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CYTOMORPHOLOGIC FEATURES OF THYROID LESIONS
Prof. Dr. İlkser Akpolat, F.I.A.C
Acıbadem University
School of Medicine
PLAN
• General approach to the thyroid fine needle aspiration (FNA) evaluation
• Basic microscopic findings
• The role of basic microscopic findings in the differential diagnosis.
Thyroid Cytopathology Evaluation Steps
• Is there Colloid ?• Scant /abundant
• How is the quality of colloid?• Watery/dense
• Other background changes• Lymphocytes/giant cell/histiocytes/amyloid
• Cellularity• Low / high
• Cell type• Variable cell types /uniform cells
• Arrangement• Well ordered/disorganisation of follicules/papillary structure/microfollicles /swirl
• Nuclear features• Oval/spindle/irregular nuclear contour/nükleol/INCI/grooves
• Chromatin• Pycnotic/pale,powdery/salt and pepper
• Cytoplasm• Location of the nucleus/ skuamoid/granules/ nuclear/cytoplasmic ratios+
Thyroid Cytopathology Evaluation Steps
• Is there Colloid ?• Scant /abundant
• How is the quality of colloid?• Watery/dense
• Cellularity• Low / high
• Cell type• Variable cell types /uniform cells
• Arrangement• Well ordered/disorganisation of follicules/papillary structure/microfollicles /swirl
• Other background changes• Lymphocytes/giant cell/histiocytes/amyloid
• Nuclear features• Oval/spindle/irregular nuclear contour/nükleol/INCI/grooves
• Chromatin• - Pycnotic/pale,powdery/salt and pepper
• Cytoplasm• Location of the nucleus/ skuamoid/granules/ nuclear/cytoplasmic ratios
BENIGN FOLLICULAR NODULE (BFN)/NEOPLASM
ABUNDANT COLLOID SCANT COLLOID
BFN/NEOPLASM
WATERY COLLOID DENSE COLLOID
WATERY COLLOID
• Watery colloid can be indistinguishable from serum.
• The presence of thyroid follicle cells favors colloid.
WATERY COLLOID
• Colloid can be lost from the glass slide during processing
• Colloid is better retained on PAP stained slides
• But it is easier to see on Romanowsky-stained slides
DENSE COLLOID
• More frequent in neoplasms
Thyroid Cytopathology Evaluation Steps
• Is there Colloid ?• Scant /abundant
• How is the quality of colloid?• Watery/dense
• Cellularity• Low / high
• Cell type• Variable cell types /uniform cells
• Arrangement• Well ordered/disorganisation of follicules/papillary structure/microfollicles /swirl
• Other background changes• Lymphocytes/giant cell/histiocytes/amyloid
• Nuclear features• Oval/spindle/irregular nuclear contour/nükleol/INCI/grooves
• Chromatin• - Pycnotic/pale,powdery/salt and pepper
• Cytoplasm• Location of the nucleus/ skuamoid/granules/ nuclear/cytoplasmic ratios
BFN/ NEOPLASM
LOW CELLULARITY HIGH CELLULARITY
CELLULARITY
– Depends on skill of the aspirator
Thyroid Cytopathology Evaluation Steps
• Is there Colloid ?• Scant /abundant
• How is the quality of colloid?• Watery/dense
• Cellularity• Low / high
• Cell type• Variable cell types /uniform cells
• Arrangement• Well ordered/disorganisation of follicules/papillary structure/microfollicles /swirl
• Other background changes• Lymphocytes/giant cell/histiocytes/amyloid
• Nuclear features• Oval/spindle/irregular nuclear contour/nükleol/INCI/grooves
• Chromatin• - Pycnotic/pale,powdery/salt and pepper
• Cytoplasm• Location of the nucleus/ skuamoid/granules/ nuclear/cytoplasmic ratios
BFN/NEOPLASM
HETEROGENEOUS CELLS UNIFORM CELLS
Uniform cells, Hurthle Cells (>%75) To diagnose a follicular neoplasma as oncocytic type more than 75% of follicular cells should be oncocytic
Uniform cells carrying papillary carcinoma
nuclear features
Thyroid Cytopathology Evaluation Steps
• Is there Colloid ?• Scant /abundant
• How is the quality of colloid?• Watery/dense
• Cellularity• Low / high
• Cell type• Variable cell types /uniform cells
• Arrangement• Well ordered/disorganisation of follicules/papillary structure/microfollicles /swirl
• Other background changes• Lymphocytes/giant cell/histiocytes/amyloid
• Nuclear features• Oval/spindle/irregular nuclear contour/nükleol/INCI/grooves
• Chromatin• - Pycnotic/pale,powdery/salt and pepper
• Cytoplasm• Location of the nucleus/ skuamoid/granules/ nuclear/cytoplasmic ratios
BFN/ NEOPLASM
WELL ORDERED SHEETS DISORDERED ARRENGEMENT
Disordered and overlapped thyroid follicular cells from a
papillary carcinoma.
Follicle size
Follicle size is a key factor in assessing follicular lesions
– Large follicules;
• Usually correlate with goiter, thyroiditis, sometimes with adenomas
• But rarely if ever with follicular carcinoma
– Microfollicules;
• Can occur in any follicular lesion
• But are more numerous in neoplasm
BFN/NEOPLASM
MACROFOLLICULES MICROFOLLICULES
Microfollicles are composed of 6-12 cells and they are rosette or ringed shaped. Can be singly or or occur in repeating patterns within groups of cells.
Microfollicullar complexes; are crowded 3-dimensional, syncytial-like aggregates of microfollicles. They are characteristic for follicular neoplasm, but not specific.
BFN/NEOPLASM
HETEROGENOUS FOLLICLES MICROFOLLICULAR PATTERN
BFN/NEOPLASM
PSEUDOPAPILLAE TRUE PAPILLAE
PAPILLARY STRUCTURESTwo types of papillary structures are important
for papillary thyroid carcinoma diagnosis.
• True Papillae
• are considered pathognomonic for papillary thyroid cancer (PTC)
• Caps
• Probably represent tips of papilla
TRUE PAPILLARY STRUCTURES• Uncommon
• Pseudopapillae can mimic true papillae
• The structure of true papillae is also important.
• Short and nonbranching true papillae usually can occur in many diseases
• Goiters, Hyperplasia , Adenoma, Pregnancy, Thyroiditis, Folicular neoplasia, Medullary carcinoma
True Papillae: pathognomonic form
Branching, 3-dimensional, finger-like projections with
fibrovascular cores
Frequent branching
Avascular, 3-dimensional, rounded, dome shaped aggregates of cells known as “caps”
Caps
CELLULAR SWIRLS
are concentrically organized aggregates
of tumor cells
Thyroid Cytopathology Evaluation Steps
• Is there Colloid ?• Scant /abundant
• How is the quality of colloid?• Watery/dense
• Cellularity• Low / high
• Arrangement• Well ordered/disorganisation of follicules/papillary structure/microfollicles /swirl
• Cell type• Variable cell types /uniform cells
• Other background changes• Lymphocytes/giant cell/histiocytes/amyloid
• Nuclear features• Oval/spindle/irregular nuclear contour/nükleol/INCI/grooves
• Chromatin• Pycnotic/pale,powdery/salt and pepper
• Cytoplasm• Location of the nucleus/ skuamoid/granules/ nuclear/cytoplasmic ratios
NUCLEAR FEATURESRound; benign, follicular neoplasia Oval, PTC
Medullary Carcinoma
Spindle cells Plasmacytoid cells
Oval and spindle cells can be present in Cystic lesions. Nuclear/cytoplasmic ratio is normal or low . Nuclear crowding or overlapping is not significant .
BFN/NEOPLASM
Nuclear membrane is smooth Nuclear membrane irregularity
Nuclear Membrane Irregularity
– Nuclear grooves (irregular folds)
– Intranuclear pseudoinclusion (cytoplasmic invaginations (INCIs) )
Nuclear Membrane Irregularity
– Nuclear grooves (irregular folds)
• Are key diagnostic features (most cells, most fields)
• Some papillary carcinomas don’t have nuclear grooves
• Some benign and other malign lesions may have nuclear grooves (focal)
A grooved nucleus should have a deep longitudinal fold, like a coffee bean. But can be as irregular and lobulated as a piece of popcorn.
Nuclear GrooveMalignancies
• Papillary thyroid Ca
• Medullary thyroid Ca
• Hürthle Cell Neoplasia
Benign lesions
• Cystic lesion
• Lymphocytic thyroiditis
Cystic lesions
– Atypical cyst-lining cells can have nuclear grooves, prominent nucleoli, elongated nucleus and cytoplasm
– If these are present in a predominantly benign sample, can be diagnosed as AUS.
– If these changes are worrisome and diffuse, can be diagnosed as suspicious for PTC.
Lymphocytic thyroiditis
– Cells may show focal mild atypia. Atypical cells can have nuclear enlargement, grooves and chromatin clearing
– If there is cytomorphologic evidence of LT,
• the diagnostic threshold for PTC should be rised slightly
– If the diagnosis of LT is not definite,
• depending on degree of nuclear atypia, you can diagnose as AUS or suspicious for malignancy.
Nuclear Membrane Irregularity: INCIs
• One real INCI is a recommendation for surgery.
• Nuclear membrane encloses a portion of cytoplasm
Intranucler Cytoplasmic Invaginations (INCIs)
• PTC, % 50-100
• Other malignancies: Medullary thyroid Ca, Poorly differentiated Ca , Anaplastic (undifferentiated) Thyroid Ca
• Benign lesions: Goiter, Follicular Adenoma, Lymphocytic thyroiditis
INCIsCompletely within the nucleus. Are round with smooth margins, are sharply demarcated. They are outlined by a rim of dark chromatin.
INCIs should be large enough to differantiate it from bubble. INCIs tend to cluster in groups of cells
INCIs can be small and multiple in a nucleus.
Artefacts, such as bubbles, overlying red blood cells can mimic INCIs.If every cell has INCIs, it is an artefact.
Erythrocytes can be misleading. INCIs must be completely within the nucleus Extension from nuclus is a hint for differentiation.
BFN/NEOPLASM
Nucleoli are inconspicuous to invisible.
Nucleoli can be prominent in benign,
hyperplastic, repair (single)
Multiple nuceloli suggest malignancy
Marginated nucleoli suggest PTC .
Prominent , central nucleoli suggest follicular neoplasia.
Thyroid Cytopathology Evaluation Steps
• Is there Colloid ?• Scant /abundant
• How is the quality of colloid?• Watery/dense
• Cellularity• Low / high
• Arrangement• Well ordered/disorganisation of follicules/papillary structure/microfollicles /swirl
• Cell type• Variable cell types /uniform cells
• Other background changes• Lymphocytes/giant cell/histiocytes/amyloid
• Nuclear features• Oval/spindle/irregular nuclear contour/nükleol/INCI/grooves
• Chromatin• - Pycnotic/pale,powdery/salt and pepper
• Cytoplasm• Location of the nucleus/ skuamoid/granules/ nuclear/cytoplasmic ratios
BFN/NEOPLASM
Dense/ picnotic/ vesicular/open. Powdery fine, PTC
Salt and pepper chromatin, Medullary thyroid Ca
Thyroid Cytopathology Evaluation Steps
• Is there Colloid ?• Scant /abundant
• How is the quality of colloid?• Watery/dense
• Cellularity• Low / high
• Arrangement• Well ordered/disorganisation of follicules/papillary structure/microfollicles /swirl
• Cell type• Variable cell types /uniform cells
• Nuclear features• Oval/spindle/irregular nuclear contour/nükleol/INCI/grooves
• Chromatin• - Pycnotic/pale,powdery/salt and pepper
• Cytoplasm• Location of the nucleus/ skuamoid/granules/ nuclear/cytoplasmic ratios
• Other background changes• Lymphocytes/giant cell/histiocytes/amyloid
BFN/NEOPLASM
Cell borders are not prominent. Dense cytoplasm with well definedcell borders , PTC
Squamoid (dense ,waxy) cytoplasm
Hürthle cells
Medullary Ca, cytoplasmic granules
Neurosecretory granules
– Are seen as a fine red (metachromatic) cytoplasmic granules (Romanowsky )
– Are highly characteristic of medullary carcinoma but not pathognomonic and not required for diagnosis
– Can also occur rarely in other thyroid tumors
• Follicular neoplasm neoplazi
• Anaplastic Ca
• Parathyroid tumors
• Paragangliomas
Thyroid Cytopathology Evaluation Steps
• Is there Colloid ?• Scant /abundant
• How is the quality of colloid?• Watery/dense
• Cellularity• Low / high
• Arrangement• Well ordered/disorganisation of follicules/papillary structure/microfollicles /swirl
• Cell type• Variable cell types /uniform cells
• Nuclear features• Oval/spindle/irregular nuclear contour/nükleol/INCI/grooves
• Chromatin• - Pycnotic/pale,powdery/salt and pepper
• Cytoplasm• Location of the nucleus/ skuamoid/granules/ nuclear/cytoplasmic ratios
• Other background changes• Lymphocytes/giant cell/histiocytes/amyloid
BACKGROUND FEATURES
• Amyloid;
– Resembles dense colloid
– The texture ranges from hyaline to cloudy to fibrillary
– Stains metchromatically (Romanowsky ) but does not always.
– Special stains are used to confirm the presence of amyloid (Congo red).
BACKGROUND FEATURES
• Psammoma bodies
– Are concentrically laminated, calcified structures
– Are highly characteristic of PTC but not pathognomonic
• Colloid, dystrophic calcification and oxalate crystals can mimic psammoma bodies
Concentrically laminations are needed for psammoma diagnosis.
Clear and colorless in Romonowsky stains, rose to dark purple in PAP
They can be fragmented. These fragments are not adequate for definite diagnosis.
PSAMMOMA BODIES
• Occur rarely in other malignancies and very rarely in benign thyroid conditions
– Medullary Ca
– Mucoepidermoid Ca, metastasis
– Hashimoto thyroiditis
– Graves
– MNG
BACKGROUND FEATURES
• Lymphocytes
– Normal thyrocyte nucleus is about the size of lyphocytes. Bare follicular nuclei are easily mistaken for lymphocytes !
– Auotoimmune thyroiditis
– PTC (Warthin like)
Thyrocyte Lymphocyte
Lymphocytes can be crushed easily. Crushedartefact is a sign of lymphoid cells.
Hashimoto thyroiditisLymphoplasmacytic infiltrate with follicular germinal center formation
Florid lymphoid phaseThe cytology resembles an aspirate of reactive lymph nodeMajor differantial diagnosis is malignant lymphoma
BACKGROUND FEATURES
• Multinucleated giant cells
– Giant cells with foamy vacuolated cytoplasm occur in goiter, Hashimoto thyroiditis occasionally in neoplasms
– Epitheloid giant cell histiocytes characteristic of granulomatous conditions
– Epitheloid giant cell histiocytes with dense epitheloid cytoplasm are common in papillary carcinoma
Granulomatous Thyroiditis, De Quervain (subacute) Thyroiditis:Giant cells engulfing colloid with 50 to more than 200 nuclei can be either foreign body type or Langhan typeAcute and chronic inflamation, dense, scant colloid
Granulomas and scant dense colloid
Follicular epithelium tends to be sparse but reactive .Hurthle cells and numerous follicular center lymphocytes which are typical for Hashimato thyroid can not be seen
Thyroid FNA Summary• FNA of thyroid nodule is benign until proven
otherwise.
• Most thyroid nodules are benign – Most of benign nodules are colloid nodules
– Most colloid nodules can be diagnosed by cytology.
• Most malignant nodules are PTC. – Most PTCs can be diagnosed by FNA.
• Most other thyroid cancers can be diagnosed by FNA.
• Most other nonneoplastic conditions can be diagnosed FNA (Hashimoto).
• FNA is useful in the diagnosis for most of the thyroid lesions.
– It is safe for benign lesions.
– It is succesful for the PTC diagnosis which is the commonest thyroid malignancy.
Thyroid FNA SummaryMost diagnostic problems are related to highly
cellular follicular lesions.
– Most cellular follicular lesions are benign.
• Follicular carcinomas cannot be diagnosed or excluded with certainly by FNA.
• Hurthle cell lesions can not be diagnosed by FNA.
• Most aggresive follicular carcinomas can at least be suspected by FNA.
Thyroid FNA Summary
• FNA is a useful screening test for nodules with high malignancy suspicion.
• The main aim is to identify all potential follicular carcinomas.
Features Suggest Follicular Carcinoma
• MARKED ARCHİTECTURAL ABNORMALİTİES
• Crowded, 3d groups
• İrregular microfollicles
• İncreased single cells
• 2) MARKED CYTOLOGIC ATYPIA
• Nuclear enlargement
• Pleomorphism
• Abnormal chromatin
• Prominent or multiple nucleoli
• Atypical mitotic figures
• Necrosis
Hurthle Cell Nodule
• A thyroid lesion exclusively Hurthle cells on FNA has about 75% chance of being neoplastic.
• If neoplastic there is 33% chance of being malignant
• Overall risk of malignancy is 25%
• Therefore, a cytodiagnosis of “suspicious for Hurthle cell neoplasm” is appropriate which requires surgery.
• Inflamation can reduce but does not eliminate the risk of malignancy
Follicular lesions
• Both the cytologic and histologic diagnosis suffer from problems with reproducibility and this affect cytologic and histologic correlation.
3 KEY FEATURES OF PTC
1) PAPİLLARY FORMATİONS;
• true papillae
• caps
2)IRREGULAR MEMBRANES;
• grooves (most cells, most fıelds)
• INCIs (even one good one)
3)SQUAMOID CYTOPLASM (some cells)
When all three features are present PTC can be diagnosed with confidence.
PTCs lacking classical nuclear features are difficult to imposibble to diagnose.
CLUES FOR PTC
• 3-dimensional tissue fragments
• Nuclear grooves and INCIs
• Powdery chromatin
• Conspicuous micronucleoli
• Squamoid cytoplasm
• Psammoma bodies
Findings requiring surgery in FNA
• HARD FINDINGS (Surgery usually indicated)
– INCIs
– Psammoma bodies
– True papillae
– Atypical mitoses
• SOFT FINDINGS (Evaluate in clinical context)
– Hurthle cells without lymphocytes
– Hypercellular with microfollicules
– Nuclear grooves
– Mitoses
THANKS