evrything you need to know about pathology of thyroid tumours, classification, TNM staging,

1. By- Dr. Kanwalpreet kaur

3.  Thyroid is located opposite C5,C6,C7 ,C8 vertebrae.
 Weighs – 25g
 Each lobe-5X3X2
 Capsules:
 Inner/true capsule- formed by peripheral
condensation of the fibrous stroma of gland.
 Outer/false capsule- formed by splitting of pretracheal
fascia.

4.  APEX- inferior constrictor medially
sternothyroid laterally
 BASE- inferior thyroid artery
recurrent laryngeal nerve
 LATERAL SURFACE-sternothyroid
sternohyoid
superior belly of omohyoid
 MEDIAL SURFACE-trachea and esophagus
inferior constrictor and cricothyroid
cricoid and thyroid
 POSTERIOLATERAL SURFACE- carotid sheath and its contents
 ANTERIOR BORDER- anterior branch of superior thyroid artery
 POSTERIOR BORDER-anastomosis between superior and
inferior thyroid arteries; parathyroid glands

6. 1.Tumours of thyroid follicular or metastatic epithelium
i) Follicular adenoma( including Hurthle cell adenoma)
ii) Follicular carcinoma(including Hurthle cell carcinoma)
iii)Papillary carcinoma
iv)Mucoepidermoid carcinoma
v)Sclerosing mucoepidermoid carcinoma with eosinophilia
vi)Mucinous carcinoma
vii)Poorly differentiated thyroid carcinoma
viii) Undifferentiated (anaplastic)carcinoma including squamous cell
carcinoma

7. 2. Tumours showing C-cell differentiation
i) Medullary cell carcinoma
3. Tumours showing both follicular and C-cell
differentiation
i)Collision tumour: follicular/papillary and medullary carcinomas
ii)Mixed medullary and follicular cell carcinoma
4. Tumours showing thymic or related branchial pouch
differentiation
i) Ectopic thymoma
ii)Spindle epithelial tumour with thymus like
differentiation(SETTLE)
iii)Carcinoma showing thymus like element (CASTLE)

8. 5. Tumors of lymphoid cells
i)Malignant lymphoma
ii) Extramedullary plasmacytoma
6. Intrathyroid parathyroid tumours
i) Parathyroid adenomas
ii) Parathyroid carcinoma
7. . Mesenchymal and other tumors
i) Benign and malignant mesenchymal tumours
ii) Paraganlioma
iii) Teratoma

9. TX- primary tumour cannot be assessed
T0-no evidence of primary tumour
T1a- Tumour <1cm; limited to thyroid
T1b- Tumour >1 cm but not > 2cm in greatest dimension
limited to thyroid
T2 – tumour >2 cm but not > 4 cm
limited to thyroid
T3- tumour > 4cm in greatest dimension limited to thyroid
or
any tumour with minimal extrathyroid extension
T4a- tumour of any size extending beyond the thyroid capsule to invade
subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent
laryngeal nerve
T4b- tumour invading prevertebral fascia or encasing carotid artery or
mediastinal vessels
ALL ANAPLASTIC TUMOURS ARE CONSIDERED T4 TUMOURS

10. NX- regional lymph nodes cannot be assessed
NO- no regional lymph node metastasis
N1a- metastasis to level VI( PRETRACHEAL, PARATRACHEAL,
PRELARYNGEAL/DELPHIAN LYMPH NODES)
N1b- metastasis to unilateral, bilateral or contralateral CERVICAL
( level I,II,III,IV or V) or RETROPHARYNGEAL or SUPERIOR
MEDIATINAL LYMPH NODES (level VII)
MX- distant metastasis cannot be assessed
M0- no distant metastasis
M1- distant metastasis

11.  Most common type of thyroid malignancy
 Defined as a “malignant epithelial tumor showing
evidence of follicular cell differentiation and
characterized by distinctive nuclear features.’’
 Sex- Female predominance (M/F 1 : 2.5)
 Age- any age group; mean age 40 years
 Presentation-painless thyroid or neck mass. Some
may initially present with lymph node metastasis

12.  Following factors may increase risk of papillary
carcinoma-
1.Previous irradiation to the head and neck region
2. Radiation exposure from nuclear accident (e.g., the
Chernobyl accident) or atomic bomb (e.g., survivors of
the atomic bomb explosion from Hiroshima)
3. Hashimoto thyroiditis

13. Usually infiltrative; ill
defined borders; white to
tan; fibrosis

14. Cystic metastasis
in cervical lymph
node

15. Complex branching randomly
oriented papillae with central
fibrovascular core; single or
stratified lining of cuboidal cells

16. Follicles are frequently present; usually elongated and
filled with dark staining colloid

17. complex tubulopapillary pattern

18. 1.Ground glass appearance(orphan annie eye)-
empty-looking nuclei with scanty marginated dusty
chromatin
2.Nuclear pseudoinclusion-invaginations of cytoplasm
and appear as sharply outlined round acidophilic vacuoles
3.Nuclear grooves-deep folding of the nuclear membrane;
oocur in oval or spindle nuclei; arranged along the longest
nuclear axis
4.Nuclear microfilaments-seen in few cases; nuclear
clearing is because of accumulation of thread like fibrils

19. large, crowded, ovoid, ground-glass
(hypochromatic) nuclei;
Up and down placement of nuclei
Mitotic figures are generally absent or sparse

20. Nuclear grooves

21. Nuclear pseudoinclusion

22. Dense hyaline fibrosis has been suggested to be a useful feature for distinguishing
papillary carcinoma (89% of cases) from follicular carcinoma (18% of cases).
Desmoplastic stromal reaction

23. PSAMMOMA BODY in papillary stalk

24. Calcified colloid materials, which are fairly
common in Hürthle cell neoplasms and
hyalinizing trabecular adenoma, are
distinguishable from psammoma bodies by their
exclusive location in the follicular lumens.

25. 1.FOLLICULAR VARIANT:
-Composed of follicles throughout; no papillae
-infiltrative type
-encapsulated type=LINDSAY TUMOUR
-The diagnosis rests on identification of the
typical nuclear features of papillary carcinoma.

26. INFILTRATIVE TYPE ENCAPSULATED TYPE

27. Elongated and irregular follicles
dark staining and scalloped colloid
INFILTRATIVE TYPE

28. Tumor cells
forms islands ;
traversed by delicate
blood vessels;nuclear
features of papillary
carcinoma.

29. Distant
metastasis
nearly zero;
nodal
metastases
may be seen

30. Islands of tumour cells
Dense sclerosis; lymphocytic
infiltration
children and young adults; diffuse involvement of one or both thyroid lobes

31. Prominent permeation of
intrathyroid lymph vessels
nodal metastasis nearly always present, lung metastases are common, multiple
brain metastases may supervene
Psammoma bodies are
typically abundant

32. Single layer of tall cells;
Height >3times width
Abundant acidophillic
cytoplasm; growth pattern-
highly papillary
Older patients; extranodal extension common; more aggressive than conventional
form

33. pseudostratified layer of
spindle tumor cells;

34. Abundant eosinophillic
cytoplasm akin to hurthle
cells.

35. large follicles distended with
colloid, mimicking colloid nodule

36. blending of cribriform
structures, variably fused
follicles, and papillae;
absence of colloid in lumen

37. Papillary carcinoma measuring 1 cm or less in
diameter
TYPICAL STELLATE
APPERANCE

38. 1)Locally invasive
2) Lymphatic spread
 lymph node metastasis in approximately 40% cases
 Cervical lymph nodes involvement common
3) Distant metastasis is rare, mostly to the lungs if it
occurs. Can involve bones, soft tissues, central
nervous system, pancreas, breast.

40.  Markers reported to be useful for differentiating
follicular variant of PTC from follicular adenoma:
 1)HBME-1
 2)CK-19
 3)Galectin 3
 But not used widely; diagnosis ultimately rests on
H&E.

41.  ACTIVATION OF MAP KINASE (MITOGEN
ACTIVATED PROTEIN KINASE) PATHWAY
 Rearrangements of Point mutations in
 RET or NTRK1 BRAF


42.  10q11
 Encodes for transmembrane tyrosine kinase not normally
expressed in follicular cells.
PAPILLARY CANCERS-
 i)paracentric inversion of chr.10
 ii) reciprocal translocation between chr 10 and 17
 RET/PTC fusion protein(RET/PTC-1 fusion is the most
 common, followed by RET/PTC-3)
constitutive activation of tyrosine kinase
activation of MAP kinase pathway

43.  NTKR1 (neurotrophic tyrosine kinase receptor 1)
 1q21
 Paracentric inversions or translocations  fusion proteins
constitutively expressed activation of MAP kinase
pathway
 BRAF GENE
 Gain of function mutation thymine to adenine
transversions in nucleotide 1799 of exon 15 valine to
glutamate change on codon 600 (V600E)
 a/w adverse prognostic factors like metastatic disease and
extra-thyroidal extension
 RAS GENE
confined to the encapsulated follicular variant

44.  Indolent neoplasm with an excellent long-term
prognosis
 Total thyroidectomy
 For more advanced cancers, such as T3 or T4
tumors, or cancers that have spread to lymph
nodes or distant sites, RAI therapy is often given
 Areas of distant spread that do not respond to RAI
may need to be treated with external beam
radiation therapy, targeted therapy,
or chemotherapy.

45.  Less common(10%-15%)
 DEFINITION-Follicular epithelial cell
differentiated thyroid neoplasm, not belonging to
thyroid papillary carcinoma, with evidence of
invasion (i.e., capsular and/or vascular invasion)
and/or metastatic disease
 Types-
1.MINIMALLY INVASIVE
2.WIDELY INVASIVE

46.  Sex-Female predominance (M/F 1 : 2.5 to 1 : 4)
 Age- Minimally invasive type: mean 48 yr
Widely invasive type: mean 55 yr
 Presentation- Slow-growing thyroid nodule; some
present with fast-growing thyroid mass or distant
metastasis
 Always UNIFOCAL

47. 1.Minimally invasive follicular carcinoma-
-solid, fleshy, and tan to light brown
-Well encapsulated; grossly indistinguishable from
follicular adenomas.
-size ranges from less than 1 cm to over 10 cm
2. Widely invasive follicular carcinomas-
-may lack a discrete capsule
-extensive invasion of surrounding gland and/or soft
tissue beyond thyroid

48.  Patternwell-formed follicles to solid to trabecular
 Nuclei round to oval with granular chromatin
 Mitotic activity present
 Necrosis absent
 Oncocytic variant(hurthle cell )major variant

49. Significant nuclear
atypia seen in
some cases

50. CAPSULAR INVASION VASCULAR INVASION

51.  WHO definition-
1) involves blood vessels located within or outside the
fibrous capsule
2)presence of intravascular tumour cells either
covered by endothelium or associated with thrombus.

53. polypoid tumor plug within blood vessel
attachment to the wall
this is not an essential criterion for recognition of vascular invasion

54. tumor plug lying within the vascular
lumen covered by endothelium
tumor plug within the vascular
space is not covered by endothelium
but associated with thrombus

55.  WHO DEFINITION-
 Tumour penetration through the capsule not caused
by previous fine needle aspiration
 Complete transgression of the fibrous capsule must
be seen i.e. the tumor bud has to extend beyond an
imaginary line drawn through the external contour
of the capsule
 Invasion needs to be definitive and takes shape of
‘’mushrooming ‘’of tumour outward

57. tumor bud penetrated through the
fibrous capsule, reaching beyond the
external contour of the capsule

58.  High risk counterpart of minimally invasive subtype
 Widespread infiltration of blood vessels and/or
adjacent thyroid tissue
 Lacks encapsulation

59.  Follicular carcinoma classified as:
 1) ENCAPSULATED
 - With capsular ( but no vascular invasion)
 -with limited (<4) vascular invasion ( with or
 without capsular invasion)
- With extensive (>4)vascular invasion ( with or
without capsular invasion)
 2) WIDELY INVASIVE

60.  Reactive for thyroglobulin
 TTF-1
 low molecular weight keratins
 EMA
 basement membrane components

61. ACTIVATION OF PHOSPHATIDYLINOSITOL-3-
KINASE(PI-3K)/AKT PATHWAY
 i) gain of function point mutations of RAS and
PIK3CA
 ii) amplification of PIK3CA
iii)loss of mutations of PTEN
t(2;3)(q13;p25)fusion of PAX8 and peroxisome
proliferator-activated receptor gene(PPRAG)

62.  1) Low tendency for local spread beyond the
thyroid capsule except widely invasive types
 2) Lymph node metastasis uncommon
 3) Blood borne metastasis- common
 most common sites- lungs and bone;
 kidney , skin
 THROGLOBULIN and/or TTF-1 staining is
essential in confirming the thyroid origin of
metastatic tumour

63.  Major histopathological variant of follicular
carcinoma
 Comprises 20% to 25% of all follicular carcinomas
 DEFINITION- Should be composed of atleast 75%
oncocytic cells with abundant ,brightly
eosinophilic, granular cytoplasm (caused by
accumulation of mitochondria) and
nuclei vesicular ; prominent single nucleoli

64.  Most Hurthle cell neoplasms are follicular in
pattern, the criterion for distinguishing benign from
malignant is the same as for follicular neoplasms -
identification of capsular or vascular invasion

65. mahogany
brown multilobated mass;
haemorrhage and necrosis

66.  Growth pattern:the follicular(most common in
adenoma), trabecular/solid, or papillary
 Can show calcifications, which may be confused
with psammoma bodies, but these calcifications are
present within the colloid
 nuclei may show pleomorphism and prominent
nucleoli, with occurrence of isolated bizarre forms,
these not being features of malignancy
 Proof of malignancy is vascular and capsular
invasion

67. SOLID GROWTH PATTERN VASCULAR INVASION

68. DIFFERNTIAL
DIAGNOSIS
HISTOPATHOLOGY IHC
1)Follicular adenoma
( from minimally
invasive type)
Lack of capsular and
vascular invasion
2) Medullary carcinoma
of thyroid
MTC- rarely follicular;
nuclei are spindle shaped
MTC +ve for neuroendocrine
markers,CEA, calcitonin( -ve
in follicular carcinoma)
-ve for thyroglobulin(+ve in
follicular carcinoma)
3)Poorly differentiated
( insular) carcinomas
(differentiated from
widely invasive type)
Insular carcinoma- less
cytoplasm; minimal
follicular archietecture;
marked mitotic activity ;
marked necrosis
4)Hashimoto thyroiditis
and dyshormogenesis
Lack of capsular and
vascular invasion

69.  Total thyroidectomy + central compartment or
modified neck dissection (if lymph nodes are
involved)
 Spread to nearby lymph nodes and to distant sites
that shows up on the scan can be treated by
radioactive iodine (RAI)
 Distant metastases may need to be treated with
external beam radiation therapy, targeted therapy,
or chemotherapy if they do not respond to RAI

70. DEFINITION-evidence of follicular differentiation;
morphologically and biologically fits between well-
differentiated and undifferentiated thyroid carcinomas
 More common in women(F/M = 1.6 : 1-2 : 1)
 Age- after 60 years
 Presentation-asymptomatic masses
 GROSS-large; solid grey to white nodules; necrosis
common

71. solid and firm, with a gray-
white cut surface; areas
of necrosis and hemorrhage
are frequently present

73. INSULAR PATTERN
TRABECULAR PATTERN

74. Coagulative necrosis
Sheets and islands of
tumour cells

75. Small uniform tumour cells;round
hyperchromatic nuclei;mitotic figures seen;
absence of nuclear features of papillary
carcinoma

76.  Positive for TTF-1
 PAX-8
 thyroglobulin
Decreased expression of the cyclin-dependent kinase
inhibitor p27 and increased Ki-67 index are seen-
Helps to differentiate from differentiated thyroid
carcinomas

77. 1)MEDULLARY
CARCINOMA
MTC more prominent vasculature, granular
cytoplasm, and finely stippled chromatin
+ve for calcitonin
Insular +ve for thyroglobulin
2)SOLID VARIANT OF
PAPILLARY CARCINOMA
extensive presence of typical nuclear features of
papillary carcinoma
3)UNDIFFERENTIATED
THYROID CARCINOMA
POORLY DIFFERENTIATED-
Maintenance of follicular cell differentiation;
Immunoreactivity for thyroglobulin and TTF-1;
UNDIFFERENTIATED-
Completely lacks evidence of follicular
cell differentiation ;prominent nuclear
pleomorphism and frequent mitoses;
Immunostaining for thyroglobulin and TTF-1 is
generally negative

78. Incidence-2-3%
M/F ratio 1 : 1.1 to 1 : 2
Mean age-70 years
Etiological factors-a)iodine deficiency
b)radiation exposure
c)pre existing thyroid disease
(long-standing goitre)
Presentation- rapidly growing neck mass with local signs
and symptoms like hoarseness, dysphagia,pain,vocal cord
paralysis

79. fleshy and white-tan,
with frequent necrosis and
hemorrhage; entirely
replacing the gland and
extending into the
surrounding skeletal muscle

80.  Two major categories:
1.Squamoid
2.Sarcomatoid: spindle cell and giant cell
Undifferentiated carcinoma of the
spindle cell type
Undifferentiated carcinoma of giant
cell type

81.  Cells have moderate amount of eosinophilic
cytoplasm
 Brisk mitotic activity
 Abundant apoptosis.

82.  Positive for cytokeratin(80% cases)
 EMA(30-50% cases)
 Useful when there is no obvious carcinomatous
differentiation present on H& E. IHC helps to confirm
that the neoplasm is a carcinoma rather than high grade
sarcoma
 Lack of staining with epithelial markers doesn’t exclude
the diagnosis of UTC
 Nuclear reactivity PAX 8(80% cases)

83.  TTF-1 and thyroglobulin- typically negative
 Calcitonin and neuroendocrine makers- negative

84.  TP53 mutation
 Mutations in the β-catenin (CTNNB-1) gene
 RAS mutation (approximately 30%),BRAF mutation
(approximately 30%), or RET/PTC fusion gene may
be seen in some cases

85. 1)SARCOMA any “sarcoma looking”tumor of the thyroid should
be regarded as undifferentiated carcinoma unless
strong proof exists otherwise
2)SOLID VARIANT OF
PAPILLARY
CARINOMA
Solid variant- nuclear features of papillary
carcinoma
Lack of mitosis
3)LARGE CELL
LYMPHOMA
Lymphoma- less cellular cohesion; presence of
plasmacytoid cytoplasm or stuffing of follicular
lumina
IHC can readily differntiate
4)PARATHYROID
CARCINOMA
It shows presence of clear cells, a mixture of cell
types, and paucity of mitotic figures
5)POORLY
DIFFERENTIATED
CARCINOMA

86.  surgery is often not helpful .Goal of surgery is to
remove as much cancer in the neck area as possible
 Radioactive iodine treatment- no role
 External beam radiation therapy may be used alone or
combined with chemotherapy:
 1)To try to shrink the cancer before surgery to increase
the chance of complete tumor removal
2)After surgery to try to control any disease that
remains in the neck
3)When the tumor is too large or widespread to be
treated by surgery

87.  DEFINITION-Medullary carcinoma is a malignant
tumor showing parafollicular C-cell differentiation
 Characteristically secretes calcitonin
 Incidence-5-10%
 20% cases are familial; strong association with
MEN type 2

88. SPORADIC AND NON-
MEN FAMILIAL MTC FAMILIAL MTC
 50-60 years
 Unilateral
 MEN2A- younger age
group(mean age third
decade); multifocal;
bilateral
 MEN2B- adolescence or
childhood

89. solid, firm, unencapsulated ,
Circumscribed,tan yellow to
white

90. solid proliferation of round to
polygonal cells of granular
amphophilic cytoplasm and
medium-sized nucleus,
highly vascular stroma,
hyalinized collagen, amyloid

91. prominent
trabecular
growth pattern

92. round nuclei;
fine chromatin;
nucleoli not
prominent;
finely granular
cytoplasm

93. 1) cytoplasmic dense-core secretory granules seen
argyrophilic with Griemelius stain
2) Mucin stains often positive

95. tumor cells are
strongly positive
for calcitonin.

96. 36 – 66% of sporadic MTC – somatic RET gene mutations

97. 1)Poorly differentiated (insular) thyroid carcinoma
2) Undifferentiated carcinoma
3) Hyalinizing trabecular adenoma.
4) Paraganglioma
5) Hürthle cell neoplasm
6) Metastatic neuroendocrine carcinoma
7) Parathyroid neoplasm

98.  Screening for pheochromocytoma is particularly
important( MEN2a) , since the unknown presence of
this tumor can make anesthesia and surgery extremely
dangerous
 Stages I and II: Total thyroidectomy+ bilateral central
compartment or modified radical neck dissection
 Stages III and IV: Surgery is the same as for stages I
and II .
When the tumor is extensive and invades many
nearby tissues or cannot be completely
removed, external beam radiation therapy may be given
after surgery

99.  Genetic testing can find mutations in
the RET gene
 close family members should be tested as well
 anyone who has a RET gene mutation 
prophylatically thyroidectomy is done

100. THANK YOU…