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Thyroid & parathyroid

Cytology

Bethesda system

AUS

Author: Ayana Suzuki, Ph.D.

Deputy Editor-in-Chief: Andrey Bychkov, M.D., Ph.D.

Last staff update: 19 August 2025 (update in progress)

Copyright: 2019-2025, PathologyOutlines.com, Inc.

PubMed Search: Atypia of undetermined significance

Page views in 2025 to date: 8,038

Table of Contents

Cite this page: Suzuki A. AUS. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/thyroidatypia.html. Accessed August 27th, 2025.

Definition / general

Bethesda category III, atypia of undetermined significance (AUS) is used for cases with a minor degree of atypia, primarily cytologic or architectural in nature, insufficient to qualify for either of the indeterminate categories (category IV - V) and higher

Essential features

AUS includes cases with few cells that have distinct but mild nuclear atypia or with more extensive but very mild nuclear atypia
Frequency: 1 - 20%
Resection rate: 43.0 - 64.7%
Risk of malignancy (ROM): 13 - 30%
Repeat fine needle aspiration (FNA) results in a more definitive cytologic interpretation (70 - 90%)

Terminology

AUS can be subdivided into AUS with nuclear atypia (AUS-N) and other atypia (AUS-O)
- AUS-N: a low level of concern for papillary thyroid carcinoma (PTC) or noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP)
- AUS-O: nonnuclear features result in an AUS interpretation
Follicular lesion of undetermined significance (FLUS), previously considered synonymous with AUS or often used as a synthetic term AUS / FLUS, was removed in the third edition to avoid confusion

Clinical features

Frequency: 8% in meta analysis (Expert Rev Endocrinol Metab 2014;9:97)
- AUS is considered as the last resort after excluding all the rest of the Bethesda categories
- Goal is to have 7 - 10% and ideally AUS:malignant ratio should not exceed 3:1 (used as quality control criteria in the individual laboratory) (Cancer Cytopathol 2015;123:713, Cancer Cytopathol 2012;120:111)
- Architectural atypia (41%) > nuclear atypia (32%) > oncocytic atypia (17%)
Resection rate: 43.0 - 64.7% (Thyroid 2014;24:832, Arch Pathol Lab Med 2013;137:1664)
Risk of malignancy: 13 - 30% (Ali: The Bethesda System for Reporting Thyroid Cytopathology, 3rd Edition, 2023, Cancer Cytopathol 2012;120:111)
- Nuclear atypia (36 - 44%) > other atypia (15 - 23%) (Acta Cytol 2011;55:518)
- 16% when NIFTP is implicated (Ali: The Bethesda System for Reporting Thyroid Cytopathology, 3rd Edition, 2023, Cancer Cytopathol 2012;120:111)

Diagnosis

Aspirates containing cells (follicular, lymphoid or other) with architectural or nuclear atypia that is not sufficient to be classified as follicular neoplasm (FN), suspicious for malignancy or malignant (Ali: The Bethesda System for Reporting Thyroid Cytopathology, 3rd Edition, 2023)

Case reports

10 year old girl with multifocal NIFTP (F1000Res 2020;9:645)
43 year old man with follicular thyroid carcinoma with large sternal metastasis (Int J Surg Case Rep 2023;112:108973)
59 year old man with intrathyroid thyroglossal duct cyst (Cureus 2021;13:e20399)
65 year old man with synchronous papillary - medullary thyroid microcarcinoma (AME Case Rep 2022;6:27)

Cytology description

AUS-N
- Can be focal or can show most cells with mild nuclear atypia
- Most of the aspirate appears benign but rare cells have
  - Nuclear enlargement
  - Pale chromatin
  - Irregular nuclear contours
  - No nuclear pseudoinclusions
Reference: Thyroid 2023;33:1039

Cytology images

Contributed by Ayana Suzuki, Ph.D.

AUS-N (nuclear atypia)

AUS-O (architectural atypia)

AUS-O (oncocytic atypia)

AUS-O (atypical lymphoid cells)

Images hosted on other servers:

AUS-N (nuclear atypia)

AUS-N (atypical cyst lining cells)

AUS-O (architectural atypia)

AUS-O (atypical lymphoid cells)

Explanatory notes

AUS is an interpretation of last resort and should be used judiciously
Specimen preparation artifacts may potentially raise concern for AUS
AUS with nuclear atypia is associated with papillary thyroid carcinoma (28 - 56%) (Am J Clin Pathol 2011;136:572, Diagn Cytopathol 2012;40:410)
- Rare cells (< 20 cells) with enlarged, often overlapping nuclei, pale chromatin, irregular nuclear outlines and nuclear grooves
- Well defined, intranuclear pseudoinclusions or psammomatous calcifications (more suspicious) (Acta Cytol 2008;52:320)
AUS subclassification in children also provides further risk stratification, similar to adults

Management

2015 American Thyroid Association Management Guidelines recommend either repeat FNA or molecular testing (Thyroid 2016;26:1)
Molecular testing of AUS nodules can reduce the need for diagnostic surgery
65 - 87% of AUS cases have a negative molecular testing result (architectural atypia > cytologic atypia)
- Oncocytic AUS has a lower rate of gene expression classifier (GEC) benign results despite its very low risk of malignancy (Thyroid 2015;25:789)
- Surgery versus continued observation is based on a synthesis of cytologic, molecular, clinical and radiologic findings as well as clinical risk factors and patient preference
- NIFTP will diminish the overall risk of malignancy for AUS (Thyroid 2015;25:987, Cancer Cytopathol 2016;124:181)

Videos

Atypical thyroid FNA

Head and tail of the Bethesda system for thyroid

Thyroid cytology - Bethesda classification

How to observe thyroid FNA

Sample pathology report

Thyroid, ultrasound guided FNA:
- AUS-O (see comment)
- Sparsely cellular aspirate comprised of follicular cells with microfollicular pattern colloid is absent
- Comment: Repeat FNA or molecular testing may be helpful if clinically indicated.
Thyroid, ultrasound guided FNA:
- AUS-N (see comment)
- Follicular cells with mild nuclear irregularity
- Comment: Repeat FNA or molecular testing may be helpful if clinically indicated.
Thyroid, ultrasound guided FNA:
- AUS-N (see comment)
- Follicular cells, predominantly benign appearing, with focal nuclear atypia
- Comment: Repeat FNA or molecular testing may be helpful if clinically indicated.
Thyroid, ultrasound guided FNA:
- AUS-O (see comment)
- Numerous relatively monomorphic lymphoid cells
- Comment: An additional aspiration, with apportioning of needle washout fluid for flow cytometry, may be helpful if clinically indicated.

Differential diagnosis

AUS-N
- Extensive but mild cytologic atypia:
  - Many if not most cells have mildly enlarged nuclei with
    - Slightly pale chromatin
    - Only limited nuclear contour irregularity
    - No nuclear pseudoinclusions
- Atypical cyst lining cells:
  - Cyst lining cells may appear atypical (rare cases), such as
    - Nuclear grooves
    - Prominent nucleoli
    - Elongated nuclei and cytoplasm
    - Rare intranuclear pseudoinclusions
  - Associated with hemosiderin laden macrophages
  - Reactive follicular or mesenchymal cells associated with cystic degeneration of thyroid nodules
  - Most cases are benign (Cancer 2005;105:71)
- Histiocytoid cells:
  - Compared with histiocytes
    - Larger
    - Rounder nuclei
    - Higher N:C ratio
    - Harder (glassier) cytoplasm
    - Larger, discrete vacuoles without the hemosiderin or microvacuolization of histiocytes
  - Characteristic of cystic papillary thyroid carcinoma (Cancer 2002;96:240)
  - Immunostaining: keratins (papillary thyroid carcinoma cells), CD68 (histiocytes)
AUS-O
- Architectural atypia:
  - Rare clusters with microfollicles or crowded 3 dimensional groups with scant colloid
    - Low risk
    - Follicular neoplasm diagnosis if the specimen were more cellular
  - 50 - 70% of follicular cells exhibit microfollicles but without a marked predominance
    - DICER1 mutated nodules may be associated with this pattern in pediatric samples
  - Focally prominent microfollicles with minimal nuclear atypia
    - More prominent than usual population of microfollicles but not sufficient for a diagnosis of follicular neoplasm
    - Should not be confused with an overall mixed but predominantly macrofollicular aspirate (benign)
- Oncocytic atypia:
  - Sparsely cellular aspirate comprised of oncocytes with minimal colloid
    - Very low risk
    - Oncocytic follicular neoplasm diagnosis if the specimen were highly cellular
  - Markedly cellular sample composed of oncocytes with sparse colloid, yet the clinical setting suggests benign
    - Clinically suggesting lymphocytic thyroiditis or a multinodular goiter
    - More highly predictive of a hyperplastic oncocytic nodule than usual (Am J Clin Pathol 2011;135:139)
    - Specimens with oncocytes in cohesive flat sheets without nuclear atypia and abundant colloid indicate benign (if high risk clinical or radiologic findings are absent)
- Atypia, not otherwise specified (NOS):
  - Minor population of follicular cells with nuclear enlargement and prominent nucleoli
    - Does not raise concern for papillary thyroid carcinoma and best classified as NOS
    - Specimens from patients with a history of radioactive iodine, carbimazole or other pharmaceutical agents can usually be diagnosed as benign
  - Psammomatous calcifications in the absence of follicular cells with nuclear features of papillary thyroid carcinoma
    - Psammoma bodies raise concern for papillary thyroid carcinoma and should prompt careful scrutiny of papillary thyroid carcinoma cells
    - Lamellar bodies of inspissated colloid may be indistinguishable from true psammomatous calcifications
- Atypical lymphoid cells, rule out lymphoma:
  - There is an atypical lymphoid infiltrate but the degree of atypia is insufficient for suspicious for malignancy
  - Repeat aspirate for flow cytometry is desirable
- Parathyroid lesion:
  - Triangular cell clusters with 1 sharp corner (wedge pattern), salt and pepper chromatin and no colloid (Head Neck 2002;24:157, Acta Cytol 2004;48:133, Diagn Cytopathol 2021;49:70)
  - 25 - 30% of parathyroid lesions can be recognized
  - Immunohistochemistry (especially GATA3 antibody) and ancillary studies (parathyroid hormone assays, molecular studies) can confirm the diagnosis (Diagn Cytopathol 2021;49:70, Endocr J 2016;63:621)

Practice question #1

Which case belongs to architectural atypia?

Atypical lymphoid infiltration
Focally prominent microfollicles with minimal nuclear atypia
Most of the aspirate appears benign but rare cells have irregular nuclear contours
Psammomatous calcifications in the absence of nuclear features of papillary thyroid carcinoma
Sparsely cellular aspirate comprised of oncocytes with minimal colloid

Practice answer #1

B. Focally prominent microfollicles with minimal nuclear atypia. Microfollicles are architectural atypia, suggesting follicular neoplasm. Answer A is incorrect because atypical lymphoid infiltration belongs to atypical lymphoid cells. Answer C is incorrect because most of the aspirate appearing benign but rare cells having irregular nuclear contours belongs to nuclear atypia. Answer D is incorrect because psammomatous calcifications in the absence of nuclear features of papillary thyroid carcinoma (PTC) belongs to atypia, not otherwise specified. Answer E is incorrect because sparsely cellular aspirate comprised of oncocytes with minimal colloid belongs to oncocytic atypia.

Comment Here

Reference: AUS

Practice question #2

A 70 year old man underwent FNA for a thyroid nodule in the right lobe. A cytological image of the lesion is shown above. Which marker would most likely show positive staining?

Calcitonin
GATA3
PAX8
Thyroglobulin
TTF1

Practice answer #2

B. GATA3. The lesion shown in the image is an intrathyroidal parathyroid adenoma. Answer A is incorrect because calcitonin is a marker for medullary thyroid carcinoma. Answers C, D, and E are incorrect because PAX8, thyroglobulin and TTF1 are markers for follicular cells.

Comment Here

Reference: AUS

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