Thyroid Cancer May 10, 2006

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

Classification & Incidence of Thyroid Cancer Follicular cell origin Differentiated Papillary 80% Follicular 10% Hurthle cell 3-5% Undifferentiated Anaplastic 1-2% Parafollicular cell origin – Medullary 5%

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

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

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

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….

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 ~ 4 - 6 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.

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

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

Lymphoma of the Thyroid Usually non-Hodgkin’s B cell type Pts with Hashimoto’s thyroiditis have 70-80 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

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

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

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?

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.

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

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

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%

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

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.

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

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.

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

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……

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

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.

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.

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

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

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?

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%.

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

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

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?

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

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.

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.

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.

TMN Classification for differentiated thyroid cancer T1  2cm T2 2-4cm 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)

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?

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

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

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

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)

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

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.

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

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

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

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)

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

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

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.

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

Surgical Anatomy: The Parathyroids

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.