PAPILLARY THYROID CARCINOMA

1. PAPILLARY THYROID CARCINOMA AltamimiSupervisorDr:Abd alhakem Prepared by Dr:khaled altargamy

2. Thyroid Embyrology and Anatomy Develops as a median endodermal downgrowth from the first and second pharyngeal pouches, migrates caudally, then contacts the ultimobranchial bodies developing from the fourth pharyngeal pouches When it reaches the position it occupies in the adult, with the isthmus situated just below the cricoid cartilage, the thyroid divides into two lobes The path the gland follows may result in thyroglossal remnants (cysts) or ectopic thyroid tissue (lingual thyroid). A pyramidal lobe is frequently present. Agenesis of one thyroid lobe, almost always the left, may occur. The normal thyroid weighs 15–25 g and is attached to the trachea by loose connective tissue. highly vascularized organ, blood supply principally from the superior and inferior thyroid arteries. Also possible thyroid ima artery.

5. Physiology • function -> to synthesize, store, and secrete the thyroid hormones (TH): thyroxine (T4) and triiodothyronine (T3) • Iodide is absorbed from the GI tract, actively trapped by the acinar cells of the thyroid, then oxidized and combined with tyrosine in thyroglobulin to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) • MIT and DIT are coupled to form the active hormones T4 and T3, initially stored in the colloid of the gland • Following hydrolysis of the thyroglobulin, T4 and T3 are secreted into the plasma, becoming almost instantaneously bound to plasma proteins • T3 in euthyroid individuals, however, is produced by extrathyroidal conversion of T4 to T3.

6. Thyroid function regulation • Thyroid function is regulated by a feedback mechanism via the hypothalamus and pituitary • Thyrotropin-releasing factor (TRF) formed in hypothalamus  stimulates release of TSH (thyroid-stimulating hormone) from the pituitary  TSH binds to TSH receptors on the thyroid  stimulates release of TH (T3/T4) / thyroid cellular function • TH suppresses TSH and TRF • TSH suppresses TRF • TSH also stimulates thyroid growth

7. Lab tests • Thyroid function • assessed by highly sensitive TSH assays: hypothyroidism (increased TSH levels), euthyroidism, and hyperthyroidism (decreased TSH levels) • Hence most of the time, serum T3, T4, and other variables need not be measure • free T4 level is helpful after treatment for Graves disease because the TSH level may remain suppressed despite the patient being euthyroid • A serum T3 level is useful for diagnosing T3 toxicosis (high T3 and low TSH), or the euthyroid sick, low T3 syndrome (low T3 and normal or slightly increased TSH) • Radioactive iodine (RAI) uptake • useful for differentiating between hyperthyroidism and increased secretion of thyroid hormone (low TSH and increased radioactive iodine uptake) vs subacute thyroiditis (low TSH and low radioactive iodine uptake) • Patients with the latter "leak" thyroid hormone from the gland, which suppresses serum TSH levels and, consequently, iodine uptake by the thyroid • Patients with Graves disease have increased levels of thyroid-stimulating immunoglobulins that increase iodine uptake despite low TSH levels.

8. Normal thyroid tissue Normal thyroid tissue with follicles filled with colloid . Thyroid cells form follicles, spheres of epithelial cells (always single-layered in health, usually more-or-less cuboidal, variably tall or short). The C-cells (parafollicular cells) of the thyroid are visible between the follicles

9. Normal thyroid tissue

10. Thyroid Cancer

11. Classification of Malignant Thyroid Neoplasms • Medullary Carcinoma • Miscellaneous • Sarcoma • Lymphoma • Squamous cell carcinoma • Mucoepidermoid carcinoma • Clear cell tumors • Pasma cell tumors • Metastatic • - Direct extention • -Kidney • -Colon • -Melanoma • Papillary carcinoma • * Follicular variant • *Tall cell • * Diffuse sclerosing • * Encapsulated • Follicular carcinoma • *Overtly invasive • *Minimally invasive • Hurthle cell carcinoma • Anaplastic carcinoma • *Giant cell • *Small cell

12. Thyroid cancer 1.5% of all cancer Papillary carcinoma(75-85% of cases) Follicular carcinoma(10-20%) Medullary carcinoma(5%) Anaplastic carcinoma(<5%) Primary thyroid lymphoma Metastatic thyroid carcinoma

13. Risk Stratification of Variables Influencing Cancer Recurrences and Cancer Death Patient Variables - Age <15 or >45 yrs - Family hx of thyroid ca Tumor Variables - Tumor >4 cm - Bilateral disease - Extrathyroidal extension - Vascular invasion - Cervical or mediastinal LN mets - Certain tumor subtypes (e.g. Hurthle) - Histologic grade - Tumors that do not concentrate iodine well - Distant metastases

14. PapillaryCarcinoma Papillary carcinoma is an unencapsulated tumor with papillary and follicular structures that is characterized by overlapping cell nuclei that have a groundglass appearance and longitudinal grooves, with invaginations of cytoplasm into the nuclei. Encapsulated, follicular, tall-cell, columnar-cell, clearcell, and diffuse sclerosing carcinomas are recognized histologic variants; they are classified as papillary carcinomas because of their characteristic nuclear features.

15. The tumor is multicentric in 20 to 80 percent of patients (with the wide range attributable to variations in the care used to examine the thyroid) and bilateral in about one third. It spreads through the lymphatics within the thyroid to the regional lymph nodes and, less frequently, to the lungs.

16. PAPILLARY ADENOCARCINOMA • 85% of cancers of the thyroid gland • usually appears in early adult life • presents as a solitary nodule • spreads via intraglandular lymphatics within the thyroid gland and then to the subcapsular and pericapsular lymph nodes. • 50% of children and 20% of adults present with LAD • may metastasize to lungs or bone • Microscopically, papillary projections of columnar epithelium. • Psammoma bodies are present in about 60% of cases • rate of growth may be stimulated by TSH • BRAF mutation associated with lymph node metastases and a higher recurrence rate

17. Papillary Carcinoma • 80% of thyroid cancers • Follicular variant of papillary has same behavior • Average age 30 -40 • Women twice as frequent as men • Most common thyroid malignancy in children • Most common after low dose radiation

18. Thyroid Cancer -- Papillary • Papillary Carcinoma • Psammoma bodies, intranuclear cytoplasmic inclusions (Orphan Annie nuclei) • Poor prognosis, aggressive, radioiodine resistant: • Tall cell, insular, columnar, clear cell variants • Multicentric • Intrathyroidal lymphatic spread • Cervical Lymph node spread

19. Papillary Carcinoma • Lower risk • Men age 20 - 40, Women age 20-50 • Tumor < 1 cm - 1.5 cm • Recurrence risk 7% • 50% mortality in 15-25 years if recurrence • “Berry picking” of gross lymph nodes • LN’s present in 30% of all papillary CA’s • LN’s present in 90-100% if age <15

20. Oncogenes Recent advances in molecular biology have improved our understanding of the pathogenesis of thyroid carcinomas. Rearrangements of the tyrosine kinase domains of the RET and TRK genes with the amino-terminal sequence of an unlinked gene are found in some papillary carcinomas. Activating point mutations of the RAS genes are found with a similarly high frequency in thyroid adenomas and follicular carcinomas, suggesting that RAS mutations represent an early event in thyroid tumorigenesis.

21. Thyroid Irradiation External irradiation to the neck during childhood increases the risk of papillary thyroid carcinoma The latency period between exposure and diagnosis is at least five years. The risk is maximal at about 20 years, remains high for about 20 years, and then decreasesgradually. The risk is increased after a mean dose to the thyroid as low as 10 cGy. At higher doses (up to 1500 cGy), there is a linear relation between the dose and the risk of carcinoma.

22. At doses higher than 1500 cGy, the risk per gray decreases, probably because of cell killing. The risk of thyroid carcinoma is not increased in patients given iodine-131 for diagnostic or therapeutic purposes.

23. Other Factors In countries where iodine intake is adequate, differentiated cancers account for more than 80 percent of all thyroid carcinomas, with the papillary histologic type being the more frequent (accounting for 60 to 80 percent of cases). There is no increase in the incidence of thyroid carcinomas in countries where iodine intake is low, but there is a relative increase in follicular and anaplastic carcinomas.

24. A high incidence of papillary carcinomas has been reported in patients with adenomatous polyposis coli and Cowden’s disease (the multiple hamartoma syndrome). About 3 percent of cases of papillary carcinoma are familial.

25. Papillary Thyroid Carcinoma solitary or multifocal lesions Some tumors well-circumscribed and encapsulated; others infiltrate the adjacent parenchyma with ill-defined margins may contain areas of fibrosis and calcification and are often cystic

26. Papillary Thyroid Carcinoma can contain branching papillae having a fibrovascular stalk covered by a single to multiple layers of cuboidal epithelial cells NUCLEI of papillary carcinoma cells contain finely dispersed chromatin, which imparts an optically clear or empty appearance, giving rise to the designation ground glass or Orphan Annie eye nuclei invaginations of the cytoplasm may in cross-sections give the appearance of intranuclear inclusions ("pseudo-inclusions") or intranuclear grooves

27. Papillary Thyroid Carcinoma • the diagnosis of papillary carcinoma is based on these nuclear features even in the absence of papillary architecture. • Concentrically calcified structures termed psammoma bodies are often present within the lesion, usually within the cores of papillae • These structures are almost never found in follicular and medullary carcinomas, and so, when present, they are a strong indication that the lesion is a papillary carcinoma • whenever a psammoma body is found within a lymph node or perithyroidal tissues, a hidden papillary carcinoma must be considered

28. Papillary Thyroid Carcinoma Foci of lymphatic invasion by tumor are often preFoci of lymphatic invasion by tumor are often present, but involvement of blood vessels is relatively uncommon Metastases to adjacent cervical lymph nodes are estimated to occur in up to half the cases. .

29. Papillary Thyroid Carcinoma

30. Papillary Thyroid Cancer calcified sphere, or psammom Papillary thyroid carcinoma accounts for about 80% of all thyroid carcinomas

31. Papillary Thyroid Cancer Psammoma body within a papillary cancer . large clear areas within the nuclei which look like "Little Orphan Annie" eyes are circled in blue . Although these nuclear features are characteristic of papillary carcinoma, they are not pathognomonic Papillary cancer (low resolution). Notice the frond-like projections.

32. Papillary Thyroid Cancer- Variants • Encapsulated variant • constitutes about 10% of all papillary neoplasms • has an excellent prognosis • Follicular variant • has the characteristic nuclei of papillary carcinoma but has an almost totally follicular architecture • Tall cell variant • tall columnar cells with intensely eosinophilic cytoplasm lining the papillary structures • Occur in older individuals and are usually large with prominent vascular invasion, extrathyroidal extension, and cervical and distant metastases

33. Papillary Thyroid Cancer- Variants • Diffuse sclerosing variant • occurs in younger individuals, including children. These tumors do not present with a mass, but rather with a bilateral goiter • nodal metastases are present in almost all cases • Hyalizing trabecular tumors • includes both adenomas and carcinomas, have recently been reconsidered as a variant of papillary carcinomas, based on the presence of ret/PTC gene rearrangements in 30% to 60% of these tumors

34. DIAGNOSIS Most differentiated thyroid carcinomas present as asymptomatic thyroid nodules, but the first sign of the disease is occasionally lymph-node metastases or in rare cases lung or bone metastases. Hoarseness, dysphagia, cough, and dyspnea suggest advanced disease. On physical examination, the carcinoma, usually single, is firm, moves freely during swallowing, and is not distinguishable from a benign nodule.

35. Among patients with thyroid nodules, the nodule is more likely to be a carcinoma in children and adolescents, patients older than 60 years, and men than in women 20 to 60 years old. Carcinoma should be suspected if a hard, irregular thyroid nodule is found, ipsilateral lymph nodes are enlarged or compressive symptoms are present, and there is a history of a progressive increase in the size of the nodule. Virtually all patients with thyroid carcinoma are clinically euthyroid and have normal serum thyrotropin concentrations.

36. Whatever the presentation, fine-needle aspiration cytology is the best test for distinguishing between benign and malignant thyroid nodules. Provided an adequate specimen is obtained, three cytologic results are possible: benign, malignant, or indeterminate (or suspicious). False negative results, usually from sampling or interpretive errors, and false positive results are rare. Only about 20 percent of patients with indeterminate findings have malignant nodules.

37. Thyroid ultrasonography is useful for assessing the size of the nodule, detecting other nodules, and guiding fine-needle biopsy in the case of a nodule that is small or difficult to palpate.

38. 14 staging systems applied to 589 PTC patients from 1961-2001at one center in Hong Kong • Evaluated those with best predictive system for cancer-specific survival • Top three systems: • MACIS (Metastases, Age, Completeness of Resection, Invasion, Size) • TNM (Tumor, Node, Metastasis) • EORTC (European Organization for Research and Treatment of Cancer)

39. AGES: • (age, grade, extent, size) • AMES: • (age, metastases (distant), extent, size) • MACIS: • (metastasis, patient age, completeness of resection, local invasion, and tumor size)

40. TNM Staging System

41. INITIAL TREATMENT Surgery Iodine-131 Therapy External Radiotherapy

42. Surgery The goal of surgery is to remove all tumor tissue in the neck. Therefore, the thyroid gland and affected cervical lymph nodes should be resected. Although there is still some controversy about the extent of thyroid surgery, there are strong arguments in favor of a total or near-total thyroidectomy (leaving no more than 2 to 3 g of thyroid tissue) in all patients.

43. Total or near-total thyroidectomy results in a lower recurrence rate than more limited thyroidectomy because many papillary carcinomas are multifocal and bilateral. Furthermore, removal of most, if not all, of the thyroid gland facilitates total ablation with iodine-131. The argument against total thyroidectomy is that it increases the risk of surgical complications such as recurrent laryngeal-nerve injuries and hypoparathyroidism. Even with total thyroidectomy, often some thyroid tissue remains, as detected by postoperative scanning with iodine-131.

44. Papillary Thyroid Carcinoma: (SURGERY) • Lobectomy with isthmectomy acceptable for minimal papillary thyroid CA • Total thyroidectomy (near total) if: • Size: if tumor > 3cm • Age: male > 40y/o female > 50y/o • Angioinvasion • Distant metastases • Thyroidectomy w/ modified radical neck dissection: • If with clinically palpable cervical lymphadenopathy • Not done for prophylaxis • Reasons for total thyroidectomy: • 85% is multifocal • To decrease incidence of anaplasia in any residual tissue • Facilitate the diagnosis of unsuspected metastatic disease by RAI scanning or treatment • Greater sensitivity of blood thyroglobulin level to predict recurrent or persistent of the disease.

45. Management (WDTC)- Papillary • Rationale for total thyroidectomy • 1) 30%-87.5% of papillary carcinomas involve opposite lobe (Hirabayashi, 1961, Russell, 1983) • 2) 7%-10% develop recurrence in the contralateral lobe (Soh, 1996) • 3) Lower recurrence rates, some studies show increased survival (Mazzaferri, 1991) • 4) Facilitates earlier detection and tx for recurrent or metastatic carcinoma with iodine (Soh, 1996) • 5) Residual WDTC has the potential to dedifferentiate to ATC

46. Rationale for subtotal thyroidectomy • 1) Lower incidence of complications • Hypoparathyroidism (1%-29%) (Schroder, 1993) • Recurrent laryngeal nerve injury (1%-2%) (Schroder, 1993) • Superior laryngeal nerve injury • 2) Long term prognosis is not improved by total thyroidectomy (Grant, 1988)

47. Indications for total thyroidectomy • 1) Patients older than 40 years with papillary or follicular carcinoma • 2) Anyone with a thyroid nodule with a history of irradiation • 3) Patients with bilateral disease

48. Managing lymphatic involvement • pericapsular and tracheoesophageal nodes should be dissected and removed in all patients undergoing thyroidectomy for malignancy • Overt nodal involvement requires exploration of mediastinal and lateral neck • if any cervical nodes are clinically palpable or identified by MR or CT imaging as being suspicious a neck dissection should be done (Goldman, 1996) • Prophylactic neck dissections are not done (Gluckman)

49. Radioactive iodine was first introduced in 1942, by Chapman at the Massachusetts General Hospital. The first pediatric patient with radioactive iodine was also treated at Massachusetts General Hospital by Dr. John D. Crawford.

50. RAI-Refractory Disease 25-50% of metastatic thyroid cancers lose ability to take up Iodine. Iodine Uptake inversely correlates with survival. Limited treatment options for unresectable thyroid cancer refractory to RAI.