undifferentiated thyroid carcinoma university of pisa p rof. p aolo v itti d epartment of e...
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UNDIFFERENTIATED THYROID CARCINOMAUNDIFFERENTIATED THYROID CARCINOMA
UNIVERSITY of PISA
PROF. PAOLO VITTI
DEPARTMENT OF ENDOCRINOLOGY AND
METABOLISM
THYROID TUMORS
Patel K. N., Shaha A.R. – Poorly differentiated and Anaplastic thyroid cancer Cancer Control, April 2006, Vol. 13 No. 2
THYROID TUMORS
Patel K. N., Shaha A.R. – Poorly differentiated and Anaplastic thyroid cancer Cancer Control, April 2006, Vol. 13 No. 2
Poorly differentiated thyroid cancer
Nonglandular components with a solid, trabecular, and/or scirrhous growth pattern.
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 poorly differentiated as defined by the tumor architecture is not justified
THYROID TUMORS
Burman KD, Ringel MD, Wartofsky L, et al. Unusual types of thyroidneoplasms. Endocrinol Metab Clin North Am. 1996;25:49-68.
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).
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.
Undifferentiated thyroid cancer: Pathology
No follicular structure
Survival vs Histotype: The Pisa Experience
THYROID TUMORS
Elisei R, Molinaro E. et al. JCEM 2010.
Surv
ival
%
PTC
FTC
MTC
ATC
0
5 0
1 0 0
0 2 5 1 0 1 5 2 0
What is the biological difference?
Differentiated vs Undifferentiated Thyroid Cancer
Differentiated Undifferentiated
Thyroglobulin production Yes No
Iodide uptake Yes No
Expression of TSH receptor Yes No
Fast tumor growth No Yes
Early metastasis No Yes
THYROID TUMORS
Undifferentiated thyroid cancer
Pathogenesis ?
Genetic alterations in thyroid carcinoma
GENETICS
Genetic alteration PTC FTC ATC MTC
RET rearrangement 13-43%
RET mutation 30-50%(MEN2:100)
NTRK1 rearrangement 5-13%
BRAF mutation 29-69% 10-35%
RAS mutation 0-21% 40-53% 20-60%
PPAR-γ rearrangement 25-63%
P53 mutation 67-88%
Modified from Kondo T, et al.Nat Rev Cancer. 2006
GENETICS – p53
J Clin Invest 91: 179-84, 1993
Papillarycarcinoma
Follicularcarcinoma
Poorly differentiated
carcinoma
Undifferentiatedcarcinoma
%
Hypothesis: two different pathways
PATHOGENESIS
Follicularcell
Follicularcell
PapillarycarcinomaPapillary
carcinoma
AnaplasticcarcinomaAnaplasticcarcinoma
BRAFRET-PTC
TRK MET
P53other genes
P53, other genes
FollicularcarcinomaFollicularcarcinomaRAS
PPAR-γ
P53other genes
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.
THYROID TUMORSUndifferentiated thyroid cancer
Clinical Features
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
Prevalence of Thyroid Hystotypes (n=7382)
THYROID TUMORS
Papillary Follicular Medullary Anaplastic Lymphoma Unknown
% o
f all
thyr
oid
tum
ors
Department of Endocrinology, Pisa, 1969-2004
THYROID TUMORS
The incidence of undifferentiated thyroid carcinoma has steadily decreased over the past few decades. Many hypothesis:
Improved iodine nutrition
THYROID TUMORS
American Journal of Medicine, vol. 93, no. 4, pp. 363–369, 1992.
Adequate iodine intake
Iodine deficiency
%
THYROID TUMORS
The incidence of undifferentiated thyroid carcinoma has steadily decreased over the past few decades. Many hypothesis:
Early diagnosis
Early treatment
THYROID TUMORS
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).
ECOGRAPHIC FEATURES
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.
Cytologic features:
PATHOLOGY - CITOLOGY
Higly malignant and bizarre cells
High-grade nuclear features: marked pleomorphism dark clumped chromatin macronucleoli atypical mitosis
Tumor diathesis
METASTASES
Regional nodal metastases and vocal cord paralysis are seen in up to 40% and 30%, respectively, of the patients with ATC.
Distant spread is present 75% of the time at diagnosis.
Lung: 80%
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
METASTASES
THERAPY
Many Therapeutical OptionsMany Therapeutical Options
SURGERY
EXTERNAL RADIOTHERAPY
CHEMOTHERAPY
MULTIMODALITY THERAPY
NEW THERAPIES
THERAPY
Target of therapies
Radical treatment, rarely possible
Palliative treatment
THERAPY – SURGERY
Most patients present at an advanced stage, making curative surgical resection not feasible.
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.
Some studies find that neither the extent of surgery nor the completeness of resection has a significant effect on survival.
THERAPY – SURGERY
Palliative management
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.
Airway obstruction occurs by one of three mechanisms:
THERAPY – SURGERY
external compression of the trachea (the most
common cause)
intraluminal tumor extension
bilateral vocal cord paralysis
Patients with either stridor or rapid tumor growth should be considered for tracheostomy since further airway compromise can be expected.
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.
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.
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.
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).
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.
Antitumor vascular targeting agents
NEW THERAPIES
One target, two ways: both inhibit tumor blood-supply
Antiangiogenic approach
Prevent new vessel formation
Acts slowly – weeks
Promiscuous for all angiogenesis; impairs wound-
healing
Tolerability issues
Vascular-disrupting approach
Collapse and occlude pre-existing tumor vessels
Acts rapidly – hours
Highly selective for abnormal vasculature
Well tolerated
Tyrosine kinase inhibitors
NEW THERAPIES - ANTIANGIOGENETICS
Compound Target
Gefitinib EGFR
Axitinib VEGFR
Motesanib RET- PDGF – VEGFR-KIT
Sorafenib RET-RAS-RAG- VEGF-VEGFR- PDGF-cKIT
Tyrosine kinase inhibitors: sorafenib
NEW THERAPIES - ANTIANGIOGENETICS
Angiogenesis
Raf
Endothelial cell or pericyte
Nucleus
VEGFR-2PDGFR-β
MEK
Apoptosis
Tumour cell
Proliferation
PDGF
VEGF
EGF
Survival
Ras
Nucleus
Ras
ERK
Raf
MEKApoptosis
ERK
PDGF-β VEGFParacrine stimulation
KIT/Flt-3/RET
SORAFENIB
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
SPONTANEOUS “OFF LABEL” StudyDept of Endocrinology, Pisa
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
SORAFENIB
Before sorafenib After 20 days of therapy
Bases of selective action of vascular disrupting agents on tumor vessels: differences between normal and tumoral vessels
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).
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).
from nature to medicine
COMBRETASTATIN A4P (CA4P)
CA4P (disodium combretastatin-A-4 –3-O-phosphate) is a prodrug and is rapidly dephosphorylated to the active compound CA4.
CA4P
CA4
The drug is structurally similar to colchicine, binds the colchicine-binding site on tubulin, and inhibits tubulin polymerization.
Colchicine
Combretastatin is a small organic molecule found in the bark of the African bush willow tree Combretum caffrum.
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.
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).
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
Conclusions
ANAPLASTIC THYROID CARCINOMA
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)
Thank you for your attention!
University of Pisa
Department of Endocrinology and
Metabolism
Prof. Rossella Elisei
Thank you for your attention!
Dr. Angelo Molinaro
Dr.ssa Eleonora Molinaro
Dr. Filippo Niccolai
GENETICS
J Oncol. 2010;2010:351679
BRAF RASPI3K/AKT and PTEN P53 CTNNB1
%
TNM classification
STAGING
All anaplastic carcinoma are stage IVThere are three stage IV:
IV-A where tumor is limited to the thyroid and considered surically resectable
IV-C where tumor is present with distant metastases.
IV-B where tumor extending beyond the thyroid and considered surgically unresectable