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Minimizing Grey Zones

in Thyroid Pathology

Sylvia L. Asa, MD, PhDPathologist-in

Medical Director

Laboratory Medicine Program

University Health Network, Toronto

Minimizing Grey Zones

in Thyroid Pathology

Sylvia L. Asa, MD, PhDin-Chief

Medical Director

Laboratory Medicine Program

University Health Network, Toronto

Controversies

• Nodules in Thyroiditis

• Sporadic Nodular Goitre/Follicular nodular disease

• Papillary adenomas

• Follicular Variant Papillary Carcinoma/Follicular • Follicular Variant Papillary Carcinoma/Follicular carcinoma

• Capsular Invasion

• Extrathyroidal Extension

• Vascular invasion

Controversies

Sporadic Nodular Goitre/Follicular nodular disease

Follicular Variant Papillary Carcinoma/Follicular Follicular Variant Papillary Carcinoma/Follicular

Hashimoto’s Thyroiditis

• Lymphoplasmacytic infiltrate with follicle infiltrate with follicle formation

Thyroiditis: Morphology

Hashimoto’s Thyroiditis

• Oncocytic or Hürthle cell Hürthle cell metaplasia

Thyroiditis: Cytology

Hashimoto’s Thyroiditis: Cytology

• Oncocytic or Hürthle cell metaplasiametaplasia

• With atypia!

• IS THIS DYSPLASIA?

Hashimoto’s Thyroiditis: Cytology

Nodules in ThyroiditisNodules in Thyroiditis

Hyperplasia in Thyroiditis

• Not encapsulated

• Cellular

• Bland cytology

• ? Due to TGI• ? Due to TGI

• ? Destruction of follicular epithelium ±regeneration

Hyperplasia in Thyroiditis

Carcinoma

in Thyroiditis

Nuclear features of papillary carcinoma

Controversies








Controversies



Sporadic Nodular Goiter

• Multinodular “colloid” goiter

• Occasionally associated with hyperthyroidism hyperthyroidism

– “Plummer’s disease”

• Etiology and pathogenesis NOT understood


Thyroid Morphology

• Multifocal, bilateral, assymetrical nodularity nodularity

• variable architecture and cytology

Thyroid Morphology

1

3 2

Follicular Nodular Disease

Colloid-rich, variable architecture

& cytology, Sanderson’s polsters


Focal degeration, stellate scar,

hemorrhage & hemosiderin

Follicular Nodular Disease:

Is It Hyperplasia?

Follicular Nodular Disease:

Adenomatoid

Nodule

• Encapsulated

• Uniform architecture

• B land cytology

• Different from • Different from

surrounding gland

• Compresses

surrounding gland

• Is it adenoma?

Definitions:

Hyperplasia vs

• An increase in the

number of cells in an

organ or tissue that is

induced by known

•

induced by known

stimuli

• A controlled process

that stops when the

environmental

stimulus is removed

•

Definitions:

vs Neoplasia

• A proliferation of cells that

exceeds and is

uncoordinated with that of

normal tissues normal tissues

• An uncontrolled process

that persists independent of

environmental stimulation

Classical Criteria:

Hyperplasia vs

• Multiple

• Poorly encapsulated

• Architectural heterogeneity

• Cytological heterogeneity• Cytological heterogeneity

• Comparable areas in adjacent gland

• No compression of surrounding gland

Classical Criteria:

vs Neoplasia

Architectural heterogeneity

Cytological heterogeneity

• Solitary

• Encapsulated

• Uniform architecture

• Cytological homogeneityCytological heterogeneity • Cytological homogeneity

• Different from surrounding gland

• Compresses surrounding gland

Clonality Patterns in

Sporadic Nodular Goiter:Multiple Monoclonal Nodules

Apel et al; Diagn. Mol. Pathol. 1995; 42:113

Patterns in

Sporadic Nodular Goiter:Multiple Monoclonal Nodules

Apel et al; Diagn. Mol. Pathol. 1995; 42:113-121

Clonality of Nodules in


• Polyclonal OR Monoclonal

i.e. hyperplastic OR neoplastic

• Nodules may show LOH or aberrant methylation

i.e. features of neoplasiai.e. features of neoplasia

• Multiple nodules from a single goiter exhibit

activation of the same allele ? predisposition

?Diagnostic criteria

? Hyperplasia-neoplasia

Apel et al; Diagn. Mol. Pathol. 1995; 42:113

Clonality of Nodules in


Polyclonal OR Monoclonal

hyperplastic OR neoplastic

Nodules may show LOH or aberrant methylation

features of neoplasiafeatures of neoplasia

Multiple nodules from a single goiter exhibit

activation of the same allele ? predisposition

neoplasia sequence

Apel et al; Diagn. Mol. Pathol. 1995; 42:113-121

Terminology When Not Goiter:


• Avoids controversy

• Avoids misunderstanding

Clarifies lack of understanding• Clarifies lack of understanding

Terminology When Not Goiter:


Avoids controversy

Avoids misunderstanding

Clarifies lack of understandingClarifies lack of understanding

Follicular Nodular Disease: Pearls

• Follicular nodular disease is common

• Some may be hyperplasia, but much is

multifocal neoplasiamultifocal neoplasia

• Nodules in FND/SNG are usually benign

• Nodules in FND/SNG may be malignant!

• Watch out for generation, but …..

• Watch out for cancer!

Follicular Nodular Disease: Pearls

Follicular nodular disease is common

Some may be hyperplasia, but much is

Nodules in FND/SNG are usually benign

Nodules in FND/SNG may be malignant!

Watch out for generation, but …..

Watch out for cancer!

Controversies








Controversies



Follicular Adenoma with Papillary Architecture:Papillary Adenoma

• Hot nodules on scan

• Biologically benign

• Papillary architecture • Papillary architecture

but benign cytology

• Solitary or Plummer’s

• Molecular features:– monoclonal

– activating mutations of

TSH receptor or Gsα

Follicular Adenoma with Papillary Architecture:

G-Protein Activation and Action

αβ

γ

ReceptorGDP

GTP

Effector

OFF

GTP

αβ

γ

Receptor

GDP� GTP

Effector

Protein Activation and Action

αβ

γ

Receptor

GTP GDP

Effector

Ligand

GTP GDP

αβγ

Receptor

GTP

Effector

ON

Controversies








Controversies



Follicular Adenoma or

Papillary Carcinoma?

Follicular Adenoma or

Papillary Carcinoma?

The Answer:

5 Years Later

• Do we overcall many

to catch this one?

• Do we undercall many • Do we undercall many

and miss this one?

• Do we find scientific

markers to predict

behavior?

Do we undercall many Do we undercall many

Follicular Adenoma

A follicular neoplasm

that:

does NOT exhibit

invasive features invasive features

and

does NOT have

nuclear features of

papillary carcinoma

Follicular Adenoma

Follicular Adenoma Follicular Adenoma vs Carcinoma

• Distinguished

by features

of invasion

Follicular Variant PTC

• A follicular neoplasm of thyroid

defined by the presence of a

unique set of nuclear features:

1. Enlarged, overlapping nuclei

2. Pale vacuolated nucleoplasm

with peripheral margination of

chromatin

3. Irregular nuclear membrane

4. Nuclear grooves

5. Nuclear pseudoinclusions

Follicular Variant PTC

A follicular neoplasm of thyroid

defined by the presence of a

unique set of nuclear features:

Enlarged, overlapping nuclei

Pale vacuolated nucleoplasm

with peripheral margination of

Irregular nuclear membrane

3D-Reconstruction

Virchows Arch (2004) 444:350

econstruction of PTC Nuclei

Virchows Arch (2004) 444:350–355

Emerin Identifies Nuclear Features

Asioli et al

Histopathology. 2009;54:571-9

Asioli et al

Virchows Archiv 2010:457:43-51

Emerin Identifies Nuclear Features

FVPTC vs Follicular Carcinoma

• Both differentiated thyroid malignancy

• Both follicular architecture

• Similar biologic behavior

• Similar genetic profiles• Similar genetic profiles

• Are they really the same thing?

• Are the criteria wrong?

• Does the distinction matter?

Follicular Carcinoma

Both differentiated thyroid malignancy

Both follicular architecture

Similar biologic behavior

Similar genetic profilesSimilar genetic profiles

Are they really the same thing?

Are the criteria wrong?

Does the distinction matter?

Markers of Thyroid Malignancy:

HBME-1

• Monoclonal antibody

• Unknown epitope

• Unknown significance

• Identified in 60% of • Identified in 60% of

thyroid malignancies, not

in normal or benign

lesions


thyroid malignancies, not


Galectin-3

• 31kD β-galactoside-

binding lectin

• High percentage of • High percentage of

malignant thyroid

tumors, not in

normal or benign

lesions


Markers of Papillary Carcinoma:

CK19• one of many keratins

• identified diffusely in 60% of papillary carcinomas

• also seen in reactive • also seen in reactive nontumorous thyroid

Markers of Papillary Carcinoma:

identified diffusely in 60% of

Raphael et al, Mod Pathol.

1995;8(8):870-2

Controversies








Controversies



Capsules in Endocrine Tissues

• The pituitary and adrenals


The pituitary and adrenals have capsules


• The thyroid and parathyroid

don’t

• The pancreatic islets, adrenal

medulla and other dispersed medulla and other dispersed

endocrine cells don’t


The thyroid and parathyroid

The pancreatic islets, adrenal

medulla and other dispersed medulla and other dispersed

Normal Thyroid Histology

Mete et al, Ann Surg Oncol 2010, 17(2): 386

Normal Thyroid Histology

Mete et al, Ann Surg Oncol 2010, 17(2): 386

Capsules in Thyroid Tumors

• Thyroid tumors may NOT

have a capsule

• Capsular invasion cannot

be evaluatedbe evaluated

• Invasion must be

assessed as

infiltration into

surrounding

parenchyma, perineural

or vascular involvement

Capsules in Thyroid Tumors

Thyroid tumors may NOT

Capsular invasion cannot

parenchyma, perineural

Capsular Invasion by

Thyroid Neoplasms

• Refers to TUMOR capsule

• Generally accepted as

evidence of malignancy evidence of malignancy

IF there is a capsule in

thyroid follicular neoplasms

Capsular Invasion by

Thyroid Neoplasms

Refers to TUMOR capsule

Generally accepted as

evidence of malignancy evidence of malignancy

IF there is a capsule in

thyroid follicular neoplasms

Definitions: Capsular Invasion

• Nests, cords or cells in

capsule

• Islands in capsule

associated with

perpendicular rupture

of collagenof collagen

• In capsule beyond bulk

of lesion

• Total thickness into

adjacent parenchyma

?? Artefactual trapping

?? postFNA

Definitions: Capsular Invasion

?? Artefactual trapping

Capsular Invasion

• Most agree with “Yes”

• Many agree • Many agree with “No”

• Few agree with “Not yet”

FROM: Chan JKC. The thyroid gland. In: Fletcher CDM, ed.

of Tumours.

Capsular Invasion

FROM: Chan JKC. The thyroid gland. In: Fletcher CDM, ed. Diagnostic Histopathology

of Tumours. 3rd ed. Edinburgh; Churchill Livingstone Elsevier; 2007:1018.

Classification of

Thyroid Carcinoma

• Minimally invasive carcinoma

up to 100% 10 year survival

• Widely invasive carcinoma

25-45% 10 year survival

What is Minimally vs Widely Invasive?

- You can see wide invasion grossly!

Classification of

Thyroid Carcinoma

Minimally invasive carcinoma

10 year survival

Widely invasive carcinoma

10 year survival

What is Minimally vs Widely Invasive?

You can see wide invasion grossly!

Controversies








Controversies



Extra-Thyroidal Invasion

• Since the thyroid has no capsule

and

normal thyroid can be found in fat:

• Skeletal Muscle invasion is the • Skeletal Muscle invasion is the

hallmark of ETE in the lateral lobes

� The interpretation of ETE is

problematic in the isthmus because

of the normal proximity of muscle

and thyroid follicles (Soemmering

muscle)

Thyroidal Invasion

normal thyroid can be found in fat:

hallmark of ETE in the lateral lobes

problematic in the isthmus because

and thyroid follicles (Soemmering

What is the Significance of

Extra-Thyroidal Invasion?

• Primary Tumor (pT)

• ___ pTX: Cannot be assessed

• ___ pT0: No evidence of primary tumor

• ___ pT1: Tumor size 2 cm or less, limited to thyroid

• ___ pT1a: Tumor 1 cm or less in greatest dimension limited to the thyroid.• ___ pT1a: Tumor 1 cm or less in greatest dimension limited to the thyroid.

• ___ pT1b: Tumor more than 1 cm but not more than 2 cm in greatest dimension, limited to the thyroid

• ___ pT2: Tumor more than 2 cm, but not more than 4 cm, limited to thyroid

• ___ pT3: Tumor more than 4 cm limited to thyroid or any tumor with minimal extrathyroid extension (eg, extension to sternothyroid

• ___ pT4a: Moderately advanced disease. Tumor of any size extending beyond the thyroid capsule to invade subcutaneous soft tissues, larynx, trachea, esophagus or recurrent laryngeal nerve

• ___ pT4b: Very advanced disease. Tumor invades carotid artery or mediastinal vessels

What is the Significance of

Thyroidal Invasion?

No evidence of primary tumor

Tumor size 2 cm or less, limited to thyroid

Tumor 1 cm or less in greatest dimension limited to the thyroid.

Maybe

because this

is not really

ETE??Tumor 1 cm or less in greatest dimension limited to the thyroid.

Tumor more than 1 cm but not more than 2 cm in greatest dimension,

Tumor more than 2 cm, but not more than 4 cm, limited to thyroid

Tumor more than 4 cm limited to thyroid or any tumor with minimal sternothyroid muscle or perithyroid soft tissues)

Moderately advanced disease. Tumor of any size extending beyond the thyroid capsule to invade subcutaneous soft tissues, larynx, trachea, esophagus or recurrent

Very advanced disease. Tumor invades prevertebral fascia or encases

Controversies








Controversies



PseudoVascular Invasion

by Thyroid Neoplasms

1. Tumor cells bulging into an

endothelial-lined lumen

2. Intravascular tumor nests 2. Intravascular tumor nests

covered with endothelium

3. Tumor casts within vessel

lumen

Mete and Asa, Modern Pathol Dec 2011

Invasion

Neoplasms

1

23

? artificial

implantation

True Vascular Invasion

by Thyroid Neoplasms

• Intravascular tumor

associated with

thrombusthrombus

• Rigid criteria predict

high likelihood of

metastasis

EVEN in differentiated

thyroid carcinomaMete and Asa, Modern Pathol ,Dec 2011

True Vascular Invasion

Neoplasms

Angioinvasion

Differentiated Thyroid Carcinoma

• Must be defined properly

• Must be distinguished from lymphatic invasion

– The term “lymphovascular invasion” should be – The term “lymphovascular invasion” should be discarded in this field! *

• Is predictive of aggressive behavior

* the CAP worksheets need to be revised

Angioinvasion in

Differentiated Thyroid Carcinoma

Must be defined properly

Must be distinguished from lymphatic

The term “lymphovascular invasion” should be The term “lymphovascular invasion” should be discarded in this field! *

Is predictive of aggressive behavior

* the CAP worksheets need to be revised

Controversies in Thyroid Pathology

Controversy

prolonged public dispute or debate,

usually concerning a matter of opinionusually concerning a matter of opinion

It is time for some science!

Controversies in Thyroid Pathology

Controversy is a state of

prolonged public dispute or debate,

usually concerning a matter of opinionusually concerning a matter of opinion

It is time for some science!

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