Dr. Varun Goel MEDICAL ONCOLOGISTRAJIV GANDHI CANCER INSTITUTE, DELHI
Introduction The most common endocrine malignancy 95% of all endocrine cancers accounts for ~3% of all cancers Female to Male Ratio 3:1 sixth most frequently diagnosed cancer in women continued increased incidence with an estimated 48,020 new cancer cases in 2011. six deaths per 1 million people occur annually.
based on pathology can be divided into three general subtypes differentiated (papillary, follicular, and Hürthle cell), more than 90% of thyroid cancers medullary, and anaplastic thyroid cancers The prognosis is excellent for most patients with thyroid cancer overall survival rate of 85% at 10 years. Most effectively treated by thyroidectomy and use of radioactive iodine. Despite low mortality rates, local recurrence occurs in up to 20% of patients, and distant metastases in approximately 10% at 10 years.
HistorySymptoms The most common presentation painless mass in the region of the thyroid gland (Goldman, 1996). Symptoms consistent with malignancy Pain dysphagia Stridor hemoptysis rapid enlargement hoarseness
Important History Radiation to neck / chest MEN syndrome Family history Diarrhoea Adrenal tumour
History (continued...)Risk factors Thyroid exposure to irradiation low or high dose external irradiation (40-50 Gy [4000-5000 rad]) especially in childhood for: large thymus, enlarged tonsils, cervical adenitis, sinusitis, and malignancies 30%-50% chance of a thyroid nodule to be malignant (Goldman, 1996)
History (continued...)Risk factors (continued…) Age and Sex Benign nodules occur most frequently in women 20-40 years (Campbell, 1989) 5%-10% of these are malignant (Campbell, 1989) Men have a higher risk of a nodule being malignant Belfiore and co-workers found that: the odds of cancer in men quadrupled by the age of 64 a thyroid nodule in a man older than 70 years had a 50% chance of being malignant
History (continued…) Family History family member with medullary thyroid carcinoma family member with other endocrine abnormalities (parathyroid, adrenals) familial polyposis (Gardner’s syndrome)
Evaluation of the thyroid Nodule Physical Exam Blood Tests Ultrasonography CT Scan PET Scan Radioisotope Scanning FNAC
Physical ExamExamination of the thyroid nodule: consistency - hard vs. soft size Multinodular vs. solitary nodule multi nodular - 3% chance of malignancy (Goldman, 1996) solitary nodule - 5%-12% chance of malignancy (Goldman, 1996) Mobility with swallowing Mobility with respect to surrounding tissues Well circumscribed vs. ill defined borders
UltrasonographyAdvantages Sensitive for identifying lesions in the thyroid (2-3mm) 90% accuracy in categorizing nodules as solid, cystic, or mixed (Rojeski, 1985) Best method of determining the volume of a nodule (Rojeski, 1985) Can detect the presence of lymph node enlargement and calcifications Noninvasive and inexpensive
Ultrasonography (Continued…)Disadvantages Unable to reliably diagnose true cystic lesions Cannot accurately distinguish benign from malignant nodules
CT Scan Not commonly needed Better when suspecting mediastinal disease PET Scan FNAC Accurate for PTC and MTC Cannot diagnose FTC
Radioisotope Scanning Prior to FNA, was the initial diagnostic procedure of choice Performed with: technetium 99m pertechnetate or radioactive iodine Technetium 99m pertechnetate cost-effective readily available short half-life trapped but not organified by the thyroid - cannot determine functionality of a nodule
Radioisotope Scanning (Continued…) Radioactive iodine radioactive iodine (I-131, I-125, I-123) is trapped and organified can determine functionality of a thyroid nodule
Radionuclide Scan Possibilities Cold Hot
Limitations of Radionuclide Scan Cold nodules usually benign... but could be cancer Hot nodules never cancer… and revealed by low TSH
Radioisotope Scanning (continued...)Limitations Not as sensitive or specific as FNA in distinguishing benign from malignant nodule 90%-95% of thyroid nodules are hypofunctioning, with 10%-20% being malignant (Geopfert, 1994, Sessions, 1993) Campbell and Pillsbury (1989) performed a meta-analysis of 10 studies 17% of cold nodules, 13% of warm or cool nodules, and 4% of hot nodules to be malignant
Fine-Needle Aspiration Currently considered to be the best first-line diagnostic procedure in the evaluation of the thyroid nodule: Advantages: Safe Cost-effective Minimally invasive Leads to better selection of patients for surgery than any other test (Rojeski, 1985)
Fine-NeedleAspiration (continued…) FNA halved the number of patients requiring thyroidectomy (Mazzaferri, 1993) FNA has double the yield of cancer in those who do undergo thyroidectomy (Mazzaferri, 1993)
Fine-Needle Aspiration (continued…)Limitations skill of the aspirator Sampling error in lesions <1cm, >4cm, multinodular lesions, and hemorrhagic lesions Error can be diminished using ultrasound guidance expertise of the cytologist difficulty in distinguishing some benign cellular adenomas from their malignant counterparts (follicular and Hurthle cell) False negative results = 1%-6% (Mazzeferri, 1993) False positive results = 3%-6% (Rojeski, 1985, Mazzeferri, 1993, Hall, 1989)
Molecular Pathogenesis of Thyroid Cancer
Thyroid Cancer Type Mutation Prevalence, %Papillary BRAF[V600E] 45 BRAF copy gain 3 RET/PTC 20 RAS 10 PI3KCA 3 PI3KCA copy gain 12 PTEN 2Follicular BRAF copy gain 35 RAS 45 PAX8-PPARγ 35 PTEN < 10 PI3KCA < 10 PI3KCA copy gain 12Medullary RET (familial) > 95 RET (sporadic) 50
In last 30 years, it has become clear that thyroid cancers are associated with genetic mutations that lead to aberrant intracellular signaling inhibition of intracellular signaling cascades including MAPK and PI3K pathways may be effective in the treatment . Ahmed 2011; Hong 2011; Carr 2010; Robinson 2010; Lam 2010; Sherman 2008;Gupta-Abramson 2008
WDTC - Papillary Carcinoma Pathology Gross - vary considerably in size - often multi-focal - unencapsulated but often have a pseudocapsule Histology - closely packed papillae with little colloid - psammoma bodies - nuclei are oval or elongated, pale staining with ground glass appearanc - Orphan Annie cells
WDTC - Follicular Carcinoma Pathology Gross - encapsulated, solitary Histology - very well-differentiated (distinction between follicular adenoma and carcinomaid difficult) - Definitive diagnosis - evidence of vascular and capsular invasion FNA and frozen section cannot accurately distinquish between benign and malignant lesions
CEA Synaptophysin Chromogranin Calcitonin ThyroglobulinS03-12297
72 yr old female, 2 week history enlarging thyroid mass2-3 day history of hoarseness and stridor FNA: poorly differentiated thyroid cancer Thyroglobulin neg Spindle cells Giant cells PTC Anaplastic
WDTC - PROGNOSIS Prognostic schemes: AMES (Lahey Clinic, Burlington, MA) GAMES (Memorial Sloan-Kettering Cancer Center, NY) AGES (Mayo Clinic, Rochester, MN) GAMES scoring (PAPILLARY & FOLLICULAR CANCER) G - Grade A - Age of patient when tumor discovered M - Metastases of the tumor (other than Neck LN) E - Extent of primary tumor S - Size of tumor (>5 cm) The patient is then placed into a high or low risk category
WDTC - Prognosis (Continued…) 1) Low risk group - men younger than 40 years and women younger than 50 years regardless of histologic type - recurrence rate -11% - death rate - 4% (Cady and Rossi, 1988)
WDTC - Prognosis (Continued…) 1) Intermediate risk group - Men older than 40 years and women older than 50 years who have papillary carcinoma - recurrence rate - 29% - death rate - 21% 2) High risk group - Men older than 40 years and women older than 50 years who have follicular carcinoma - recurrence rate - 40% - death rate - 36%
AJCC :Classification of Thyroid CancerPrimarytumorTX Primary tumor cannot be assessedT0 No evidence of primary tumorT1 Tumor < 2 cm confined to the thyroidT2 Tumor >2 cm and <4 cm confined to the thyroidT3 Tumor >4 cm confined to the thyroid or Tumor of any size with minimal extrathyroid extensionT4a Tumor of any size with extrathyroid extension to subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve or Intrathyroidal anaplastic carcinoma- resectableT4b Tumor invading prevertebral fascia/encasing carotid artery or mediastinal vessels or Extrathyroidal anaplastic carcinoma - unresectable
Regional LN(N) (central compartment, lateral cervical, and upper mediastinal)NX Regional lymph nodes cannot be assessedN0 No regional lymph node metastasisN1 Regional lymph node metastasisN1a Metastasis to level VI (pretracheal or paratracheal, and prelaryngeal)N1b Metastasis to unilateral, bilateral, or contralateral cervical(Levels I, II, III, IV or V) or superior mediastinal lymph nodes (Level VII )
Distantmetastasis(M)MX Distant metastasis cannot be assessedM0 No distant metastasisM1 Distant metastasis
Papillary/Follicular Thyroid Cancer
AJCC/UICC StagingThyroid Cancer Papillary/Follicular Stage Age < 45 yrs Age > 45 yrs I Any T, any N, M0 <2 cm, intrathyroidal, N0, M0 II Any T, Any N, M1 2- 4cm, intrathyroidal, N0, M0 III Minimal ETE, or > 4cm, N0, M0 or T1-3, N1a, M0 IV Any T, Any N, Gross ETE, or M1 Hürthle cell carcinoma is considered a follicular carcinoma. All anaplastic carcinomas are stage IV.
staging of thyroid cancer is the only one in oncology that takes patient age at diagnosis into account. age is the most important prognostic variable for mortality a large proportion of thyroid cancers (primarily PTC) occur in women under the age of 45. As a group these are highly sensitive to RAI; thus, even with metastatic disease can be cured with RAI following surgery. As the age of diagnosis increases, the mortality rate increases as well, most sharply after the age of 60 years.
Overall, the differentiated thyroid cancers are associated with a good prognosis and 10-year survival rates are 93% for papillary 85% for follicular and 76% for Hürthle cell carcinomas, respectively.
Initial ManagementSurgery is the definitive management of thyroid cancer, excluding most cases of ATC and lymphomaTypes of operations: lobectomy with isthmusectomy – minimal operation required for a potentially malignant thyroid nodule total thyroidectomy - removal of all thyroid tissue preservation of the contralateral parathyroid glands subtotal thyroidectomy anything less than a total thyroidectomy
Management (WDTC) - Papillary and FollicularSubtotal vs. total thyroidectomy
(continued…) 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) Residual WDTC has the potential to dedifferentiate to ATC
(Continued…) 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)
(continued)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
(continued)Managing lymphatic involvement pericapsular and tracheoesophageal nodes should be dissected and removed in all patients undergoing thyroidectomy 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)
Management (WDTC) - Papillary and Follicular (continued) Postoperative therapy/follow-up Radioactive iodine (administration) Scan at 4-6 weeks postop repeat scan at 6-12 months after ablation repeat scan at 1 year then... every 2 years thereafter
Management (WDTC) - Papillary and Follicular(continued)Postoperative therapy/follow-up Thyroglobulin (TG) (Gluckman) measure serum levels every 6 months Level >30 ng/ml are abnormal Thyroid hormone suppression (control TSH dependent cancer) (Goldman, 1996) should be done in – 1) all total thyroidectomy patients 2) all patients who have had radioactive ablation of any remaining thyroid tissue
neck ultrasound should be performed 6 and 12 months after surgery, and then annually for 3 to 5 years, depending on the patients risk for recurrence and Tg status. CT and PET scans has been increasingly used in the surveillance of patients with iodine-negative, differentiated thyroid carcinoma.
(WDTC) - Hurthle Cell Carcinoma Variant of follicular carcinoma Lymphatic spread seen in 30% of patients (Goldman, 1996) Distant metastases to bone and lung is seen in 15% at the time of presentation Total thyroidectomy is recommended because: 1) Lesions are often Multifocal 2) They are more aggressive than WDTCs 3) Most do not concentrate iodine
Treatment of Differentiated Thyroid Cancer[NCCN 2011;Cooper 2009]
Medullary Thyroid Carcinoma 10% Arises from the parafollicular cell or C-cells of the thyroid gland derivatives of neural crest cells of the branchial arches secrete calcitonin which plays a role in calcium metabolism Developes in 4 clinical settings: Sporadic MTC (SMTC) Familial MTC (FMTC) Multiple endocrine neoplasia IIa (MEN IIa) Multiple endocrine neoplasia IIb (MEN IIb)
Medullary Thyroid Carcinoma(continued…)Sporadic MTC: 70%-80% of all MTCs Mean age of 50 years Unilateral and Unifocal (70%) Slightly more aggressive than FMTC and MEN IIa Familial MTC: Autosomal dominant transmission Not associated with any other endocrinopathies Mean age of 43 Multifocal and bilateral Has the best prognosis of all types of MTC 100% 15 year survival
Medullary Thyroid Carcinoma(continued…) MEN IIa (Sipple’s Syndrome): MTC, Pheochromocytoma, parathyroid hyperplasia Autosomal dominant transmission Mean age of 27 100% develop MTC 85%-90% survival at 15 years MEN IIb (Wermer’s Syndrome): Pheochromocytoma, multiple mucosal neuromas, marfanoid body habitus 90% develop MTC by the age of 20 Most aggressive type of MTC 15 year survival is <40%-50%
Medullary Thyroid Carcinoma(continued…) Diagnosis Labs: 1) basal and pentagastrin stimulated serum calcitonin levels (>300 pg/ml) 2) serum calcium 3) 24 hour urinary catecholamines (metanephrines, VMA, nor- metanephrines) 4) carcinoembryonic antigen (CEA) Fine-needle aspiration Genetic testing of all first degree relatives RET proto-oncogene
Medullary Thyroid Carcinoma(Management) Recommended surgical management total thyroidectomy central lymph node dissection lateral jugular sampling if suspicious nodes - modified radical neck dissection If patient has MEN syndrome remove pheochromocytoma before thyroid surgery
Medullary Thyroid Carcinoma(Management)Postoperative management disease surveillance serial calcitonin and CEA 2 weeks postop 3/month for one year, then… biannually If calcitonin rises metastatic work-up surgical excision if metastases - external beam radiation
Anaplastic Carcinoma of the Thyroid Highly lethal form of thyroid cancer Median survival <8 months 1%-10% of all thyroid cancers Affects the elderly (30% of thyroid cancers in patients >70 years) Mean age of 60 years 53% have previous benign thyroid disease 47% have previous history of WDTC
Anaplastic Carcinoma of the Thyroid Pathology Classified as large cell or small cell Large cell is more common and has a worse prognosis Histology - sheets of very poorly differentiated cells little cytoplasm numerous mitoses necrosis extrathyroidal invasion
Anaplastic Carcinoma(Management) Most have extensive extrathyroidal involvement at the time of diagnosis surgery is limited to biopsy and tracheostomy Current standard of care is: maximum surgical debulking, possible adjuvant radiotherapy and chemotherapy
Recurrent DTC 85% of patients with DTC :disease-free after initial treatment 10–15% : recurrent disease Most recurrences occur within the first five years after initial treatment 5%: distant metastases lungs (50%), bones (25%), lungs and bones (20%) , 10-year-survival rates ranging from 25% to 42%
Treatment methods Surgery (when feasible) Radioiodine treatment in presence of radioiodine uptake in tumor foci Other local treatments (dependent on location and extent of disease): external radiation beam treatment, embolisation, radiofrequency New treatment methods, eg, molecularly targeted treatments,
Selection of patients with metastases for treatment Candidates for radioiodine treatment Younger age Well differentiated tumour High radioiodine uptake Small metastases Location in lungs Low uptake of fluorodeoxyglucose Loss of RAI uptake is often associated with the increased uptake of PET scanning. Repeated radioiodine treatment (response rate: 85%, with 96% of complete responses seen with a cumulative activity <600 mCi)
Advanced Disease when recurrent or metastatic lesions either no longer take up radioactive iodine (RAI) or have grown in the setting of recent treatment with RAI (RAI-refractory), or if the recommended lifetime dose of RAI (600 mCi) has been exceeded. survival drops to an average of 2.5-3.5 years.[Robbins 2006
Very few treatment options. Cytotoxic chemotherapy The experience with chemotherapy is limited benefits have been marginal.
Among 49 patients with metastatic differentiated thyroid carcinoma treated with five chemotherapy protocols, a combination of doxorubicin, etoposide, 5-fluorouracil and cyclophosphamide; elliptinium acetate; doxorubicin; cisplatin; and the combination of doxorubicin and cisplatin. only two (3%) patients had objective responses. (Droz et al, 1990) In a review of published series, 38% of patients had a response defined as a reduction in tumor mass to doxorubicin. three most widely applied cytostatics are adriamycin, bleomycin and cis-platinum, and it seems that adriamycin monotherapy, is superior to all other therapies, even combinations (Ahuja and Ernst, 1987)
Doxorubicin, approved by the U.S FDA for use in advanced thyroid cancer in the 1970s Tumor response rates with doxorubicin, range between 0% and 22% and are short-lived and without survival benefit .
Administration of doxorubicin with cisplatin has been equally disappointing. Randomized phase II study - ECOG Cisplatin/Doxorubicin vs. Doxorubicin Cisplatin/Doxorubicin Arm (43 patients) CR 5; PR 5; SD 13 Doxorubicin (41 patients) CR 0; PR 7; SD 9 Shimaoka K, et al: Cancer 56:2155-2160, 1985 Combination chemotherapy is not clearly superior to doxorubicin therapy alone. (Mazzaferri, 1993)
The role of external beam radiation therapy (EBRT) to control cervical disease in patients with progressive DTC is not well-defined. Progress in the knowledge of genetic alterations in thyroid cancer cells is rapidly offering several opportunities to develop new drugs directed to speciﬁc targets
Targets in cell signalling and angiogenesis Papillary carcinomas : 80% :mutations of genes of mitogen- activated protein kinase (MAPK) pathway. 5–30%: RET/PTC rearrangements 10%: RAS mutations 40%: BRAF mutations Follicular carcinomas: 20–35% : RAS mutations 30% :PAX8/PPARɣ rearrangements Medullary Thyroid Cancer RET Anaplastic Thyroid Cancer p53, Vascular Structures
Drugs currently proposed for molecular therapy include: (a) monoclonal antibodies; (b) kinase inhibitors; (c) anti-angiogenetic drugs; (d) proteasome inhibitors; (e) retinoic acid and PPAR-c ligands; (f) radionuclide therapy; (g) epigenetic drugs (deacetylase inhibitors and demethylating agents). The results of several phase II trials using molecular drugs look promising. None of the treated patients, however, had CR, and only a minority of them had a PR.
Several tyrosine kinase inhibitors have shown activity majority (motesanib, sunitinib, sorafenib, and pazopanib) target the mitogen-activated protein kinase and antiangiogenic pathways. [Ahmed 2011; Hong 2011; Carr 2010; Robinson 2010;Lam 2010]
Phase II studies in advanced thyroid cancer
VANDETANIB Vandetanib is a tyrosine kinase inhibitor activity against RET, VEGFR and endothelial growth factor receptor pathways. Vandetanib was approved by FDA in 2011 for use in patients with unresectable metastatic medullary thyroid cancer on the basis of a phase III clinical trial (N = 331). • [Wells 2011]
Once-Daily Vandetanib 300mg or Placebo. significantly prolonged PFS (median 30.5 months vs 19.3 months; ORR 45% Versus 13% No difference in OS Wells SA Jr, J Clin Oncol. 2010 associated with a higher incidence of QT prolongation Elevated rates of hypertension and diarrhea also observed.