By- Dr. Kanwalpreet kaur

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 pretrachealfascia.

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

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

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 likedifferentiation(SETTLE)

iii)Carcinoma showing thymus like element (CASTLE)

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

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 dimensionlimited to thyroid

T2 – tumour >2 cm but not > 4 cmlimited to thyroid

T3- tumour > 4cm in greatest dimension limited to thyroidor

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

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

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

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

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

Cystic metastasis in cervical lymph node

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

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

complex tubulopapillary pattern

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

large, crowded, ovoid, ground-glass (hypochromatic) nuclei;

Up and down placement of nuclei

Mitotic figures are generally absent or sparse

Nuclear grooves

Nuclear pseudoinclusion

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

PSAMMOMA BODY in papillary stalk

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.

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.

INFILTRATIVE TYPE ENCAPSULATED TYPE

Elongated and irregular follicles

dark staining and scalloped colloid

INFILTRATIVE TYPE

Tumor cellsforms islands ;traversed by delicate blood vessels;nuclearfeatures of papillary carcinoma.

Distant metastasis nearly zero; nodal metastases may be seen

Islands of tumour cells

Dense sclerosis; lymphocytic infiltration

children and young adults; diffuse involvement of one or both thyroid lobes

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

Single layer of tall cells;Height >3times widthAbundant acidophilliccytoplasm; growth pattern-highly papillary

Older patients; extranodal extension common; more aggressive than conventional form

pseudostratified layer of spindle tumor cells;

Abundant eosinophilliccytoplasm akin to hurthlecells.

large follicles distended withcolloid, mimicking colloid nodule

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

Papillary carcinoma measuring 1 cm or less in diameter

TYPICAL STELLATE APPERANCE

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.

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.

ACTIVATION OF MAP KINASE (MITOGEN

ACTIVATED PROTEIN KINASE) PATHWAY

Rearrangements of Point mutations in

RET or NTRK1 BRAF

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

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

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.

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

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

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

Patternwell-formed follicles to solid to trabecular

Nuclei round to oval with granular chromatin

Mitotic activity present

Necrosis absent

Oncocytic variant(hurthle cell )major variant

Significant nuclear atypia seen in some cases

CAPSULAR INVASION VASCULAR INVASION

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.

polypoid tumor plug within blood vessel

attachment to the wall

this is not an essential criterion for recognition of vascular invasion

tumor plug lying within the vascular lumen covered by endothelium

tumor plug within the vascularspace is not covered by endothelium but associated with thrombus

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

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

High risk counterpart of minimally invasive subtype

Widespread infiltration of blood vessels and/or

adjacent thyroid tissue

Lacks encapsulation

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

Reactive for thyroglobulin

TTF-1

low molecular weight keratins

EMA

basement membrane components

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)

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

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

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

mahoganybrown multilobated mass; haemorrhage and necrosis

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

SOLID GROWTH PATTERN VASCULAR INVASION

DIFFERNTIAL DIAGNOSIS

HISTOPATHOLOGY IHC

1)Follicular adenoma( from minimallyinvasive 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( -vein 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

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

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

solid and firm, with a gray-white cut surface; areasof necrosis and hemorrhageare frequently present

INSULAR PATTERNTRABECULAR PATTERN

Coagulative necrosis

Sheets and islands of tumour cells

Small uniform tumour cells;roundhyperchromatic nuclei;mitotic figures seen; absence of nuclear features of papillary carcinoma

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

1)MEDULLARYCARCINOMA

MTC more prominent vasculature, granular cytoplasm, and finely stippled chromatin+ve for calcitoninInsular +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 follicularcell differentiation ;prominent nuclear pleomorphism and frequent mitoses;

Immunostaining for thyroglobulin and TTF-1 isgenerally negative

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

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

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

Cells have moderate amount of eosinophiliccytoplasm

Brisk mitotic activity

Abundant apoptosis.

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)

TTF-1 and thyroglobulin- typically negative

Calcitonin and neuroendocrine makers- negative

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

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 papillarycarcinomaLack of mitosis

3)LARGE CELL LYMPHOMA

Lymphoma- less cellular cohesion; presence of plasmacytoid cytoplasm or stuffing of follicular luminaIHC can readily differntiate

4)PARATHYROIDCARCINOMA

It shows presence of clear cells, a mixture of cell types, and paucity of mitotic figures

5)POORLYDIFFERENTIATED CARCINOMA

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

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

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

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

solid proliferation of round to polygonal cells of granular amphophilic cytoplasm and medium-sized nucleus,

highly vascular stroma, hyalinized collagen, amyloid

prominent trabeculargrowth pattern

round nuclei;fine chromatin; nucleoli not prominent; finely granularcytoplasm

1) cytoplasmic dense-core secretory granules seen

argyrophilic with Griemelius stain

2) Mucin stains often positive

tumor cells arestrongly positive for calcitonin.

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

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

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 manynearby tissues or cannot be completely removed, external beam radiation therapy may be given after surgery

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

THANK YOU…