Thyroid cytopathology

Benign thyroid cells. FNA specimens. (WC)

Thyroid cytopathology is a large part of cytopathology.

This article deals only with thyroid cytopathology. An introduction to cytopathology is in the cytopathology article. Head and neck cytopathology is dealt with in the Head and neck cytopathology article.

Normal thyroid

Radiology

Benign features - terms:

• Spongiform configuration.
• Colloid clot - cyst.
• Giraffe pattern.
• Diffuse hyperechogenicity.

Follicular cells

• Uniform spacing of cells.
• "Cracks" (spaces) between cell - "crazy paving".

Note:

• It is interesting that uniform spacing in the context of thyroid is benign... in breast suggests DCIS.

Microfollicles

Definition:

• <15 follicular cells forming at least two thirds of a circle.
• Usually flat, i.e. not three dimensional.

Note:

• A small number of microfollicles is considered normal.

Images

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  Thyroid - high mag. (WC)

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  Thyroid - very high mag. (WC)

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  Colloid and endocrine atypia - high mag. (WC)

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  Colloid and endocrine atypia - very high mag. (WC)

Colloid

Paucicellular/acellular material with:

• Irregular/sharp borders.
• Cracks - key feature.
• Bubble pattern.
• Dark (uniform) staining with Romanowsky type stains.
  • Green edge + red/orange centre with Pap stain.
• +/-Entraped red blood cells (RBCs).

Images

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  Colloid - high mag. (WC)

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  Colloid - very high mag. (WC)

Hurthle cells

May be spelled Hürthle cells.

Features:

• Large epithelioid cells with red granular material on Pap stain.
• Should not form 3-D balls.

Images

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  HC - high mag. (WC)

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  HC - very high mag. (WC)

Normal parathyroid cytology

Main article: Parathyroid gland

General

• May be confused with thyroid.
  • No single feature can be use to reliably separate them, though several features may allow this.
• FNAs are not useful for parathyroid lesions; however, a parathyroid may be sampled inadvertently.

Cytology

Chief cells:

• Small round-to-oval nucleus.
• Granular chromatin.
• Cytoplasm - often not distinct.
• Scattered naked nuclei.
• +/-Nuclear moulding.
• +/-Nuclear overlap.
• +/-Papillary fragments - uncommon.

Images:

• Parathyroid gland (nih.gov).

DDx of naked nuclei:

• Granular cell tumour.
• Parathyroid.

Adequacy criteria

• >=60 follicular cells. †
  • If abundant colloid is present less follicular cells are accepted.
• No atypical cells.

Note 1:

• † Typically described as: at least 6 groups (with 10 or more follicular cells) on at least two smears.

Note 2:

• The inadequate & suspicious rate with these criteria is 10-30%. In excision specimens, 75-80% are benign.
  • The above begs the question - should the criteria be changed?

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Thyroid Gland, Right Lobe, Fine Needle Aspiration:
- Unsatisfactory; specimen processed and examined, but unsatisfactory due to insufficient 
  material. Scant follicular cells, Hurthle cells and colloid present in a background of 
  mixed inflammatory cells and abundant macrophages.  

Note: A repeat aspiration should be considered if clinically warranted. 

Alternate

Thyroid Gland, Right Lobe, Fine Needle Aspiration:
- Non-diagnostic. (Category I)
 
Specimen processed and examined, but unsatisfactory due to scant cellularity.  
Some cellular degeneration noted, rare colloid and inflammatory cells present.

Note: A repeat aspiration should be considered if clinically warranted. 

Abundant colloid

Left Thyroid, FNA: BENIGN, see comment.

Note: 
The specimen has abundant colloid. The background consists of histiocytes in keeping with a cyst.  The number of follicular cells falls below the typically desired threshold; however, the case is sufficient on the basis of the abundant colloid, as per the 2023 Bethesda System for Reporting Thyroid Cytopathology. The clinical impression is noted.

Standard sign-out language

There is a standard way of describing thyroid cytopathology results.

Bethesda (2023)

• A new iteration of Bethesda 2009.

Bethesda (2009)

This is formally known as the "The Bethesda System for Reporting Thyroid Cytopathology"; it is based on the NCI classification of 2008:

Preferred	Plain language	Risk of malignancy	Usual management
Benign	Benign	~ 0-3%	Follow-up, clinical
Follicular lesion of undetermined significance (FLUS) or atypia of undetermined significance	Uncertain, favour benign	5-15%	Repeat FNA
Follicular neoplasm or suspicious for follicular neoplasm; if oncocytic type it should be noted	Uncertain, favour malignant	15-30%	Hemithyroidectomy
Suspicious for malignancy	Probably malignant	60-75%	Repeat vs. hemithyroidectomy
Malignant	Cancer	~ 97-99%	Excise (total thyroidectomy)
Nondiagnostic or unsatisfactory	Lesion missed or inadequate	1-4%	Repeat FNA

NCI (2008)

A National Cancer Institute (NCI) consensus conference in 2008:

Preferred (NIC)	Alternate (NIC)	Plain language	Risk of malignancy	Usual management
Benign	-	Benign	~ 1%	Follow/nothing
Follicular lesion of undetermined significance (FLUS)	1. Atypia of undetermined significance 2. Rule-out neoplasm 3. Atypical follicular lesion 4. Cellular follicular lesion	Uncertain, favour benign	5-10%	Repeat FNA in 3 months
Follicular neoplasm	Suspicious for follicular neoplasm	Uncertain, favour malignant	20-30%	Hemithyroidectomy
Hurthle cell neoplasm	Suspicious for Hurthle cell neoplasm	Uncertain, favour malignant	20-30%	Hemithyroidectomy
Suspicious for malignancy	-	Probably malignant	50-75%	Repeat vs. hemithyroidectomy
Malignant	-	Cancer	~ 99%	Excise
Nondiagnostic	-	Lesion missed or inadequate	Unknown	Repeat FNA in 3 months

Benign disease

Adenomatoid nodule

Main article: Adenomatoid nodule of the thyroid gland

General

• Diagnosis benign thyroid tissue.

Cytology

Features:

• Benign follicular cells (abundant) with relatively little colloid.

DDx:

• Colloid nodule - has more colloid.

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Thyroid Gland, Left, Fine Needle Aspiration: 
- Benign. 
- Cellular aspirate. 
- Benign-appearing follicular cells with colloid, consistent with an adenomatous nodule. 

Colloid nodule

General

• Diagnosis benign thyroid tissue.

Cytology

Features:

• Colloid - paucicellular material:
  • "Thick" colloid = dense appearing blob, well-circumscribed +/- "cracking".
  • "Watery" colloid = light, whispy/fluffy material.
• Macrofollicles:
  • Ball of cells ~ 20 cells across.

Images

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  Colloid - high mag. (WC)

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  Colloid - very high mag. (WC)

Graves disease

Main article: Graves disease

General

• Clinical diagnosis - based on serology.

Cytology

Features:

• +/-Flame cells on Romanowsky stain, e.g. Diff-Quik.
  • Red granular discolourization of the cytoplasm - thought to be endoplasmic reticulum.

Notes:

• Flame cells are indicative of cellular hyperactivity.
  • Not pathognomonic for Graves disease, e.g. may be seen in early Hashimoto disease,

Images:

• Flame cells (ouhsc.edu).
• Flame cells (ouhsc.edu).

Lymphocytic thyroiditis

General

• Non-specific finding.
  • May represent Hashimoto thyroiditis.
  • Can be seen in Graves' disease.

Cytology

Features:

1. Lymphocytes not typical of circulating blood:
   • Centrocytes.
     • Small lymphocytes with a cleft.
   • Centroblasts.
     • Large lymphocytes with nucleolus and eccentric nucleus.
   • Plasma cells.
     • Cells with a "clockface nucleus".
2. Small mature lymphocytes in fragments of follicular cells - raise the suspicion of lymphocytic thyroiditis.
   • Small mature lymphocytes are not a reliable indicator of inflammation, as cells may layer during tissue preparation.

Notes:

• Usually #1 and #2 are seen.

Hashimoto thyroiditis

Main article: Hashimoto thyroiditis

General

• This is a clinical diagnosis.
  • It should be reported by the pathologist as "lymphocytic thyroiditis".

Associations:

• AMA +ve.
• Antithyroid antibody +ve.
  • Antimicrosomal (antithyroid peroxidase).
  • Antithyroglobulin.
• Increased risk of B-cell lymphoma.

Cytology

Features:

• Polymorphous lymphoplasmacytic infiltrate with germinal centres.
• Tingible body macrophages.
  • Found in germinal centres; have condensed chromatin fragments.
• Lymphoid tangles.
  • Found in almost 100% of cases.
• Lymphoglandular bodies.
  • Cytoplasmic fragment of a lymphoid cell.

Note:

• Lymphocyte infiltration into fragments of oncocytic cells - strongly suggestive of Hashimoto disease. (???)

Waffle category

Follicular lesion of undetermined significance

• Abbreviated FLUS.
• Also known as atypia of undetermined significance (abbreviated AUS).

General

• This is waffle diagnosis, i.e. something the pathologist diagnoses when they cannot decide whether it is benign or suspicious for malignant (follicular neoplasm or suspicious for malignancy).
  • Like all waffle diagnoses...
    • Use should be minimized; < 7% is suggested, though it varies considerably between pathologists and institutions.

Cytology

Features:

• Mild nuclear atypia - that by definition is insufficient for follicular neoplasm or suspicious for malignancy.
  • Mild irregularities in the nuclear contour.
  • Mild size variation or nuclear enlargement.
  • Mild accentuation of nuclear staining.

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Atypia of undetermined significance (AUS).

Neoplastic and malignant

Papillary carcinoma

Main article: Papillary thyroid carcinoma

General

• Papillary thyroid carcinoma is basically the only entity (in cytopathology) that has near universally accepted criteria.
  • This is why radiation oncologists say... "Basing stuff on pathology is like basing something on shifting sand."

Cytology

Criteria for papillary thyroid carcinoma:

1. Nuclear inclusion (really pseudoinclusions):
   1. Edge of inclusion must be sharp (nuclear membrane-like).
   2. Size: at least 1/4 of the nucleus.
   3. Round, regular.
   4. Within epithelial cell.
   • Additional criteria: Inclusion center should match cytoplasm.
2. Nucleoli (micro or macro).
3. Nuclear grooves.
   • No universal criteria; some believe grooves should go from edge-to-edge, i.e. across the nucleus.
4. Nuclear enlargement.
5. Changes in chromatin - patterns:
   • Granular.
   • Washed-out.

Additional features:

• Papillary architecture (not commonly seen).
  • Clump of epithelial cells with attached fibrous tissue "tail" - that has a smooth edge.
• Cellular/nuclear membrane overlapping; cells do not respect one another (very common).
• +/-Psammoma bodies (uncommon - but helpful if seen).

Notes:

• Nuclear enlargement may be seen in Hashimoto's disease.
• Nuclear grooves may be seen in Hashimoto's disease.
• Papillary architecture may be seen in Graves disease.
• Thick (dense) colloid common - described as "bubble gum". (???)

Images

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  PTC - intermed. mag. (WC)

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  PTC - high mag. (WC)

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  PTC - very high mag. (WC)

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  PTC - high mag. (WC)

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  PTC - very high mag. (WC)

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  PTC. (WC)

Variants of PTC

• Tall cell variant.
  • May mimic Hurthle cell neoplasm.
• Warthin-like variant.
  • Superficially resembles Warthin tumour (presence of lymphocytes).
• Follicular variant of PTC; memory device ECT: Elongation, Clearing, Thick membranes.
  • Nuclear elongation.
  • Chromatin clearing.
  • Thick nuclear membranes.
    • Classic features of PTC (esp. pseudo-inclusions) are usually scarce in this variant.

Follicular neoplasm

General

• Can be thought of as a (neoplasm) garbage category for the thyroid gland - may represent:
  • Follicular adenoma.
  • Follicular carcinoma.

Management:

• Hemithyroidectomy.

Cytology

Features:

1. Hypercellular lesion.
2. 3-dimensional clusters of cells.
3. Nuclear overlap/crowding.
4. +/-Microfollicles, numerous.
   • Microfollicles are defined as: <15 cells forming at least two thirds of a circle.
5. +/-Atypia marked.

Diagnosis (follicular neoplasm) per MB:

• Either: 1-3 or 3-5.

Notes:

• A few microfollicles are normal.
• Atypia alone - "suspicious for malignancy" or "malignant".
• Nuclei are described as having the shape of an orange in follicular neoplasms... and potatoes in papillary thyroid carcinomas.

Oncocytic neoplasm

Main article: Hürthle cell neoplasm

• AKA Hurthle cell neoplasm.

General

• Oncocytic perferred by WHO over Hurthle cell.

Cytology

Features:

1. Single cells or sheets of oncocytic cells.
   • 3-D clusters.
   • +/-Transgressing vessels - cluster of oncocytes surrounding vessels.
2. Oncocytic cells:
   • Well-defined cellular borders.
   • Finely granular abundant cytoplasm.
   • Nucleoli, may be prominent.

Notes:

• Benign (oncocytic) thyroid tissue may have:
  • Significant nuclear pleomorphism.
  • Multinucleation.

DDx:

• Granular cell tumour.

Images

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  Hurthle cell neoplasm. (WC)

www:

• ON - Diff-Quik - intermed. mag. (ouhsc.edu).
• ON - Pap stain - high mag. (ouhsc.edu).

Medullary thryoid carcinoma

Main article: Medullary thyroid carcinoma

General

• May be familial - associated with MEN II syndrome.
• Sometimes described as the melanoma of the thyroid - as it can look like almost anything.

Cytology

Features:

1. Single or loosely cohesive cells.
   • Spindle cell morphology common.
2. Abundant eosinophilc granular cytoplasm - key feature
3. Salt and pepper chromatin - key feature; no nucleoli.
4. Nucleus eccentric and round/oval - plasmacytoid appearance.
5. Amyloid - acellular, amorphous material may be present; cotton candy-like.
   • May be confused with fibrin...
     • Fibrin = fluffy edge vs. amyloid = sharp border. (???)
     • Fibrin - associated with PMNs/has PMNs within it.
   • Amyloid cannot be definitively differentiated on morphologic grounds from colloid.
   • Described by Halliday et al. as:
     • Romanowsky type staining: "amorphous, irregular, waxy basophilic to metachromatic clump".
     • Pap staining: "cyanophilic-organophilic clumps of material + occasional prominent fissures".

Notes:

• May have pseudoinclusions - mimic papillary thyroid carcinoma.

DDx:

• Anaplastic carcinoma.

Images:

• Amyloid - Halliday et al. (wiley.com).
• Cotton candy (wordpress.com).

IHC

• Calcitonin +ve - it arises from C cells (which produce calcitonin)
• CEA +ve (often better staining than calcitonin).
• Congo-red +ve (if amyloid present) - mnemonic: CRAP -- congo red amyloid protein.

Anaplastic thyroid carcinoma

Main article: Anaplastic thyroid carcinoma

General

• Prognosis: very crappy.
• Classically rapid growth.

Note:

• Other fast growing lesion:
  • Lymphoma (faster than anaplastic carcinoma).
  • Blood accumulation.

Cytology

Features:

• Nuclear atypia - marked.
• Spindle cell morphology common.
• Nucleolus.
• Usually scant cellularity.
• Necrosis very common.

DDx:

• Medullary thyroid carcinoma.

See also

• Cytopathology.
• Thyroid gland.