Anaplastic Thyroid Cancer

1. Anaplastic Thyroid Cancer

2. Introduction • Anaplastic thyroid cancers (ATC) are undifferentiated tumors of the thyroid follicular epithelium. • Anaplastic cancers are extremely aggressive, with a disease-specific mortality approaching 100 percent. • Given the very rapid course of disease progression and the poor treatment outcomes, end-of-life issues and plans for comfort care measures are an integral part of initial disease management planning.

3. Epidemiology • The age-adjusted annual incidence: 1 -2 per million persons • 0.9 - 9.8 percent of all thyroid cancers globally • Patients with ATC are older than those with differentiated cancer. • The mean age at diagnosis: 65 years • <10 percent: younger than 50 years • 60 - 70 percent of tumors occur in women

4. Antecedent ThyroidDisease  • 20% of patients with ATC have a history of differentiated thyroid cancer • 20 - 30% have a coexisting differentiated cancer • The majority of synchronous thyroid tumors are papillary cancers, but coexisting follicular cancers have also been reported • Nearly 10% of patients with Hürthle cell cancers have foci of ATC

5. ATC develops from more differentiated tumors as a result of dedifferentiating events. • Early events in the progression pathway: activating mutations in BRAF and RASthat are seen in both well-differentiated thyroid malignancies and ATC. • Late events in the progression pathway: mutations in p53 tumor suppressor protein, catenin beta1, andPIK3CAthat are seen more commonly in ATC rather than the well-differentiated tumor.

6. Clinical Manifestations  • The primary symptom of ATC: rapidly enlarging neck mass, occurring in 85% of patients. • The enlarging thyroid tumor causes: neck pain and tenderness, and compression (or invasion) of the upper aerodigestivetract that resulting in: - dyspnea (35%) - dysphagia (30%) - hoarseness (25%) - cough (25%) • Less common symptoms: chest pain, bone pain, headache, confusion, or abdominal pain from metastases

7. Constitutional symptoms: anorexia, weight loss, fatigue, and fever of unknown origin • Rapid growth of the tumor within the thyroid → thyroiditis with symptoms of hyperthyroidism and more severe neck pain and tenderness. • On physical examination: most patients have bilateral but asymmetric thyroid enlargement • The goiter is typically hard and nodular and may be tender. • A dominant nodule is often present. Some nodules may be softer and fluctuant, indicating focal tumor necrosis.

8. 50% of ATC have enlarged cervical lymph nodes • Most ATC have normal serum TSH concentrations, except for patients with tumor-related thyroiditis and hyperthyroidism • The findings on thyroid ultrasound are not specific for ATC • Ultrasonography cannot distinguish benign from malignant intrathyroidal tumors (both tend to be hypoechoic). • Ultrasonography of the neck also can accurately identify involvement of local and regional nodes.

9. Diagnosis • The diagnosis of ATC by cytologicexamination: cells obtained by fine needle aspiration biopsy tissue obtained by large needle or surgical biopsy • On cytopathology, morphologic patterns of ATC include: spindle cell, pleomorphic giant cell, and/or squamoid • Many ATC have a mixed morphology of two or all three patterns. • One common mixed morphologic type is biphasic spindle and giant cell tumor • ATC cells are much less likely to stain positive for TTF1 or PAX-8 and do not stain positive for thyroglobulin

12. Differential Diagnosis • Other malignancies that are similar to ATC: poorly differentiated thyroid cancer, medullary thyroid cancer, lymphoma, melanoma, and sarcoma. • Careful attention to morphology and immunohistochemicalstudies: required to distinguish ATC from poorly differentiated thyroid cancer and other malignancies

13. Evaluation • Laboratory evaluation typically measures: thyroid function tests (TSH, free thyroxine [T4]), CBC, electrolytes, BUN, creatinine, glucose, liver function tests • serum calcium and phosphorus: → to assess for hypercalcemia of malignancy or hypocalcemia due to compromise of the parathyroid glands secondary to invading ATC • serum thyroglobulin: → to assess the possibility of metastatic well- differentiated thyroid cancer → to assist in determining if the metastatic lesions are from the well-differentiated component of the tumor

14. Imaging studies • According to the American Thyroid Association (ATA) guidelines: ultrasound of the neck, Positron Emission Tomography (PET) using 18 F-fluorodeoxyglucose and brain MRI or Computed Tomography (CT) • If PET scanning is not readily available, cross-sectional imaging of the brain, neck, chest, abdomen, and pelvis with CT or MRI provides adequate initial staging information. • CT of the neck and mediastinum can accurately delineate the extent of the thyroid tumor and identify tumor invasion of the great vessels and upper aerodigestive tract. • MRI is similarly useful for defining the local extent of disease and for identifying distant metastases.

15. Metastatic Disease  • In patients with metastatic differentiated thyroid cancer, the thyroglobulin level is markedly elevated, whereas it should be normal in patients with ATC. • Patients with ATC who present with a rapidly growing neck mass and voice hoarseness require evaluation by an otolaryngologist/head and neck surgeon to assess for vocal cord function, airway invasion, and resectability. • Promising target genes that are seen in ATC and should be considered in the evaluation include:  BRAF, TSC1, TSC2, ALK fusion genes and NTRK fusion genes.

16. Staging  • In the updated staging system, the T category follows the same definitions as those used for differentiated thyroid cancers, rather than classifying all ATC as T4 disease. • All ATC are considered as stage IV cancers. • IVA: Intrathyroidal anaplastic cancers • IVB: Anaplastic cancers with gross extrathyroidal extension or cervical lymph node metastases • IVC: Anaplastic cancers with distant metastases

17. Treatment • Tumor Localized to The Thyroid or Locally Advanced Operable Disease: • For patients who present with resectable tumors, complete resection followed by combined radiotherapy and chemotherapy is recommended. • Locally Advanced Inoperable Disease: • For patients who present with locally advanced inoperable disease who desire active therapy (rather than palliative care), combined radiotherapy and chemotherapy for local control of disease is recommended.

18. Metastatic Disease: • There is no effective therapy for metastatic ATC, and the disease is uniformly fatal. • In patients with advanced disease, palliation of symptoms is a high priority. • For patients with bone metastases, palliative radiotherapy may be beneficial in improving pain. • Locoregional resection may be necessary for palliation of airway or esophageal obstruction. • End-of-Life Dare:  • Given the very rapid course of disease progression and the poor treatment outcomes, end-of-life issues and plans for comfort care measures are an integral part of initial disease management planning.

19. Surgery: • Is often not indicated, because the disease is advanced at the time of diagnosis in most patients. • If the tumor appears localized to the thyroid or if locoregional disease is resectable, complete resection should be attempted. • After complete resection, some patients have prolonged survival (>2 years), often in conjunction with postoperative adjuvant therapy. • For intrathyroidal tumors, thyroid lobectomy with wide margins of adjacent soft tissue on the side of the tumor is an aggressive surgical approach. • For locally advanced disease, the extent of surgery depends upon the degree of soft tissue involvement. Options include total thyroidectomy, lobectomy with wide margins of adjacent soft tissue.

20. Radiation Therapy: • External beam radiotherapy (EBRT) may be administered in the adjuvant setting, after surgical resection, or as primary treatment in patients who have inoperable disease. • Analysis of the Surveillance, Epidemiology, and End Results (SEER) database found that surgery and EBRT improved survival for patients with disease extending into adjacent tissues who did not have distant metastases. • The most appropriate radiation volumes remain uncertain and require further investigation. • Hyperfractionation administers multiple daily treatments with smaller than conventional fraction sizes given over approximately the same treatment duration.

21. This strategy, which enables high "radical" doses (>40 Gy) to be delivered over a short time with acceptable toxicity, appears to be associated with improved local control of disease in patients with ATC. • There was also a trend towards improved survival with twice-daily compared with once-daily fractionation. • For patients with locally advanced disease, hyperfractionated radiotherapy combined with radiosensitizing doses of doxorubicin may increase the local response rate to approximately 80 percent, with subsequent median survival of one year; distant metastases then become the leading cause of death. • Several centers have changed from using hyperfractionated radiation therapy to intensity-modulated radiation therapy (IMRT).

22. Chemotherapy: • In a phase II study of doxorubicin versus cisplatin/doxorubicin in patients with advanced thyroid cancer, 39 subjects with ATC were included. • There were six (34%) responses in the cisplatin/doxorubicin arm (three complete, three partial response), whereas there was only one (5 %) response (partial) in the doxorubicin alone arm. • Two of the three subjects with a complete response remained without evidence of disease, 34 and 41 months after starting treatment. • Overall, the response duration for any agent is generally short, and long-term survival is probably unaffected. • Several drugs, such as vascular disrupting agents and receptor tyrosine kinase inhibitors, are actively being studied.

23. Mutation directed: • BRAF and p53 mutations are common in ATC. • A study showed a 29% response rate in patients with BRAF-mutated ATC who were treated with the BRAF inhibitor, vemurafenib. • In 16 patients with BRAF-mutated ATC, the BRAF inhibitor dabrafenib (150 mg twice daily) and the mitogen-activated protein kinase (MEK) inhibitor trametinib (2 mg once daily) improved the overall response rate (69%, median follow-up 47 weeks), with seven ongoing responses. • Adverse effects: fatigue 38%, fever 37%, and nausea 35%. • A prolonged response was reported in a phase II study with everolimus in a patient with ATC containing a TSC2 mutation.

26. Combined Modality Therapy:  • Multiple reports support a possible survival advantage for combined modality therapy combining radiation and chemotherapy, although selection bias is a major confounding factor in determining the effect of treatment on outcome. • Patients who undergo resection followed by adjuvant therapy often have less extensive disease. • The optimal timing of the individual components and the selection of chemotherapy regimen are uncertain.

27. Radioactive Iodine Scanning and Therapy: • Radioactive iodine (RAI) has no role in the primary treatment of ATC. • However, RAI scanning/ablation/therapy should be considered in survivors, one to two years after initial therapy, if a significant component of the original tumor was well differentiated or if the serum thyroglobulin level remains inappropriately elevated during follow-up.

28. Monitoring • Patients who respond to initial management require surveillance for recurrence. • Computed tomography (CT) scan (neck, chest, abdomen, pelvis) every 1-3 months for the first 24 months and then less frequently (every 4-6 months) thereafter is recommended. • Brain imaging during the first three months after treatment is recommended. • In patients with no clinical evidence of disease on CT scan, positron emission tomography (PET) scan may show disease recurrence. Thus, PET imaging 3-6 months after initial therapy (in patients with no disease on CT) is recommended.

29. Patients who have total thyroidectomy require thyroid hormone therapy to replace normal thyroid hormone production. • T4 (approximately 1.6 mcg/kg of body weight) should be started immediately after surgery. • The adequacy of therapy should be evaluated clinically and by measurement of serum TSH in one month. • The goal of T4 therapy should be to restore and maintain euthyroidism.

30. Prognosis • ATCs are extremely aggressive, with a disease-specific mortality approaching 100%. • The median survival from diagnosis ranges from 3-7 months, and the one- and 5-year survival rates are 20-35% and 5-14%, respectively. • Other variables that may predict a worse prognosis include older age at diagnosis, male sex, and dyspnea as a presenting symptom. • Relatively favorable prognostic factors include unilateral tumor, diameter of less than 5 cm, and the absence of extrathyroidal invasion or cervical lymph node involvement.

31. Case Study • A 60 Y/O male , Disease start : 10 years ago! • Presentation : Thyroid mass, Hoarseness , Dyspnea , • Imaging :Mediastinal mass, • Primary diagnosis : Medulary carcinoma • Pathology : undiffreciated carcinoma • Lab tests : normal calcium , CBC , TGs ?

35. Treatments • Surgical resection : total thyroidectomy +tumor resection , LN dissection? • Concurrent chemoradiation ( total dose + ADR + Cisplatin) • Post op follow ups :medical treatments (levothyroxin + …) • Side effects : hourseness, TVC paralysis, dysphagia and odynophagia , cosmetics ?