THE BETHESDA SYSTEM FOR REPORTING THYROID

CYTOPATHOLOGY( BSRTC)

Dr.Indira shastry.k

Kasturba medical college

Manipal university, Manipal.

History• Introduced and formed in 2007 , “NCI- thyroid FNA state of science

conference “ Bethesda , Maryland, by various cytopathologists and summarised by Baloch et al.

• Why ? critical for cytopathologist to communicate thyroid FNA

interpretation to referring physician in terms that are succinct, unambiguous and helpful clinically .

Uniform reporting.

Format of reporting • Clarity of communication, the BSRTC recommends that each

thyroid FNA report begin with general diagnostic category .

• For each categories some degree of sub categorization can be informative and often appropriate.

• Each category has an implied cancer risk association – linked to evidence based clinical management guidelines.

The BSRTC recommended diagnostic categories I. Non diagnostic or unsatisfactory cyst fluid only virtually a cellular smear other ( obscuring blood, clotting artefact , etc ,.)

II. Benign Consistent with a benign follicular nodule ( adenomatoid nodule , colloid nodule, etc) Consistent with lymphocytic (Hashiomoto’s) thyroiditis ; in proper clinical context Consistent with granulomatous ( subacute ) thyroiditis other

III. Atypia of Undetermined significance or Follicular Lesion of Undetermined significance

VI. Follicular neoplasm or Suspicious of follicular neoplasm Specify if Hurthle cell ( oncocytic ) type

V. Suspicious for malignancy Suspicious for papillary carcinoma suspicious for medullary carcinoma suspicious for metastatic carcinoma suspicious for lymphoma other

The BSRTC recommended diagnostic categories

VI. Malignant Papillary carcinoma of thyroid Poorly differentiated carcinoma Medullary carcinoma of thyroid Undifferentiated ( Anaplastic ) carcinoma Squamous cell carcinoma Carcinoma with mixed features ( specify) Metastatic carcinoma Non-Hodgkin’s Lymphoma Other

BSRTC implied risk of malignancy and recommended clinical management

Diagnostic category Risk of malignancy Usual Management a

Non diagnostic or Unsatisfactory

Depends on type of lesion in USG

Repeat FNA under Ultrasound guidance

Benign 0 - 3 % Clinical follow-up

Atypia of Undetermined significance or Follicular Lesion of Undetermined significance

Approx 5 -15 % Repeat FNA

Follicular neoplasm or Suspicious for a follicular neoplasm

15 - 30 % Surgical lobectomy

Suspicious for malignancy 60 - 75 % Near total thyroidectomy or Surgical lobectomyb

Malignant 97 - 99 % Near total thyroidectomyb

a) Actual management depends on other factors ( clinical , USG etc ,.) besides FNA interpretation b) In case of “ suspicious of metastatic tumour “ or a “ malignant “ interpretation indicating metastatic

tumour rather than primary malignancy , surgery may not be indicated .

Criteria for adequacy • Minimum of six groups of well visualised ( i.e., Well stained,

undistorted and un obstructed ) follicular cells with at least ten cells per group ( preferably on a single slide )

• Exceptions : minimum no of follicles not required. • Solid nodules with significant cytologic atypia - comment on cellularity

as a limiting factor . • Solid nodules in patients with lymphocytic ( Hashimoto’s) thyroiditis,

thyroid abscess or granulomatous thyroiditis may contain only numerous inflammatory cells .

• Colloid nodules: abundant thick colloid considered benign and satisfactory.

Non diagnostic or Unsatisfactory

• Cellularity / adequacy is dependent not only on technique of aspirator but also on type of lesion ( solid or cystic ).

Example :

1. NONDIAGNOSTIC : due to insufficient cellularity

2. NONDIAGNOSTIC : cyst fluid only

3. UNSATISFACTORY : due to poor fixation and preservation

NOTE : A repeat aspiration should be considered if clinically indicated /

Recommended correlation with cyst size and complexity on ultrasound to assist with further management of lesion.

Management:

Re-aspirated but not sooner than 3 months . ( to prevent false positive interpretation due to reactive or reparative changes)

Poor cell preservation

Benign

• Subclassification : • Benign follicular nodule • Thyroiditis • Others

BENIGN FOLLICULAR NODULE (BFN) : • Nodular goiter(NG)• Hyperplastic (Adenomatoid ) nodule • Colloid nodules• Nodules in grave’s • Subset of follicular adenoma ( macrofollicular type )

• Distinction among these different histological entities are not possible by FNA but of little importance bec all are benign and managed in similar conservative manner.

DEFINITION :

“ benign follicular nodule “ applies to cytologic sample that is adequate for evaluation and consists predominantly of colloid and benign appearing follicular cells in varying proportion.

CRITERIA: • Adequate with moderate to sparse cellularity. • Colloid : thick / thin • Follicular cells : monolayered sheets or follicles (microfollicles +/-)• No nuclear atypia / pleomorphism • Minimal/no nuclear overlapping and crowding .• Cytoplasmic granules (+/-) • Hurthal cells (+/-) • Macrophages and may contain haemosiderin pigment.

Adenomatous nodule ( macro-follicular type )

Graves’ disease (GD)

• Cytological features is non specific, and clinical correlation is required for definitive diagnosis.

• Aspirates - cellular and show similar features of non graves’ BFN (abundant collloid and variable no of follicular cells ) .

• Follicular cells : loose cohesive sheets, with abundant delicate foamy cytoplasm with frayed edges (+/-). Nuclei are often enlarged, vesicular and prominent nucleoli, mild pleomorphism may be present.

• Lymphocytes and oncocytes may be seen.

NOTE : focal chromatin nuclear clearing and rare nuclear grooves if not diffuse should not be confused with papillary ca thyroid .

Lymphocytic ( Hashimoto’s ) thyroiditis

DEFINITION :

many polymorphic lymphoid cells associated with Hurthle cells

CRITERIA : • Hypercellular to adequate cellularity ( does not require minimum

cellularity ) • Polymorphic lymphoid population, occasional plasma cells and

may infiltrate epithelial cell groups. • Intact lymphoid follicles and lympho-histiocytic aggregates (+/-)• Hurthle cells +( may have prominent anisonucleosis)

Granulomatous ( subacute, de quervain’s) thyroiditis

CRITERIA : • variable cellularity • Clusters of epitheliod histiocytes , i.e., granulomas present along with

many multinucleated giant cells • Early stages : demonstrates many neutrophils and eosinophils • Late stage : smears are hypocellular. Show giant cells engulfing

colloid, epitheliod cells, lymphocytes, macrophages and scant degenerated follicular cells.

Subacute thyroiditis

Acute thyroiditis

CRITERIA : • Numerous neutrophils associated with necrosis, fibrin,

macrophages and blood. • Bacterial or fungal organisms are occasionally seen.

Riedel’s thyroiditis / disease

• Progressive fibrosis of thyroid gland with extension in to neck soft tissue.

• CRITERIA : • Often acellular. • Colloid and follicular cells are usually absent. • Collagen strands and bland spindle shaped cells. • Chronic inflammatory cells may be +

Atypia of undetermined significance ( AUS/FLUS ) • Used when FNAs are not easily classified in to Benign, suspicious or

malignant categories. • AUS result has been reported in 3 – 18 % of thyroid FNA • Used as a last resort

• CRITERIA : mc sinerios • Prominent populations of microfollices that does not fulfil the

criteria for “ follicular neoplasm/ suspicious for follicular neoplasm” - scant cellularity

• Predominance of Hurthle cells with scant cellularity

• Interpretation of follicular neoplasm hindered by sample preparation artefact ( air drying and clotting )

• Clinical setting suggestive of benign nodule ( predominant Hurthle cells ) ; Hashimoto’s / MNG .

• Focal appearance of malignancy ( papillary ca ) in an otherwise predominantly benign appearing sample .

• Cyst lining cells which appear atypical due to presence of nuclear grooves, prominent nucleoli, elongated nuclei and cytoplasm and / or intra cytoplasmic inclusions in an otherwise benign appearing sample.

• A minor population of cells showing atypia in patients with : • H/O radioactive iodine , carbimazole, and other pharmaceutical agents

ingestion. • Repair due to involution changes - cystic degeneration &/ haemorrhage

• Atypical lymphoid infiltrate but the degree of atypia is insufficient .

MANAGEMENT : • For initial diagnosis – clinical correlation and repeat FNA at

appropriate interval .• 20 – 25 % of the nodule repeated as AUS • In resected thyroid only 20 – 25 % found to have malignancy • Overall risk of malignancy for all AUS nodule is 5 – 15 %

Follicular neoplasm / suspicious for follicular neoplasm

• To identify nodule that might be FC and triage it to surgical lobectomy

• Does not differentiate between FA and FC ; FN or suspicious of FN used instead -> lobectomy -> definitive diagnosis.

• Some prefer suspicious of FN bec significant proportion of cases (35% ) are due to hyperplasic proliferation in MNG.

• Rate of malignancy is 12 – 32 %. Most of them are follicular variant of papillary ca thyroid.

• Parathyroid adenomas are often misinterpreted as FN / SFN

CRITERIA :• Cytomorphology : high cellularity, scant to absent colloid , micro

follicles to trabacular arrangement with cellular crowding and overlapping ( altered architectural pattern )

• Nuclear atypia ( mild ) / mitosis: uncommon

• If majority of follicles are arranged in macrofollicle fragments ( variably sized with out overlapping or crowding ) considered benign.

• Conspicuous cellularity alone does not qualify for FN/SFN

• Sparsely cellular fragments with cytomorphology of FN/SFN reasonable to interpret as AUS / FLUS .

Microfollicle - <15 cells in a circle that is at least 2/3 rd complete

FN Hurthle cell type / SFN , Hurthle cell type

• Defn : Refers to cellular aspirate that consists exclusively of ( or almost exclusively ) of hurthle cells. (>75%)

• Criteria : • Highly cellular aspirate , abundant finely granular cytoplasm • Enlarged centrally or eccentrically located nucleus with prominent

nucleolus. • Small cell dysplasia : small cells with high N:C ratio• Large cell atypia : large cells with at least 2X variability in nuclear

size • Crowded or syncytial arrangement with or with out colloid

moderate to markedly cellular aspirates

Colloid

Small / large cell dysplasia

Benign Note : although predominance of

hurthle cells arises the possibility of hurthle cell neoplasm, the absence

of atypia suggest it is benign

Benign lesion ( with out atypia )

+ -

+ -

FNHCT/SFNHCT

Mimickers : • MNG with focal hurthe cell change : mixture of elements , flat

cohesive sheets of hurthle cells admixed with normal follicular cells, colloid + and clinico-cytologic correlation.

• LT nodules : hurthle cells are atypical in stereotypical way i e., they form small cohesive clusters of 3-10 cells, large nuclei, smudgy sometimes glassy chromatin . Can mimic cells in Pap ca . Clinical correlation is of importance.

Hurthle cell metaplasia in MNG

• Oncocytic variant of papillary carcinoma thyroid : attention to nuclear details. If not diagnosed as suspicious for malignancy. ( diagnosed at the time of frozen )

• Medullary carcinoma of thyroid : MGG - cytoplasm of hurthle cells are blue . Medullary carcinoma thyroid are red.

• Parathyroid adenomas : radiological correlation, serology or frozen .

Medullary carcinoma of thyroid Hurthle cell neoplasm

Suspicious for malignancy ( SFM )

• SFM interpritation indicates the less than definitive nature of the diagnosis and allows alternative management options ( frozen / lobectomy ) before definitive surgery ( total thyroidectomy )

• The target PPV of this cat is 55-85 %.

Definition :

Strong suspicion for malignancy, but findings are not sufficient for a conclusive diagnosis.

Suspicious of papillary carcinoma of thyroid : • Pattern A (“ patchy nuclear changes “ ) • Benign follicular cells ( macrofollicles ) admixed with cells that

have nuclear enlargement, nuclear pallor, nuclear grooves, NM irregularities, &/ nuclear moldings.

• Intranuclear cytoplasmicinclusions ( INCIs )are rare / absent

• Pattern B ( “ incomplete nuclear changes “) • Generalised mild to moderate nuclear enlargement with mild

nuclear pallor .• Evident nuclear grooves, NM irregularities and nuclear

moulding are minimal or absent. • INCIs are rare / absent

• Pattern C ( “ sparsely cellular specimen “) • Cellular features of PTC present but very sparsely cellular

• Pattern D (“ cystic degeneration “) • Haemosiderin laden macrophages + • Scattered groups and sheets of follicular cells , enlarged , pale

nuclei, some have nuclear grooves .• INCIs rare / absent • Occ atypical histiocytoid cells + , calcification +

Mimickers : • Lymphocytic thyroiditis • Cystic degenerative changes with reactive atypia • Radioiodine and carbimazole treatment.

no definitive / reliable cytological features can differentiate these from pap ca

• Hyalinising trabecular tumor ( HTT ) : definitive features are difficult to appreciate in FNAC .

Suspicious for medullary carcinoma thyroid :• Thyroid FNA has higher sensitivity for detection of MTC than

PTC

• Sparse to moderatley cellular • Monomorphic population of noncohesive small to medium

sized cells , high N:C ( ? Lymphoid / ? Medullary ) • Small amt of ? Colloid/? amyloid • Clinico-pathologial correlation : S. Calcitonin

• Diagnostic pitfall : cellularity and preservation

Amyloid Colloid

Suspicious for Lymphoma • Monomorphic small to intermediate lymphoid cells. • Diagnostic limitation : • DLBCL : technical ( cellularity and preservation ) • Low grade lymphoma ( MALT / follicular ) : MALT is difficult to

distinguish from LT with out Immunophenotyping .

• False positive results have been reported with LT. • Definitive diagnosis : Flow cytometry

Ex:• Suspicious for papillary carcinoma thyroid • Suspicious for medullary thyroid carcinoma • Note : correlation with S.calcitonin level or re-aspiration for

IHC studies might be helpful for definitive diagnosis if clinically indicated.

• Suspicious for lymphoma • Re- aspiration for immunophenotyping studies by flow

cytometry might be helpful for definitive diagnosis if clinically indicated.

Papillary thyroid carcinoma

• Criteria : • Follicular cells are arranged in papillae &/ syncytial monolayers.

• Characteristic nuclear features : enlarged nuclei , oval or irregularly spaced/ moulded nuclei, longitudinal nuclear grooves, INCI, pale nuclei with powdery chromatin ( “Orphan Annie eye” nuclei ), marginally placed micronucleoli (solitary or multiple ).

• Psammoma bodies +/-

• Amount of colloid is variable ( ropy / bubble gum colloid )

• None of nuclear features are diagnostic of PTC in isolation, only when widespread and in combination they are diagnostic of PTC.

• crowding, overlapping, and moulding are important diagnostic features – distinguish from benign follicular cells.

• various subtypes/ variants can be identified in FNA.

• Precise sub-typing is not possible ; prominent pattern may not have been sampled in FNA.

• Awareness of cytological characteristics of various subtypes can diminish the risk of misdiagnosis.

Variants of PTC

Follicular variant : ( Mc variant of PTC – 30% )

• Tumor composed of almost completely of small to medium sized follicles lined by cells with nuclear features of PTC.

• Some colloid may be present : dense • INCI, PB, papillary architecture, cystic changes are typically absent.

Macrofollicular variant : • Over 50 % of the follicles are arranged as macrofollicles /

variably sized follicles.

• With convincing nuclear features of PTC often subtle. • Abundant thick colloid may be present. • DD: follicular nodule in nodular goiter and follicular adenoma

of macrofollicular type.

Cystic variant : • PTC predominantly cystic , comprised of thin watery fluid, abundant

histiocytes and hyper-vacoulated ( histiocytoid )tumor cells.

• Neoplastic cells typically arranged in small groups with irregular borders; sheets, papillae/ follicles +.

• Hemosidrin laden macrophages , variable amt of colloid +. • Usually diagnosed as nondiagnostic : cyst fluid only. • DD: cystic change in benign nodule regenerating cells arranged in

streaming sheets but can be distinguished their elongated shape, lack of nuclear crowding and INCI.

Cystic change in papillary thyroid carcinoma

Oncocytic variant : • Nuclear features are characteristic of PTC but composed

predominantly of oncocytic cells. • Cyto : • papillae, sheets or isolated cells. • Lymphocytes are typically absent.

• DD: hurthle cell neoplasm : rounder nuclei and prominent nucleoli

Warthin-like variant : • Circumscribed thyroid tumor with papillary architecture

and lymphoid follicles mimic warthin tumor of salivary gland.

• Cyto : oncocytic cells arranged in papillae , singly dispersed. Lymphoplasmacytic background, permeating the fibrovascular stalk.

• DD: Hashimoto’s thyroiditis

Tall cell variant :• An aggressive form of PTC, occur in elderly more in males. • Cyto : papillae lined by single layer of elongated( tall – to

width ratio of at least 3:1 ) tumor cells with abundant granular cytoplasm. At least 50% tumor .

• INCI tend to be more frequent imparting “soap bubble” appearance to nucleus .

EXAMPLE • MALIGNANT ;• Papillary thyroid carcinoma

• MALIGNANT : • Papillary thyroid carcinoma , favour tall cell variant

Medullary thyroid carcinoma

• MTC comprises of approximately 7 % of thyroid neoplasm's. • Derived from and morphologically recapitulate the parafollicular

cells. • The diagnosis of MTC can be suggested by cytomorphology, but

confirmed by IHC . • DD : Hurthle cell neoplasm • Papillary carcinoma• Anaplastic carcinoma • plasmacytoma

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Syncitia like clusters alternate with numerous islands of cells. Plasmacytoid, polygonal, round and / or spindle shaped. Mild to moderate pleomorphism. Nuclei : round , eccentrically placed ,“ salt pepper “ chromatin. Cytoplasm : granular , MGG stain : pink granules ( 80% ) Amyloid often present. Bizarre giant cells may be seen : giant cell variant.

IHC calcitonin

Poorly differentiated carcinoma

• Rare malignancy – 4 – 7 % • Criteria : • Cellular aspirates : Insular, solid, or trabecular cytoarchitecture.• Un-uniform population of follicular cells , scant cytoplasm ( sometimes

plasmacytoid) • High N:C ratio ; marked nuclear atypia • Apoptosis & mitotic activity + , necrosis +. • Insular form : ch endothelial cell wrapping

• Pitfall : less specificity. • WHO( endocrine ): “definitive diagnosis of poorly differentiated

carcinoma can be made only at histological level”

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DD :

follicular neoplasm ( SFN- 42 % ),

Papillary carcinoma ( 15 % ),

carcinoma NOS ( 10 % ),

Medullary carcinoma,

lymphoma.

Undifferentiated ( Anaplastic )carcinoma

• K/S “ giant and spindle cell carcinoma “ - < 5%• High grade pleomorphic, epithelial derived malignancy with

epitheloid and / spindle cell features. • Plasmacytoid / Rhabdoid cell features may be seen.• Nucleus : pleomorphic, irregular, clumping of chromatin with

parachromatin clearing. • Necrosis – extensive ; abscess like , neutrophilic infiltration of

tumor cells. • Osteoclast like giant cells +/-

Squamous cell carcinoma

• 1 % of primary thyroid malignancy• Poorly differentiated : large, pleomorphic, keratinised cells • Morphologically and immunohistochemically

Indistinguishable from mets from other organs .• EX :

malignant :

consistent with SCC of thyroid

Note : the distinction B/W primary / mets from other organs not possible. Correlation with clinical and imaging is advised.

Metastatic tumors • Metastasis to thyroid from other organs is rare: lung, breast,

skin ( melanoma ), colon, and kidney.

• Malignant lymphomas: can arise in thyroid as primary but secondary involvement is MC .

• Lymphomas represent 5 % of thyroid malignancy, usually associated with Hashimoto’s thyroiditis.

• Criteria : • Cellular mostly lymphocytes.• Lymphocytes : 2 X small mature lymphocyte• Background of numerous lymphoglandular bodies• Vesicular nuclei / coarse chromatin with prominent nucleoli

Patterns of lymphoma on FNA

Monomorphous population of small

lymphocytes

Monotonous population of large

lymphocytes

Mixture of small and large lymphocytes

Absence of oncocytes, follicular cells, and plasma cells favour

lymphoma

DD : Hashimoto’sMorphologically

diagnostic DD: inactive thyroiditis

Definitive diagnosis : flow cytometry / IHC on HP

• Secondary involvement by MALT / DLBCL is 20% in disseminated lymphoma.

• MALT : monocytoid / plasmacytoid B cells in isolation / in clusters.

• DLBCL : monotonous large lymphocytes in non cohesive clusters.

MALT DLBCL

References

• Syed ali. Edmund S. Cibas : The Behtesda system for reporting thyroid cytopathology.

• Orell & sterrett’s FNAC . 5th ed • Gray . Diagnostic cytopathology . 3rd ed

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