UNDIFFERENTIATED THYROID CARCINOMA

1. UNIVERSITY of PISA UNDIFFERENTIATED THYROID CARCINOMA Prof. Paolo Vitti Department of Endocrinology and Metabolism

2. THYROID TUMORS Patel K. N., Shaha A.R. – Poorly differentiated and Anaplastic thyroid cancer Cancer Control, April 2006, Vol. 13 No. 2

3. THYROID TUMORS Nonglandular components with a solid, trabecular, and/or scirrhous growth pattern. Poorly differentiated thyroid cancer Some authors included aggressive papillary thyroid carcinoma variants such as columnar cell, tall cell, diffuse sclerosing and solid. These variants tend to show a more aggressive behavior pattern than the classic type of differentiated thyroid cancer, but the term poorlydifferentiated as defined by the tumor architecture is not justified Patel K. N., Shaha A.R. – Poorly differentiated and Anaplastic thyroid cancer Cancer Control, April 2006, Vol. 13 No. 2

4. THYROID TUMORS Poorly differentiated thyroid cancer Poorly differentiated thyroid carcinoma is a concept proposed to include carcinomas of follicular thyroid epithelium that retain sufficient differentiation to produce scattered small follicular structures and some thryroglobulin, but generally lack the usual morphologic characteristics of papillary and follicular carcinoma. PDTCs fall into two main categories: insular and other (large cell). Burman KD, Ringel MD, Wartofsky L, et al. Unusual types of thyroid neoplasms. Endocrinol Metab Clin North Am. 1996;25:49-68.

5. Undifferentiated thyroid cancer: Pathology No follicular structure • giant cells • spindle cells with a sarcomatous appearance • squamoid There is no prognostic difference in these patterns. All three variants have numerous mitotic figures, with large areas of necrosis, hemorrhage and vascular invasion.

6. Survival vs Histotype: The Pisa Experience 1 0 0 PTC FTC Survival % 5 0 MTC ATC 0 0 2 5 1 0 1 5 2 0 THYROID TUMORS Elisei R, Molinaro E. et al. JCEM 2010.

7. What is the biological difference? Differentiated vs Undifferentiated Thyroid Cancer

8. THYROID TUMORS Undifferentiated thyroid cancer Pathogenesis ?

9. Genetic alterations in thyroid carcinoma GENETICS Modified from Kondo T, et al.Nat Rev Cancer. 2006

10. GENETICS – p53 % Poorly differentiated carcinoma Papillary carcinoma Follicular carcinoma Undifferentiated carcinoma J Clin Invest 91: 179-84, 1993

11. Hypothesis: two different pathways PATHOGENESIS BRAFRET-PTC TRK MET Papillary carcinoma P53 othergenes P53, other genes Follicular cell Anaplastic carcinoma Follicular carcinoma P53 othergenes RAS PPAR-γ

12. PATHOGENESIS • coexistence of WDTC and ATC with zones of transition have been described; • 76% of ATC had a previous or concurrent thyroid disorders, with 47% related to WDTC; • papillary thyroid carcinoma is the most common type associated with ATC. Cancer Control, vol. 13, no. 2, pp. 119–128, 2006.

13. Undifferentiated thyroid cancer Clinical Features THYROID TUMORS Is the most aggressive and lethal form of thyroid cancer. Fortunately, only 1% to 2% of all thyroid tumors. Median survival of 4 to 12 months from the time of diagnosis. Long term survivors are so rare that the diagnosis is questionated in reports describing 5-year survival rates. Patel K. N., Shaha A.R. – Poorly differentiated and Anaplastic thyroid cancer Cancer Control, April 2006, Vol. 13 No. 2

14. Prevalence of Thyroid Hystotypes (n=7382) THYROID TUMORS % of all thyroid tumors Papillary Follicular Medullary Anaplastic Lymphoma Unknown Department of Endocrinology, Pisa, 1969-2004

15. THYROID TUMORS • The incidence of undifferentiated thyroid carcinoma has steadily decreased over the past few decades. Many hypothesis: • Improved iodine nutrition

16. THYROID TUMORS % Adequate iodine intake Iodine deficiency American Journal of Medicine, vol. 93, no. 4, pp. 363–369, 1992.

17. THYROID TUMORS • The incidence of undifferentiated thyroid carcinoma has steadily decreased over the past few decades. Many hypothesis: • Early diagnosis • Early treatment

18. THYROID TUMORS

19. CLINICAL CHARACTERISTICS Peak of incidence: 6° - 7° decade of life. Mean age of diagnosis: 55 to 65 years. There are no significant gender differences. Often they have a history of long-standing multinodular goiter. Most patients present with a rapidly growing, painful, low anterior neck mass that is often firm and fixed to underlying structures. Mean size of the mass is 8 cm (3 – 20 cm).

20. ECOGRAPHIC FEATURES

21. CT SCANS Most patients demonstrate local compressive symptoms including dysphagia, dysphonia, stridor, dyspnea, and neck pain and tenderness. Over 70% of patients with ATC have direct invasion of surrounding tissues, such as fat, trachea, muscle, esophagus and larynx.

22. PATHOLOGY - CITOLOGY • Higly malignant and bizarre cells Cytologic features: • High-grade nuclear features: • marked pleomorphism • dark clumped chromatin • macronucleoli • atypical mitosis • Tumor diathesis

23. METASTASES Regional nodal metastases and vocal cord paralysis are seen in up to 40% and 30%, respectively, of the patients with ATC. Lung: 80% Distant spread is present 75% of the time at diagnosis. Bone: 6 to 15% Brain: 5 to 15% Patel K. N., Shaha A.R. – Poorly differentiated and Anaplastic thyroid cancer Cancer Control, April 2006, Vol. 13 No. 2

24. METASTASES

25. THERAPY Many Therapeutical Options • SURGERY • EXTERNAL RADIOTHERAPY • CHEMOTHERAPY • MULTIMODALITY THERAPY • NEW THERAPIES

26. THERAPY Target of therapies Radical treatment, rarely possible Palliative treatment

27. THERAPY – SURGERY Most patients present at an advanced stage, making curative surgical resection not feasible. Some studies find that neither the extent of surgery nor the completeness of resection has a significant effect on survival. Some studies suggest that in a select subset of patients with localized disease, survival can be improved by achieving complete resection of all gross disease.

28. THERAPY – SURGERY

29. THERAPY – SURGERY One of the central issues in the management of ATC is palliation. Palliative management is meant to prevent death from asphyxiation. Securing a safe airway is a critical component of this effort. Airway management may be elective or emergent, depending on the patient’s presentation. Palliative management

30. THERAPY – SURGERY • external compression of the trachea (the most common cause) • intraluminal tumor extension • bilateral vocal cord paralysis Airway obstruction occurs by one of three mechanisms: Patients with either stridor or rapid tumor growth should be considered for tracheostomy since further airway compromise can be expected.

31. THERAPY – RADIOTHERAPY Achieving local control is important since death from ATC is usually a consequence of uncontrolled local disease. The indications for ext RT range from providing palliation to improving survival. It is used either alone or in combination with surgery and/or chemotherapy.

32. THERAPY – RADIOTHERAPY Although ATC is relatively radioresistant, some studies have shown palliative local control in 68% to 80% of patients. Possible complications include pharyngoesophagitis, tracheitis, and myelopathy. Fractioned dose: 1,6 Gy/session, twice a day, triweekly, for a total dose of 57,6 Gy in 40 days.

33. THERAPY – CHEMOTERAPY Chemotherapy plays an important role in the management of ATC since the majority of patients present with or develop distant metastases Most studies about the effects of chemotherapeutic agents on ATC have been unsuccessful in altering the fatal outcome of this disease.

34. THERAPY – CHEMOTERAPY Monotherapy with doxorubicin demonstrated a response rate of approximately 20% with no evidence of a complete response (De Besi P, 1991). Combination therapy with cisplatin or bleomycin demonstrated little improvement in the clinical response (Williams SD, 1986).

35. THERAPY – MULTIMODALITY THERAPY The rationale of combining treatment modalities stems from the failure of any one individual therapy. Ext RT combined with surgery can improve local control, and chemotherapy combined with Ext RT can increase the radiosensitivity of ATC. Others have used the effects of radiation and chemotherapy preoperatively to allow for the potential resection of the tumor. Possible schedule: surgery, cisplatin (120 mg/m2) and doxorubicin (10 mg/m2), hyperfractionated radiotherapy.

36. NEW THERAPIES One target, two ways: both inhibit tumor blood-supply Antitumor vascular targeting agents

37. NEW THERAPIES - ANTIANGIOGENETICS Tyrosine kinase inhibitors

38. VEGF Paracrine stimulation PDGF-β Ras Ras Apoptosis Raf Raf MEK Apoptosis EGF MEK PDGF VEGF Angiogenesis Proliferation Survival Nucleus Nucleus ERK ERK NEW THERAPIES - ANTIANGIOGENETICS Tyrosine kinase inhibitors: sorafenib VEGFR-2 PDGFR-β KIT/Flt-3/RET Tumour cell Endothelial cell or pericyte

39. SORAFENIB SPONTANEOUS “OFF LABEL” StudyDept of Endocrinology, Pisa Up to date, 17 patients have been enrolled All had histologically confirmed, locally advanced or metastatic de-differentiated or anaplastic thyroid cancer and documented evidence of disease progression The primary end point was to evaluate objective response

40. SORAFENIB – STUDY DESIGN Daily dose 800 mg/die (400 mg bidaily) Treatment of less severe side effects: diarrhoea, nausea, vomiting; rash, alopecia e “hand-foot syndrome”; abdominal pain. Drug dose reduction or interruption in the presence of severe side effects. Administration of appropriate therapy until resolution and reconsideration to start again with the drug

41. SORAFENIB Before sorafenib After 20 days of therapy

42. NEW THERAPIES – VASCULAR-DISRUPTING Healthy vasculature is characterized by orderly architecture and mature blood vessels (in green at right) that are stabilized and supported externally by smooth muscle and pericyte coats (shown in red). Bases of selective action of vascular disrupting agents on tumor vessels: differences between normal and tumoral vessels Abnormal vasculature like that found in a tumor is newly formed, highly fractured and architecturally disordered with fragile, immature blood vessels (shown in green at right) which lack external smooth muscle and pericyte support (shown in red).

43. from nature to medicine

44. CA4P COMBRETASTATIN A4P (CA4P) Combretastatin is a small organic molecule found in the bark of the African bush willow tree Combretum caffrum. CA4P (disodium combretastatin-A-4 –3-O-phosphate) is a prodrug and is rapidly dephosphorylated to the active compound CA4. CA4 The drug is structurally similar to colchicine, binds the colchicine-binding site on tubulin, and inhibits tubulin polymerization. Colchicine

45. COMBRETASTATIN A4P (CA4P) Histological studies have shown that several tubulin-binding and other antineoplastic agents can induce vascular damage within tumors but only at doses approximating the MTD, which has limited their applicability. In contrast, CA4P induces vascular shutdown within tumors at doses less than one-tenth of the MTD in murine models. Dark, G. G., Hill, S. A., Prise, V. E., Tozer, G. M., Pettit, G. R., and Chaplin, D. J Combretastatin A-4, an agent that displays potent and selective toxicity toward tumor vasculature. Cancer Res., 57: 1829–1834, 1997.

46. COMBRETASTATIN A4P (CA4P) Combretastatin reduce the vessel lumen (changing the endethelial cell shape) and then reduce the blood flow to tumoral cells (Clinical trial in phase II/III).

47. COMBRETASTATIN A4P (CA4P) Multicentric study: open-label, randomized, fase II/III to evaluate safety and efficacy of Combretastatin A-4 phosphate in combination with Paclitaxel and Carboplatin (ARM 1)vs Paclitaxel and Carboplatin (ARM 2)in Anaplastic thyroid cancer Dept of Endocrinology, Pisa Up to date, 12 patients (3 in ARM 1; 9 in ARM 2) have been enrolled The primary end point was to evaluate the survival

48. ANAPLASTIC THYROID CARCINOMA Conclusions • Undifferentiated thyroid carcinoma is the most aggressive and lethal form of thyroid cancer • The effect of the conventional therapies is up to now discouraging • Multimodal approach • Probably, the future are the new therapies (vascular target therapy)

49. Thank you for your attention! University of Pisa Department of Endocrinology and Metabolism Prof. Rossella Elisei

50. Thank you for your attention! Dr.ssa Eleonora Molinaro Dr. Filippo Niccolai Dr. Angelo Molinaro