vania nosé, m.d., ph.d. harvard medical school differentiated and...poorly differentiated thyroid...

Poorly Differentiated Thyroid Carcinoma

Vania Nosé, M.D., Ph.D.

Harvard Medical School

Follicular Cell-derived Thyroid

Carcinomas

Poorly Differentiated

Anaplastic/Undifferentiated

2007 Estimated US Cancer Cases*

*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.Source: American Cancer Society, 2007.

Men766,860

Women678,060

•26% Breast

•15% Lung & bronchus

•11% Colon & rectum

•6% Uterine corpus

• 4% Non-Hodgkinlymphoma

•4% Melanoma of skin

• 4% Thyroid

• 3% Ovary

• 3% Kidney

•3% Leukemia

•21% All Other Sites

Prostate 29%

Lung & bronchus 15%

Colon & rectum 10%

Urinary bladder 7%

Non-Hodgkin 4% lymphoma

Melanoma of skin 4%

Kidney 4%

Leukemia 3%

Oral cavity 3%

Pancreas 2%

All Other Sites 19%

Thyroid Carcinomas, Follicular Cell Origin

Poorly Differentiated Undifferentiated/Anaplastic

Follicular Carcinomas

Low GradeMinimallyInvasive

WidelyInvasive

Well-differentiated

PapillaryFollicular

PapillaryVariants

High Grade

InsularTrabecular

Spindle-cellEpithelioidGiant Cell

Paucicellular

Poorly Differentiated Carcinoma

Poorly Differentiated CarcinomaThyroglobulin and TTF1

Immunohistochemistry

• Positive for thyroglobulin and TTF-1, even if in

scattered cells

• High MIB-1 index (10-30% of cells)

PDTC metastases to bone

Epidemiology

Source: WHO Classification of Tumours: Tumours of Endocrine Organs. (2004)

• More common in women

• Majority of patients older than 50 years

• Uncommon (4-7% of thyroid carcinomas in Italy), even less common in USA

• Arise within well-differentiated thyroid carcinomas or de novo

• Difficulty in classifying this lesion makes its incidence unclear, as it is often over or under-called

• Mean 5 year survival approximately 50%

– Regional and distant mets rather than local invasion

Diagnostic CriteriaPoorly Differentiated Carcinoma

• Presence of a solid/trabecular/insular pattern of growth

• Absence of the conventional nuclear features of papillary carcinoma

• Presence of AT LEAST one of the following:

– Convoluted nuclei

– Mitotic activity ≥ 2 x 10 HPF

– Tumor necrosisPoorly Differentiated Thyroid Carcinoma: The Turin Proposal for the Use of Uniform Diagnostic Criteria and an

Algorithmic Diagnostic Approach. Volante M, Collini P, Nikiforov YE, Sakamoto A, Kakudo K, Katoh R, Lloyd RV,

LiVolsi VA, Papotti M, Sobrinho-Simoes M, Bussolati, and Rosai J

Am J Surg Path 31(8):1256-1264. August 2007

Volante M. et al., Am J Surg Path 31(8):1256-1264. August 2007

• Seen in consultation on 10/07

• 34 year old man who noticed a mass growing

in his neck over past 4 years

• Fixed mass on clinical exam

• Mass and thyroid resected (10.5 cm mass)

mitoses

Tumor Necrosis

vascular invasion

paucicellular

Spindle cell

Final Anatomic Diagnosis

• Anaplastic Thyroid Carcinoma Arising in a

Anaplastic Thyroid Carcinoma

Anaplastic Thyroid Carcinoma (ATC):Clinical Features

• Accounts ~ 1.7% of all thyroid carcinomas in the United States

• Female predominance (2.4:1 female to male ratio)

• Peak incidence in the seventh to eighth decade of life

• Most patients present with a rapidly enlarging neck mass

Anaplastic Thyroid Carcinoma (ATC):Clinical Features

The most frequently associated signs and symptoms are dysphagia, hoarseness,

and stridor

• A history of goiter has been reported in 25% of patients with anaplastic thyroid

carcinoma

• Very poor prognosis

Anaplastic Thyroid Carcinoma (ATC)

• Gross Findings:

• - Median tumor size is 5 cm

• - Tumors are often white/tan in color with areas of necrosis and hemorrhage and an

infiltrative growth pattern

Histologic Findings

• Although every type of DTC has been reported in association with ATC, papillary cancer is the

most common type, especially tall cell and insular types

• Anaplastic thyroid carcinomas showing osteosarcomatous or chondrosarcomatous

differentiation are very rare

• Immunohistochemical studies of these tumors have shown that they are rarely positive for TTF-

1 and CEA, but are often positive for keratins (78.1%) and EMA (31.3%) (Ordonez)

Anaplastic Carcinoma

• Patterns:• Spindle/giant cell

• Angiosarcomatous• MFH-like

• Hemangiopericytoma-like• May show chondroid and osteoid

(Carcinosarcoma)• Epithelial

• Arises as dedifferentiationof low grade lesion

• Evidence:• History

• Histology• Molecular biology

• History• Low grade lesion with recurrences and

metastases• Seen next to and admixed

with low grade lesion

• Histology• Blending of low and high grade lesions

• Transitions between the two

• Variants:–Osteoclastic

–Paucicellular Anaplastic Carcinoma –Lymphoepithelioma-like Carcinoma

• Patterns:• Spindle cell• Giant cell

• Hemangiopericytoma-like• May show chondroid and osteoid differentiation

• Plasmacytoid

IV tumor

Invasion vessel wall

Histologic Findings

• Tumors can be spindle cell, giant cell, squamoid, or mixed type

• Necrosis, a high mitotic rate, vascular invasion, and extra-thyroidal extension are

frequent findings

• The reported rate of differentiated thyroid carcinoma [DTC] found in association with

ATC ranges from 23% to 90%

• Widely invasive tumors• Composed of an admixture of spindle cells,

pleomorphic giant cells, epithelioid cells• Cytokeratin (80%)

• EMA (30-50%)• CEA (<10%)

• Thyroglobulin –• TTF1 –

• TP53 strongly positive

Clinical History

• The patient is a 79-year-old man with severe aortic stenosis

• In his preoperative evaluation for aortic valve replacement, he was found to have mediastinal goiter (FNA performed at outside hospital and not reviewed) that was producing significant compression of his trachea and esophagus

• It was decided to remove the mediastinal goiter in conjunction with the aortic valve replacement

surgery

Extra-capsular Extension

ANAPLASTIC CARCINOMA

• IMMUNOHISTOLOGY• Cytokeratin AE1/3, CK903, less Cam 5.2

• EMA may be +• Thyroglobulin negative except diffusion

• TTF1 <1/3 said to be +• P53 +

• KI-67 up to 100%

• TTF-1 • In squamous type, may help distinguish

from collision tumor of PTC and SCC of head and neck origin

• Whether all ATC represents dedifferentiation of a DTC or whether

some cases arise de novo, has not been resolved

• The finding of ATC with a DTC component suggests that the ATC may represent

dedifferentiation of DTC

• In addition, there is molecular evidence supporting this hypothesis

• ATCs with BRAF mutations and p53 mutations have been found coincident with

papillary thyroid carcinomas with BRAFmutations, suggesting that these ATCs

may be derived from BRAF-mutated PTC with additional p53 mutation

• 75% patients over 60 years• Female to male ratio is 1.5:1

• 1-2 cases per million• Mortality over 90% with mean survival of 6

months after diagnosis• Evidence of a pre-existing differentiated or

poorly differentiated carcinoma

Anaplastic Carcinoma• Rapidly expanding neck mass

• Hoarseness• Dysphagia

• Vocal cord paralysis• Cervical pain

• Dyspnea• Fixed and hard tumors (75%)

• Single (60%) or multiple nodules (40%)• Bilateral involvement (25%)

• Distant metastases at time of diagnosis (40%)

• Differential diagnosis:– Desmin, Myogenin, Myo-D1 negative

(Rhabdomyosarcomas)– SMA, Desmin (Leiomyosarcomas)

– CD31, CD34, FVIII (Angiosarcomas)– HMB-45, Mart1, Melan-A (Melanomas)

– CD45 (Large cell Lymphomas)

References1. Cancer. 2000 July;89(1): 202-217. Initial Results from a Prospective Cohort Study of

5583 Cases of Thyroid Carcinoma Treated in the Unit ed States during 1996. Hundahl S, Cady B, Cunningham M, Mazzaferri E, McKe e R, Rosai J, Shah J,

Fremgen AM, Stewart AK, Holzer S.

2. Arch Pathol Lab Med. 1987 Dec;111(12):1169-72. Th yroid carcinosarcoma. Donnell CA, Pollock WJ, Sybers WA.

3. Pathol Res Pract. 1994 May;190(5):507-12. Anaplas tic thyroid carcinoma with osteosarcomatous differentiation. Blasius S, Edel G , Grünert J, Böcker W, Schmid

4. Annals of Surgical Oncology, 13(4): 453-464. Anap lastic Thyroid Carcinoma: Biology, Pathogenesis, Prognostic Factors, and Trea tment Approaches. Are C,

Shaha AR.

5. Am J Clin Pathol. 1991 Jul;96(1):15-24. Anaplasti c thyroid carcinoma. Immunocytochemical study of 32 cases. Ordóñez NG, E l-Naggar AK, Hickey RC,

Samaan NA.

6. Cancer. 2005 Jun 1;103(11):2261-8. Evidence tha t one subset of anaplastic thyroid carcinomas are derived from papillary carcinomas du e to BRAF and p53 mutations.

Quiros RM, Ding HG, Gattuso P, Prinz RA, Xu X.

HISTORY

• Elderly woman with neck mass with difficulty breathing when lying down

• Physical exam: 10 cm mass left neck involving thyroid

• Surgery attempted—subtotal removal of mass

HISTORY

• History 15 years ago of papillary thyroid carcinoma

• Underwent total thyroidectomy and RaI• After 5 years, she was “released” from

continuing medical care

TRANSITION AREA

Mitoses in “bland” cell

Another transition area

PAPILLARY CA

SPINDLE CELL CA

KERATINIZED CELLS

TUMOR NECROSIS

CYTOKERATIN

ANAPLASTIC CARCINOMA

• Elderly individuals usually over 60 years old

• Rare under 50 years old• Often large and extrathyroidal

• Makes up about 5% of thyroid cancer• Awful prognosis

• Patterns:• Spindle/giant cell

• Hemangiopericytoma-like• May show chondroid and osteoid

• Arises as dedifferentiationof low grade lesion

• Evidence:• History

• Histology• Molecular biology

• History• Low grade lesion with recurrences and

metastases• Seen next to and admixed

with low grade lesion

• Histology• Blending of low and high grade lesions

• Transitions between the two

• Epithelial Types• “Large cell” carcinoma

• Spindle cell squamous carcinoma

• Spindle Cell Squamous Carcinoma• Always from tall cell papillary carcinoma

• May develop in recurrences or metastases or in primary site

• Spindle Cell Squamous Carcinoma• Immunohistology

• Thyroglobulin• Cytokeratin

• TTF-1

Squamous

• The Variable Presentations of Anaplastic Spindle Cell Squamous Carcinoma associated with Tall Cell Variant of

Papillary Thyroid Carcinoma: A Report of 29 Patients

• Montone et al 2010 (presented at ITC)

• Three clinical scenarios for SSCC were identified:

• Type I: TCV with SSCC at the time of presentation: 19 patients

• Type II: SSCC arising as a recurrence in patients with a known history of TCV: 4 patients

• Type III: SSCC presenting like primary laryngeal SCC in a patient with or without a known history of TCV: 6

patients

TTF-1 in squamous type, may help distinguish from collision tumor of PTC and SCC of head and neck origin

• Molecular Biology• Compare LOH in low grade lesion

(papillary cancer) and anaplastic carcinoma

• Similar LOH with greater abnormalities in anaplastic tumor—progression

• Molecular Biology 2• The BRAF story

• BRAF mutations occur in 45% of papillary carcinoma-mostly classic and tall cell

types• BRAF mutations in about 33% of

anaplastic carcinoma• Possibility of targeted therapy

• Prognosis• Awful 90% dead of tumor in 6 months• Rare survivals if found incidentally in

thyroid or in metastasis• If patient survives question the diagnosis -

??malignant lymphoma• Remember: Paucicellular variant

vania nosé, m.d., ph.d. harvard medical school differentiated and...poorly differentiated thyroid...

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