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