UNDIFFERENTIATED THYROID CARCINOMA

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UNIVERSITY of PISA
UNDIFFERENTIATED THYROID CARCINOMA
Department of Endocrinology and Metabolism
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THYROID TUMORS
Patel K. N., Shaha A.R. Poorly differentiated
and Anaplastic thyroid cancer Cancer Control,
April 2006, Vol. 13 No. 2
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Poorly differentiated thyroid cancer
THYROID TUMORS
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
Patel K. N., Shaha A.R. Poorly differentiated
and Anaplastic thyroid cancer Cancer Control,
April 2006, Vol. 13 No. 2
4
Poorly differentiated thyroid cancer
THYROID TUMORS
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. 19962549-68.
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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.
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Survival vs Histotype The Pisa Experience
THYROID TUMORS
Elisei R, Molinaro E. et al. JCEM 2010.
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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
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Undifferentiated thyroid cancer
THYROID TUMORS
Pathogenesis ?
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Genetic alterations in thyroid carcinoma
GENETICS
Genetic alteration PTC FTC ATC MTC
RET rearrangement 13-43 ? ? ?
RET mutation ? ? ? 30-50 (MEN2100)
NTRK1 rearrangement 5-13 ? ? ?
BRAF mutation 29-69 ? 10-35 ?
RAS mutation 0-21 40-53 20-60 ?
PPAR-? rearrangement ? 25-63 ? ?
P53 mutation ? ? 67-88 ?
Modified from Kondo T, et al.Nat Rev Cancer. 2006
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GENETICS p53
J Clin Invest 91 179-84, 1993
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Hypothesis two different pathways
PATHOGENESIS
BRAFRET-PTC TRK MET
Papillary carcinoma
P53 other genes
P53, other genes
Follicular cell
Anaplastic carcinoma
Follicular carcinoma
P53 other genes
RAS PPAR-?
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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. 119128, 2006.
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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
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Prevalence of Thyroid Hystotypes (n7382)
THYROID TUMORS
of all thyroid tumors
Department of Endocrinology, Pisa, 1969-2004
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THYROID TUMORS

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

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THYROID TUMORS
American Journal of Medicine, vol. 93, no. 4, pp.
363369, 1992.
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THYROID TUMORS

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

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THYROID TUMORS
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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).
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ECOGRAPHIC FEATURES
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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.
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Cytologic features
PATHOLOGY - CITOLOGY

• Higly malignant and bizarre cells

• High-grade nuclear features
• marked pleomorphism
• dark clumped chromatin
• macronucleoli
• atypical mitosis

• Tumor diathesis

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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.
Patel K. N., Shaha A.R. Poorly differentiated
and Anaplastic thyroid cancer Cancer Control,
April 2006, Vol. 13 No. 2
24
METASTASES
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THERAPY
Many Therapeutical Options

• SURGERY
• EXTERNAL RADIOTHERAPY
• CHEMOTHERAPY
• MULTIMODALITY THERAPY
• NEW THERAPIES

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THERAPY
Target of therapies
Radical treatment, rarely possible Palliative
treatment
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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.
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THERAPY SURGERY
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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 patients presentation.
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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.
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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.
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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.
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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.
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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).
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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.
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Antitumor vascular targeting agents
NEW THERAPIES
One target, two ways both inhibit tumor
blood-supply
Vascular-disrupting approach
Collapse and occlude pre-existing tumor vessels
Acts rapidly hours
Highly selective for abnormal vasculature
Well tolerated
Antiangiogenic approach
Prevent new vessel formation
Acts slowly weeks
Promiscuous for all angiogenesis impairs wound-healing
Tolerability issues
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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
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Tyrosine kinase inhibitors sorafenib
NEW THERAPIES - ANTIANGIOGENETICS
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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
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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
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SORAFENIB
Before sorafenib
After 20 days of therapy
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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).
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from nature to medicine
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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.
The drug is structurally similar to colchicine,
binds the colchicine-binding site on tubulin, and
inhibits tubulin polymerization.
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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 18291834, 1997.
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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).
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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
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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)

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Thank you for your attention!
University of Pisa Department of Endocrinology
and Metabolism Prof. Rossella Elisei
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Thank you for your attention!
Dr.ssa Eleonora Molinaro
Dr. Filippo Niccolai
Dr. Angelo Molinaro
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GENETICS
J Oncol. 20102010351679
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TNM classification
STAGING
All anaplastic carcinoma are stage IV There are
three stage IV

• IV-A where tumor is limited to the thyroid and
  considered surically resectable

• IV-B where tumor extending beyond the thyroid
  and considered surgically unresectable

• IV-C where tumor is present with distant
  metastases.