8a.  Perpendicular positioning of the fine-gauge needle for thyroid nodule biopsy.
Figure 8a.  Perpendicular positioning of the fine-gauge needle for thyroid nodule biopsy. (a) Diagram shows insertion of the needle in a plane perpendicular to that of scanning. A shorter needle may be used with this option, and it is less likely that the carotid artery or jugular vein may be punctured. (b) US image, obtained as the needle crossed from the skin entry site through the tissues of the neck and into the nodule, shows only the needle tip (arrow) where it intersected with the scanning plane.
Kim M J et al. Radiographics 2008;28:
©2008 by Radiological Society of North America

41. Figure 8b.  Perpendicular positioning of the fine-gauge needle for thyroid nodule biopsy.
Figure 8b.  Perpendicular positioning of the fine-gauge needle for thyroid nodule biopsy. (a) Diagram shows insertion of the needle in a plane perpendicular to that of scanning. A shorter needle may be used with this option, and it is less likely that the carotid artery or jugular vein may be punctured. (b) US image, obtained as the needle crossed from the skin entry site through the tissues of the neck and into the nodule, shows only the needle tip (arrow) where it intersected with the scanning plane.
Kim M J et al. Radiographics 2008;28:
©2008 by Radiological Society of North America

42. Figure 9a.  Aspiration (a) and nonaspiration (b) techniques for needle biopsy of thyroid nodules.
Figure 9a.  Aspiration (a) and nonaspiration (b) techniques for needle biopsy of thyroid nodules. In aspiration, the needle tip is advanced into various positions in the nodule and moved to and fro while suction is performed (arrow in a). Suction is halted before the needle is removed from the lesion. This procedure is repeated at least five times before the needle is finally withdrawn. In nonaspiration (capillary action), the needle is advanced into the nodule and vigorously moved to and fro while being rotated on its axis until a small amount of cellular material collects inside the needle hub. No suction is performed. This technique is useful in very hypervascular nodules, in which there is a high probability of obtaining a bloodstained specimen that is inadequate for accurate cytologic analysis.
Kim M J et al. Radiographics 2008;28:
©2008 by Radiological Society of North America

43. Figure 9b.  Aspiration (a) and nonaspiration (b) techniques for needle biopsy of thyroid nodules.
Figure 9b.  Aspiration (a) and nonaspiration (b) techniques for needle biopsy of thyroid nodules. In aspiration, the needle tip is advanced into various positions in the nodule and moved to and fro while suction is performed (arrow in a). Suction is halted before the needle is removed from the lesion. This procedure is repeated at least five times before the needle is finally withdrawn. In nonaspiration (capillary action), the needle is advanced into the nodule and vigorously moved to and fro while being rotated on its axis until a small amount of cellular material collects inside the needle hub. No suction is performed. This technique is useful in very hypervascular nodules, in which there is a high probability of obtaining a bloodstained specimen that is inadequate for accurate cytologic analysis.
Kim M J et al. Radiographics 2008;28:
©2008 by Radiological Society of North America

44. Investigations Fine-needle aspiration Complications Local pain
Bleeding or hematoma
Infection
Vasovagal reaction

45. Fine-needle Aspiration

46. Fine-needle Aspiration
Purely cystic nodule
Any size  No FNA
Abnormal cervical lymph nodes
Any size  FNA

47. Fine-needle Aspiration
High-risk history
> 5mm  FNA
Microcalcifications
> 1cm  FNA

48. Fine-needle Aspiration
Solid nodule
Hypoechoic
>1cm  FNA
Isoechoic or hyperechoic
>1-1.5cm  FNA

49. Fine-needle Aspiration
Mixed cystic-solid
Suspicious ultrasound features
> 1.5-2cm  FNA
No suspicious sonographic features
> 2cm  FNA
Spongiform nodule

50. Investigations

51. Pathology
FNA results
Historically, FNA cytopathology reports were quite variable
In 2007, Bethesda System for Reporting Thyroid Cytopathology was created
Recommended the use of 6 general categories
Each category associated with a risk of malignancy and linked to a management recommendation

52. Pathology Bethesda System Categories Nondiagnostic or Unsatisfactory
Benign
Atypia of Undetermined Significance (AUS) or Follicular Lesion of Undetermined Significance (FLUS)
Follicular Neoplasm or Suspicious for a Follicular Neoplasm
Suspicious for Malignancy
Malignant

53. Pathology Bethesda System Categories Sample is adequate if:
Not obscured (blood, air drying, thick smears, etc)
At least 6 groups of benign follicular cells
Each group composed of at least 10 cells
Above criteria present in at least 2 aspirates
Exceptions:
Abundant colloid  benign
Any atypia
Specific diagnosis can be made (eg lymphocytic thyroiditis)

54. Pathology Bethesda System Categories Nondiagnostic or Unsatisfactory
Cyst fluid only
Sonographic correlation required to determine malignancy risk
Virtually acellular specimen
Other
Obscurring blood
Cloting artifact

55. Pathology Bethesda System Categories Benign
Consistent with a benign follicular nodule
Hyperplastic/Adenomatoid nodule
Colloid nodule
Consistent with lymphocytic (Hashimoto’s) thyroiditis in the proper clinical context
Consistent with granulomatous (subacute) thyroiditis
Other

56. Pathology Bethesda System Categories
Atypia of Undetermined Significance (AUS) or Follicular Lesion of Undetermined Significance (FLUS)
For FNAs that do not easily fit into one of the other categories
e.g. prominent population of microfollicles, but not sufficient for diagnosis of follicular neoplasm

57. Pathology Bethesda System Categories
Follicular Neoplasm or Suspicious for a Follicular Neoplasm
Follicular carcinomas and adenomas have similar cytomorphologic features
Specify if Hürthle neoplasm
Considered variant of follicular adenoma or carcinoma by WHO

58. Pathology Bethesda System Categories Suspicious for Malignancy
Used if a malignant diagnosis cannot be made with certainty
Suspicious for papillary carcinoma
Only 1 or 2 characteristics of papillary carcinoma
Abnormalities are focal
Sample is sparsely cellular
Suspicious for medullary carcinoma
Suspicious for metastatic carcinoma
Suspicious for lymphoma

59. Pathology Bethesda System Categories Malignant
Papillary thyroid carcinoma
Poorly differentiated carcinoma
Medullary thyroid carcinoma
Undifferentiated (anaplastic) carcinoma
Squamous cell carcinoma
Carcinoma with mixed features (specify)
Metastatic carcinoma
Non-Hodgkin lymphoma
Other

60. Pathology Diagnostic Category % of FNAs
Nondiagnostic or Unsatisfactory
2-20
Benign
60-70
Atypia of Undetermined Significance
or Follicular Lesion of Undetermined
Significance
3-6
Follicular Neoplasm or Suspicious for a
Follicular Neoplasm
5-11
Suspicious for Malignancy
1-7
Malignant
3-7

61. Pathology

62. Management

63. Management Nondiagnostic or Unsatisfactory
Repeat FNA with ultrasound guidance
Satisfactory specimen in 75% of solid nodules
Satisfactory specimen in 50% of cystic nodules
On-site cytologic evaluation may improve yield
7% of nodules continue to be nondiagnostic (and may still be malignant)
Close observation or surgery (particularly if nodule is solid) is recommended

64. Management Malignant or Suspicious for malignancy Surgery
Malignant: total thyroidectomy
Suspicious for malignancy: total thyroidectomy or lobectomy

65. Management Follicular Neoplasm (not Hürthle cell)
Malignancy risk 15-30%
If TSH is in low-normal range, can consider 123I thyroid scan
If no autonomously functioning nodule seen, lobectomy or total thyroidectomy should be considered
Hürthle cell Neoplasm
No need for 123I thyroid scan
Lobectomy or total thyroidectomy (depending on other risk factors)

66. Management
Benign
Immediate diagnostic studies or treatment are not routinely required
Follow-up is required
Low, but not negligible false-negative rate (up to 5%), especially with larger nodules (greater than 4cm)
Repeat US recommended at 6-18 months after initial FNA
If nodule is stable in size (<50% increase in volume or <20% increase in 2 dimensions), can increase interval of follow-up
If evidence of nodule growth present (>50% increase in volume or >20% increase in 2 dimensions with minimal increase of 2mm) then FNA should be repeated

67. Management AUS or FLUS Malignancy risk 5-15%
Diagnostic accuracy may be improved by considering clinical risk factors
The use of 18FDG-PET is not recommended for or against to improve diagnostic accuracy
In one study, sensitivity 57%, specificity 50%
Can consider molecular markers to help guide management
e.g. BRAF, RAS, RET/PTC, Pax8-PPAR-gamma, or galectin-3

68. Management Molecular markers
Haugen et al (International Thyroid Congress, 2010)
Developed a molecular classifier using approximately 200 genes
Tested classifier to 66 initially indeterminate FNA samples that have underwent surgery and pathology review
Sensitivity 95%, specificity 63%, NPV 96%
Conclude that this can be used to reduce number of unnecessary surgeries
Li et al (JCEM 2011)
Created decision making model and used on a hypothetical group of adult patients
Showed that using molecular test avoided ¾ of surgeries in indeterminate group and lowered cost of health care

70. Multiple Nodules
Solitary nodules have higher malignancy risk than nonsolitary nodules
Patients with multiple nodules have same risk of malignancy as those with solitary nodules
Should aspirate nodules > 1cm with suspicious sonographic appearance
If TSH is low or low-normal, can use thyroid scintigraphy to direct FNA to iso- or nonfunctioning nodules

71. Questions?