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Thyroid & parathyroid

Cytology

Bethesda system

Benign

Author: Ayana Suzuki, C.T.

Last author update: 21 April 2022

Last staff update: 12 December 2024 (update in progress)

Copyright: 2014-2025, PathologyOutlines.com, Inc.

PubMed Search: Bethesda guidelines thyroid benign

Table of Contents

Cite this page: Suzuki A. Benign. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/thyroidbenign.html. Accessed January 3rd, 2025.

Definition / general

Designation "benign follicular nodule" applies to a cytologic sample that is adequate for evaluation and consists of colloid and benign appearing follicular cells in varying proportions (Ali: The Bethesda System for Reporting Thyroid Cytopathology, 2nd Edition, 2017)
Most common fine needle aspiration (FNA) interpretation (60 - 70% of all cases) (Clin Lab Med 1993;13:699, Cancer 2007;111:508)
Primary benefit of thyroid FNA is ability to reliably make a benign diagnosis, which spares many patients with nodular thyroid disease unnecessary surgery (Ali: The Bethesda System for Reporting Thyroid Cytopathology, 2nd Edition, 2017)
Approximately 10 - 20% of patients with benign cytology require surgery due to clinical indications (large goiter, suspicious sonogram, rapid growth, coexistent nodule, etc.) and cosmetic reasons (Diagn Cytopathol 2000;23:233)
Nodular goiter (colloid, hyperplastic, adenomatous) is the most common lesion, followed by chronic thyroiditis

Essential features

Cytologic sample that is adequate for evaluation and consists of colloid and benign appearing follicular cells
60 - 70% of all thyroid FNA, resection rate 10 - 20%, risk of malignancy (ROM) 0 - 3%
Role of benign diagnosis is to avoid unnecessary surgery

Terminology

Equal to negative for malignancy and nonneoplastic
Term "benign" preferred over negative for malignancy and nonneoplastic
Category II in the Bethesda system

Radiology description

Adenomatoid nodules: multinodular goiter on ultrasound
Chronic lymphocytic (Hashimoto) thyroiditis: heterogeneous appearance on ultrasound

Radiology images

Contributed by Ayana Suzuki, C.T.

Isoechoic nodule

Hypoechoic nodule

Large cyst

Large multilocular cyst

Case reports

35 year old woman with IgG4 related thyroiditis (Korean J Intern Med 2016;31:399)
35 year old woman with microfilaria in aspirated thyroid nodule (Ci Ji Yi Xue Za Zhi 2016;28:27)
46 year old woman with Hashimoto thyroiditis associated with Hürthle cell adenoma (Rom J Morphol Embryol 2017;58:241)
48 year old woman with subacute thyroiditis mimicking malignacy (Diagn Cytopathol 2016;44:682)
69 year old man with acute exacerbation of Hashimoto thyroiditis mimicking anaplastic carcinoma (Ear Nose Throat J 2014;93:E18)
80 year old woman with acute suppurative thyroiditis (Clin Case Rep 2017;5:1238)

Prognostic factors

0 - 3% of cytologically proven benign thyroid nodules have a malignancy on resection; usually these nodules are clinically suspicious (Endocr Pract 2001;7:237, JAMA 2015;313:926, Thyroid 2007;17:1061)

Treatment

American Thyroid Association (ATA) recommends that followup should be determined by risk stratification based on ultrasound pattern (Thyroid 2016;26:1)
- High suspicion: repeat ultrasound and FNA within 12 months
- Low to intermediate suspicion: repeat ultrasound 12 - 24 months → growth or development of new suspicious ultrasound features → repeat FNA
- Very low suspicion: ultrasound surveillance is not necessary; if ultrasound is repeated, it should be done after 24 months
Repeat FNA or surgery is considered only for a selected subset including those that are large, symptomatic or have worrisome clinical or sonographic characteristics (Thyroid 2016;26:1)

Cytology description

Benign follicular nodule
- Adequate, consists of colloid and benign appearing follicular cells
- Classified histologically as nodular hyperplasia in nodular goiter, hyperplastic (adenomatoid) nodules, colloid nodules and nodules in Graves disease
- Cytology: cellularity: sparse to moderate
  - Colloid: viscous, shiny, light yellow or gold (gross), dark blue-violet-magenta (Romanowsky stain), green or orange-pink (Pap stain)
  - Watery colloid: cellophane coating, film with frequent folds (crazy pavement, chicken wire or mosaic appearance)
  - Thick (dense, hard) colloid: a hyaline quality, cracks
- Macrophages: common, containing hemosiderin pigment
- Follicular cells
  - Appearance: monolayered sheets, spaces (honeycomb-like) within the sheets, intact 3D variably sized balls
  - Cytoplasm: scant or moderate, stripped (may be misinterpreted as lymphocytes), paravacuolar granules (Cancer 2003;99:217)
  - Nuclei: variable in size, low N/C ratio, round to oval, anisonucleosis, uniformly granular chromatin pattern
  - In abundant colloid: shrunken, spindled, degenerated
  - In cystic lesion: focal reparative changes (cyst lining cells with enlarged nuclei, finely granular chromatin, squamoid or spindle shaped appearance)
  - Minor components: oncocytes, microfollicles, papillary hyperplasia (Cancer 2003;99:217, Cancer Cytopathol 2014;122:666)
  - Liquid based cytology preparations (LBC): decrease in the amount of colloid, superior nuclear details
Graves disease
- Features similar to non-Graves benign follicular nodules (Acta Med Scand;205:263)
Lymphocytic thyroiditis (Hashimoto thyroiditis)
- Many polymorphic lymphoid cells associated with benign thyroid follicular cells or oncocytes (Acta Cytol 1987;31:687)
- Oncocytes: flat sheets or isolated, abundant granular cytoplasm, large nuclei, prominent nucleoli, anisonucleosis, mild nuclear atypia (Acta Cytol 1999;43:400)
- Lymphocytes: background or infiltrating epithelial cell groups, polymorphic (small mature lymphocytes, larger reactive lymphoid cells, occasional plasma cells), variable chromatin pattern (rich and granular heterochromatin in small lymphocytes, diminished and fine in large lymphocytes)
- Monomorphic lymphoid population should prompt additional samples for flow cytometry if lymphoma suspected
- LBC: decrease in lymphocytes, oncocytes with irregular nuclei (Acta Cytol 2018;62:93, Diagn Cytopathol 2012;40:404)
Granulomatous (de Quervain) thyroiditis (Acta Cytol 1997;41:238)
- Cellularity: variable (depends on the stage of disease)
- Granulomas: clusters of epithelioid histiocytes, numerous multinucleated giant cells
- Early stage: many neutrophils and eosinophils, similar to acute thyroiditis
- Later stage: hypocellular, giant cells surrounding and engulfing colloid, epithelioid cells, lymphocytes, macrophages, scant degenerated follicular cells
- Involutional stage: absent giant cells and inflammatory cells
Acute thyroiditis (Exp Ther Med;9:860)
- Numerous neutrophils associated with necrosis, fibrin, macrophages, blood
- Scant reactive follicular cells and limited to absent colloid
- Bacterial or fungal organisms (immunocompromised patients)
Riedel thyroiditis (Diagn Cytopathol 2004;30:193)
- Cellularity: acellular
- Collagen strands and bland spindle cells
- Rare chronic inflammatory cells, absence colloid and follicular cells
Black thyroid (Diagn Cytopathol 1991;7:640, Diagn Cytopathol 2006;34:106)
- Follicular cells with abundant dark brown cytoplasmic pigment (darker than hemosiderin, similar to melanin)
Amyloid goiter
- Abundant purple to pink-orange amorphous material (Cytopathology 2006;17:262)

Cytology images

Contributed by Ayana Suzuki, C.T.

Colloid nodule

Adenomatous nodules

Hashimoto thyroiditis

Granulomatous thyroiditis

Thyroglossal duct cyst

Videos

Thyroid cytology: colloid nodule

Essential thyroid cytopathology

Differential diagnosis

Differential with benign follicular nodule (Kini: Color Atlas of Differential Diagnosis in Exfoliative and Aspiration Cytopathology, 2nd Edition, 2011)
- Follicular neoplasm
  - Background: clean, sometimes hyaline colloid
  - Follicular pattern: small, uniform
  - Cytoplasm and nuclei: uniform, high N/C ratio, enlarged nuclei
- Follicular neoplasm, Hürthle cell type
  - Background: clean, sometimes cystic
  - Presentation: isolated, in loosely cohesive groups, sheets, syncytial tissue fragments
  - Cytoplasm and nuclei: uniform, high N/C ratio, enlarged nuclei, binucleation to multinucleation
- Papillary thyroid carcinoma
  - Nuclear psedoinclusions (Orphan Annie nuclei)
Differential with lymphocytic thyroiditis
- Papillary thyroid carcinoma
  - Nuclear psedoinclusions (Orphan Annie nuclei)
- Follicular neoplasm, Hürthle cell type
  - Background: clean, sometimes cystic
- MALT lymphoma
  - Lymphoglandular bodies in the background (Acta Cytol 2018;62:93)
  - Similar chromatin pattern of lymphoid cells regardless of the difference in size
  - Absence of oncocytic cells (Acta Cytol 2018;62:93)
Differential with granulomatous thyroiditis
- Papillary thyroid carcinoma
  - Nuclear psedoinclusions (Orphan Annie nuclei) can mimic macrophages with enlarged nuclei, nuclear irregularity
- Lymphocytic thyroiditis
  - Absence of epithelioid histiocytes
Differential with acute thyroiditis
- Anaplastic carcinoma
  - Carefully observe whether large atypical cells are present or absent
Differential with thyroid cyst (nonthyroid lesions)
- Thyroglossal duct cyst (Thyroid Res & Prac 2013;10:104)
  - Differential diagnosis of thyroid cystic lesions
  - Cytology: proteinaceous material, inflammatory cells, rare degenerated squamous or ciliated columnar cells
  - Appropriate clinical presentation (anterior midline neck cyst, above the thyroid isthmus, below the hyoid bone)
- Parathyroid cyst (Case Rep Surg 2015;2015:243527)
  - Cyst fluid: characteristic watery, clear gross appearance
  - Cytology: acellular or hypocellular
  - Preoperative Dx: elevated parathormone levels in the cyst fluid

Board review style question #1

What risk of malignancy is associated with benign thyroid cytology?

0 - 3%
5 - 10%
12 - 15%
20 - 30%
40 - 50%

Board review style answer #1

A. 0 - 3% Most published studies reported that a benign FNA diagnosis is associated with a very low false negative rate, estimated to be in the range of 0 - 3%. It should be noted that the precise risk of malignancy for cytologically benign nodules is difficult to assess because only a minority of these patients undergo surgery.

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