Bethesda system

Cervix

Cytology

Bethesda system

Authors: Rachel Jug, M.B.B.Ch., B.A.O., Sarah M. Bean, M.D.

Editor-in-Chief: Debra Zynger, M.D.

Minor changes: 29 September 2020

Copyright: 2002-2020, PathologyOutlines.com, Inc.

PubMed Search: Bethesda system 2001 cervicovaginal cytology

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Table of Contents

Cite this page: Jug R, Bean SM. Bethesda system. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/cervixcytologybethesda.html. Accessed October 20th, 2020.

Definition / general

The Bethesda system provides a framework for consistent interlaboratory terminology for the reporting of cervicovaginal cytology specimens

Essential features

Report elements include specimen type, specimen adequacy, general categorization, interpretation / result and other optional elements such as ancillary testing, computer assisted interpretation, educational notes and comments
Interpretations / results include the general categories of negative for intraepithelial lesion or malignancy (NILM), epithelial cell abnormalities and other malignancies
Prognosis and management of cervical cytology screening diagnostic categories is based on the 2019 ASCCP Risk Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors (J Low Genit Tract Dis 2020;24:102)

Background

The Bethesda system provides a framework for consistent interlaboratory terminology for the reporting of cervicovaginal cytology specimens
It was first conceived in 1988 with updates in 1991, 2001 and 2014 (JAMA 2002;287:2114, Nayar: The Bethesda System for Reporting Cervical Cytology, 3rd Edition, 2015)
By 2016, the 2014 update was implemented by most labs (67.2%) in College of American Pathologists' PAP education Program and 20.1% planned to implement the updates (Arch Pathol Lab Med 2019;143:1196)
Coexistent squamous and glandular lesions are not uncommon due to similar etiology driving the majority of cases (high risk HPV) or adenocarcinomas may show partial squamous differentiation

2014 Bethesda system for reporting cervical cytology - report elements

Specimen type: conventional smear, liquid based preparation or other
Specimen adequacy (mandatory):
- Satisfactory or unsatisfactory for evaluation
- Satisfactory:
  - Adequate number of well visualized or preserved squamous or squamous metaplastic cells
  - Conventional smear: minimum 8,000 - 12,000 cells
  - Liquid based preparation: minimum 5,000 cells
  - Woman's postchemotherapy, radiotherapy, postmenopausal, atrophic changes or posthysterectomy may have < 5,000 cells and be deemed adequate at laboratory's discretion (if > 2,000 cells)
  - Exception: adequate if any abnormal cells are present
- Unsatisfactory:
  - More than 75% of cells obscured by inflammation, bacteria or interfering substances (lubricants and blood)
  - 50 - 75% of cells obscured, include a disclaimer describing how and the percentage of cells obscured
  - Report specific reason for unsatisfactory evaluation whether specimen is rejected or not processed or processed but unsatisfactory for evaluation
- Quality indicators:
  - Presence or absence of endocervical or transformation zone component
  - At least 10 well preserved endocervical or metaplastic cells
  - Absence of transformation zone does not necessitate repeat testing (Nayar: The Bethesda System for Reporting Cervical Cytology, 3rd Edition, 2015)
General categorization (optional)
- Negative for intraepithelial lesion or malignancy
- Epithelial cell abnormality: see Interpretation / result (specify squamous or glandular)
- Other: see Interpretation / result (e.g. endometrial cells in a woman ≥ 45 years of age) (Nayar: The Bethesda System for Reporting Cervical Cytology, 3rd Edition, 2015)
Interpretation / result (mandatory)
- Negative for intraepithelial lesion or malignancy (NILM)
  - State NILM in General categorization or Interpretation / result sections of report and then specify nonneoplastic findings, including organisms, if present
  - Nonneoplastic cellular findings:
    - Squamous metaplasia
    - Keratotic changes
    - Tubal metaplasia
    - Atrophy
    - Pregnancy associated changes
    - Reactive cellular changes with association specified:
      - Inflammation (with or without repair)
      - Lymphocytic (follicular) cervicitis
      - Radiation
      - Intrauterine contraceptive device changes
    - Glandular cells posthysterectomy
    - Organisms
      - Trichomonas vaginalis
      - Fungal organisms morphologically consistent with Candida species
      - Shift in flora suggestive of bacterial vaginosis
      - Bacteria morphologically consistent with Actinomyces species
      - Cellular changes associated with herpes simplex virus
      - Cellular changes associated with cytomegalovirus
    - Other
    - Endometrial cells (in a woman ≥ 45 years of age)
- Epithelial cell abnormalities
  - Squamous cell
    - Atypical squamous cells
      - Of undetermined significance (ASC-US)
      - Cannot exclude HSIL (ASC-H)
    - Low grade squamous intraepithelial lesion (LSIL)
    - High grade squamous intraepithelial lesion (HSIL)
      - With features suspicious for invasion (if invasion suspected)
    - Squamous cell carcinoma
  - Glandular cell
    - Atypical
      - Endocervical cells (NOS or specify in comment)
      - Endometrial cells (NOS or specify in comment)
      - Glandular cells (NOS or specify in comment)
      - Endocervical cells, favor neoplastic
      - Glandular cells, favor neoplastic
    - Endocervical adenocarcinoma in situ
    - Adenocarcinoma
      - Endocervical
      - Endometrial
      - Extrauterine
      - Not otherwise specified (NOS)
  - Other malignant neoplasms (specify) (Nayar: The Bethesda System for Reporting Cervical Cytology, 3rd Edition, 2015)
Other reporting considerations (optional)
- Ancillary testing: describe test method and report result, e.g. immunohistochemical stains performed on cell block material
- Computer assisted interpretation of cervical cytology: specify automated instrument used, whether specimen was successfully processed by device, result and whether additional manual screening / review of specimen was performed
- Educational notes and comments: may be appended to cytology reports, e.g. references to relevant publications such as clinical guidelines published by professional organizations (Nayar: The Bethesda System for Reporting Cervical Cytology, 3rd Edition, 2015)

Definitions of interpretation categories

Negative for intraepithelial lesion or malignancy (NILM)
- Adequate squamous cells in the absence of an intraepithelial lesion or malignancy with or without presence of notable nonneoplastic cellular findings, reactive cellular changes, organisms and glandular cells (posthysterectomy or endometrial in origin ≥ 45 years old)
Epithelial cell abnormalities
- Squamous cells
  - Atypical squamous cells
    - Cytologic changes in squamous cells suggestive of a squamous intraepithelial lesion (increased nuclear to cytoplasmic ratio and minimal nuclear changes) but qualitatively or quantitatively insufficient for a definitive interpretation
    - ASC:SIL ratio is used as a quality assurance measure and while the median ratio is 1.5:1, laboratories serving high risk populations should aim for an ASC:SIL ratio at or below 3:1 (Diagn Cytopathol 2010;38:180, Cibas: Cytology - Diagnostic Principles and Clinical Correlates, 4th Edition, 2014)
    - Atypical squamous cells of undetermined significance (ASC-US)
      - Changes suggestive of LSIL, including nuclei 2.5 - 3 times the size of a normal intermediate cell nucleus with or without minimal nuclear hyperchromasia and mildly irregular nuclear contours or poorly formed cytoplasmic halos or vacuoles, resembling koilocytes
      - Includes atypical parakeratosis, atypical repair and atypia in postmenopausal women and in atrophy
    - Atypical squamous cells cannot exclude HSIL (ASC-H)
      - Scant atypical cells with changes suggestive of HSIL
      - Includes atypical immature metaplastic cells, crowded sheets of cells, markedly atypical repair, severe atrophy and postradiation changes suspicious for recurrent or residual carcinoma
  - Low grade squamous intraepithelial lesion (LSIL)
    - Synonyms: mild dysplasia / CIN I (terms not recommended)
    - Large squamous cells with intermediate or superficial (mature) squamous cell type cytoplasm
    - Nuclear enlargement (3 times the size of normal intermediate cell nuclei)
    - Nuclear hyperchromasia, anisonucleosis, uniform chromatin, variable nuclear membranes, bi or multinucleation, inconspicuous nucleoli and koilocytosis or perinuclear cavitation
  - High grade squamous intraepithelial lesion (HSIL)
    - Synonyms: moderate dysplasia, severe dysplasia, CIN2, CIN3, CIS (terms not recommended)
    - Smaller squamous cells than LSIL occurring singly, in sheets or in syncytial-like aggregates (hyperchromatic crowded groups) with a high nuclear to cytoplasmic ratio, nuclear hyperchromasia, nuclear contour irregularities with indentations and grooves and generally absent nucleoli
    - Specify presence of features suspicious for invasion (if invasion suspected), including highly pleomorphic HSIL cells without background features of invasion (necrosis or tumor diathesis) or background features of tumor diathesis without overtly malignant cells
    - Includes HSIL involving endocervical glands
  - Squamous cell carcinoma
    - Single or (less commonly) cellular aggregates of variable cell sizes and shapes with nuclear membrane irregularities, dense opaque nuclei, coarsely granular chromatin, tumor diathesis (necrotic debris and broken down blood elements) and keratotic changes if keratinizing squamous cell carcinoma
    - Encompasses invasive squamous cell tumors of varying degrees of differentiation, including nonkeratinizing and keratinizing carcinomas
    - Nonkeratinizing squamous cell carcinoma may be differentiated from adenocarcinoma using immunohistochemistry on cell blocks made from residual liquid based material
- Glandular cells
  - Atypical NOS
    - Atypical glandular cells should be categorized by site of origin whenever possible to guide management but can be labelled as not otherwise specified (NOS) when further classification is not possible
    - Endocervical cells (NOS or specify in comment)
      - Endocervical cell nuclear atypia (mild nuclear enlargement 3 - 5 times normal endocervical nuclei, overlap, pseudostratification, variation in size or shape, hyperchromasia, chromatin irregularities, rare nucleoli and mitoses) beyond reactive or reparative changes and without definite features of in situ or invasive endocervical adenocarcinoma
    - Endometrial cells (NOS or specify in comment)
      - Small groups of endometrial cells with enlarged nuclei, mild hyperchromasia, chromatin heterogeneity, occasional small nucleoli, scant with or without vacuolated cytoplasm and ill defined cell borders
    - Glandular cells (NOS or specify in comment)
    - Interpretive category used when unable to distinguish between mildly atypical endocervical and endometrial cells
  - Atypical, favor neoplastic
    - Endocervical cells, favor neoplastic
      - Atypical endocervical cell morphology (nuclear atypia [above] plus nuclear elongation with rare cells forming rosettes or glands) quantitatively or qualitatively insufficient for a diagnosis of in situ or invasive endocervical adenocarcinoma
    - Glandular cells, favor neoplastic
      - Interpretive category used when unable to distinguish between atypical endocervical and endometrial cells quantitatively or qualitatively insufficient for a diagnosis of in situ or invasive adenocarcinoma
  - Endocervical adenocarcinoma in situ (AIS)
    - Groups of cells in clusters, pseudostratified strips and rosettes with nuclear crowding, enlargement, hyperchromasia, coarsely granular chromatin, inconspicuous nucleoli, pseudostratiﬁcation, apoptotic bodies and mitotic activity in a clean background
  - Adenocarcinoma
    - Endocervical
      - Cytologic findings seen in endocervical AIS with the addition of more pleomorphism, macronucleoli, nuclear clearing with uneven distribution of chromatin and features indicative of invasion, including background tumor diathesis
    - Endometrial
      - Single or small clusters of cells with variation in nuclear size (dependent on grade), loss of nuclear polarity, moderate hyperchromasia, chromatin clearing (in higher grade tumors), increasing prominence on nucleoli with grade, scant vacuolated cytoplasm, intracytoplasmic neutrophils and finely granular, watery tumor diathesis
    - Extrauterine
      - Adenocarcinoma cells without tumor diathesis raise suspicion for tumors originating outside the uterus and cervix
      - Some cytologic features may provide insight into the site of origin (such as psammoma bodies and papillary clusters suggestive of Müllerian origin), otherwise extra material can be made into a cell block on which immunohistochemical stains may be performed to help define a site of origin
    - Not otherwise specified (NOS)
      - Cells consistent with adenocarcinoma without features differentiating between site of origin (endocervical, endometrial or extrauterine)
Other malignant neoplasms (apart from squamous cell carcinoma or adenocarcinoma; specify), e.g. gynecologic primaries involving cervix or vagina by direct extension or secondary or metastatic tumors to the uterine cervix (Nayar: The Bethesda System for Reporting Cervical Cytology, 3rd Edition, 2015)

Prognosis & management

According to the 2019 ASCCP Risk Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors, the prognosis of cervical cytology screening results is expressed as their threshold of risk for having or developing CIN 3+ and is based on current and previous screening results as well as history of previous precancer treatment
Thresholds of risk are used to guide management recommendations
Management options include return to routine screening, 1 year or 3 year surveillance, colposcopy or treatment corresponding to a risk stratum (J Low Genit Tract Dis 2020;24:102)

Cytology images

Contributed by Rachel Jug, M.B.B.Ch., B.A.O. and Sarah M. Bean, M.D.