Thyroid CytologyThyroid Cytology

Teresa Alasio, MDTeresa Alasio, MD

FNA of ThyroidFNA of Thyroid

Indications:Indications:– Solitary nodule or dominant noduleSolitary nodule or dominant nodule– Radionuclide studies (not specific for Radionuclide studies (not specific for

malignancy): malignancy): Cold nodule (non-functioning)Cold nodule (non-functioning)

Hot nodules are almost always benign (toxic Hot nodules are almost always benign (toxic adenomas)adenomas)

AdequacyAdequacy

Number of passes performed variesNumber of passes performed varies

Presence of cytopathologist or Presence of cytopathologist or cytotechnologist can decrease number of cytotechnologist can decrease number of passes because accuracy is improvedpasses because accuracy is improved

Direct smears and LBP are performedDirect smears and LBP are performed– Diff-quikDiff-quik– Pap stainPap stain– Ultrafast Pap stainUltrafast Pap stain

Evaluation of SmearsEvaluation of Smears

Non-diagnostic:Non-diagnostic:– Blood, thick smears, air driedBlood, thick smears, air dried

Counting groups of benign follicular cellsCounting groups of benign follicular cells– At least 6 groups of 10 cells each required by At least 6 groups of 10 cells each required by

some cytopathologistssome cytopathologists– ExceptionsExceptions

Groups can be broken up (macrofollicles)Groups can be broken up (macrofollicles)Abundance of colloidAbundance of colloidSpecific diagnosis can be rendered (e.g. Specific diagnosis can be rendered (e.g. Hashimoto’s)Hashimoto’s)

Normal Thyroid Gland: Normal Thyroid Gland: Follicular CellsFollicular Cells

UniformUniform

Orderly honeycomb sheetsOrderly honeycomb sheets

Single cells are sparseSingle cells are sparse

Intact follicles can be aspiratedIntact follicles can be aspirated

Benign follicular cells

Normal Thyroid Gland: Normal Thyroid Gland: Flame CellsFlame Cells

Aka “flare cells”Aka “flare cells”

Follicular cells with cytoplasmic vacuoles Follicular cells with cytoplasmic vacuoles containing metachromatic materialcontaining metachromatic material

Flame cell change indicates that the Flame cell change indicates that the individual cells are hyperfunctioningindividual cells are hyperfunctioning

Numerous in toxic goiters but can also be Numerous in toxic goiters but can also be seen in nontoxic goiters, Hashimoto seen in nontoxic goiters, Hashimoto thyroiditis, neoplasmsthyroiditis, neoplasms

Flame Cells

Normal Thyroid Gland:Normal Thyroid Gland:Hurthle CellsHurthle Cells

Aka oncocytesAka oncocytesAbundant, dense, finely granular Abundant, dense, finely granular cytoplasmcytoplasmEnlarged nucleiEnlarged nucleiProminent nuceoli Prominent nuceoli Binucleation and multinucleation are Binucleation and multinucleation are commoncommonAssociated with Hashimoto’s, goiters and Associated with Hashimoto’s, goiters and neoplasmsneoplasms

Hurthle CellsHurthle Cells

Diff-Quik Pap

Miscellaneous CellsMiscellaneous Cells

Ciliated cells (respiratory epithelial cells)Ciliated cells (respiratory epithelial cells)– Trachea was enteredTrachea was entered

FibrocartilageFibrocartilage

Skeletal muscleSkeletal muscle

SkinSkin

Adipose tissueAdipose tissue

Cystic ChangeCystic ChangeDiff-Quik

Pap

H&E

Clinical Features Favoring Clinical Features Favoring MalignancyMalignancy

Young (<20) or old (>70)Young (<20) or old (>70)

MaleMale

History of external neck irradiation during History of external neck irradiation during childhoodchildhood

Recent changes in breathing, speaking or Recent changes in breathing, speaking or swallowingswallowing

Family history of thyroid cancer or MEN2Family history of thyroid cancer or MEN2

Firm, irregularly shaped or fixed thyroid glandFirm, irregularly shaped or fixed thyroid gland

Cervical lymphadenopathyCervical lymphadenopathy

Clinical Features Favoring a Benign Clinical Features Favoring a Benign NoduleNodule

Hypothyroidism or hyperthyroidismHypothyroidism or hyperthyroidism

Family history of Hashimoto’s thyroiditis or Family history of Hashimoto’s thyroiditis or other benign thyroid diseaseother benign thyroid disease

Sudden increase in size with pain or Sudden increase in size with pain or tendernesstenderness– s/o spontaneous infarction and hemorrhages/o spontaneous infarction and hemorrhage

Normal Thyroid Gland: ColloidNormal Thyroid Gland: Colloid

Two basic forms:Two basic forms:

Watery colloidWatery colloid– Seen in Diff-Quik stainSeen in Diff-Quik stain– Blood serum can mimic watery colloid microscopicallyBlood serum can mimic watery colloid microscopically

Dense colloidDense colloid– Irregular chips of translucent homogenous materialIrregular chips of translucent homogenous material– Deep purple on Diff-Quik, blue on Papanicolaou stainDeep purple on Diff-Quik, blue on Papanicolaou stain

ColloidColloid

Thin Thick

Amyoid GoiterAmyoid Goiter

Focal or diffuse enlargement of the thyroid Focal or diffuse enlargement of the thyroid glandgland

Rapid growth, dyspnea, dysphagia, Rapid growth, dyspnea, dysphagia, hoarsenesshoarseness

Chronic illness predisposing patient to Chronic illness predisposing patient to systemic amyloidosissystemic amyloidosis

Amyoid vs. ColloidAmyoid vs. Colloid

Thyroid Pathology: Thyroid Pathology: InflammatoryInflammatory

Inflammatory DiseaseInflammatory Disease– Acute thyroiditisAcute thyroiditis– Granulomatous (deQuervain or subacute) Granulomatous (deQuervain or subacute)

thyroiditisthyroiditis– Hashimoto thyroiditisHashimoto thyroiditis

Acute ThyroiditisAcute Thyroiditis

Immunosuppressed patientsImmunosuppressed patients

Usually bacterial in originUsually bacterial in origin– Strep pyogenes, Staph aureus, Strep pneumoStrep pyogenes, Staph aureus, Strep pneumo

Numerous neutrophils and histiocytes are Numerous neutrophils and histiocytes are characteristiccharacteristic

Granulation tissue, necrosis and debris Granulation tissue, necrosis and debris may be presentmay be present

Granulomatous ThyroiditisGranulomatous Thyroiditis

Aka deQuervain or Subacute ThyroiditisAka deQuervain or Subacute Thyroiditis

Postviral syndromePostviral syndrome

Classic cause of painful thyroidClassic cause of painful thyroid

Young womenYoung women– Fever, chills, fatigueFever, chills, fatigue

Rarely aspirated because clinically apparent Rarely aspirated because clinically apparent without biopsywithout biopsy

If no pain and forms a nodule, then may be If no pain and forms a nodule, then may be subject to aspiration biopsysubject to aspiration biopsy

Granulomatous ThyroiditisGranulomatous Thyroiditis

Scanty aspirateScanty aspirate

Not well toleratedNot well tolerated

Giant cellsGiant cells

Noncaseating granulomasNoncaseating granulomas

Chronic inflammationChronic inflammation

Hurthle cells are unusualHurthle cells are unusual

Hashimoto ThyroiditisHashimoto Thyroiditis

Diagnosis is usually clinically apparent and Diagnosis is usually clinically apparent and patients don’t get FNApatients don’t get FNA

Some patients with non-classic findings Some patients with non-classic findings may get FNAmay get FNA

Hashimoto’s Thyroiditis

Black ThyroidBlack Thyroid

Dark brown pigmentation of thyroid Dark brown pigmentation of thyroid follicular cells in patients who take follicular cells in patients who take antibiotics of the tetracycline groupantibiotics of the tetracycline group

Thyroid gland appears black grosslyThyroid gland appears black grossly

Benign condition – no treatment necessaryBenign condition – no treatment necessary

Thyroid Pathology: Thyroid Pathology: Follicular LesionsFollicular Lesions

GoiterGoiter

Follicular neoplasmsFollicular neoplasms– Follicular adenomaFollicular adenoma– Follicular carcinomaFollicular carcinoma

Adenoma vs. GoiterAdenoma vs. Goiter

Follicular AdenomaFollicular Adenoma– Single noduleSingle nodule– Complete Complete

encapsulationencapsulation– Uniform folliclesUniform follicles– Different inside from Different inside from

outsideoutside– PreservationPreservation– No invasion, no No invasion, no

metastasismetastasis

GoiterGoiter– Multiple nodulesMultiple nodules– Variable encapsulationVariable encapsulation– Variable folliclesVariable follicles– Same or different Same or different

inside vs. outsideinside vs. outside– Degeneration Degeneration

/regeneration/regeneration– No invasion, no No invasion, no

metastasismetastasis

Zone IZone I Zone IIZone II Zone IIIZone III

Cytologic DiagnosisCytologic Diagnosis Colloid NoduleColloid Nodule Cellular NoduleCellular Nodule Follicular NoduleFollicular Nodule

More diagnostic More diagnostic cluesclues

Multiple nodules, Multiple nodules, honeycomb patter, honeycomb patter, favor goiterfavor goiter

See Zones I and IISee Zones I and II Solitary nodule; Solitary nodule; microfollicular microfollicular pattern, favor pattern, favor neoplasmneoplasm

Risk of neoplasmRisk of neoplasm Low (<10%)Low (<10%) Moderate (20%)Moderate (20%) High (40%)High (40%)

Risk of cancerRisk of cancer Very lowVery low LowLow ModerateModerate

III

III

Colloid Cells

C06-6739

S07-670

Architecture and BackgroundArchitecture and Background

Degenerative and regenerative changes Degenerative and regenerative changes favor goiter over neoplasmfavor goiter over neoplasm– Hemorrhage, fibrosis, cystic degeneration, Hemorrhage, fibrosis, cystic degeneration,

foam cells, macrophages, cholesterol crystalsfoam cells, macrophages, cholesterol crystals

Overlapping and crowding of nuclei with Overlapping and crowding of nuclei with pleomorphism favors neoplasm over goiterpleomorphism favors neoplasm over goiter

CytologyCytology

Many well-differentiated follicular Many well-differentiated follicular carcinomas look cytologically benigncarcinomas look cytologically benign

A few benign but atypical adenomas look A few benign but atypical adenomas look cytologically malignantcytologically malignant

Often it is not possible to distinguish Often it is not possible to distinguish follicular adenomas and follicular follicular adenomas and follicular carcinomas by cytology alonecarcinomas by cytology alone

Carcinoma: Cytologic FeaturesCarcinoma: Cytologic Features

High cellularityHigh cellularityMarkedly crowded, irregular folliclesMarkedly crowded, irregular folliclesNumerous single cellsNumerous single cellsLarge pleomorphic nuclei (3-4X normal)Large pleomorphic nuclei (3-4X normal)Abnormal chromatinAbnormal chromatinEtc.Etc.Marked cytologic atypia = suspicious for Marked cytologic atypia = suspicious for follicular carcinomafollicular carcinoma

Goiter vs. Follicular NeoplasmGoiter vs. Follicular Neoplasm

GoiterGoiter Follicular NeoplasmFollicular Neoplasm

ColloidColloid AbundantAbundant ScantyScanty

CellularityCellularity LowLow HighHigh

Cell typesCell types MultipleMultiple SingleSingle

NucleiNuclei SmallSmall LargeLarge

NucleoliNucleoli InconspicuousInconspicuous VariableVariable

FolliclesFollicles

SizeSize

MicrofolliclesMicrofollicles

VariableVariable

Less commonLess common

UniformUniform

More commonMore common

HoneycombHoneycomb MaintainedMaintained LostLost

DegenerationDegeneration CommonCommon UncommonUncommon

Clinical NodulesClinical Nodules MultipleMultiple SolitarySolitary

Patient HistoryPatient History

79 year old female79 year old female

Co-morbidities: diabetes, hypertension, Co-morbidities: diabetes, hypertension, hypothyroidismhypothyroidism

Right thyroid noduleRight thyroid nodule

Nuclear changes in PTC

Fischer AH, et al. Papillary thyroid carcinoma oncogene (RET/PTC) alters the nuclear envelope and chromatin structure. Am J Pathology 1998; 153:1443-50.Viral injection of RET/PTC oncogene to follicular cells in tissue cultureDisorganization of nuclear lamins A, B, CNuclei of cultured cells changed from follicular to papillary.

Follow upFollow up

Patient had a total thyroidectomy one Patient had a total thyroidectomy one month later…month later…

Right thyroid lobe – 5.5cm circumscribed nodule

Inclusions

Nuclear clearing

Grooves

PTCPTC

Most frequent primary malignancy of the Most frequent primary malignancy of the thyroid (60%)thyroid (60%)

Most are slow growing neoplasmsMost are slow growing neoplasms

Metastasize via lymphatics to regional Metastasize via lymphatics to regional lymph nodeslymph nodes

Cytologic Diagnosis of PTCCytologic Diagnosis of PTC

Smears are usually cellularSmears are usually cellular

Papillary fronds with columnar and Papillary fronds with columnar and cuboidal epithelium predominatecuboidal epithelium predominate

Can undergo cystic change, which can Can undergo cystic change, which can cause one to mistake it for a cystic goiter cause one to mistake it for a cystic goiter (9% of cases in one study)(9% of cases in one study)

Papillary fronds Chewing gum colloid

Nuclear grooves/clearing Inclusions

PTC – other cytologic featuresPTC – other cytologic features

Psammoma bodiesPsammoma bodies

MNGsMNGs

Oncocytic (Hurthle cell) changeOncocytic (Hurthle cell) change

Diagnosis of PTC cannot be established Diagnosis of PTC cannot be established on the basis of any single feature, but on on the basis of any single feature, but on several features in the appropriate clinical several features in the appropriate clinical setting.setting.

Medullary CarcinomaMedullary Carcinoma

Numerous single cellsNumerous single cellsLoose clustersLoose clustersEpithelioid, plasmacytoid and/or spindle shaped Epithelioid, plasmacytoid and/or spindle shaped cellscellsNucleiNuclei– Round or elongatedRound or elongated– Finely or coarsely granular chromatinFinely or coarsely granular chromatin– Inconspicuous nucleiInconspicuous nuclei– PseudoinclusionsPseudoinclusions

Red cytoplasmic granulesRed cytoplasmic granulesAmyloidAmyloid

Medullary CarcinomaMedullary Carcinoma

Poorly Differentiated Carcinoma, Poorly Differentiated Carcinoma, Including Insular CarcinomaIncluding Insular Carcinoma

Carcinomas which are neither well Carcinomas which are neither well differentiated nor anaplasticdifferentiated nor anaplastic

Cannot fit into any category (follicular, Cannot fit into any category (follicular, Hurthle cell, papillary)Hurthle cell, papillary)

Mixed patterns can be seenMixed patterns can be seen

4-7% of all thyroid carcinomas4-7% of all thyroid carcinomas

Poor prognosisPoor prognosis– Not as poor as anaplastic thoughNot as poor as anaplastic though

Insular CarcinomaInsular Carcinoma

Highly cellularHighly cellularMostly single cellsMostly single cellsSome microfollicles, trabeculae, spheresSome microfollicles, trabeculae, spheresMonomorphous round nucleiMonomorphous round nucleiCan have grooves, INCIsCan have grooves, INCIsMay have features of papillary carcinoma or May have features of papillary carcinoma or medullary carcinomamedullary carcinomaThyroglobulin positiveThyroglobulin positiveCalcitonin negativeCalcitonin negative

Poorly Differentiated PTCPoorly Differentiated PTC

Greater degree of atypia than classic PTCGreater degree of atypia than classic PTC

Nucler changes, including grooving and Nucler changes, including grooving and pseudoinclusions, are still seenpseudoinclusions, are still seen

Insular CarcinomaInsular Carcinoma

Hypercellular pattern, may think about follicular Hypercellular pattern, may think about follicular lesionlesion

Single cells resemble medullary carcinomaSingle cells resemble medullary carcinoma– Calcitonin negativeCalcitonin negative

Anaplastic CarcinomaAnaplastic Carcinoma

Mostly single cellsMostly single cells

Marked nuclear pleomorphismMarked nuclear pleomorphism

Large cellsLarge cells

Epithelioid or spindle shapedEpithelioid or spindle shaped

Squamous differentiationSquamous differentiation

Giant cellsGiant cells– Tumor typeTumor type– Osteoclast typeOsteoclast type

Anaplastic CarcinomaAnaplastic Carcinoma

Isolated large cellsIsolated large cells

Keratinization can be seenKeratinization can be seen

Other NeoplasmsOther Neoplasms

LymphomaLymphoma– Primary thyroid NHLs – 2% of all thyroid cancersPrimary thyroid NHLs – 2% of all thyroid cancers– Arise in setting of Hashimoto’sArise in setting of Hashimoto’s

20-30 years after 20-30 years after

– Can be large tumorsCan be large tumors– MZL and DLBLMZL and DLBL

Metastatic carcinomaMetastatic carcinoma– 0.1-0.3% of thyroid aspirates0.1-0.3% of thyroid aspirates– Breast, lung, kidney most commonBreast, lung, kidney most common