WHO classification of thyroid tumors

WORLD HEALTH ORGANISATION CLASSIFICATION : 

WORLD HEALTH ORGANISATION CLASSIFICATION THYROID TUMOURS - Shamsuz Zaman Dept of Pathology JNMCH Aligarh Muslim University University, Aligarh-India Email; movingantibody@gmail.com

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THYROID CARCINOMAS THYROID ADENOMA AND RELATED TUMORS OTHER THYROID TUMORS

THYROID CARCINOMAS : 

THYROID CARCINOMAS Papillary carcinoma Follicular carcinomaPoorly differentiated carcinoma Undifferentiated (anaplastic) carcinoma Squamous cell carcinoma Mucoepidermoid carcinomaSclerosing mucoepidermoid carcinoma with eosinophilia Mucinous carcinoma Medullary carcinoma Mixed medullary and follicular carcinoma Spindle cell tumor with thymus-like differentiation Carcinoma showing thymus-like differentiation

THYROID ADENOMA AND RELATED TUMORS : 

THYROID ADENOMA AND RELATED TUMORS Follicular adenoma Hyalinizing trabecular tumor

OTHER THYROID TUMORS : 

Teratoma Primary lymphoma and plasmacytoma Ectopic thymoma Angiosarcoma Smooth muscle tumors OTHER THYROID TUMORS Peripheral nerve sheath tumors Paraganglioma Solitary fibrous tumor Follicular dendritic cell tumor Langerhans cell histiocytosis Secondary tumors

THYROID CARCINOMAS : 

THYROID CARCINOMAS Papillary carcinoma Follicular carcinomaPoorly differentiated carcinoma Undifferentiated (anaplastic) carcinoma Squamous cell carcinoma Mucoepidermoid carcinomaSclerosing mucoepidermoid carcinoma with eosinophilia Mucinous carcinoma Medullary carcinoma Mixed medullary and follicular carcinoma Spindle cell tumor with thymus-like differentiation Carcinoma showing thymus-like differentiation

Papillary carcinoma : 

Papillary carcinoma “A malignant epithelial tumor showing evidence of follicular cell differentiation and characterized by distinctive nuclear features” -W.H.O.

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Most common thyroid malignancy Palpable nodule Nodule in multinodular goitre (in iodine insufficient areas) More common in females Rare before 15 years Mean age at diagnosis approximately 40 years Accounts for >90% of thyroid malignancies in children.

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In 5–10% history of neck irradiation Increased incidence in Hashimoto's thyroiditis disease localized to: thyroid gland in 67% thyroid and lymph nodes in 13% lymph nodes alone in 20% Overall survival excellent

localisation : 

localisation Normal situated thyroid gland Ectopic thyroid tissue (e.g. struma ovarii)

FNAC : 

FNAC Nuclear Size and Shape Chromatin Features Nuclear Grooves and Pseudoinclusions Associated Features

Low-Magnification AppearancePTC. Low-magnification appearance of PTC demonstratinghypercellularity and the monolayered appearance of groups.(Smear, Papanicolaou.) : 

Low-Magnification AppearancePTC. Low-magnification appearance of PTC demonstratinghypercellularity and the monolayered appearance of groups.(Smear, Papanicolaou.)

PTC. Monolayered sheet of PTC showing disorderly andoverlapping arrangement of cells and nuclei. (Smear, Papanicolaou.) : 

PTC. Monolayered sheet of PTC showing disorderly andoverlapping arrangement of cells and nuclei. (Smear, Papanicolaou.)

Chromatin Features : 

Chromatin Features Unique pattern among thyroid lesions Ethanol-fixed, Papanicolaou-stained samples, the chromatin appears Pale, finely textured, Evenly distributed PTC nuclei contain a small, eccentrically placed nucleolus.

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FINE PALE CHROMATIN Classic features of PTC, including enlarged, oval nuclei with extensive nuclear grooves and fine pale chromatin. (Smear, Papanicolaou.)

Nuclear Size and Shape : 

Nuclear Size and Shape The nuclei oval, rather than round, and are enlarged, relative to normal follicular nuclei exception to this is the follicular variant of PTC, in which the nuclei can be smaller than classic PTC nuclei. Classic nuclear features of PTC, including enlarged, oval nuclei with extensive nuclear grooves and fine pale chromatin. (Smear, Papanicolaou.)

Nuclear Grooves : 

Nuclear Grooves important diagnostic feature when associated with an oval, enlarged nucleus with fine chromatin caused by an infolding of the nuclear membrane. parallel to the long axis of the oval nuclei, giving a “coffee bean appearance

Pseudoinclusions : 

Pseudoinclusions highly suggestiveof PTC finger-like invaginations of cytoplasm into the nucleus. 90% of PTC aspirates

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Nuclear pseudoinclusions of PTC are large, often occupying 50% or more of the nuclear area more optically clear than the surrounding chromatin, Bounded by a distinct membrane, and are surrounded by a thin condensed rim of basophilic chromatinic material

Nuclear pseudoinclusions of PTC showingmembrane-bound structures (Smear, Papanicolaou.) : 

Nuclear pseudoinclusions of PTC showingmembrane-bound structures (Smear, Papanicolaou.)

Assosiated features : 

Assosiated features Dense squamoid cytoplasm multinucleated giant cells Densely staining, “ropey” colloid (also called “bubble gum” colloid) Psammoma bodies

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cytoplasm moderately abundant and exhibits a densely staining squamoid” or waxy quality

PTC. Dense, hyperchromatic colloid may be seen inassociation with PTC. (Smear, Papanicolaou.) : 

PTC. Dense, hyperchromatic colloid may be seen inassociation with PTC. (Smear, Papanicolaou.)

PTC. Concentrically laminated psammoma bodies aresometimes associated with PTC. (Smear, H&E.) : 

PTC. Concentrically laminated psammoma bodies aresometimes associated with PTC. (Smear, H&E.)

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Features of Papillary Carcinoma • Diagnostic Hypercellular Monolayered sheets with crowding and disorganization Enlarged, oval nuclei Fine, evenly-dispersed chromatin Longitudinal nuclear grooves Nuclear pseudoinclusions •Associated Dense squamoid cytoplasm Multinucleated giant cells Densely staining “ropey” colloid Psammoma bodies

GROSS pathology (PTC) : 

GROSS pathology (PTC) Size of the primary ranges from microscopic to huge Many thyroid cancers measuring <1 cm in diameter are papillary Most: solid whitish firm clearly invasive <10% are surrounded by a complete capsule

Histopathology (PTC) : 

Histopathology (PTC) Numerous true papillae Papillae are usually: complex, branching, and randomly oriented, with a central fibrovascular core and a single or stratified lining of cuboidal cells Stroma of the papillae: edematous or hyaline may contain lymphocytes, foamy macrophages, hemosiderin, or - exceptionally - adipose tissue Follicles tend to be irregularly shaped, tubular, and branching Cells have characteristic nuclear features

NUCLEAR FEATURESPTC : 

NUCLEAR FEATURESPTC (optically clear) nuclei: often large with an overlapping quality nucleolus usually inconspicuous and pushed against the nuclear membrane, which appears thickened particularly prominent in tissue fixed in high concentrations of formalin

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Nuclear pseudoinclusions: represent invaginations of the cytoplasm appear as sharply outlined acidophilic formation readily apparent in frozen section specimens and aspirations immunoreactivity for β-catenin and sometimes type IV collagen

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Nuclear grooves: tend to occur in oval or spindle nuclei usually arranged along the longest nuclear axis represent infoldings of a redundant nuclear membrane Mitoses are scanty or absent intranuclear grooves (400×).

PTCpsammoma bodies : 

PTCpsammoma bodies laminated basophilic structures that: stain for mucin, calcium, and iron appear to arise from necrosis of individual tumor cells, which occasionally may be seen at their center in approximately 50% of cases may be located in: the papillary stalk fibrous stroma between tumor cells in solid foci

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if found in normal thyroid tissue or lymph nodes from the neck, a papillary carcinoma is likely in the immediate vicinity Psammoma body formation in papillary carcinoma beneath the capsule of a cervical lymph node, without identifiable tumor cells

OTHER CHANGES IN PTC : 

OTHER CHANGES IN PTC LYMPHOCYTIC INFILTRATION OF THE STROMA: -25% of cases MANY TUMORS ALSO EXHIBIT: -a heavy infiltrate S-100 protein-positive dendritic/Langerhans' cells SCATTERED MULTINUCLEATED GIANT CELLS: -may be present -probably a response to leakage of colloid. BLOOD VESSEL INVASION: -5% of cases

metastases : 

metastases Papillary carcinoma invades the glandular lymphatics Cervical lymph nodes metastases: common (particularly in young patients) may be the first manifestation Blood-borne metastases: less frequent than with other thyroid carcinomas most common site is lung also in bones, central nervous system, other organs

metastases : 

metastases Regional lymph node metastases are extremely common (≥50%) This feature does not adversely affect long-term prognosis. Frequently the nodal metastasis will involve one node that may be cystic

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Papillary thyroid carcinoma metastatic to cervical lymph node. Small papillary formations are seen focally

Special Stains and Immunohistochemistry (PTC) : 

Special Stains and Immunohistochemistry (PTC)

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Tumors with papillary and follicular structures should be classified as papillary carcinoma Thyroglobulin and TTF-1: crucial markers when a papillary neoplasm is in a lymph node or other extrathyroidal site to establish whether the tumor is of thyroid nature or not most specific marker in existence (shared with the pulmonary epithelium)

Morphological variants of PTC : 

Morphological variants of PTC Papillary microcarcinoma Encapsulated variant Follicular variant -Solid variant -Macrofollicular variant -Diffuse multinodular variant -Encapsulated follicular variant Diffuse sclerosing variant Oncocytic (oxyphilic) variant Tall cell and columnar cell carcinoma Cribriform-morular variant Papillary carcinoma with exuberant nodular fasciitis-like stroma

Papillary microcarcinoma : 

Papillary microcarcinoma Found incidentally 1 cm or less Common incidental finding (≥25%) in thyroids removed for other reasons More common in males Most common form of papillary carcinoma Stellate appearance Nonencapsulated, white to tan nodule often located subcapsularly. Histologically, the tumors may be totally follicular or show papillary areas as well the lesions can infiltrate the surrounding thyroid

Typical stellate appearance of papillary microcarcinoma. : 

Typical stellate appearance of papillary microcarcinoma.

Papillary microcarcinoma in a patient with a benign follicular nodule. This lesion was an incidental finding in the thyroid lobectomy specimen. : 

Papillary microcarcinoma in a patient with a benign follicular nodule. This lesion was an incidental finding in the thyroid lobectomy specimen.

Microscopic features mutational profile same as their larger counterpart : 

Microscopic features mutational profile same as their larger counterpart

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incidentally found microcarcinoma confined within the thyroid is probably of no clinical importance and should not be overtreated

Morphological variants of PTC : 

Morphological variants of PTC Papillary microcarcinoma Encapsulated variant Follicular variant -Solid variant -Macrofollicular variant -Diffuse multinodular variant -Encapsulated follicular variant Diffuse sclerosing variant Oncocytic (oxyphilic) variant Tall cell and columnar cell carcinoma Cribriform-morular variant Papillary carcinoma with exuberant nodular fasciitis-like stroma

Encapsulated variant : 

Encapsulated variant presents grossly as an adenoma comprises from 8% to 13% of papillary cancers Microscopically, such lesions usually show total encapsulation; however, there are cytologic features of papillary cancer, including nuclear changes and psammoma bodies. The prognosis is excellent.

Morphological variants of PTC : 

Morphological variants of PTC Papillary microcarcinoma Encapsulated variant Follicular variant -Solid variant -Macrofollicular variant -Diffuse multinodular variant -Encapsulated follicular variant Diffuse sclerosing variant Oncocytic (oxyphilic) variant Tall cell and columnar cell carcinoma Cribriform-morular variant Papillary carcinoma with exuberant nodular fasciitis-like stroma

Follicular variant of PTC : 

Follicular variant of PTC PTC composed of entirely or almost entirely of follicles. Diagnosis is largely based on the nuclear features Supportive features for the diagnosis are: invasive growth pattern psammoma bodies strongly eosinophilic colloid with scalloped edges abortive papillae

Follicular variant of papillary thyroid carcinoma(FVPTC). Follicular architecture combined with nuclear features ofPTC. (Smear, Papanicolaou.) : 

Follicular variant of papillary thyroid carcinoma(FVPTC). Follicular architecture combined with nuclear features ofPTC. (Smear, Papanicolaou.)

Follicular variant of papillary carcinoma. Note the clear overlapping nuclei. : 

Follicular variant of papillary carcinoma. Note the clear overlapping nuclei.

Follicular variant of papillary thyroid carcinoma : 

Follicular variant of papillary thyroid carcinoma balanced result of two opposing biologic properties of the tumor cell: differentiation in the form of secretory activity (making colloid-filled follicles) proliferation When one of these forces predominates, two further variants emerge: -solid variant -macrofollicular variant Two additional variants depend on the tumor boundaries, taking as the standard a single invasive mass: -the diffuse (multinodular) variant -the encapsulated follicular variant

FVPTCSolid Variant : 

FVPTCSolid Variant Particularly common in children Proliferation predominates over secretion Characterized by solid nests of generally round shape that can be viewed as filled-up follicles Distinguish from poorly differentiated carcinoma: the nuclear features are those of papillary carcinoma behavior is that of papillary carcinoma (or a little worse), but notably different from that of poorly differentiated neoplasms Solid variant of papillary carcinoma. The nests are separated by fibrohyaline strands

Macrofollicular Variant : 

Macrofollicular Variant Rarest form of PTC Opposite of the solid variant in that secretory activity results in large dilated follicles so it resembles a hyperplastic nodule Some follicles are lined by cells with large clear nuclei with grooves and pseudoinclusions Low incidence of metastasis macrofollicular variant’ of papillary carcinoma. This lesion simulates nodular hyperplasia. The nuclear features that allow the diagnosis cannot be seen at this magnification.

Encapsulated Follicular VariantSynonym - Lindsay's tumor : 

Encapsulated Follicular VariantSynonym - Lindsay's tumor A neoplasm surrounded by a capsule and having the cytoarchitectural (especially nuclear) features of papillary carcinoma May be capsular or blood vessel invasion To diagnose this variant: the nuclear alterations should be widespread and well developed some supportive features (e.g. intratumoral sharply defined fibrohyaline bands, elongated and branching follicles, abortive follicles, and dense eosinophilic colloid) should be present excellent prognosis Because of this peculiar morphologic presentation, these tumors can be misdiagnosed as adenomatoid nodule or follicular adenoma

Morphological variants of PTC : 

Morphological variants of PTC Papillary microcarcinoma Encapsulated variant Follicular variant -Solid variant -Macrofollicular variant -Diffuse multinodular variant -Encapsulated follicular variant Diffuse sclerosing variant Oncocytic (oxyphilic) variant Tall cell and columnar cell carcinoma Cribriform-morular variant Papillary carcinoma with exuberant nodular fasciitis-like stroma

Diffuse Sclerosis Variant : 

Diffuse Sclerosis Variant 3% of all papillary carcinomas affects children and young adults, may present as bilateral goiter. permeates the gland outlining the intraglandular lymphatics. Characterized by: diffuse involvement of one or both thyroid lobes without formation of dominant mass dense sclerosis abundant psammoma bodies extensive solid foci squamous metaplasia heavy lymphocytic infiltration extensive lymph vessel permeation Numerous psammoma bodies are found

Diffuse sclerosing variant of papillary carcinoma. Note the diffuse pattern of growth, the heavy lymphocytic infiltrate, and the sclerosis : 

Diffuse sclerosing variant of papillary carcinoma. Note the diffuse pattern of growth, the heavy lymphocytic infiltrate, and the sclerosis

Prominent permeation of intrathyroid lymph vessels in diffuse sclerosing papillary carcinoma. Psammoma bodies are evident : 

Prominent permeation of intrathyroid lymph vessels in diffuse sclerosing papillary carcinoma. Psammoma bodies are evident

Morphological variants of PTC : 

Morphological variants of PTC Papillary microcarcinoma Encapsulated variant Follicular variant -Solid variant -Macrofollicular variant -Diffuse multinodular variant -Encapsulated follicular variant Diffuse sclerosing variant Oncocytic (oxyphilic) variant Tall cell and columnar cell carcinoma Cribriform-morular variant Papillary carcinoma with exuberant nodular fasciitis-like stroma

Oncocytic variant : 

Oncocytic variant Nuclear features are those of papillary carcinoma Cytoplasm is abundant and has a granular oxyphilic quality Pattern of growth may be papillary or follicular May be encapsulated or invasive, resulting in a number of possible combinations: oncocytic encapsulated oncocytic oncocytic follicular encapsulated oncocytic follicular variants important to recognize this variant because it may be confusedwith a Hurthle cell neoplasm

FNAC (ONCOCYTIC VARIANT) : 

FNAC (ONCOCYTIC VARIANT) Cellular aspirate with polygonal cells in loose papillary clusters abundant granular eosinophilic cytoplasm nuclei exhibit conventional PTC nuclear features, which distinguish

Tall cell variant : 

Tall cell variant important subtype because of its potentially aggressive clinical course. elderly patients, and often presents as a large tumor with extrathyroidal extension and metastases.

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composed predominantly of cells whose heights are at least twice times their widths. characterized by: papillae lined by a single layer of ‘tall’ cells (the height being at least twice the width) an abundant acidophilic, quasi-oncocytic cytoplasm These features should be present in at least 50% of the tumor Growth pattern is usually highly papillary Nuclei usually lack the optically clear appearance, grooves, and pseudoinclusions of papillary carcinoma and its other variants More aggressive behaviour

PTC, tall cell variant.The cells contain abundant cytoplasmand are about three times as tall as they are wide. H&E.) : 

PTC, tall cell variant.The cells contain abundant cytoplasmand are about three times as tall as they are wide. H&E.)

Tall cell variant of papillary carcinoma. Note the abundant granular acidophilic cytoplasm with oncocyte-like features. : 

Tall cell variant of papillary carcinoma. Note the abundant granular acidophilic cytoplasm with oncocyte-like features.

Columnar cell variant : 

Columnar cell variant In the columnar cell carcinoma: there is prominent stratification The cytoplasm is clear (sometimes with subnuclear vacuolization) Outcome is largely predicated by tumor stage Encapsulated columnar cell carcinomas have a favorable course Occasionally tall and columnar cells coexist in papillary carcinoma These tumors have advanced local growth and extrathyroidal extension and show aggressive clinical behaviour

Columnar cell variant of papillary carcinoma. The papillae are lined by a pseudostratified layer of spindle tumor cells. : 

Columnar cell variant of papillary carcinoma. The papillae are lined by a pseudostratified layer of spindle tumor cells.

PTC, columnar cell variant. Nuclei are enlarged,crowded, and elongate. (Smear, Papanicolaou.) : 

PTC, columnar cell variant. Nuclei are enlarged,crowded, and elongate. (Smear, Papanicolaou.)

Cribriform-morular Variant : 

Cribriform-morular Variant Characterized by: cribriform pattern of growth morular formations Strong nuclear-cytoplasmic staining for β-catenin (in contrast to cell membrane staining of normal thyroid) Sometimes sporadic. Sometimes part of a genetically determined syndrome that includes colonic adenomatous polyposis Most syndrome-associated cases studied genetically have shown: germline mutations of the APC gene somatic RET/PTC rearrangement evidence of alterations of the Wnt signaling pathway A sporadic case had somatic mutation of the APC gene

Cribriform-morular variant of papillary carcinoma. : 

Cribriform-morular variant of papillary carcinoma.

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Cardinal molecular alteration is an alteration of RET,which: is a proto-oncogene on chromosome 10q11.2 encodes a transmembrane receptor with tyrosine kinase activity Alteration of RET not a germline point mutation (as in familial medullary carcinoma)

PROGNOSIS : 

PROGNOSIS Age Nearly all the deaths occur when the tumor manifests after the age of 40 years Gender Females usually have a better prognosis Extrathyroidal extension Adversely affects prognosis Microscopic variant History of previous irradiation Does not affect prognosis Tumor size Roughly an inverse correlation between tumor size and prognosis

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Capsule and margins Tumors that are encapsulated or have pushing margins have a better outcome Multicentricity If this is prominent there is a greater incidence of metastasis and a lower chance of disease-free survival Distant metastases Lung metastases have an adverse influence on prognosis This influence is even greater for distant metastases in other sites, such as the skeletal system

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Poorly differentiated, squamous, or anaplastic foci These features have a markedly detrimental effect on prognosis Present in <5% of cases EMA and Leu-M1 positivity Immunoreactivity for EMA and Leu-M1 may be associated with a more aggressive clinical course DNA ploidy A good correlation has sometimes been shown between aneuploidy and aggressive behavior, Rb protein pRB expression level is a reliable predictor of recurrence Circulating tumor cells Presence of circulating tumor cells (as determined with an RT-PCR assay for thyroglobulin mRNA) seems to be associated with a higher likelihood of metastatic disease

Factors Not Generally Found To Relate To Prognosis : 

Factors Not Generally Found To Relate To Prognosis Relative proportion of papillae and follicles Presence or amount of fibrosis Presence or amount of squamous metaplasia or psammoma bodies Microvessel density Cervical node metastases

THYROID CARCINOMAS : 

THYROID CARCINOMAS Papillary carcinoma Follicular carcinomaPoorly differentiated carcinoma Undifferentiated (anaplastic) carcinoma Squamous cell carcinoma Mucoepidermoid carcinomaSclerosing mucoepidermoid carcinoma with eosinophilia Mucinous carcinoma Medullary carcinoma Mixed medullary and follicular carcinoma Spindle cell tumor with thymus-like differentiation Carcinoma showing thymus-like differentiation

Follicular carcinoma : 

Follicular carcinoma “A malignant epithelial tumor showing evidence of follicular cell differentiation and lacking the diagnostic nuclear features of papillary carcinoma” - W.H.O

Follicular carcinoma : 

Follicular carcinoma Relatively rare (10 to 15% of thyroid malignancies ) Predilection for females Incidence higher in iodine deficient areas Mean age at diagnosis approximately 50 years Almost always: solitary not occult Two types minimally invasive and widely invasive

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Asymptomatic intrathyroidal mass lesion Hoarsness dysphasia rare peak incidence between 40 and 60 years

TYPES OF FOLLICULAR CA. : 

TYPES OF FOLLICULAR CA. Minimally invasive type Widely invasive type

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Grossly encapsulated tumor Often: solid and fleshy cut surface. Most of the tumor is bound by a capsule (irregular whitish band around the lighter central nodule). the capsule is breached

Capsular invasion in minimally invasive follicular carcinoma. : 

Capsular invasion in minimally invasive follicular carcinoma.

Vascular invasion in minimally invasive follicular carcinoma. : 

Vascular invasion in minimally invasive follicular carcinoma.

Widely invasive follicular carcinoma : 

Widely invasive follicular carcinoma High-risk counterpart of the minimally invasive subtype Widespread infiltration of blood vessels and/or adjacent thyroid tissue Often lacks encapsulation Many are poorly differentiated carcinomas at the cytoarchitectural level

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Diagnosis of malignancy: depends entirely on blood vessel or capsular invasion blood vessel invasion is almost never evident grossly. The vessels should: be venous caliber be in or immediately outside the capsule (rather than within the tumor) contain one or more clusters of tumor cells attached to the wall and protruding into the lumen interruption of the capsule must be full thickness to qualify as capsular invasion distinguish foci of capsular invasion: from capsular rupture from fine needle aspiration, which results in a fissure-like quality with foci of recent or old hemorrhage and florid stromal reparative changes

Metastases : 

Metastases common with the widely invasive type <5% of minimally invasive tumors with blood vessel invasion <1% of tumors diagnosed as carcinoma only on the basis of minimal capsular invasion Usually blood-borne (particularly to lung and bones) rather than regional nodes Skeletal metastases: usually multicentric have a predilection for the shoulder girdle, sternum, skull, and iliac bone6 sometimes pulsate because of their vascularity (a feature shared with metastatic renal cell carcinoma)

TERMINOLOGY : 

TERMINOLOGY Capsular invasion: tumor penetration through the tumour capsule unassosiated with the site of previous FNAC Vascular Invasion: presence of intravascular tumour cells either covered by endothelium or associated with thrombus INVOLVED VESSELS MUST BE WITHIN OR BEYOND CAPSULE FOCI OF VASCULAR INVASION SHOULD BE DISTINGUISHED FROM SUBENDOTHELIAL COLLECTION Of tumor cells

A bone marrow core biopsy showing replacement of the marrow space by thyroid follicles. This patient had a follicular carcinoma of the thyroid removed 20 years prior to the marrow biopsy. : 

A bone marrow core biopsy showing replacement of the marrow space by thyroid follicles. This patient had a follicular carcinoma of the thyroid removed 20 years prior to the marrow biopsy.

Special Stains and Immunohistochemistry : 

Special Stains and Immunohistochemistry Thyroglobulin Ttf-1 LMW-keratin

THYROID CARCINOMAS : 

THYROID CARCINOMAS Papillary carcinoma Follicular carcinomaPoorly differentiated carcinoma Undifferentiated (anaplastic) carcinoma Squamous cell carcinoma Mucoepidermoid carcinomaSclerosing mucoepidermoid carcinoma with eosinophilia Mucinous carcinoma Medullary carcinoma Mixed medullary and follicular carcinoma Spindle cell tumor with thymus-like differentiation Carcinoma showing thymus-like differentiation

Poorly differentiated carcinoma : 

Poorly differentiated carcinoma Thyroid tumor that is, in differentiation and behavior, intermediate between well-differentiated (papillary and follicular carcinoma) and anaplastic thyroid carcinomas.

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Occurs in an older group than well-differentiated tumors Can occur in adolescents. More common in some parts of Europe and South America than in the United States Behavior is generally aggressive High incidence of nodal and blood-borne metastases

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Usually grossly invasive Can be encapsulated

FNAC Aspirates are cellular and containuniform small follicular cells in large loosely cohesive insular-likeclusters. The crowded arrangement of cells and absence of colloidare features of a follicular neoplasm. (Smear, Papanicolaou.) : 

FNAC Aspirates are cellular and containuniform small follicular cells in large loosely cohesive insular-likeclusters. The crowded arrangement of cells and absence of colloidare features of a follicular neoplasm. (Smear, Papanicolaou.)

Individual neoplastic cells are fairlyuniform and haphazardly arranged. Cells have scant delicate cyto-plasm, mild nuclear pleomorphism, stippled chromatin, and smallindistinct nucleoli. (Smear, Papanicolaou.) : 

Individual neoplastic cells are fairlyuniform and haphazardly arranged. Cells have scant delicate cyto-plasm, mild nuclear pleomorphism, stippled chromatin, and smallindistinct nucleoli. (Smear, Papanicolaou.)

histopathology : 

histopathology Distinguishing features: nesting (‘insular’) pattern of growth solid-to-microfollicular arrangement small uniform tumor cells variable mitotic activity fresh tumor necrosis resulting in a peritheliomatous pattern

On high power, the cells show round, medium-sized nuclei with a smooth contour and hyperchromasia : 

On high power, the cells show round, medium-sized nuclei with a smooth contour and hyperchromasia

Poorly differentiated carcinoma showing trabecular growth pattern rather than insular formations : 

Poorly differentiated carcinoma showing trabecular growth pattern rather than insular formations

Special Stains and Immunohistochemistry : 

Special Stains and Immunohistochemistry Thyroglobulin 60% TTF-1: 40% Not reactive for: calcitonin Usually: focal reactivity for neuroendocrine markers concentrate radioiodine (unlike undifferentiated carcinoma) bcl-2 in over 80% of cases (rare in undifferentiated carcinoma) p53 may be expressed restricted to foci of infiltrative growth

THYROID CARCINOMAS : 

THYROID CARCINOMAS Papillary carcinoma Follicular carcinomaPoorly differentiated carcinoma Undifferentiated (anaplastic) carcinoma Squamous cell carcinoma Mucoepidermoid carcinomaSclerosing mucoepidermoid carcinoma with eosinophilia Mucinous carcinoma Medullary carcinoma Mixed medullary and follicular carcinoma Spindle cell tumor with thymus-like differentiation Carcinoma showing thymus-like differentiation

Undifferentiated(anaplastic) thyroid carcinoma : 

Undifferentiated(anaplastic) thyroid carcinoma UTC are malignant tumours that histologically appear wholely or partially composed of undifferentiated cells that exhibit immunohistochemical or ultrastructural features indicative of epithelial differentiation

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Usually elderly 5% of thyroid malignancies Presentation: rapidly growing mass hoarseness dysphagia dyspnea usually extrathyroidal extension Rapid evolution: massive growth in neck infiltration of ribbon muscles, esophagus, trachea, skin, and contiguous bones commonly nodal and distant metastases cause of death usually involvement of vital structures in the neck extremely poor prognosis, with many patients surviving less than 6 months following diagnosis

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Pathogenesis Usually a result of anaplastic transformation of a pre-existing well-differentiated tumor (or a metastatic focus): commonly papillary carcinoma Anaplastic thyroid carcinoma showing residual papillary carcinoma.

Gross Pathology : 

Gross Pathology Highly necrotic and hemorrhagic solid tumor mass

Gross anaplastic thyroid carcinoma showing a large yellow, tan, white mass with areas of hemorrhage. : 

Gross anaplastic thyroid carcinoma showing a large yellow, tan, white mass with areas of hemorrhage.

FNAC : 

FNAC The neoplastic cells are arranged in loose clusters and as dispersed, single-cells Undifferentiated thyroid carcinoma. At low-magnificationa dispersed, single cell pattern with naked nuclei is often present. (Smear, Diff-Quik.)

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cells are often dyscohesive and a dispersed single cell pattern is common, sometimes with numerous background naked nuclei. microscopic appearance of the malignant cells is variable, ranging from squamoid cells spindle cells giant multinucleated tumor cells, Combination

Undifferentiated thyroid carcinoma. A combinationof squamoid, spindled, and giant cells is often present. (Smear,Papanicolaou.) : 

Undifferentiated thyroid carcinoma. A combinationof squamoid, spindled, and giant cells is often present. (Smear,Papanicolaou.)

Undifferentiated thyroid carcinoma. Clusters of spindlecells with elongate nuclei can be seen. (Smear, Papanicolaou.) : 

Undifferentiated thyroid carcinoma. Clusters of spindlecells with elongate nuclei can be seen. (Smear, Papanicolaou.)

HISTOPATHOLOGY : 

HISTOPATHOLOGY Squamoid sarcomatoid: spindle cell and giant cell:

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sarcomatoid: spindle cell and giant cell: composed of two patterns, often seen together may exhibit: a fascicular or storiform growth pattern heavy neutrophilic infiltration prominent vascularization cartilaginous/osseous metaplasia may be osteoclast-like multinucleated giant cells: giving an appearance reminiscent of giant cell tumor of bone or soft tissues

Anaplastic carcinoma of the spindle cell type. : 

Anaplastic carcinoma of the spindle cell type.

Anaplastic carcinoma of giant cell type : 

Anaplastic carcinoma of giant cell type

Special Stains and Immunohistochemistry : 

Special Stains and Immunohistochemistry Keratin 50-100% CEA 50% Throglobulin 5% Vimentin: (consistently present in the spindle cell component) TTF-1 (generally negative)

THYROID CARCINOMAS : 

THYROID CARCINOMAS Papillary carcinoma Follicular carcinomaPoorly differentiated carcinoma Undifferentiated (anaplastic) carcinoma Squamous cell carcinoma Mucoepidermoid carcinomaSclerosing mucoepidermoid carcinoma with eosinophilia Mucinous carcinoma Medullary carcinoma Mixed medullary and follicular carcinoma Spindle cell tumor with thymus-like differentiation Carcinoma showing thymus-like differentiation

Medullary carcinoma : 

Medullary carcinoma Thyroid malignancy with C (parafollicular) cell differentiation. 5% of thyroid neoplasms secrete calcitonin, elaborate other polypeptide hormones, such as serotonin, ACTH, and vasoactive intestinal peptide (VIP). Two forms: sporadic (approximately 80% of cases) familial The remainder 20% occurs in the setting of MEN syndrome 2A or 2B Cases associated with MEN types 2A or 2B occur in younger patients, and may even arise during the first decade of life. sporadic as well as familial medullary carcinomas are lesions of adulthood, with a peak incidence in the 40s and 50s.

sporadic medullary carcinoma : 

sporadic medullary carcinoma Occurs in adults (mean age 45 years) Almost always solitary Presents as a thyroid mass that is cold on thyroid scan Sometimes accompanied by intractable diarrhea or Cushing's syndrome

Familial medullary carcinoma : 

Familial medullary carcinoma Autosomal dominant inheritance with virtually complete penetrance. Becomes clinically apparent at mean age 35 years Most cases in children are familial medullary carcinoma Often multiple and bilateral

FNAC : 

FNAC cellular aspirates of uniform, dyscohesive epithelial cells Background of blood scattered amorphous globules of amyloid eccentric nuclei ‘neuroendocrine-type’ chromatin inconspicuous nucleoli binucleated and multinucleated cells ill-defined cell borders

Cytologic appearance of medullary carcinoma. The nuclei have clumped chromatin. An amorphous material compatible with amyloid is present.(Papanicolaou) : 

Cytologic appearance of medullary carcinoma. The nuclei have clumped chromatin. An amorphous material compatible with amyloid is present.(Papanicolaou)

MTC. The aspirate is moderately cellular and consistsof a dispersed uniform population of cells with eccentric nucleiand delicate cytoplasm in a background containing focal amyloid.(Smear, Papanicolaou.) : 

MTC. The aspirate is moderately cellular and consistsof a dispersed uniform population of cells with eccentric nucleiand delicate cytoplasm in a background containing focal amyloid.(Smear, Papanicolaou.)

MTC. The dyscohesive cells in MTC often have a plasmacytoidappearance as seen here. Occasional larger atypical cellsare also present (center). (Smear, Diff-Quik.) : 

MTC. The dyscohesive cells in MTC often have a plasmacytoidappearance as seen here. Occasional larger atypical cellsare also present (center). (Smear, Diff-Quik.)

MTC. The nuclei of MTC are round to oval, withcoarsely granular “salt-and-pepper” chromatin reflecting theirneuroendocrine differentiation. (Smear, Papanicolaou.) : 

MTC. The nuclei of MTC are round to oval, withcoarsely granular “salt-and-pepper” chromatin reflecting theirneuroendocrine differentiation. (Smear, Papanicolaou.)

MTC. This aspirate shows dyscohesive cells with delicatecytoplasm and cytologically bland elongate nuclei with coarsegranular “salt and pepper” chromatin. Focal amyloid is also presentin the background. (Smear, Papanicolaou.) : 

MTC. This aspirate shows dyscohesive cells with delicatecytoplasm and cytologically bland elongate nuclei with coarsegranular “salt and pepper” chromatin. Focal amyloid is also presentin the background. (Smear, Papanicolaou.)

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Typically: solid firm nonencapsulated relatively well circumscribed in the midportion or upper half of the gland, corresponding to a greater concentration of C cells in this region unencapsulated quality, solid appearance, and yellowish tan color

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Histopathology Classically: solid proliferation of round to polygonal cells with: granular amphophilic cytoplasm medium-sized nuclei highly vascular stroma hyalinized collagen amyloid coarse calcification Low-power microscopic view showing solid pattern of growth and deposition of amyloid.

Slide 129: 

Pattern of growth can be: carcinoid-like, paraganglioma-like trabecular glandular (tubular and follicular) pseudopapillary pseudopapillary pattern of growth resulting from lack of cohesiveness of tumor cells.

Special Stains and Immunohistochemistry : 

Special Stains and Immunohistochemistry Calcitonin+ 95 % CEA++100% Chromogranin+100 Keratin AE 1/3+100 TTF-1+90 Thyroglobulin NSE Synaptophysin Medullary carcinoma showing immunocytochemical positivity for calcitonin.

Metastases : 

Metastases Cervical and mediastinal lymph nodes Distant organs, particularly lung, liver, and skeletal system More common with sporadic and multiple endocrine neoplasia (MEN)-IIB than MEN-IIA May be the first manifestation and a source of confusion

THYROID CARCINOMAS : 

THYROID CARCINOMAS Papillary carcinoma Follicular carcinomaPoorly differentiated carcinoma Undifferentiated (anaplastic) carcinoma Squamous cell carcinoma Mucoepidermoid carcinomaSclerosing mucoepidermoid carcinoma with eosinophilia Mucinous carcinoma Medullary carcinoma Mixed medullary and follicular carcinoma Spindle cell tumor with thymus-like differentiation Carcinoma showing thymus-like differentiation

SQUAMOUS CELL CARCINOMA OF THE THYROID : 

SQUAMOUS CELL CARCINOMA OF THE THYROID is very rare. occurs in older adult patients who present with histories of goiter . resemble squamous carcinomas of other organs and range from well-differentiated to poorly differentiated lesions, with or without keratinization. these tumors are radioresistant and often rapidly fatal

THYROID CARCINOMAS : 

THYROID CARCINOMAS Papillary carcinoma Follicular carcinomaPoorly differentiated carcinoma Undifferentiated (anaplastic) carcinoma Squamous cell carcinoma Mucoepidermoid carcinomaSclerosing mucoepidermoid carcinoma with eosinophilia Mucinous carcinoma Medullary carcinoma Mixed medullary and follicular carcinoma Spindle cell tumor with thymus-like differentiation Carcinoma showing thymus-like differentiation

MUCOEPIDERMOID CARCINOMA AND SCLEROSING MUCOEPIDERMOID CARCINOMA WITH EOSINOPHILIA. : 

MUCOEPIDERMOID CARCINOMA AND SCLEROSING MUCOEPIDERMOID CARCINOMA WITH EOSINOPHILIA. Composed of solid masses of squamoid cells and mucin-producing cells, sometimes forming glands The nuclei may on occasion show a ground-glass appearance, and psammoma bodies may be found. all cases show thyroglobulin and TTF-1 expression prognosis good Lesions may metastasize to regional nodes and rarely distantly. Death from disease is rare Sclerosing mucoepidermoid carcinoma with eosinophilia is usually seen in a background of lymphocytic thyroiditis Characterized by tumor cells arranged in small sheets, anastamosing trabeculae, and narrow strands associated with dense fibrosis and numerous eosinophils The tumor cells stain negative for thyroglobulin and calcitonin and positive for cytokeratin

Sclerosing mucoepidermoid carcinoma with eosinophilia showing tumor cells arranged in cords, tubules, and glands with background sclerosis and eosinophilic infiltration (inset). : 

Sclerosing mucoepidermoid carcinoma with eosinophilia showing tumor cells arranged in cords, tubules, and glands with background sclerosis and eosinophilic infiltration (inset).

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THYROID CARCINOMAS THYROID ADENOMA AND RELATED TUMORS Follicular adenoma Hyalinizing trabecular tumor 3. OTHER THYROID TUMORS

Follicular adenoma : 

Follicular adenoma Benign encapsulated thyroid tumor that shows evidence of follicular cell differentiation. Most common thyroid neoplasm Usually occurs in euthyroid adult Thyroid lump Elevated thyroglobulin levels common but clinical hyperthyroidism (toxic adenomas) uncommon Autonomously functioning tumors may be more common in regions with iodine deficiency

Gross Pathology : 

Gross Pathology Characteristically: solitary secondary degenerative changes, especially for larger tumors such as hemorrhage edema fibrosis calcification bone formation cystic degeneration surrounded by a generally thin capsule that is grossly and microscopically complete Architectural and cytologic features differ from those of surrounding gland, which usually shows signs of compression

Slide 140: 

Gross appearance of follicular adenoma showing focal hemorrhagic areas Gross appearance of follicular adenoma showing focal hemorrhagic areas.

Histopathology : 

Histopathology A variety of patterns, singly or in combination: normofollicular (simple) macrofollicular (colloid) microfollicular (fetal;) trabecular/solid (embryonal) Mitoses: rare or absent not necessarily indicators of malignancy Microfollicular pattern of growth in a follicular adenoma

Intact fibrous capsule around a follicular adenoma. : 

Intact fibrous capsule around a follicular adenoma.

Special Stains and Immunohistochemistry : 

Special Stains and Immunohistochemistry Thyroglobulin+100 % TTF+100 % Reactivity for: low-molecular-weight keratin and thyroglobulin in the cytoplasm laminin and other basement membrane components around the follicles DNA aneuploidy: found in about one-quarter of follicular adenomas slightly more common in cellular types not an indicator of clinical malignancy or increased risk of tumor recurrence

Several variants : 

Several variants Hürthle cell adenoma hyalinizing trabecular adenoma Atypical adenoma: pronounced cellular proliferation less regular cytoarchitectural patterns no capsular or blood vessel invasion Adenoma with bizarre nuclei: huge hyperchromatic nuclei, usually in clusters no features of malignancy Rare types of follicular adenoma: clear cell changes (including signet ring, mucin-producing, and lipid-rich types) adipose metaplasia of the stroma (adenolipoma) cartilaginous metaplasia (adenochondroma) massive deposition of cytoplasmic black pigment following minocycline therapy (black adenoma)

Adenoma with bizarre nuclei : 

Adenoma with bizarre nuclei

Hürthle Cell Tumors : 

Hürthle Cell Tumors Follicular neoplasms composed of oncocytes which are characterized by deeply eosinophilic cytoplasm.

Slide 147: 

Usually adult Predominance of females Decrease or loss of bcl-2 expression suggests that this is an early event

Histopathology : 

Histopathology Cytoplasmic granularity: due to accumulation of mitochondria ultrastructurally many mitochondria show morphologic abnormalities deeply eosinophilic quality in H&E-stained sections follicular (most common) trabecular/solid papillary May be: large follicles separated by long and thin fibrovascular septa inspissated intraluminal colloid with concentric laminations (an appearance similar to psammoma bodies associated with papillary carcinoma, from which they are distinguished by location) Nuclei may show: pleomorphism prominent nucleoli isolated bizarre forms

Slide 149: 

Hürthle cell tumor of thyroid gland. The cytoplasm is packed with mitochondria. Secretory product is located toward the lumen, which is filled with colloid. (×3840) Hürthle cell tumor of thyroid gland. Variably sized mitochondria with prominent cristae. (×11,230)

Hurthle Cell Carcinomas : 

Hurthle Cell Carcinomas Hürthle Cell Carcinomas Predominantly or exclusively solid/trabecular growth pattern Highly invasive Metastases: mainly to lungs and bone less commonly cervical nodes

Gross Pathology : 

Gross Pathology Characteristically: solid tan well vascularized Usually well encapsulated throughout Invasive tumors tend to grow into the parenchyma in a multinodular fashion (can be underinterpreted as nodular hyperplasia) Gross appearance of Hürthle cell carcinoma. The cut surface shows a tan color and a necrotic hemorrhagic center

Hurthle cell carcinoma : 

Hurthle cell carcinoma Older age group Less female predominance Larger Tends to have a solid/trabecular rather than a follicular growth pattern Cells: often smaller higher nucleocytoplasmic ratio Proliferative activity is higher, but the difference is not sufficient for diagnostic or prognostic us Hürthle cell carcinoma with a predominantly solid pattern of growth

Marked blood vessel invasion (hurthle cell carcinoma) : 

Marked blood vessel invasion (hurthle cell carcinoma)

Special Stains and Immunohistochemistry : 

Special Stains and Immunohistochemistry CK 7+ 66% TTF+ 33% Thyroglobulin: 100%( Establishes thyroid origin) Reactivity for: thyroglobulin (less reactive than nononcocytic follicular cells) keratin (CK14 is emerging as a selective marker for oncocytes) CEA S-100 protein surprisingly, HMB-45

Prognosis : 

Prognosis Hürthle Cell Adenomas Almost always cured by excision Hürthle Cell Carcinomas 5-year mortality rate 20–40% Unfavorable prognostic factors: older patient age large tumor size extrathyroidal extension distant metastases regional lymph node involvement possibly aneuploidy

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THYROID CARCINOMAS THYROID ADENOMA AND RELATED TUMORS Follicular adenoma Hyalinizing trabecular tumor 3. OTHER THYROID TUMORS

Hyalinizing trabecular tumour : 

Hyalinizing trabecular tumour HTT is a rare tumour of follicular cell origin with a trabecular pattern of growth and marked intra-trabecular hyalinization Female predilection Mean age 47 years Solitary nodule

Slide 158: 

Suggestion that it may be a morphologic variant of papillary carcinoma features traditionally associated with papillary carcinoma, such as nuclear grooves and pseudoinclusions and psammoma bodies expression of similar types of stratified epithelial-type keratins occasional cases contain foci of typical papillary carcinoma occasional cervical lymph node metastases of papillary carcinoma have an HTA-like pattern detection of RET/PTC mutations with a frequency similar to or higher than that in papillary carcinoma

Histopathology : 

Histopathology A peculiar adenoma exhibiting: prominent trabecular arrangement: trabeculae may be straight or curved, resulting in in the cytoplasm of tumor cells due to accumulation of intermediate filaments Growth pattern may simulate that of paraganglioma and medullary carcinoma Distinct features: nuclear grooves and psammoma bodies: may suggest papillary carcinoma, particularly fine Hyalinizing trabecular adenoma. A wide trabecula is seen in the center of the picture, with the tumor cells arranged perpendicularly to the longest axis.

Psammoma body formation in hyalinizing trabecular adenoma. : 

Psammoma body formation in hyalinizing trabecular adenoma.

Special stains and immunohistochemistry : 

Special stains and immunohistochemistry Consistent positivity for thyroglobulin Distinctive cell membrane staining with MIB-1 Focal and inconstant reactivity for neuroendocrine markers such as: neuron-specific enolase (NSE) neurotensin Heavy deposition of type IV collagen: around tumor cells (partially explaining ‘hyaline’ appearance)

OTHER THYROID TUMORS : 

Teratoma Primary lymphoma and plasmacytoma Ectopic thymoma Angiosarcoma Smooth muscle tumors OTHER THYROID TUMORS Peripheral nerve sheath tumors Paraganglioma Solitary fibrous tumor Follicular dendritic cell tumor Langerhans cell histiocytosis Secondary tumors

TERATOMA. : 

TERATOMA. neonates or infants under the age of 1 year as huge midline neck masses. Approximately 35% of women who deliver babies with teratomas experience polyhydramnios in pregnancy. predominantly or partially cystic. contained elements of all three germ layers and have been benign. Teratomas of the thyroid in adults differ from those in newborns because they are more frequently malignant

Thyroid gland almost replaced by many primitive neuroepithelial rossettes : 

Thyroid gland almost replaced by many primitive neuroepithelial rossettes

OTHER THYROID TUMORS : 

Teratoma Primary lymphoma and plasmacytoma Ectopic thymoma Angiosarcoma Smooth muscle tumors OTHER THYROID TUMORS Peripheral nerve sheath tumors Paraganglioma Solitary fibrous tumor Follicular dendritic cell tumor Langerhans cell histiocytosis Secondary tumors

Malignant Lymphoma : 

Malignant Lymphoma involve the thyroid as part of systemic lymphoma (secondary lymphoma) or may arise primarily in the thyroid Approximately 20% of patients dying of generalized malignant lymphoma will show thyroid involvement Thyroid replacement is rarely extensive enough to produce clinical hypothyroidism

Slide 167: 

1% to 3.5% thyroid cancers are malignant lymphomas. Primary malignant lymphoma of the thyroid usually arises in an immunologically abnormal gland, usually one affected by chronic lymphocytic thyroiditis Clinically, thyroid lymphoma affects women more frequently than men (ratio of 2.5 to 8.4:1). Most patients are older (age 50 to 80 years). Grossly, appear as large fleshy tan or gray masses often extending outside the thyroid capsule. The most common histologic subtype is large-cell diffuse lymphoma Most thyroid lymphomas are of B-cell lineage

Diffuse large-cell lymphoma arising in thyroid : 

Diffuse large-cell lymphoma arising in thyroid

METASTATIC TUMORS TO THE THYROID. : 

METASTATIC TUMORS TO THE THYROID. Metastases may reach the thyroid by direct extension retrograde lymphatic spread, or hematogenously. Carcinomas of the larynx, pharynx, trachea, and esophagus may invade the thyroid directly.. Hematogenous metastases to the thyroid vary according to tumor type A metastasis should always be considered when the histology is unusual for a thyroid primary. In surgical series, carcinomas of the kidney and colon and melanoma are most commonly found to metastasize to thyroid Grossly, such lesions are often solitary, circumscribed masses;.

Histology revealed a diffuse growth of neoplastic cells with an evident clear cytoplasm (hematoxylin and eosin, ×200). : 

Histology revealed a diffuse growth of neoplastic cells with an evident clear cytoplasm (hematoxylin and eosin, ×200).

Neoplastic cells strongly expressed CD10 antigen (Immunoperoxidase, ×200) : 

Neoplastic cells strongly expressed CD10 antigen (Immunoperoxidase, ×200)

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