Thyroid gland
Bethesda systems for cytology
Atypia of Undetermined Significance / Follicular Lesion of Undetermined Significance (AUS / FLUS)

Editor-in-Chief: Debra Zynger, M.D.
Ayana Suzuki, C.T.
Andrey Bychkov, M.D., Ph.D.

Topic Completed: 22 July 2019

Revised: 20 August 2019

Copyright: 2019, PathologyOutlines.com, Inc.

PubMed Search: Bethesda guidelines atypia

Ayana Suzuki, C.T.
Andrey Bychkov, M.D., Ph.D.
Page views in 2018: 3,655
Page views in 2019 to date: 3,648
Cite this page: Suzuki A, Bychkov A. Atypia of Undetermined Significance / Follicular Lesion of Undetermined Significance (AUS / FLUS). PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/thyroidatypia.html. Accessed September 20th, 2019.
Definition / general
  • The Bethesda category III, Atypia of Undetermined Significance / Follicular Lesion of Undetermined Significance (AUS / FLUS) is used for cases with a minor degree of atypia, primarily cytologic or architectural in nature, insufficient to qualify for either of the suspicious categories (category IV and higher)
Essential features
  • AUS / FLUS include cases with few cells that have distinct but mild nuclear atypia or with more extensive but very mild nuclear atypia
  • Frequency 8%, resection rate 43.0 - 64.7%, risk of malignancy 10 - 30% of all nodules (6 - 18% after noninvasive follicular thyroid neoplasm with papillary-like nuclear features exclusion) and up to 40% of resected nodules
  • The most common histopathological diagnosis of AUS nodules is nodular hyperplasia and follicular adenoma, followed by papillary thyroid carcinoma (PTC)
  • Repeat fine needle aspiration (FNA) results in a more definitive cytologic interpretation (70 - 90%)
Terminology
  • AUS: preferred term
  • FLUS: acceptable alternative for the cases with the atypia of follicular cell origin
  • Laboratory should choose the one preferable term and use it exclusively for this category
  • AUS can be subdivided into AUS with cytologic (AUS-C) and architectural (AUS-A) atypia, which have different risk of malignancy (AUS-C > AUS-A)
  • AUS-C: mostly benign appearing with mild cytologic / nuclear atypia (also called AUS-N)
  • AUS-A: cannot be denied a possibility of follicular neoplasm (applicable to FLUS), see Explanatory notes below
Clinical features
Diagnosis
Case reports
Cytology description
  • Cytologic atypia
  • Can be focal or can show most cells with mild cytologic atypia
  • Most of the aspirate appears benign but rare cells have:
    • Nuclear enlargement
    • Pale chromatin
    • Irregular nuclear contours
    • No nuclear pseudoinclusions
Cytology images

Contributed by Ayana Suzuki, C.T.
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Cytologic atypia

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Architectural atypia

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Hürthle cell atypia

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Atypical lymphocytes


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Cytologic atypia


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Atypical cyst lining cells

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Architectural atypia

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Atypical lymphocytes

Explanatory notes
  • AUS / FLUS is an interpretation of last resort and should be used judiciously
  • Specimen preparation artifacts may potentially raise concern for AUS / FLUS
  • AUS with cytologic atypia is associated with PTC (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)
Management
  • 2015 American Thyroid Association Management Guidelines recommend either repeat FNA or molecular testing (Thyroid 2016;26:1)
  • About half of AUS / FLUS cases have a negative Afirma gene expression classifier (GEC) result (architectural atypia > cytologic atypia)
    • Hürthle cell pattern of AUS / FLUS has a lower rate of 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
    • Noninvasive follicular thyroid neoplasm with papillary-like nuclear features will diminish the overall risk of malignancy for AUS / FLUS (Thyroid 2015;25:987, Cancer Cytopathol 2016;124:181)
Sample pathology report
  • Dx/Category: Atypia of undetermined significance (AUS), a possibility of follicular neoplasm. Sparsely cellular aspirate comprised of follicular cells with microfollicular pattern colloid is absent.
    • Note: A repeat FNA or molecular testing may be helpful if clinically indicated.
  • Dx/Category: Atypia of undetermined significance (AUS), a possibility of papillary thyroid carcinoma. Follicular cells with mild nuclear irregularity.
    • Note: A repeat FNA or molecular testing may be helpful if clinically indicated.
  • Dx/Category: Atypia of undetermined significance (AUS), a possibility of papillary thyroid carcinoma. Follicular cells, predominantly benign appearing, with focal cytologic atypia.
    • Note: A repeat FNA or molecular testing may be helpful if clinically indicated.
  • Dx/Category: Atypia of undetermined significance (AUS), a possibility of lymphoma. Numerous relatively monomorphic lymphoid cells.
    • Note: An additional aspiration, with apportioning of needle wash out fluid for flow cytometry, may be helpful if clinically indicated.
Videos

Atypical thyroid FNA

Head and tail of the Bethesda system for thyroid

Thyroid cytology - Bethesda classification

Differential diagnosis
    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 nuclear to cytoplasmic ratio
    • Harder (glassier) cytoplasm
    • Larger, discrete vacuoles without the hemosiderin or microvacuolization of histiocytes
  • Characteristic of cystic PTC (Cancer 2002;96:240)
  • Immunostaining: keratins (PTC cells), CD68 (histiocytes)

    Architectural atypia
  • Rare clusters with microfollicles or crowded three dimensional groups with scant colloid
    • Low risk
    • Follicular neoplasm / suspicious for a follicular neoplasm (FN / SFN) diagnosis if the specimen were more cellular

    Focally prominent microfollicles with minimal nuclear atypia
    • A more prominent than usual population of microfollicles but not sufficient for a diagnosis of FN / SFN
    • Should not be confused with an overall mixed but predominantly macrofollicular, aspirate (benign)

    Cytologic and architectural atypia
  • The presence of both mild cytologic and architectural atypia may be more common with noninvasive follicular thyroid neoplasm with papillary-like nuclear features

    Hürthle cell aspirates
  • A sparsely cellular aspirate comprised of Hürthle cells with minimal colloid
    • Very low risk
    • Follicular neoplasm, Hürthle cell type / suspicious for a follicular neoplasm, Hürthle cell type diagnosis if the specimen were highly cellular

    Markedly cellular sample composed of Hürthle cells with sparse colloid, yet the clinical setting suggests benign
  • Clinically suggesting lymphocytic thyroiditis or a multinodular goiter
  • More highly predictive of a hyperplastic Hürthle cell nodule than usual (Am J Clin Pathol 2011;135:139)
  • Hürthle cells are all in cohesive flat sheets without nuclear atypia and there is abundant colloid → benign (in the absence of high risk clinical or radiologic findings)
  • To follow a patient rather than perform a lobectomy will often be based on clinical and sonographic correlation

    Atypia, not otherwise specified (NOS)
  • A minor population of follicular cells with nuclear enlargement and prominent nucleoli
    • Does not raise concern for PTC 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 nuclear features of PTC
  • Psammoma bodies raise concern for PTC and should prompt careful scrutiny of PTC 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
  • Crowded three dimensional clusters or trabecular arrangements, abundant granular cytoplasm, salt and pepper chromatin (Head Neck 2002;24:157, Acta Cytol 2004;48:133)
  • 25 - 30% of parathyroid lesions can be recognized
  • Immunohistochemistry (GATA3, PTH, chromogranin A) and ancillary studies (parathyroid hormone assays, molecular studies) can confirm the diagnosis

    Descriptive language may occasionally influence management
  • Scant or poorly preserved → Repeat aspirate
  • Follow up of a cellular, well preserved aspirate with diffuse mild atypia → Molecular testing
  • Subclassify according to the most likely diagnosis
  • Board review question #1
      Which case belongs to architectural atypia?

    1. A sparsely cellular aspirate comprised of Hürthle cells with minimal colloid
    2. Atypical lymphoid cells
    3. Focally prominent microfollicles with minimal nuclear atypia
    4. Most of the aspirate appears benign but rare cells have irregular nuclear contours
    5. Psammomatous calcifications in the absence of nuclear features of PTC
    Board review answer #1
    C. Focally prominent microfollicles with minimal nuclear atypia. Microfollicles are architectural atypia suggesting follicular neoplasm.

    Comment Here

    Reference: Atypia of Undetermined Significance / Follicular Lesion of Undetermined Significance (AUS / FLUS)
    Board review question #2

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

    1. PAX8
    2. Calcitonin
    3. GATA3
    4. Thyroglobulin
    5. TTF1
    Board review answer #2
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