The data on thyroid tumors in the fourth edition of the World Health Organization (WHO) classification of endocrine tumors published in 2017 contain significant revisions. These revisions of the 2004 WHO classification were based on new knowledge about pathology, clinical behavior, and most importantly the genetics of the thyroid tumors.

1. PATHOLOGY OF ENDOCRINE TUMORS
UPDATE: WORLD HEALTH
ORGANIZATION NEW CLASSIFICATION
OF NON-MEDULLARY THYROID
CARCINOMA 2017
Dr. Manan Shah

2. CONTENTS
• Introduction
• Who classification 2004
• Who classification 2017
• What has changed
• Epithelial tumors
• Summary
• References

3. INTRODUCTION
• The data on thyroid tumors in the fourth
edition of the World Health Organization
(WHO) classification of endocrine tumors
published in 2017 contain significant revisions.
• These revisions of the 2004 WHO classification
were based on new knowledge about
pathology, clinical behavior, and most
importantly the genetics of the thyroid tumors.

4. WHO Classification 2004

5. Who classification 2017
1. Epithelial tumors
1. Follicular derived neoplasm
2. Other epithelial tumors
2. Non-epithelial tumors
3. Secondary tumors

6. EPITHELIAL TUMORS
Follicular cell neoplasm
• Benign folliculour tumours
– Follicular adenoma
– Hyalinizing trabacular tumour
– Hurthle cell adenoma
• Encapsulated or well circumscribed follicular
patterned tumors with well developed or
equivocal nuclear features of papillary
thyroid carcinoma
– Follicular tumours of uncertain malignent
potential (FT-UMP)
– Well differentiated tumours of uncertain
malignent potential (WDT_UMP)
– Non invasive follicular thyroid neoplasm with
papillary-like nuclear feature (NIFTP)
• Carcinomas
– Papillary carcinoma
– Follicular carcinoma
– Hurthle carcinoma
– Poorly differentiated carcinoma
– Anaplastic (undifferentiated) carcinoma
– Squamous cell carcinoma
Other epithelial tumors
• Salivary gland–type
carcinomas
• Mucoepidermoid carcinoma
• Sclerosing mucoepidermoid
carcinoma with eosinophilia
• Mucinous carcinoma
• Thymic tumors
• Ectopic thymoma
• Intrathyroid epithelial
thymoma/CASTLE
• Spindle epithelial tumor
with thymus-like
differentiation

7. NON-EPITHELIAL TUMOURS
• Paraganglioma
• Peripheral nerve sheath
tumors
– Schwannoma
– Malignant peripheral
nerve sheath tumor
• Vascular tumors
– Hemangioma
– lymphangioma
– Angiosarcoma
• Smooth muscle tumors
– Leiomyoma
– Leiomyosarcoma
• Solitary fibrous tumor
• Histiocytic tumors
– Langerhans cell histiocytosis
– Rosai-Dorfman disease
– Follicular dendritic cell
sarcoma
• Lymphoma
• Teratoma

8. WHAT HAS CHANGED..?
1. Pattern of classification
2. Addition of a borderline tumour group
3. A new histological variant of papillary thyroid
carcinoma
4. 3 groups of follicular carcinoma
5. Hurthle cell tumours as a separate entity
6. Adoption of turin criteria for diagnosis of
poorly differentiated carcinoma

9. • Most common type of neoplasm
FOLLICULAR DERIVED NEOPLASM

10. FOLLICULAR ADENOMA
• Follicular adenoma is a benign, encapsulated,
noninvasive neoplasm showing evidence of thyroid
follicular cell differentiation and without nuclear
features of papillary thyroid carcinoma.
• The main differential diagnosis is from hyperplastic
nodule in nodular hyperplasia.
• Both lesions are benign.
• The differential diagnosis between the 2 lesions is not
always possible or necessary in the absence of
molecular analysis.

11. FOLLICULAR ADENOMA
• Variants of follicular adenoma
– Classic follicular adenoma
– Hyperfunctioning adenoma,
– Follicular adenoma with hyperplasia,
– Lipoadenoma,
– Follicular adenoma with bizarre nuclei,
– Signet-ring cell follicular adenoma,
– Clear cell follicular adenoma,
– Spindle cell variant of follicular adenoma, and
– “Black” follicular adenoma newly added

13. FOLLICULAR ADENOMA
• Oncocytic variant of follicular adenoma noted in the
2004 WHO classification is not included as it becomes a
separate entity.
• Also, the fetal adenoma and mucinous follicular
adenoma in the previous classification are not listed
separately because they could be placed as
architectural pattern in classic follicular adenoma.

15. HYALINIZING TRABACULAR TUMOUR
• Hyalinizing trabecular tumor is a follicular-derived
neoplasm composed of large trabeculae of elongated
or polygonal cells admixed with variable amounts of
intratrabecular and intertrabecular hyaline material.
• More common in right lobe
• The cytological features (nuclear grooves,
pseudoinclusions, and irregular borders) in fine-needle
aspirates may suggest papillary thyroid carcinoma.

16. HYALINIZING TRABACULAR TUMOUR
• The relationship with papillary thyroid carcinoma
was suggested by the detection of RET/PTC1
rearrangements.
• However, neither RAS nor BRAF mutations have been
detected.
• Also, micro-RNA profiling did not support the link
between the 2 entities.

17. BORDERLINE FOLLICULAR TUMORS
• Also known as “Encapsulated or well-circumscribed
follicular patterned tumors with well-developed or
equivocal nuclear features of papillary thyroid
carcinoma”
• This group of follicular-derived neoplasms comprised
lesions with borderline histologic features for a
diagnosis of carcinoma of follicular differentiation.
• It is the most important and controversial concept
introduced in the new classification of thyroid
tumors.

18. BORDERLINE FOLLICULAR TUMORS
• The reason behind this categorization is the
pragmatic approach adopted for these difficult
cases in clinical management.
• This group of tumors comprises 3 entities,
namely,
• FT-UMP,
• WDT-UMP, and
• NIFTP

19. BORDERLINE FOLLICULAR TUMORS
• The important histologic criterion for the first 2
entities is the “questionable capsular or vascular
invasion.”
• If the invasion is definite and not questionable, FT-
UMP will be labeled as follicular carcinoma, whereas
WDT-UMP will be a papillary thyroid carcinoma.

20. Follicular Tumor of Uncertain
Malignant Potential
• Follicular tumor of uncertain malignant potential
is an encapsulated or well-circumscribed tumor
composed of well-differentiated follicular cells
with no papillary thyroid carcinoma–type nuclear
changes and showing questionable capsular or
vascular invasion.
• This is a tumor indeterminate between follicular
adenoma and follicular carcinoma.

21. Well-differentiated Tumor of Uncertain
Malignant Potential
• Well-differentiated tumor of uncertain malignant
potential is an encapsulated or well-
circumscribed tumor composed of well
differentiated follicular cells.
• Well or partially developed papillary thyroid
carcinoma–type nuclear changes.
• Questionable capsular or vascular invasion.

23. 4

24. NON-INVASIVE FOLLICULAR THYROID
NEOPLASM WITH PAPILLARY LIKE
NUCLEAR FEATURES (NIFTP)
• The neoplasm formally classified as noninvasive
encapsulated follicular variant of papillary thyroid
carcinoma (EFVPTC)"
• The rationale for the separation of this group of
tumor is the extremely indolent behavior when
compared with other types of papillary thyroid
carcinomas.

25. • The separation of this subgroup was also supported by
the strong association RAS mutation signatures in
NIFTP rather than BRAF mutation signatures that are
characteristics of many papillary thyroid carcinomas.
• NIFTP is the precursor of invasive form of follicular
variant of papillary thyroid carcinoma.
• The clinical implication of NIFTP by labeling the tumor
as a noninvasive cancer will result in less aggressive
treatment approach, reduction in psychological stress,
and lowering the social economic cost involved in the
management of this tumor.

26. THE HISTOLOGIC CRITERIA FOR
DIAGNOSIS OF NIFTP
1. Presence of complete capsule with clear demarcation
of the tumor from adjacent thyroid
2. No invasion of the capsule,
3. Exclusively or predominately follicular growth pattern,
4. Nuclear features of papillary thyroid carcinoma.
5. The other supportive features are…
• Absence of psammoma bodies,
• Less than 30% solid/trabecular/insular growth pattern,
• Nuclear score of 2 or 3,
• No vascular or capsular invasion, no tumor necrosis and
• No high mitotic activity.

29. PAPILLARY CARCINOMA
• Papillary carcinoma of the thyroid is the most
common endocrine malignancy and comprises
different variants with distinctive biological behavior
• Over the past decade, the WHO working group has
recognized a new entity - hobnail variant.

31. CHANGES IN PAPILLARY CARCINOMA
CATEGORY
• RECLASSIFICATION OF PREVIOUSLY
RECOGNISED VARIENTS
– Encapsulated variant
• Now included in classical variant
– Warthin-like variant
• Now separate variant, not included in hurthle cell
tumours

32. Variants With Updated Information
• Diffuse sclerosing variant
– Higher incidence of,
• Extra thyroidal extension, cervical lymph node metastases,
distant metastases, and shorter periods of disease-free
survival when compared with conventional papillary thyroid
carcinoma.
– In contrast the mortality rates of patients with this
variant are similar to those with conventional papillary
thyroid carcinoma.

33. • Tall cell variant
– defined by cancer cells that are 2 to 3 times taller
than wide in the current classification.
– At least 30% of all tumor cells that fulfill the criteria
are reasonably required for the diagnosis of this
variant.
• Cribriform-morular variant
– optically clear nuclei resulting from biotin and the
nuclear β-catenin were highlighted as characteristic
features of this variant

34. Hobnail variant – A new addition
• Micro papillae
• The carcinoma cells have an eosinophilic cytoplasm and
apically placed nucleus
• Decreased N:C ratio
• Loss of cellular cohesion resulting a “hobnail”
appearance.
• These cells must comprise more than 30% of cancer cells.
• Aggressive histologic features
• Necrosis
• Mitois
• lymphitic invasion
• High recurrence, more distance metastasis, high mortality
rate

36. Article

37. Follicular carcinomas
• The diagnosis of follicular carcinoma requires the
demonstration of definite capsular and/or
vascular invasion and in the absence of nuclear
features of papillary thyroid carcinoma.
• Follicular carcinoma is classified into 3 groups:
– (1) minimally invasive (capsule invasion only) follicular
Carcinoma
– (2) encapsulated angioinvasive follicular carcinoma
and
– (3) widely invasive follicular carcinoma.

38. • Widely invasive follicular carcinoma is the most aggressive
form and with the worst prognosis.
• Encapsulated angio-invasion follicular carcinoma is
biologically more aggressive than minimally invasive
follicular carcinoma with capsule invasion only.
• Also, the extent of vascular invasion has impact on the
prognosis.
• Follicular carcinomas with less than 4 vessels in the capsule
involved carry a better prognosis than those with extensive
vascular invasion.

39. • Variants of follicular carcinoma,
– Clear cell variant
– signet-ring-cell type,
– follicular carcinoma with glomeruloid pattern, and
– spindle cell follicular carcinoma
• It is worth noting that the oncocytic variant
has been removed and became a separate
entity.

40. Hürthle Cell Tumors
• Hürthle cell tumors are neoplasms composed of
oncocytic cells, with granular cytoplasm and large
centrally placed nuclei and often with prominent
nucleoli.
• Hürthle cell tumors are usually encapsulated. The
tumor cells have large mitochondria and accumulate
a higher frequency of mitochondrial DNA mutations
than non–Hürthle cell tumors.

41. • Also, these tumors have a genetic profile different from that
of the other common types of thyroid cancer, with
transcriptome signatures consistent with activation of
Wnt/β-catenin and PI3KAkT-mTOR pathways.
• They have a lower RAS mutation and PAX8/PPARG
rearrangement prevalence compared with follicular tumors.
• In addition, aneuploidy is common in Hürthle cell tumors.
• The clinical, pathological, and molecular profiles of Hürthle
cell tumors (adenoma/carcinoma) are different from
follicular adenoma/carcinomas, which justify them as
separate entities.

42. • Hürthle Cell Adenoma
– Hürthle cell adenoma is a Hürthle cell tumor without
capsular and/or vascular invasion.
– It is a benign tumor.
• Hürthle Cell Carcinoma
– Hürthle cell carcinoma is a Hürthle cell tumor with
capsular and/or vascular invasion.
– Male>female, older age group affected more
– they are larger and presented at higher pathological stages
– Lower patients survival rates than with follicular carcinoma
– the carcinoma is relatively radioiodine resistant.
– Hürthle cell carcinoma can spread to cervical lymph node

46. Poorly Differentiated Carcinoma
• Poorly differentiated carcinoma is a follicular-cell
neoplasm that occupies both morphologically
and behaviorally an intermediate position
between differentiated (follicular and papillary
carcinomas) and anaplastic carcinomas.
• Response to radioiodine treatment is generally
poor
• For the morphological criteria, the 2017
classification adopted the Turin proposal.

47. • The histologic criteria for poorly differentiated
carcinoma are,
1. A diagnosis of carcinoma of follicular cell derivation
2. Solid, insular, or trabecular growth;
3. Absence of conventional nuclear features of
papillary thyroid carcinoma; and
4. At least 1 of 3 features:
– convoluted nuclei (ie, “dedifferentiated” nuclear features of
papillary carcinoma),
– mitotic activity 3 or more per 10 high-power fields, or
– tumor necrosis.

48. • Genomic studies also revealed that poorly
differentiated thyroid carcinomas have a
mutation load intermediate between that of
well-differentiated papillary carcinomas and
anaplastic carcinoma.
• Also, the microRNA profile of the tumor is
different from that of well-differentiated and
anaplastic carcinoma.

49. Anaplastic Carcinoma
• Anaplastic carcinoma of the thyroid is composed of
undifferentiated follicular thyroid cells. It is one of the
most aggressive human cancers, and most patients
with anaplastic thyroid carcinoma die within a year of
diagnosis.
• The carcinoma presents at advanced T stage having
extensive local invasion, as well as metastatic spread to
regional lymph nodes and distant sites.
• The carcinoma may arise de novo or transform from
differentiated carcinoma; especially the papillary
phenotype.

50. Anaplastic Carcinoma
• Anaplastic carcinoma of the thyroid is broadly
categorized into 3 patterns: sarcomatoid, giant cell,
and epithelial.
• The carcinoma is positive for cytokeratin. TTF-1 is
usually negative, but PAX-8 is noted in
approximately of 50% of the carcinomas.
• Thus, PAX-8 is useful to confirm the thyroid origin
of the carcinoma.

51. Anaplastic Carcinoma
• The genetic profile of anaplastic thyroid
carcinoma is complex with multiple genetic
alterations.
• The most frequently mutated gene is p53.

52. Squamous Cell Carcinoma
• Squamous cell carcinoma is similar to anaplastic
carcinoma in clinical presentation, as well as prognosis of
the patients.
• By definition, squamous cell carcinoma of the thyroid
should be composed predominantly or entirely of tumor
cells with squamous differentiation.
• The carcinoma is positive for PAX-8 and p53.
• The positivity for PAX-8 is important to differentiate the
carcinoma from secondary squamous cell carcinoma

53. OTHER EPITHELIAL TUMOURS…

54. Other epithelial tumors
• Salivary gland–type carcinomas
• Mucoepidermoid carcinoma
• Sclerosing mucoepidermoid carcinoma with
eosinophilia
• Mucinous carcinoma
• Thymic tumors
– Ectopic thymoma
– Carcinoma showing thymus-like element /CASTLE
• Spindle epithelial tumor with thymus-like
differentiation

55. NONEPITHELIAL TUMORS…

56. NON-EPITHELIAL TUMOURS
• Paraganglioma
• Peripheral nerve sheath
tumors
– Schwannoma
– Malignant peripheral
nerve sheath tumor
• Vascular tumors
– Hemangioma
– lymphangioma
– Angiosarcoma
• Smooth muscle tumors
– Leiomyoma
– Leiomyosarcoma
• Solitary fibrous tumor
• Histiocytic tumors
– Langerhans cell histiocytosis
– Rosai-Dorfman disease
– Follicular dendritic cell
sarcoma
• Lymphoma
• Teratoma

57. SUMMARY
• The data on non-medullary thyroid tumors in the fourth
edition of the World Health Organization classification of
endocrine tumors contain significant revisions.
• The major modifications are seen in the follicular-derived
neoplasm.
• A “borderline” tumor group—
• follicular tumor of uncertain malignant potential,
• well-differentiated tumor of uncertain malignant potential, and
• noninvasive follicular thyroid neoplasm with papillary nuclear features
Is introduced in the current classification.

58. SUMMARY
• Papillary carcinoma comprises 15 variants, which
include a new histological variant—hobnail
variant.
• Follicular carcinomas are subdivided into 3
groups: minimally invasive (capsule invasion
only), encapsulated angioinvasive, and widely
invasive.
• Hurthle cell tumors are separated from follicular
neoplasm

59. SUMMARY
• The classification also adopted the Turin criteria for
the histological diagnosis of poorly differentiated
carcinoma.
• Overall, the new classification incorporated the new
knowledge on pathology, clinical behavior, and
genetics of the thyroid tumors, which are important
for management of patients with these tumors.

60. References
1. Lam, Alfred King-yin. Pathology of Endocrine Tumors Update: World Health
Organization New Classification 2017—Other Thyroid Tumors. AJSP.
2017;22:209-16.
2. Lloyd RV, Osamura RY, Kloppel G, et al. WHO Classification of Tumours:
Pathology and Genetics of Tumours of Endocrine Organs. 4th ed. Lyon,
France: IARC; 2017.
3. DeLellis RA, Lloyd RV, Heitz PU, et al. WHO Classification of Tumours:
Pathology and Genetics of Tumours of Endocrine Organs. 3rd ed. Lyon,
France: IARC; 2004.
4. Lam AK, Lo CY, Lam KS. Papillary carcinoma of thyroid: a 30-yr
clinicopathological reviewof the histological variants. Endocr Pathol 2005;
16:323–30.
5. Asioli S,Maletta F, Pagni F, et al. Cytomorphologic and molecular features of
hobnail variant of papillary thyroid carcinoma: case series and literature
review. Diagn Cytopathol 2014;42:78–84.

61.  TANK YOU 