Download - Malignant tumours of thyroid
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By- Dr. Kanwalpreet kaur
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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.
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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
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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
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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)
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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
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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
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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
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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
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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
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Usually infiltrative; ill defined borders; white to tan; fibrosis
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Cystic metastasis in cervical lymph node
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Complex branching randomly oriented papillae with central fibrovascular core; single or stratified lining of cuboidal cells
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Follicles are frequently present; usually elongated and filled with dark staining colloid
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complex tubulopapillary pattern
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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
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large, crowded, ovoid, ground-glass (hypochromatic) nuclei;
Up and down placement of nuclei
Mitotic figures are generally absent or sparse
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Nuclear grooves
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Nuclear pseudoinclusion
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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
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PSAMMOMA BODY in papillary stalk
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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.
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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.
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INFILTRATIVE TYPE ENCAPSULATED TYPE
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Elongated and irregular follicles
dark staining and scalloped colloid
INFILTRATIVE TYPE
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Tumor cellsforms islands ;traversed by delicate blood vessels;nuclearfeatures of papillary carcinoma.
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Distant metastasis nearly zero; nodal metastases may be seen
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Islands of tumour cells
Dense sclerosis; lymphocytic infiltration
children and young adults; diffuse involvement of one or both thyroid lobes
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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
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Single layer of tall cells;Height >3times widthAbundant acidophilliccytoplasm; growth pattern-highly papillary
Older patients; extranodal extension common; more aggressive than conventional form
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pseudostratified layer of spindle tumor cells;
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Abundant eosinophilliccytoplasm akin to hurthlecells.
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large follicles distended withcolloid, mimicking colloid nodule
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blending of cribriform structures, variably fused follicles, and papillae;absence of colloid in lumen
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Papillary carcinoma measuring 1 cm or less in diameter
TYPICAL STELLATE APPERANCE
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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.
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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.
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ACTIVATION OF MAP KINASE (MITOGEN
ACTIVATED PROTEIN KINASE) PATHWAY
Rearrangements of Point mutations in
RET or NTRK1 BRAF
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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
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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
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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.
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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
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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
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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
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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
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Significant nuclear atypia seen in some cases
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CAPSULAR INVASION VASCULAR INVASION
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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.
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polypoid tumor plug within blood vessel
attachment to the wall
this is not an essential criterion for recognition of vascular invasion
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tumor plug lying within the vascular lumen covered by endothelium
tumor plug within the vascularspace is not covered by endothelium but associated with thrombus
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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
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tumor bud penetrated through the fibrous capsule, reaching beyond the external contour of the capsule
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High risk counterpart of minimally invasive subtype
Widespread infiltration of blood vessels and/or
adjacent thyroid tissue
Lacks encapsulation
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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
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Reactive for thyroglobulin
TTF-1
low molecular weight keratins
EMA
basement membrane components
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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)
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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
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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
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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
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mahoganybrown multilobated mass; haemorrhage and necrosis
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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
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SOLID GROWTH PATTERN VASCULAR INVASION
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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
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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
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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
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solid and firm, with a gray-white cut surface; areasof necrosis and hemorrhageare frequently present
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INSULAR PATTERNTRABECULAR PATTERN
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Coagulative necrosis
Sheets and islands of tumour cells
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Small uniform tumour cells;roundhyperchromatic nuclei;mitotic figures seen; absence of nuclear features of papillary carcinoma
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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
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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
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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
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fleshy and white-tan,with frequent necrosis and hemorrhage; entirely replacing the gland and extending into the surrounding skeletal muscle
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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
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Cells have moderate amount of eosinophiliccytoplasm
Brisk mitotic activity
Abundant apoptosis.
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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)
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TTF-1 and thyroglobulin- typically negative
Calcitonin and neuroendocrine makers- negative
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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
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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
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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
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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
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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
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solid, firm, unencapsulated ,Circumscribed,tan yellow to white
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solid proliferation of round to polygonal cells of granular amphophilic cytoplasm and medium-sized nucleus,
highly vascular stroma, hyalinized collagen, amyloid
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prominent trabeculargrowth pattern
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round nuclei;fine chromatin; nucleoli not prominent; finely granularcytoplasm
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1) cytoplasmic dense-core secretory granules seen
argyrophilic with Griemelius stain
2) Mucin stains often positive
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tumor cells arestrongly positive for calcitonin.
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36 – 66% of sporadic MTC – somatic RET gene mutations
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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
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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
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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
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THANK YOU…