This document discusses several areas of controversy in thyroid pathology. It begins by outlining controversies regarding nodules found in thyroiditis, sporadic nodular goiter, papillary adenomas, follicular variant papillary carcinoma versus follicular carcinoma, capsular invasion, extrathyroidal extension, and vascular invasion. For each topic, the document provides histological images and discusses challenges in distinguishing hyperplasia from neoplasia, defining diagnostic criteria, and predicting tumor behavior. It emphasizes the need for further scientific study to help resolve some of these controversial gray zones in thyroid pathology.

1. Minimizing Grey Zones
in Thyroid Pathology
Sylvia L. Asa, MD, PhD
Pathologist-in-Chief
Medical Director
Laboratory Medicine Program
University Health Network, Toronto

2. Controversies
• Nodules in Thyroiditis
• Sporadic Nodular Goitre/Follicular nodular disease
• Papillary adenomas
• Follicular Variant Papillary Carcinoma/Follicular
carcinoma
• Capsular Invasion
• Extrathyroidal Extension
• Vascular invasion

3. Controversies
• Nodules in Thyroiditis
• Sporadic Nodular Goitre/Follicular nodular disease
• Papillary adenomas
• Follicular Variant Papillary Carcinoma/Follicular
carcinoma
• Capsular Invasion
• Extrathyroidal Extension
• Vascular invasion

4. Hashimoto’s Thyroiditis: Morphology
• Lymphoplasmacytic
infiltrate with follicle
formation

5. Hashimoto’s Thyroiditis: Cytology
• Oncocytic or
Hürthle cell
metaplasia

6. Hashimoto’s Thyroiditis: Cytology
• Oncocytic or
Hürthle cell
metaplasia
• With atypia!
• IS THIS
DYSPLASIA?

7. Nodules in Thyroiditis

8. Hyperplasia in Thyroiditis
• Not encapsulated
• Cellular
• Bland cytology
• ? Due to TGI
• ? Destruction of
follicular
epithelium ±
regeneration

9. Carcinoma
in Thyroiditis
Nuclear features of
papillary carcinoma

10. Controversies
• Nodules in Thyroiditis
• Sporadic Nodular Goitre/Follicular nodular disease
• Papillary adenomas
• Follicular Variant Papillary Carcinoma/Follicular
carcinoma
• Capsular Invasion
• Extrathyroidal Extension
• Vascular invasion

11. Sporadic Nodular Goiter
• Multinodular
“colloid” goiter
• Occasionally
associated with
hyperthyroidism
– “Plummer’s
disease”
• Etiology and
pathogenesis NOT
understood

12. Thyroid Morphology
• Multifocal,
bilateral, 1
assymetrical
nodularity
• variable
architecture 3 2
and cytology

13. Follicular Nodular Disease
Colloid-rich, variable architecture
& cytology, Sanderson’s polsters
Focal degeration, stellate scar,
hemorrhage & hemosiderin

14. Follicular Nodular Disease:
Is It Hyperplasia?

15. Adenomatoid
Nodule
• Encapsulated
• Uniform architecture
• B land cytology
• Different from
surrounding gland
• Compresses
surrounding gland
• Is it adenoma?

16. Definitions:
Hyperplasia vs Neoplasia
• An increase in the • A proliferation of cells that
number of cells in an exceeds and is
organ or tissue that is uncoordinated with that of
induced by known normal tissues
stimuli • An uncontrolled process
• A controlled process that persists independent of
that stops when the environmental stimulation
environmental
stimulus is removed

17. Classical Criteria:
Hyperplasia vs Neoplasia
• Multiple • Solitary
• Poorly encapsulated • Encapsulated
• Architectural heterogeneity • Uniform architecture
• Cytological heterogeneity • Cytological homogeneity
• Comparable areas in • Different from
adjacent gland surrounding gland
• No compression of • Compresses surrounding
surrounding gland gland

18. Clonality Patterns in
Sporadic Nodular Goiter:
Multiple Monoclonal Nodules
Apel et al; Diagn. Mol. Pathol. 1995; 42:113-121

19. Clonality of Nodules in
Sporadic Nodular Goiter
• Polyclonal OR Monoclonal
i.e. hyperplastic OR neoplastic
• Nodules may show LOH or aberrant methylation
i.e. features of neoplasia
• Multiple nodules from a single goiter exhibit
activation of the same allele ? predisposition
?Diagnostic criteria
? Hyperplasia-neoplasia sequence
Apel et al; Diagn. Mol. Pathol. 1995; 42:113-121

20. Terminology When Not Goiter:
Follicular Nodular Disease
• Avoids controversy
• Avoids misunderstanding
• Clarifies lack of understanding

21. Follicular Nodular Disease: Pearls
• Follicular nodular disease is common
• Some may be hyperplasia, but much is
multifocal neoplasia
• Nodules in FND/SNG are usually benign
• Nodules in FND/SNG may be malignant!
• Watch out for generation, but …..
• Watch out for cancer!

22. Controversies
• Nodules in Thyroiditis
• Sporadic Nodular Goitre/Follicular nodular disease
• Papillary adenomas
• Follicular Variant Papillary Carcinoma/Follicular
carcinoma
• Capsular Invasion
• Extrathyroidal Extension
• Vascular invasion

23. Follicular Adenoma with
Papillary Architecture:
Papillary Adenoma
• Hot nodules on scan
• Biologically benign
• Papillary architecture
but benign cytology
• Solitary or Plummer’s
• Molecular features:
– monoclonal
– activating mutations of
TSH receptor or Gsα

24. G-Protein Activation and Action
Ligand
γ γ
OFF β β
α α
Receptor Effector Receptor Effector
GDP GDP
GTP GTP
γ γ ON
β β α
α
Receptor Effector Receptor Effector
GDP GTP GTP

25. Controversies
• Nodules in Thyroiditis
• Sporadic Nodular Goitre/Follicular nodular disease
• Papillary adenomas
• Follicular Variant Papillary Carcinoma/Follicular
carcinoma
• Capsular Invasion
• Extrathyroidal Extension
• Vascular invasion

26. Follicular Adenoma or
Papillary Carcinoma?

27. The Answer:
5 Years Later
• Do we overcall many
to catch this one?
• Do we undercall many
and miss this one?
• Do we find scientific
markers to predict
behavior?

28. Follicular Adenoma
A follicular neoplasm
that:
does NOT exhibit
invasive features
and
does NOT have
nuclear features of
papillary carcinoma

29. Follicular Adenoma vs Carcinoma
• Distinguished
by features
of invasion

30. 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

31. 3D-Reconstruction of PTC Nuclei
Virchows Arch (2004) 444:350
444:350–355

32. Emerin Identifies Nuclear Features
Asioli et al
Histopathology. 2009;54:571-9
Asioli et al
Virchows Archiv 2010:457:43-51

33. FVPTC vs Follicular Carcinoma
• Both differentiated thyroid malignancy
• Both follicular architecture
• Similar biologic behavior
• Similar genetic profiles
• Are they really the same thing?
• Are the criteria wrong?
• Does the distinction matter?

34. Markers of Thyroid Malignancy:
HBME-1
• Monoclonal antibody
• Unknown epitope
• Unknown significance
• Identified in 60% of
thyroid malignancies, not
in normal or benign
lesions

35. Markers of Thyroid Malignancy:
Galectin-3
• 31kD β-galactoside-
binding lectin
• High percentage of
malignant thyroid
tumors, not in
normal or benign
lesions

36. Markers of Papillary Carcinoma:
CK19
• one of many keratins
• identified diffusely in 60% of
papillary carcinomas
• also seen in reactive
nontumorous thyroid
Raphael et al, Mod Pathol.
1995;8(8):870-2

37. Controversies
• Nodules in Thyroiditis
• Sporadic Nodular Goitre/Follicular nodular disease
• Papillary adenomas
• Follicular Variant Papillary Carcinoma/Follicular
carcinoma
• Capsular Invasion
• Extrathyroidal Extension
• Vascular invasion

38. Capsules in Endocrine Tissues
• The pituitary and adrenals have capsules

39. Capsules in Endocrine Tissues
• The thyroid and parathyroid
don’t
• The pancreatic islets, adrenal
medulla and other dispersed
endocrine cells don’t

40. Normal Thyroid Histology
Mete et al, Ann Surg Oncol 2010, 17(2): 386

41. Capsules in Thyroid Tumors
• Thyroid tumors may NOT
have a capsule
• Capsular invasion cannot
be evaluated
• Invasion must be
assessed as
infiltration into
surrounding
parenchyma, perineural
or vascular involvement

42. Capsular Invasion by
Thyroid Neoplasms
• Refers to TUMOR capsule
• Generally accepted as
evidence of malignancy
IF there is a capsule in
thyroid follicular neoplasms

43. Definitions: Capsular Invasion
• Nests, cords or cells in
capsule
• Islands in capsule
associated with
perpendicular rupture
of collagen
• In capsule beyond bulk
of lesion
• Total thickness into
adjacent parenchyma
?? Artefactual trapping
?? postFNA

44. Capsular Invasion
• Most agree
with “Yes”
• Many agree
with “No”
• Few agree
with “Not yet”
FROM: Chan JKC. The thyroid gland. In: Fletcher CDM, ed. Diagnostic Histopathology
of Tumours. 3rd ed. Edinburgh; Churchill Livingstone Elsevier; 2007:1018.

45. 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!

46. Controversies
• Nodules in Thyroiditis
• Sporadic Nodular Goitre/Follicular nodular disease
• Papillary adenomas
• Follicular Variant Papillary Carcinoma/Follicular
carcinoma
• Capsular Invasion
• Extrathyroidal Extension
• Vascular invasion

47. Extra-Thyroidal Invasion
• Since the thyroid has no capsule
and
normal thyroid can be found in fat:
• 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)

48. What is the Significance of
Extra-Thyroidal Invasion?
Maybe
• Primary Tumor (pT)
• ___ pTX: Cannot be assessed
because this
• ___ pT0: No evidence of primary tumor is not really
• ___ pT1: Tumor size 2 cm or less, limited to thyroid
• ___ pT1a: Tumor 1 cm or less in greatest dimension limited to the thyroid. ETE??
• ___ 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 muscle or perithyroid soft tissues)
• ___ 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 prevertebral fascia or encases
carotid artery or mediastinal vessels

49. Controversies
• Nodules in Thyroiditis
• Sporadic Nodular Goitre/Follicular nodular disease
• Papillary adenomas
• Follicular Variant Papillary Carcinoma/Follicular
carcinoma
• Capsular Invasion
• Extrathyroidal Extension
• Vascular invasion

50. 1
PseudoVascular Invasion
by Thyroid Neoplasms
1. Tumor cells bulging into an
endothelial-lined lumen 3
2
2. Intravascular tumor nests
covered with endothelium ? artificial
implantation
3. Tumor casts within vessel
lumen
Mete and Asa, Modern Pathol Dec 2011

51. True Vascular Invasion
by Thyroid Neoplasms
• Intravascular tumor
associated with
thrombus
• Rigid criteria predict
high likelihood of
metastasis
EVEN in differentiated
thyroid carcinoma
Mete and Asa, Modern Pathol ,Dec 2011

52. Angioinvasion in
Differentiated Thyroid Carcinoma
• Must be defined properly
• Must be distinguished from lymphatic
invasion
– The term “lymphovascular invasion” should be
discarded in this field! *
• Is predictive of aggressive behavior
* the CAP worksheets need to be revised

53. Controversies in Thyroid Pathology
Controversy is a state of
prolonged public dispute or debate,
usually concerning a matter of opinion
It is time for some science!