1. Thyroid Cancer
May 10, 2006

2. Thyroid Cancer Accounts for 1.5% of all cancers in the US
Most common endocrine malignancy (95%)
22,000 cases per year and estimated 500 – 1000 patients die annually
90% of thyroid cancer cases have favorable prognosis

3. Classification & Incidence of Thyroid Cancer
Follicular cell origin
Differentiated
Papillary %
Follicular %
Hurthle cell %
Undifferentiated
Anaplastic %
Parafollicular cell origin
– Medullary 5%

4. Papillary Carcinoma Accounts for 90% radiation induced cancer
Classified as microcarcinoma, intrathyroidal, and extrathyroidal
Histologic variants: tall-cell, clear-cell, columnar, diffuse sclerosing
Multicentric in 30-50% of tumors
Spreads via lymphatics with propensity for mid- and lower-anterior cervical chain (Level VI)
20-50% patients have involvement of cervical LN
Microcarcinoma (<1cm)
Histologic variants which show more aggressive behavior and poorer prognosis

5. Follicular Carcinoma
Only 10% of thyroid cancers in developed countries, although more prevalent in regions with iodine deficiency
Diagnosis depends on demonstration of vascular or capsular invasion
Classified as minimally or widely invasive
Vascular invasion tends to have a more aggressive course than capsular invasion
Uncommon to have multicentric disease
Hematogenous spread
DX: which is why FNA cannot make the diagnosis of malignancy

6. Follicular Carcinoma
Where does follicular carcinoma tend to metastasize?
Bone
Lung

7. Hurthle Cell Carcinoma
High propensity to spread to cervical lymph nodes and high incidence of distant metastasis
Less than 10% of Hurthle cell carcinomas take up radioiodine
High tumor recurrence rate
High mortality rate – 30% mortality at 10 years
Once thought to be a subset of follicular carcinoma, although now seen as its own entity based upon having its own oncogenic expression.
More aggressive, evidenced by high….

8. Anaplastic Carcinoma Increasingly rare
Arise within differentiated cancers
Pts > 60 years old with rapidly expanding neck mass
Local invasion very common at time of dx (FNA)
Surgery plays limited role given advanced stage at dx
Radiation and chemotherapy have not demonstrated any significant improvement in survival
Median survival ~ months
Perhaps rare because thyroid cancers are being diagnosed earlier.
Sometimes can be challenging to differentiate anaplastic ca from lymphoma, and on occasion will require open bx
Patients generally die from airway compromise
There was a small study at MGH involving ~60 pts who underwent extensive surgery and there was improved short-term survival compared with those without surgery. Surgery however is very extensive and may involve reconstructing the trachea, etc.

9. Medullary Thyroid Carcinoma
Originates from the parafollicular C cells
Elevation in calcitonin and CEA (50%)
80% have sporadic MTC (unifocal), remainder have genetic component
75% patients have LN metastasis at time of dx, 20% distant mets
Sporadic MTC >20% somatic RET mutation

10. Medullary Thyroid Carcinoma
MEN IIA 
MTC (100%), pheo (40%), hyperparathyroidism (35%)
AD inheritance
Missense mutation of extracellular cysteine of RET
Surgery recommended before 6 years of age
MEN IIB 
MTC (100%), pheo (50%), mucosal ganglioneuromas (100%), marfanoid habitus
Missense mutation of tyrosine kinase domain of RET
Surgery recommended in infancy
Familial MTC
MENIIA: diagnosed 1st – 3rd decade, generally multifocal and bilateral
MENIIB: far more aggressive, diagnosed in 1st decade, multifocal and bilateral. Once manifests clinically, rarely curable.
Familial: diagnosed in 5th – 6th decade, not as aggressive as MEN syndromes

11. Lymphoma of the Thyroid
Usually non-Hodgkin’s B cell type
Pts with Hashimoto’s thyroiditis have fold increase risk
Typically women > 70yo present with enlarging neck mass
FNA > 80% accuracy
Treatment includes XRT and chemotherapy
5 year survival rates 50-70%
Risk compared with general population
FNA can sometimes be difficult to determine lymphoma from anaplastic ca, although new immunocytochemistry staining has helped
No role for surgery

12. 45 year old female presents to your office with a thyroid nodule
45 year old female presents to your office with a thyroid nodule. What questions will you ask her?
Sent by her PCP

13. History Characteristics of nodule Is the patient symptomatic?
Hyperthyroid/Hypothyroid
Compressive sxs
Family history  MEN endocrinopathies
Radiation exposure
Nodule: is it hard per patient, has she noticed a rapid increase in size? Any other lumps in her neck to suggest LAD?
Symptoms: Most patients with cancer are asxs. Uncommonly patients will complain of hoarseness, dysphagia, dyspnea, coughing. Also ask whether patient has had any recent viral illnesses.
FHx:
Radiation exposure: Likely to be head and neck these days or total body for BMT. In the past, radiotherapy was used for tonsillar, thymic, and adenoid enlargement and acne in children

14. 45 year old female with thyroid nodule
Characteristics of nodule  found incidentally by PCP
Is the patient symptomatic?  No
Hyperthyroid/Hypothyroid
Compressive sxs
Family history  None
Radiation exposure  None
Now what?

15. Physical Exam Size Consistency of nodule, multiple or solitary
Fixed or mobile
Presence of cervical LAD
Nodules 0.5 – 1cm can generally be palpated. Nodules larger than 4cm are worrisome. Firm nodules more worrisome than soft. (Diffuse irregular firm thyroid gland may indicate thyroiditis.

16. Physical Exam Solitary nodule
Mobile, not obviously adherent to adjacent structures
No cervical LAD
Normal voice
Otherwise well appearing
Now what?

17. Evaluating a thyroid nodule
Thyroid nodules are common, but less than 10% are malignant
History and PE
TSH level should be obtained during initial evaluation
If low, radioisotope study
If normal or high, then proceed to ultrasound

18. Evaluating a thyroid nodule
What is the risk of a “hot” nodule on radioiodine scan being malignant?
Less than 1%
What about a “cold” nodule?
15% – 20%

19. Evaluating a thyroid nodule
Radioisotope studies may also be useful:
FNA reports “suspicious for follicular neoplasm” or “indeterminate”
Detecting neck metastasis
Hot nodule may decrease the suspicion of malignancy
Detecting metastases and therefore surveillance

20. Evaluating a thyroid nodule
What information will an ultrasound provide?
Number of nodules
Location and size of nodules
Cystic versus solid
Ultrasound can detect solid nodules 3-4mm and cystic nodules greater than 2mm.
Uncommon to have purely cystic nodules, many are mixed. Purely solid nodules carry a higher risk of malignancy.

21. Evaluating a thyroid nodule
Which of the following are concerning findings on ultrasound?
Halo sign
Hypoechogenic
Calcifications
< 1cm

22. Evaluating a thyroid nodule
Which of the following are concerning findings on ultrasound?
Halo sign
Hypoechogenic
Calcifications
< 1cm
Halo sign is usually seen with benign lesions
Calcifications  Psammoma bodies histologically seen in papillary cancer
Because findings on ultrasound are not specific for cancer, FNA typically done at the same time.

23. Evaluating a thyroid nodule
FNA is the most reliable and cost efficient way to determine malignant from benign lesion
4 categories:
Malignant, benign, suspicious, indeterminate
Limitation of FNA:
Cannot distinguish benign follicular or Hurthle cell adenoma from malignancy – based upon presence or absence of capsular or vascular invasion
False negative rate < 5%
Typically done in conjunction with ultrasound

24. 45 year old female with thyroid nodule
TSH level was normal
Underwent an ultrasound-guided FNA of the nodule, pathology revealed papillary carcinoma in a nodule measuring 2.5cm
Surgical options……

25. Management of Papillary Carcinoma
What surgical procedure would you offer her?
Near-total or total thyroidectomy is recommended if:
Tumor > 1-1.5cm
Contralateral nodules
Local or regional metastasis
+ FHx in 1st degree relative
+ history of radiation exposure
Age >45 yo
Increased extent of surgery lowers recurrence rates and has improved survival in high-risk patients
Contralateral nodules – high rate of multicentric disease
Age – recurrence rates are higher in this age group

26. Management of Papillary Cancer
When is lobectomy an acceptable surgical procedure for FNA proven papillary cancer?
According to the American Thyroid Association Guidelines Taskforce, lobectomy with isthmusectomy may be sufficient treatment for microcarcinoma ( 1cm), low-risk patients, intrathyroidal cancer without involvement of cervical LN
In that case…. Controversy here is that as mentioned previously, many of these cancers tend to be multicentric and therefore many proponents of near-total or total thryoidectomy. However, now with radioiodine ablation therapy there are more advocates of lobectomy with isthmusectomy to decrease risk to patient of injury to RLN and parathyroids.

27. Management of Papillary Cancer
Will you plan on performing a lymph node dissection?
A central compartment (Level VI) neck dissection should be considered
If nodal disease is evident clinically then a more extensive cervical lymphadenectomy should be performed
LN sampling not recommended
These are the nodes most commonly involved in differentiated thyroid cancer
80% of the time metastasis occurs to this group of LN
Some agrue that while positive LN occur in 20-30% of patients the clinical significance is unclear.

28. Surgical Anatomy: Lymphatics
Level VI: called the central component or paraglandular space includes the prelaryngeal, pretracheal, and paratracheal LN in the tracheoesophageal groove, as well as the anterior superior mediastinal LN. Generally defined as extending from hyoid bone superiorly, innominate vein inferiorly, and carotid sheaths laterally.
More extensive dissections are generally only called for with either known metastatic disease and in the case of medullary carcinoma

29. Surgical Anatomy: Lymphatics
What are the LNs located superior to the thryoid gland in the midline called?
Delphian nodes

30. 45 year old female with papillary carcinoma
Patient opted to have a total thyroidectomy and surgical specimen demonstrated unifocal disease with capsular invasion and negative LN. Does she have a favorable or unfavorable prognosis?

31. Prognostic Risk Classification for Patients with Well-Differentiated Thyroid Cancer (AMES or AGES)
Low Risk High Risk
Age <40 years >40 years
Sex Female Male
Extent No local extension, Capsular invasion, extra-
intrathyroid, no caps thyroidal extension
invasion
Metastasis None Regional/distant
Size <2 cm >4 cm
Grade Well diff Poorly diff
AMES scoring system stems from a study done in the late 1970, AGES originated from Mayo Clinic.
The AGES system describes a scoring system for presence or absence of these factors. A score of less than 4 is associated with a 20-year mortality rate of less than 1%. The more advanced stages have 5-year survival rates approaching 50%.

32. Management of Papillary Cancer
What further treatment is recommended?
TSH suppression therapy
Radioiodine ablation therapy
Levothyroxine: differentiated thyroid cancer express the thyrotropin receptor and responds to TSH stimulation by increasing the rate of cell growth – used to decrease risk of recurrence

33. 45 year old female with papillary carcinoma
She wants to know what her long-term survival is. What will you tell her?
~ 90% at 10 years for papillary carcinoma

34. 45 year old female with thyroid nodule
TSH level was normal
Underwent an ultrasound-guided FNA of the nodule, pathology suspicious for a follicular neoplasm
What is the risk that this is malignant?
Approximately 20%
What surgical procedure will you offer her?

35. Management of FNA suspicious for follicular neoplasm
Lobectomy would be a reasonable surgical procedure, particularly in low-risk patient who prefers limited surgical intervention
Near-total or total thyroidectomy still recommended for high-risk patient and/or large tumor size
Lobectomy, knowing that they may need to have a completion thyroidectomy if tumor > 2cm and widely invasive pathology

36. Management of FNA suspicious for follicular neoplasm
Intra-operative frozen sections can be helpful in this scenario? True or false
False
Need to have adequate sample to demonstrate vascular or capsular invasion. Negative frozen section will not change your management.

37. 45 year old female with thyroid nodule
You performed a lobectomy and the final pathology reveals Hurthle cell carcinoma
What further treatment do you recommend?
Completion thyroidectomy with central compartment LN dissection
TSH suppression therapy
Radioiodine ablation is not usually very effective for Hurthle cell, although may still recommend it.

38. Post-operative radioiodine remnant ablation
To whom should it be offered?
Stages III and IV disease
Stage II disease in pts under age 45
Selected pts with Stage I
Multifocal disease
Nodal metastasis
Extrathyroidal extension
Vascular invasion
Aggressive histology
Goal is to destroy residual thyroid tissue in an effort to decrease the risk of recurrent locoregional disease and to facilitate long-term surveillance with whole body iodine scans.
Only studies available at this date are retrospective. According to these studies, benefit is only conferred to those patients with larger tumors (>1.5cm) or with residual disease after surgery. There is no clear benefit for low-risk patients.

39. TMN Classification for differentiated thyroid cancer
T1  2cm
T cm
T3 >4cm, limited to thyroid
T4a Any size, invasion of SQ, trachea, esophagus, RLN
T4b Any size invasion of prevertebral fascia or encasing carotid/mediastinal vessels
N0 no nodes
N1a Level VI
N1b All other levels
Stages
Stage I T1, N0, M0
Stage II T2, N0, M0
Stage III T3, N0, M0
T1-3, N1a, M0
Stage IVA T4a, N0, M0
T4a, N1a, M0
T1-3, N1b, M0
Stage IVB T4b, any N, M0
Stage IVC Any T and N, M1
T4a – includes invasion of subc tissue, trachea, esophagus and RLN
T4b – invades prevertebral fascia or encases carotid or mediastinal vessels
Level VI (pretracheal, paratracheal, prelaryngeal)

40. 45 year old female with thyroid nodule
She asks what her overall 10 year survival will be with her diagnosis of Hurthle cell carcinoma?
~70%
What if she had follicular carcinoma?

41. Recommendations for follow-up (differentiated cancers)
Thyroid cancer recurs in 20-40% patients, most commonly within the first 2 years
Thyroglobulin used as tumor marker checked every 6-12 months
Whole body scan may be useful in intermediate and high-risk patients 6-12 months after ablation
Ultrasound should be done 6-12 months after surgery, then annually for the next 3-5 years
Thyroglobulin glycoprotein produced by normal thyroid tissue and after total thyroidectomy and radioiodine ablation therapy should be undetectable. Checked every 6-12 months for the first 1-2 years
Endocrinologist is managing most of this

42. Management of recurrent and metastatic disease
Surgery mainstay of treatment for locoregional disease  radioiodine  radiation
Metastatic disease treated with radioiodine
Older patients with bony mets are less likely to respond to radioiodine and have poor prognosis
Pulm mets more radio responsive than bone mets
Locoregional disease: if surgery not feasible or not complete then proceed with radioiodine therapy, if this is unsuccessful then external beam radiation

43. 55 year old male presents to your office with MTC on FNA
Palpable thyroid nodule and cervical LN
Diarrhea and flushing
No FHx of MEN endocrinopathies
Calcitonin elevated, FNA reveals MTC
Any further tests that you should order?
Genetic testing
CT scan to see extent of disease

44. 55 year old male presents to your office with MTC on FNA
What surgical procedure will you recommend to him?
Total thyroidectomy with LN dissection in Level VI and LN sampling in lateral regions (frozen sectioning intra-operatively)

45. 55 year old male presents to your office with MTC on FNA
What do you want to check for before bringing him into the operating room?
Presence of a pheochromocytoma
Hypertension issues

46. 55 year old male presents to your office with MTC on FNA
How would you handle the parathyroid glands?
Some recommend performing a total parathyroidectomy with autotransplantation in either the forearm or SCM
Thought here being that in order to remove all thyroid tissue, it is best to remove the glands and then reimplant them. In patients with MEN2A, implantation should be done in the forearm, as easier access.

47. 55 year old male presents to your office with MTC on FNA
Further treatment remains controversial but includes radiation therapy and chemotherapy
Surveillance using calcitonin levels
MTC cells do not take up radioiodine. Unfortunately XRT and chemo have not proved all that successful and long-term survival depends on complete surgical removal of the thyroid tissue

48. Surgical Anatomy: Vasculature
Thyroid gland extends from the cricoid cartilage covering the anterior tracheal rings wrapping around the anterolateral portion of the trachea.
Consists of right and left lobes connected by the isthmus which usually extends anterior to the 2nd and 3rd tracheal rings. Not uncommonly, a pyramidal lobe is present extending superiorly to the hyoid bone from the isthmus. If fibrous band connection between the hyoid and pyramidal lobe it is termed the “levator of the thyroid gland”
Posterior medial aspects of the thyroid lobes are attached to the cricoid cartilage by the ligament of Berry (aka suspensory ligament of the thyroid).
Vascular anatomy: Although the thyroid accounts for only 0.4% of our body weight, it accounts for 2% of the total blood flow. It is estimated that during disease states, the flow through the gland can increase 100-fold. Superior thyroid artery (1st branch off the external carotid) bifurcates into a dominant anterior and smaller posterior branch at the upper lobes. The external branch of the superior laryngeal nerve is often closely associated with the superior thyroid artery at the upper lobe and at risk for injury during dissection. Want to ligate the individual branches of this artery because ligating the main trunk risks injury to the nerve.
The inferior thyroid artery emanates from the thyrocervical trunk and passes behind the carotid sheath. It is intimately associated with the RLN.
Cannot neglect to mention the thyroid ima artery which is occasionally present and stems from the aorta or the innominate, entering the inferior aspect of the isthmus.
Venous drainage: superior, middle, and inferior thryoid veins

49. Surgical Anatomy: Vasculature and nerves
The relationship between the external branch of the superior laryngeal nerve (black) and the superior thyroid artery. The nerve can course inferiorly and medially and may run partly along with or around the artery or the branches of the artery as they enter the superior lobe of the thyroid

50. Surgical Anatomy
What is the consequence of injurying the external branch of the superior laryngeal nerve?
Injury results in paralysis of the cricothyroid muscle
Inability to tense the vocal cord, thereby unable to attain high-pitched notes or project one’s voice (professional speakers/singers)

51. Surgical Anatomy: Anatomical variations of the Right RLN
This demonstrates the possible anatomic variations of the RLN.
Fig A occurs in about 1% of the population. RLN is arising from the vagus at the level of the cricoid and directly enters the larynx. It can be mistaken for an arterial branch. (Left non-recurrent nerve very rare and usually associated with major arterial abnormalities.)
Fig B the normal course of the RLN. Running posterior to the CCA then along the tracheoesophageal groove. It can pass behind, in front of, or between the branches of the ITA. It can also have a variant course with regard to the ligament of berry.
Fig. C – Rare nonrecurrent nerve and recurrent laryngeal nerve join to form common distal nerve

52. Surgical Anatomy
What is the result of an injury to the recurrent laryngeal nerve?
Ipsilateral paralysis
Contralateral paralysis

53. Surgical Anatomy
What is the result of an injury to the recurrent laryngeal nerve?
Ipsilateral paralysis
Contralateral paralysis
The cord is immobilized in the paramedian position
Many advocate monitoring the RLN intra-operatively. However this requires that the patient is not paralyzed.

54. Surgical Anatomy What would you do if the tumor involved the RLN?
If vocal cord is paralyzed pre-operatively, then consider resecting the RLN along with specimen
If no vocal cord paralysis, dissect tumor off nerve

55. Surgical Anatomy: The Parathyroids

56. Surgical Anatomy: The Parathyroids
What are your options if the blood supply to the parathyroids has been compromised?
Implantation within the sternocleidomastoid muscle or forearm muscle for easy access
Particularly at risk during thyroid surgery because of end artery blood supply. If this terminal branch of the ITA is damaged, it results in ischemic necrosis of the gland.