Thyroid Tumours From Well to Poorly Differentiated and Undifferentiated CarcinomasAlgiers, Nov 25, 2008

Porto, Portugal

WHO book on Endocrine Tumours, 2nd edition, Zurich 1986

THYROID CARCINOMA

Follicular carcinomaPapillary carcinoma(Hürthle cell carcinoma)Medullary carcinomaPoorly differentiated carcinomaUndifferentiated carcinoma

WHO books on Endocrine Tumours, 2nd & 3rd editions, 1988 & 2004

WHO book on Endocrine Tumours, 3rd edition, 2004

THYROID CARCINOMASFollicular carcinomaPapillary carcinoma

Hyalinizing trabecular tumourMucoepidermoid carcinomaSclerosing mucoepidermoid ca

with eosinophilia

Medullary carcinoma Mixed medullary and follicular cell caPoorly differentiated ca

Squamous cell carcinomaMucinous carcinoma

Undifferentiated ca

Questions to be made whenever facing a strange lesion in the thyroid

Is it a primary thyroid tumour?If yes, is it made of follicular or C-cells?

Immunohistochemistry is mandatory: TG and calcitonin (and, if necessary, TTF1)

Thyroglobulin

Calcitonin

Most frequent problems of thyroid pathology in a consultancy practice

1. Is there a focus (or some foci) of papillary carcinoma in “this” Hashimoto’s thyroiditis or “this” nodular goiter?2. Is this lesion an adenoma, a follicular carcinoma or a follicular variant of papillary carcinoma?3. How would you classify this Hürthle cell lesion?4. Is this a well differentiated carcinoma with a solid pattern of growth or a poorly differentiated carcinoma?

Diagnosis of (incipient) PTCIn our experience the most frequent doubts arise in four different settings:

a. Hashimoto’s thyroiditisb. Nodular (adenomatous) goiterc. Encapsulated well differentiated neoplasmsd. Oncocytic (Hürthle cell) neoplasms

Microdissected areas with PTC nuclei withinHashimoto’s thyroiditis

RET/PTC rearrangements – contradictory, positive and negative findingsSheils et al, Nikiforov et al, ...

B-RAF mutations – no mutations (n=6) Trovisco et al, 2005

Microdissected areas with PTC nuclei withinadenomas/nodular goiters

RET/PTC rearrangements – Yes Fusco et al, Am J Surg Pathol, 2002

B-RAF mutations – no (?) (few cases) Trovisco et al, 2005

Hashimoto’s thyroiditis and Adenoma/nodular goiter

Dispersed cells with PTC-nucleiwith or without molecular alterations

Clusters of cells with PTC-nuclei forming a microtumourwith or without molecular alterations

CONCLUSION

KEEP THE DIAGNOSIS

PTC

Encapsulated follicular neoplasm

Follicular patterned, encapsulated neoplasms

Adenoma

Follicularvariant of PTC

Minimallyinvasive

follicular ca

Malignancy in follicular patterned thyroid tumours

Capsular and/or VASCULAR INVASIONSolid, insular, trabecular

Pattern of growth Embryonal, fetalNormofollicularMacrofollicular

Nuclear features PTC NUCLEI

Follicular tumours

RAS activationOther factors

Chromosomalinstability (CINphenotype)Aneuploidy

PAX 8 - PPAR γOther alterations

Adenomaand

Follicular carcinoma

Follicularcell

A preoperative diagnostic test that distinguishes benign from malignant thyroid carcinoma based on gene expressionCerutti et al, J Clin Invest 113:1234, 2004

Follicular adenoma vs follicular carcinoma4 genes – predictive accuracy of 0.832 immunohistochem markers – estimated concordance of 0.76

Conclusion: A simple test based on a combination of these markers might improve preoperative diagnosis of thyroid nodules.

What is the best way to diagnose vascular invasion?

Histopathology Yes

Detection of biomarkers in the May beplasma/blood

High throughput approaches No

Encapsulated follicular tumour

Benign vs Malignant

Follicular adenoma

Follicular tumour of uncertainmalignant potential

Follicular carcinoma

Williams et al, Int J Surg Pathol, 8:181, 2000WHO book on Endocrine Tumours, 3rd ed, 2004

Follicular carcinoma

Minimally invasive

?Widely invasive

Follicular carcinoma

Minimally invasive

Widely invasive

Number and type of invaded vessels

Rosai et al, 2004WHO book on Endocrine Tumours, 2004

Papillary carcinoma

The optically clear nucleus:A reliable sign of papillary carcinoma of the thyroid?

Hapke MR & Dehner LP, Am J Surg Pathol 3:31, 1979

PROGNOSTIC MEANING OF HISTOLOGICAL VARIANTS OF PTC

DIFFUSE SCLEROSING VARIANTTALL CELL VARIANTCOLUMNAR CELL CARCINOMAMULTINODULAR TYPE OF FOLL VAR

MICROCARCINOMA

Papillary microcarcinomaOccult papillary carcinomaLatent papillary carcinomaSmall papillary carcinomaNonencapsulated thyroid tumourOccult sclerosing carcinomaOccult papillary tumour

Rosai et al Int J Surg Pathol 11:249, 2003

RENAMING PAPILLARY MICROCARCINOMA OF THE THYROID GLAND: THE PORTO PROPOSAL

Juan Rosai, Virginia A. LiVolsi, Manuel Sobrinho-Simões and E.D. Williams

International Journal of Surgical Pathology 11:249-251, 2003

MIB1

Molecular features of papillary thyroid carcinoma

RET/PTC rearrangements (15% - 40%)TRK rearrangements (5% - 10%)MET overexpression (>50% ?)............................................................B-RAF mutations (30% - 50%) [0% - 75%]

Trovisco et al, J Pathol 2004Lima et al, JCEM 89:4267, 2004

RET/PTC rearranged papillary carcinomas display a Bonsai phenotype

PROGNOSTIC MEANING OF HISTOLOGICAL VARIANTS OF PTC

DIFFUSE SCLEROSING VARIANTTALL CELL VARIANTCOLUMNAR CELL CARCINOMAMULTINODULAR TYPE OF FOLL VAR MICROCARCINOMA

PROGNOSTIC FACTORS IN PAPILLARY AND FOLLICULAR THYROID CARCINOMA

Completeness of surgery and responsiveness to radioactive iodine

A – Age M – Distant metastasesE – Extrathyroid extensionS – Size of the tumours

Still debatable: aneuploidy (D…AMES), vascular invasion and molecular features (MIB1, p53)

Conventional papillary carcinoma

Follicular variant of PTC

Follicular variant of PTC Three problems

1.Questionable diagnosis2.Prognosis3.Relationship with follicular carcinoma

Follicular patterned, encapsulated neoplasms

Adenoma

Follicularvariant of PTC

Minimallyinvasive

follicular ca

Am J Clin Pathol, Jan 2002• Chan JKC: Strict criteria should be applied in the

diagnosis of encapsulated follicular variant of papillary thyroid carcinoma

• Renshaw AA & Gould EW: Why there is the tendency to “overdiagnose” the follicular variant of papillary thyroid carcinoma

• Baloch ZW & LiVolsi VA: Follicular-patterned lesions of the thyroid: the bane of the pathologist

DIAGNOSTIC HINTSCapsular or, more importantly, vascular invasionNuclear features

WHAT ABOUT QUESTIONABLE CASES?

DOES IMMUNOHISTOCHEMISTRY OR MOLECULAR BIOLOGY HELP?

IMMUNOHISTOCHEMICAL MARKERS OF PAPILLARY THYROID CARCINOMA

• Cytokeratin 19• Lewis X and S Lewis X• Galectin 3 • HBME1• Fibronectin 1• ...................

S-Lex

Galectin-3 and HBME-1 expression in well-differentiated thyroid tumors with follicular architecture of uncertain malignant potential

8 cases with questionable invasion13 cases with questionable nuclear changes

GAL3 and HBME1 are more frequently present in the second group (10/13 and 9/13, respectively) than in the first group (3/8 and 5/8, respectively)

Papotti M et al, Mod Pathol 18:541, 2005

Observer variation in the diagnosis offollicular variant of PTC

(11 Reviewers - 87 cases – concordance 39%)

Asa SL Lloyd RVChan JKC Rosai JDeLellis RA Sebo TJHarach HR Sobrinho-Simões MKakudo K Wenig BMLiVolsi VA

Lloyd RV et al, Am J Surg Pathol, 2004

Usefulness of HBME-1, cytokeratin 19 and galectin-3 immunostaining in the diagnosis of thyroid malignancy

“Unfortunately, in contrast to many reports concerning the differential diagnosis of follicular patterned lesions, we found none of these markers sufficient to confer a sensitive and specific diagnosis”

Matos PS et al, Histopathology 47:391, 2005

B-RAF MUTATIONS IN176 PAPILLARY THYROID CARCINOMAS

Warthin-like PTC > 75%Conventional PTC ~ 50%

Follicular variant PTC < 5%

Soares et al, Oncogene 2003Trovisco et al, J Pathol, 2004

Lima et al, JCEM 89:4267, 2004

• Well differentiated tumor of uncertain malignant potential

• Well differentiated carcinoma, NOS

Williams et al, Int J Surg Pathol 8:181, 2000WHO book on Endocrine Tumours, 3rd edition, 2004

Follicular variant of PTCThree main types:• Encapsulated• Poorly circumscribed• Diffuse, aggressive, multinodular

Multicentricity Vascular invasivenessLung and bone metastases

PROGNOSIS

Diffuse follicular variant of PTCSobrinho-Simões et al, Surg Pathol 3:189, 1990Mikuzami et al, Histopathology 27:575, 1995

Aggressive follicular variant of PTCGuo et al, Lab Invest 79:67A, 1999

Solid variant of PTCNikiforov et al, Am J Surg Pathol 25:1478,2001

Multinodular follicular variant of PTCIvanova et al, Virchows Arch 440: 418, 2002

Encapsulated follicular variant of papillary thyroid carcinoma with bone metastases

5 cases with minimal invasion and distant metastasesBaloch ZW & LiVolsi VA, Mod Pathol 13:861, 2000

RELATIONSHIP WITH FOLLICULAR CARCINOMA

Follicular variant of PTC

Expanding tumours RAS mutationsVascular invasiveness BRAF K601ELung and bone metastases (No BRAF V600E)Less frequent nodal metast PAX8-PPARγ rearr ?

Aneuploidy?

Zhu et al, Am J Clin Pathol 120:71, 2003Trovisco et al, J Pathol 2002:247, 2004Castro P et al, J Clin Endocrinol Metab, 2006Castro P et al, 2008 (submitted)

Castro P et al, J Clin Endocrinol Metab, 2006

Follicular variant

Encapsulated follicular variant

PTCPTC

Papillarycarcinoma

Follicularcarcinoma

FVPTC

Prone to give rise to blood born metastases?Encapsulated follicular variant of PTC with PAX8-PPARg rearrangement?

Castro et al, J Clin Endocrinol Metab 91:213, 2006

Poorly differentiated carcinoma

Follicular caPoorly diff ca

Undifferentiatedca

Poorly diff ca

Papillary ca

Soares et al, Virchows Arch 444:572, 2004

B-RAF mutations in poorly differentiated carcinomaPure insular carcinoma – no B-RAF mutations

PTC + foci of poorly differentiated ca – with B-RAF mutations

Nikiforova et al, J Clin Endocrinol Metab 88:5399, 2003Soares et al, Virchows Arch 444:572, 2004

MultiMulti--continental study on poorly continental study on poorly differentiated thyroid carcinoma (PDCa)differentiated thyroid carcinoma (PDCa)

Turin, March 3-4 2006

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Volante M et al, Am J Surg Pathol, 2007 (Turin Proposal - Multicontinental study)

IPATIMUP

FACULDADE DE MEDICINA/HOSPITAL S.JOÃO

PORTO, PORTUGAL