3.Malignant thyroid disease.pptx Dr yonas 2019

Discribes pathophysiology,diagnosis ,treatment modalities of primery and methastagic thyroid tumors
Also describes prognosis of thyroid tumors.

1. Malignant thyroid disease Yonas Ademe Nov, 2019

2. Introduction It is the most common endocrine malignancy , accounting for 94.6% of the total new endocrine cancer Female to male ratio is 2.5:1 Thyroid nodule in men is more likely to be malignant than in women Although less than 25% of thyroid carcinomas occur in men, men account for 45% of mortality from thyroid carcinoma The median age at diagnosis is earlier in women than in men Most present as thyroid nodule

3. Risk factors Non-modifiable Old age Female gender Family history MTC (FMTC, MEN2), FTC (Cowden's disease), PTC (FAP, Gardner’s disease) M odifiable Exposure Iodine deficiency Radiation exposure Predisposing condition Colloid goiter Thyroiditis (chronic lymphocytic)

4. Molecular Genetics Several oncogenes and tumor suppressor genes are involved in thyroid tumorigenesis The RET proto-oncogene plays a significant role Other: p53, p16, PTEN. Ras

5. cont. The vast majority of thyroid cancers present as thyroid nodules 5-10% chance of malignancy in all thyroid nodules for the general population Men and patients at the extremes of age are at higher risk for malignancy Nodules found in a patient with a history of childhood neck irradiation carry a 33% to 37% chance of malignancy

6. Differentiated Thyroid Cancer

7. Papillary Carcinoma

8. Introduction It accounts for 80% of all thyroid malignancies in iodine-sufficient areas and is the predominant thyroid cancer in children and individuals exposed to external radiation It occurs more often in women , with a 2:1 female-to-male ratio, and the mean age at presentation is 30 to 40 years

9. Pathology Macroscopic PTCs generally are hard and whitish Calcification, necrosis, or cystic changes may be apparent Microscopic May exhibit papillary projections , a mixed pattern of papillary and follicular structures, or a pure follicular pattern (follicular variant) Cells are cuboidal with pale, abundant cytoplasm, crowded nuclei that may demonstrate “grooving,” and intranuclear cytoplasmic inclusions ( Orphan Annie nuclei ) Diagnostic Psammoma bodies (calcified deposits representing clumps of sloughed cells) may be present Multifocality may be present in up to 85% of cases A ssociated with an increased risk of cervical nodal metastases, and these tumors may rarely invade adjacent structures such as the trachea, esophagus, and RLNs

10. Cont. Mixed papillary-follicular tumors and follicular variant of papillary thyroid carcinoma (FVPTC) are classified as papillary carcinomas because they behave biologically as papillary carcinomas 2 main subtypes of FVPTC are recognized: Encapsulated C hallenging to diagnose Nonencapsulated (infiltrative )

11. Cont. Minimal or occult/ microcarcinoma refers to tumors of 1 cm or less in size with no evidence of local invasiveness through the thyroid capsule or angioinvasion , and that are not associated with lymph node metastases They are nonpalpable and usually are incidental findings at imaging, operative , histologic , or autopsy examination These tumors are generally associated with a better prognosis than larger tumors, but they may be more aggressive than previously appreciated About 25% of patients with these tumors have associated occult lymph node metastases

12. Clinical features Most patients are euthyroid and present with a slow-growing painless mass in the neck Dysphagia , dyspnea , and dysphonia usually are associated with locally advanced invasive disease Lymph node metastases are common , especially in children and young adults, and may be the presenting complaint “ Lateral aberrant thyroid ” almost always denotes a cervical lymph node that has been invaded by metastatic cancer Distant metastases are uncommon at initial presentation, but may ultimately develop in up to 20% of patients The most common sites are lungs , followed by bone, liver, and brain

13. Diagnosis FNAB Diagnostic Neck U/S Once thyroid cancer is diagnosed on FNAB, a complete neck ultrasound is strongly recommended to evaluate the contralateral lobe and for lymph node metastases in the central and lateral neck compartments

14. Prognostic indicators Patients with PTC have an excellent prognosis with a >95% 10-year survival rate Several prognostic indicators (high risk Vs. low risk) AGES A ge , histologic G rade , E xtrathyroidal invasion, and metastases and tumor S ize MACIS M etastases, A ge at presentation (< 40 or >40 years old), C ompleteness of original surgical resection, extrathyroidal I nvasion, and S ize of original lesion Best and widely used AMES A ge (men <40 years old, women <50 years old), M etastases, E xtrathyroidal spread , and S ize of tumors (< or >5 cm) TNM

15. Cont. Acronyms Prognostic indicators Low risk group High risk group AMES AGES MACIS A ge Male <40, female<50 Male>40 female>50 M etastasis No metastasis Metastasis (LN, Regional E xtent Confined to thyroid Extra thyroidal extension S ize of primary tumor <4cm >4cm Tumor G rade Well differentiated/low grade Poorly differentiated/ high grade I nvasion Minimal capsular invasion Significant capsular invasion C ompleteness of excision Complete resection (Post op) Incomplete resection(post op)

16. Treatment Most authors agree that patients with high-risk tumors (judged by any of the prognostic classification systems) or bilateral tumors should undergo total or near-total thyroidectomy The optimal surgical strategy in the majority of patients with low-risk ( small, unilateral ) cancers was controversial for many years Proponents of total thyroidectomy indicate that: R ecurrence rates are lowered and that survival is improved TT enables the use of RAI to effectively detect and treat residual thyroid tissue or metastatic disease TT makes serum Tg level a more sensitive marker of recurrent or persistent disease

17. Cont. T he American Thyroid Association 2009 guidelines for the evidence-based management of thyroid cancers recommended a near total or total thyroidectomy for primary cancers >1 cm unless there are contraindications to the surgery However, additional studies since then have demonstrated no survival differences based on initial surgical procedure when adjusting for complexity/risk and comorbid diseases This finding, coupled with a trend for increased use of ultrasound and Tg measurements to assess for recurrences and the declining use of RAI ablation , led to revised guidelines in 2015 Accordingly , either near-total/total thyroidectomy or lobectomy constitute appropriate initial treatment for tumors >1 cm and <4 cm without extrathyroidal extension or lymph node involvement T he guidelines do state that the treatment team may elect near-total/total thyroidectomy to facilitate RAI therapy , enhance follow-up based on disease features , or if the patient expresses a preference for complete thyroid excision

18. Cont. Indications for lobectomy Tumor <4 cm No extra-thyroidal extension No lymph node involvement No history of radiation No family history

19. Cont. Thyroid lobectomy alone is considered sufficient treatment for small (<1 cm), incidentally discovered, low-risk, unifocal , intrathyroidal papillary carcinomas In the absence of prior head and neck irradiation or radiologically or clinically involved cervical nodal metastases There has been in change in the management of these tumors since at least two trials from Japan have shown that active surveillance (defined as observation without immediate surgery) can be a viable and safe first line of treatment for these very-low-risk tumors without extrathyroidal extension or lymph node metastases Tumors that progress during monitoring are treated by surgery

20. Cont. Patients with a nodule that is suspicious for papillary cancer should be treated by thyroid lobectomy , isthmusectomy , and removal of any pyramidal lobe or adjacent lymph nodes If intraoperative frozen-section examination of a lymph node or primary tumor confirms carcinoma, completion total or near-total thyroidectomy is performed

21. Cont. Lymph node dissection During thyroidectomy, enlarged or obviously involved central neck nodes should be removed ( therapeutic central-compartment, level VI), along with nodes with known lateral neck metastases Some investigators recommend routine bilateral central neck dissection due to the high incidence of microscopic metastases and data showing improved rates of recurrence and survival (compared to historic controls ) However, these risks need to be balanced with the increased risk of hypoparathyroidism with routine central neck dissection and the fact that some studies do not show any difference in recurrence rates or rates of low or undetectable Tg levels The updated 2015 ATA guidelines for thyroid cancer management suggest that prophylactic (ipsilateral or bilateral) dissection may be performed in patients with: A dvanced (T3 or T4) papillary thyroid carcinoma I f the lateral neck nodes are involved with tumor If the information will help in treatment planning

22. Cont. Lymph node dissection Biopsy-proven lymph node metastases detected clinically or by imaging in the lateral neck in patients with papillary carcinoma are managed with modified radical or functional neck dissection Dissection of the posterior triangle and suprahyoid dissection usually are not necessary unless there is extensive metastatic disease in levels 2, 3, and 4, but should be performed when appropriate Prophylactic lateral neck node dissection is not necessary in patients with PTC because these cancers do not appear to metastasize systemically from lymph nodes, and micrometastases often can be ablated with RAI therapy

23. Follicular Carcinoma

24. Introduction Follicular carcinomas account for 10% of thyroid cancers and occur more commonly in iodine-deficient areas Women have a higher incidence of follicular cancer, with a female-to-male ratio of 3:1 , and a mean age at presentation of 50 years old Unlike papillary cancers, cervical lymphadenopathy is uncommon at initial presentation ( about 5% ), although distant metastases may be present (15-30 % of patients will have distant disease at the time of diagnosis)

25. Pathology Macroscopic Follicular carcinomas usually are solitary lesions, and the majority are surrounded by a capsule Microscopic Follicles are present, but the lumen may be devoid of colloid Malignancy is defined by the presence a ngioinvasion and capsular invasion

26. Clinical features Follicular cancers usually present as solitary thyroid nodules, occasionally with a history of rapid size increase, and long-standing goiter Pain is uncommon, unless hemorrhage into the nodule has occurred In <1% of cases, follicular cancers may be hyperfunctioning , leading patients to present with signs and symptoms of thyrotoxicosis

27. Diagnosis Preoperative clinical diagnosis of cancer is difficult unless distant metastases are present FNAB is unable to distinguish benign follicular lesions from follicular carcinomas Therefore, preoperative clinical diagnosis of cancer is difficult unless distant metastases are present Large follicular tumors (>4 cm) in older men are more likely to be malignant A number of studies have focused on identifying molecular markers to distinguish benign from malignant follicular lesions

28. Treatment Patients diagnosed by FNAB as having a follicular lesion should undergo thyroid lobectomy because at least 70% to 80% of these patients will have benign adenomas Indications for total thyroidectomy Older patients (>45 years) F ollicular lesions >4 cm Extrathyroidal extension Lymph node involvement Family history of thyroid cancer A history of radiation exposure Atypia on FNA Total thyroidectomy should be performed when thyroid cancer is diagnosed

29. Cont. Intraoperative frozen-section examination usually is not helpful, but should be performed when there is evidence of capsular or vascular invasion or when adjacent lymphadenopathy is present Prophylactic nodal dissection is not needed because nodal involvement is infrequent, but in the unusual patient with nodal metastases, therapeutic neck dissection is recommended Prophylactic central neck dissection may be considered in patients with large tumors

30. Prognosis The cumulative mortality from follicular thyroid cancer is approximately 15% at 10 years and 30% at 20 years Poor long-term prognosis is predicted by: A ge over 50 years old at presentation T umor size >4 cm H igher tumor grade M arked vascular invasion E xtrathyroidal invasion D istant metastases at the time of diagnosis

31. Hürthle Cell Carcinoma

32. Introduction Hurthle cell carcinomas account for approximately 3% of all thyroid malignancies U nder the WHO classification, they are considered to be a subtype of follicular thyroid cancer They are defined by presence of more than 75% of follicular cells with oncocytic feature They are characterized by vascular or capsular invasion and, therefore, cannot be diagnosed by FNAB Tumors contain sheets of eosinophilic cells packed with mitochondria, which are derived from the oxyphilic cells of the thyroid gland

33. Cont. Hurthle cell tumors differ from follicular carcinomas in that: T hey are more often multifocal and bilateral (about 30 %) They are more likely to metastasize to local nodes (25%) and distant sites They usually do not take up RAI (about 5 %) They are associated with a higher mortality rate (about 20% at 10 years ) Even if hurthle cell adenoma is well encapsulated it is potentially malignant ( 13-67 %)

34. Treatment Management is similar to that of follicular neoplasms , with lobectomy and isthmusectomy being sufficient surgical treatment for unilateral Hurthle cell adenomas When the neoplasms are found to be invasive on definitive paraffin section histology , then total thyroidectomy should be performed These patients should also undergo routine central neck node removal , similar to patients with MTC, and modified radical neck dissection when lateral neck nodes are palpable or identified by ultrasonography

35. Postoperative Management of Differentiated Thyroid Cancer

36. Thyroid Hormone replacement T4 is necessary as replacement therapy in patients after total or near-total thyroidectomy, and also has the additional effect of suppressing TSH and reducing the growth stimulus for any possible residual thyroid cancer cells TSH suppression reduces tumor recurrence rates Current guidelines advise maintaining initial TSH levels: < 0.1 mU /mL in patients with high-risk thyroid cancer I n the range of 0.1 to 0.5 mU /mL in patients with intermediate-risk disease At the lower end of the reference range (0.5–2 mU /L) in low-risk patients The initial effective dose is about 1.6 to 2 μ g/Kg body weight The adequacy of therapy is monitored by measuring serum TSH every 3 months

37. Radioiodine Therapy The issue of whether RAI therapy offers any benefit to patients with differentiated thyroid cancer remains controversial in the absence of prospective, randomized controlled trials Long-term cohort studies demonstrate that postoperative RAI therapy reduces recurrence and provides a small improvement in survival, even in low-risk patients RAI has screening and therapeutic effects Screening with RAI is more sensitive than chest X-ray or CT scanning for detecting metastases H owever , it is less sensitive than Tg measurements for detecting metastatic disease in most differentiated thyroid cancers except Hurthle cell tumors Therapeutic value is facilitated by the removal of all normal thyroid tissue, which effectively competes for iodine uptake Metastatic differentiated thyroid carcinoma can be detected and treated by 131 I in about 75% of patients

38. Cont. The current (2015) ATA guidelines recommend RAI therapy after surgical treatment for all patients with high-risk disease Stage 3 and 4 patients Stage 2 patients younger than 45 years Stage 1 patients with: Large tumor LN metatsases Vascular invasion Multi- focality Residual diseases Intermediate differentiation

39. Follow up Thyroglobulin measurement ( Tg and anti- Tg antibody) I nitially at 6 to 12 month intervals and more frequently in patients with high-risk tumors In patients showing good response, it can be followed every 12 to 24 months while on thyroid hormone, as their risk of recurrence is low Imaging RAI (not routine) Scan at 4-6 weeks post op Repeat scan at 6-12 months after ablation Repeat scan at 1 year Every 2 years thereafter Cervical U/S At 6 and 12 months after thyroidectomy and then annually for at least 3 to 5 year PET scan and PET-CT scan They have been shown to be useful to localize recurrent or persistent thyroid cancer in patients who have Tg -positive, RAI scan–negative disease

40. Radiotherapy, Thermal Ablation, and Chemotherapy External beam radiotherapy is occasionally required to control unresectable , locally invasive or recurrent disease and to treat metastases in support bones to decrease the risk of fractures It also is of value for the treatment and control of pain from bony metastases when there is minimal or no RAIU Percutaneous thermal ablation by increasing ( radiofrequency ablation ) or decreasing temperature ( cryoablation ) in the lesion to induce irreversible cellular damage has shown promise for lung, bone, and liver lesions Single-drug and multidrug chemotherapy has been used with little success in disseminated thyroid cancer, and there is no role for routine chemotherapy Doxorubicin (Adriamycin ) and paclitaxel (Taxol) were previously the most frequently used agents

41. Poorly differentiated thyroid cancer

42. Medullary Carcinoma

43. Introduction MTC accounts for about 5% of thyroid malignancies and arises from the parafollicular or C cells of the thyroid The female-to-male ratio is 1.5:1 and most patients present between 50 and 60 years old, although patients with familial disease present at a younger age Most MTCs occur sporadically However , approximately 25 % occur within the spectrum of several inherited syndromes such as MEN2A , MEN2B , and familial MTC MEN2A: MTC, primary hyperparathyroidism , pheochromocytoma , lichen planus amyloidosis MEN2B: MTC , pheochromocytoma , Marfanoid habitus , mucocutaneous ganglioneuromatosis F amilial MTC: MTC

44. Pathology MTCs typically are unilateral (80%) in patients with sporadic disease and multicentric in familial cases, with bilateral tumors occurring in up to 90% of familial patients It is common in the upper lobe Cervical LN involvement occurs in 50% of cases Microscopically, tumors are composed of sheets of infiltrating neoplastic cells separated by collagen and amyloid The presence of amyloid is a diagnostic finding , but immunohistochemistry for calcitonin is more commonly used as a diagnostic tumor marker

45. Clinical features Patients with MTC often present with a neck mass that may be associated with palpable cervical lymphadenopathy (15% to 20%) Pain or aching is more common in patients with these tumors , and local invasion may produce symptoms of dysphagia , dyspnea , or dysphonia Distant blood-borne metastases to the liver , bone (frequently osteoblastic ), and lung occur later in the disease Patients with extensive metastatic disease frequently develop diarrhea

46. Cont. Paraneoplastic features Calcitonin Prostaglandins E2 Serotonin ACTH ( Cushing’s syndrome in 2 % to 4% of patients) Carcinoembryonic antigen (CEA) Calcitonin gene-related peptide H istaminadases

47. Diagnosis The diagnosis of MTC is established by: History 25% of patients with MTC have familial disease P hysical examination R aised serum calcitonin or CEA levels Both are used to identify patients with persistent or recurrent MTC Calcitonin is a more sensitive tumor marker, but CEA is a better predictor of prognosis FNAB of the thyroid mass ( it may miss up to 50% of MTC ) A neck ultrasound is recommended to evaluate the central and lateral neck compartments and the superior mediastinum Patients should be screened for RET point mutations , pheochromocytoma , and hyperparathyroidism

48. Cont. Required investigations Serum calcitonin and serum CEA RET proto-oncogene mutation testing Serum calcium Serum and urine catecholamines Neck ultrasound

49. Treatment Surgery is the only option EBRT and chemotherapy have no benefit Total thyroidectomy is the treatment of choice for patients with MTC because of the high incidence of multicentricity , the more aggressive course, and the fact that 131 I therapy usually is not effective Lymph node dissection Central compartment nodes frequently are involved early in the disease process, so that a bilateral prophylactic central neck node dissection should be routinely performed In patients with no distant disease but nodal involvement, an ipsilateral or bilateral lateral neck dissection (levels IIA, III, IV, and V) is performed Less aggressive neck surgery should be considered to preserve speech and swallowing while maintaining locoregional control in patients with limited metastatic disease The role of prophylactic lateral neck dissection is controversial Some groups favor this procedure if central neck lymph nodes are involved or if the primary tumor is ≥1.5 cm

50. Cont. If patients are found to have pheochromocytoma , this must be operated on first Primary hyperparathyroidism, if present, is treated at the time of thyroidectomy O nly obviously enlarged parathyroid glands should be removed The other parathyroid glands should be preserved and marked When a normal parathyroid cannot be maintained on a vascular pedicle , it should be removed, biopsied to confirm that it is a parathyroid, and then autotransplanted to the sternocleidomastoid muscle or to the forearm of the nondominant arm

51. Cont. Advanced disease In the case of locally recurrent or widely metastatic disease, tumor debulking is advised not only to ameliorate symptoms of pain, flushing, and diarrhea, but also to decrease risk of death from recurrent central neck or mediastinal disease External-beam radiotherapy is controversial but can be considered for patients with: Resected T4 disease Unresectable residual or recurrent tumor Symptomatic bony metastases There is no effective chemotherapy regimen Various targeted therapies directed against the RET kinase have been approved for the treatment of advanced MTC

52. Post-op follow up Patients are followed by: History P hysical examination C alcitonin and CEA (annually) Imaging U ltrasound , CT, MRI, and/or FDG-PET/CT scans

53. Prognosis Prognosis is related to: Disease stage The 10-year survival rate is approximately 80% but decreases to 45% in patients with lymph node involvement D isease type It is best in patients with non-MEN familial MTC , followed by those with MEN2A, and then those with sporadic disease Prognosis is the worst (survival of 35% at 10 years) in patients with MEN2B FMTC > MEN2A > Sporadic > MEN2B

54. Anaplastic Carcinoma

55. Introduction Anaplastic carcinoma accounts for approximately 1% of all thyroid malignancies Women are more commonly affected, and the majority of tumors present in the 7 th and 8 th decade of life Patients have a history of prior or coexistent DTC, and up to 50% have history of goiter

56. Pathology Macroscopic On gross inspection, anaplastic tumors are firm and whitish in appearance Microscopic S heets of cells with marked heterogeneity The 3 main histologic growth patterns are spindle cell, squamoid , and pleomorphic giant cell Foci of more differentiated thyroid tumors, either follicular or papillary, may be seen, suggesting that anaplastic tumors arise from more well-differentiated tumors

57. Clinical features The typical patient has a long-standing neck mass, which rapidly enlarges and may be painful Associated symptoms such as dysphonia , dysphagia , and dyspnea are common The tumor is large and may be fixed to surrounding structures or may be ulcerated with areas of necrosis Lymph nodes usually are palpable at presentation Evidence of metastatic spread also may be present Distant spread is present in 90% of patients at the time of diagnosis most commonly to the lungs

58. Diagnosis Diagnosis is confirmed by FNAB revealing characteristic giant and multinucleated cells Differential diagnoses on FNA can include: Medullary carcinomas Lymphomas Metastatic carcinomas Melanoma Direct extension from a laryngeal carcinoma Core or incisional biopsy O ccasionally needed to confirm the diagnosis, especially when there is necrotic material on the FNA Imaging (ultrasound, CT, MRI , or PET-CT) S hould be obtained to assess resectability Preoperative laryngoscopy (for all patients) To assess the status of the vocal cords

59. Treatment This tumor is one of the most aggressive thyroid malignancies, with few patients surviving 6 months beyond diagnosis All forms of treatment have been disappointing

60. Cont. Options Surgery Total or near-total thyroidectomy with therapeutic lymph node dissection Recommended for patients with an intrathyroidal mass Lobectomy It may be appropriate, particularly if there is concern for vocal cord paralysis Tracheostomy Should be avoided as long as possible unless there is impending airway loss Adjuvant r adiotherapy Should be offered to patients with a good performance status and no metastatic disease Chemo Typically given concurrently with radiotherapy and has been associated with prolonged survival A lso being used in a neoadjuvant fashion , particularly in patients with unresectable disease

61. Lymphoma

62. Introduction Lymphomas account for <1% of thyroid malignancies, and most are of the non-Hodgkin’s B-cell type Although the disease can arise as part of a generalized lymphomatous condition, most thyroid lymphomas develop in patients with chronic lymphocytic thyroiditis

63. Clinical features Patients usually present with symptoms similar to those of patients with anaplastic carcinoma, although the rapidly enlarging neck mass often is painless Patients may present with acute respiratory distress

64. Diagnosis FNAB It can be non-diagnostic , particularly in the setting of low-grade lymphomas Therefore , needle core or open biopsy may be necessary for definitive diagnosis Ultrasound It can be useful for early diagnosis, and lymphoma appears as a well-defined hypoechoic mass

65. Treatment Patients with thyroid lymphoma respond rapidly to chemotherapy ( CHOP ) Combined treatment with radiotherapy and chemotherapy often is recommended Thyroidectomy and nodal resection are used to alleviate symptoms of airway obstruction in patients who do not respond quickly to the above regimens or who have completed the regimen before diagnosis

66. Metastatic Carcinoma

67. Introduction The thyroid gland is a rare site of metastases from other cancers, including kidney , breast , lung , and melanoma FNAB usually provides definitive diagnosis Diagnosis can be suggested by history and P/E Resection of the thyroid , usually lobectomy , may be helpful in many patients, depending on the status of their primary tumor

68. End!