Cervix

• Negative for intraepithelial lesion or malignancy (NILM)
  • Adequate squamous cells in the absence of an intraepithelial lesion or malignancy with or without the 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 N:C ratio and minimal nuclear changes) but qualitatively or quantitatively insufficient for a definitive interpretation
      • Atypical squamous cell: squamous intraepithelial lesion (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 (ASCUS)
        • 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 / cervical intraepithelial neoplasia (CIN) I; these terms are 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, carcinoma in situ (CIS); these terms are not recommended
      • Smaller squamous cells than LSIL occurring singly, in sheets or in syncytial-like aggregates (hyperchromatic crowded groups) with a high N:C 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 labeled 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 of 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)

• 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 CIN3+ 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)

• See Definitions of interpretation categories section

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

• Cervix, Pap smear:
  • Cytologic diagnosis:
    • Specimen adequacy:
      • Satisfactory for evaluation - endocervical component absent
  • Interpretation:
    • Epithelial cell abnormality
    • Low grade squamous intraepithelial lesion (LSIL)
    • Fungal organisms morphologically consistent with Candida species
  • Comment: This specimen has been analyzed by the ThinPrep Imaging System (Hologic Corp), along with an additional manual rescreening by a cytotechnologist or pathologist.

• Human papillomavirus DNA, high risk:
  • HPV 16: negative
  • HPV 18: negative
  • HPV OTH: positive
  • Human papillomavirus 16, 18 or high risk pool (31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68) is detected by an FDA approved DNA amplification test. Positive for the high risk pool indicates that one or more of the genotypes was detected. A negative for any of the genotypes indicates that the genotype(s) was undetectable or below the threshold of the test.

B. 5,000. A minimum of 5,000 well visualized / well preserved squamous or squamous metaplastic cells is considered adequate for a liquid based preparation from a woman with a cervix. Certain circumstances based on the patient’s clinical history may allow for a lower adequacy threshold of 2,000 cells in the instance of postmenopausal atrophic changes, prior chemotherapy / radiation therapy or women posthysterectomy. The cellularity threshold for a conventional preparation is a minimum of 8,000 to 12,000 well preserved and well visualized squamous epithelial cells.

Comment Here

Reference: Bethesda system

Under the interpretation category of the Bethesda system, which epithelial cell abnormality is described by squamous cells with nuclear enlargement 3 times the size of the normal intermediate cell nucleus, hyperchromasia, anisonucleosis, uniform chromatin, bi or multinucleation and koilocytosis or perinuclear cavitation?


1. Atypical glandular cells, not otherwise specified
2. Atypical squamous cells of undetermined clinical significance (ASCUS)
3. High grade squamous intraepithelial lesion (HSIL)
4. Low grade squamous intraepithelial lesion (LSIL)
5. Negative for intraepithelial lesion or malignancy (NILM)

D. Low grade squamous intraepithelial lesion (LSIL). In contrast to normal squamous epithelial cells of the cervix (consistent with a diagnosis of NILM), squamous type epithelial cell abnormalities feature changes in nuclear size and features along a spectrum. ASCUS nuclei are enlarged by 2 to 3 times, have smooth to slightly irregular nuclear membranes, finely granular chromatin, inconspicuous nucleoli and questionable cytoplasmic cavitations. LSIL nuclei are enlarged by 3 to 4 times, have smooth to slightly irregular nuclear membranes, slightly more granular chromatin, absent nucleoli and diagnostic HPV cytoplasmic cavitations. HSIL nuclei are more variable than LSIL but the cytoplasmic area is decreased, resulting in a higher N:C ratio. HSIL nuclei have more irregular membranes, nuclear hyperchromasia with fine or coarse chromatin, generally absent nucleoli and can occur singly or in sheets or syncytial-like aggregates. Atypical glandular cells have features such as increased N:C ratio, mitotic activity, feathering and may show pseudostratification.

Comment Here

Reference: Bethesda system

B. Adenocarcinoma, endometrial. Endometrial adenocarcinoma cells may be seen in Pap smears as single or small clusters of cells with variably sized nuclei, loss of nuclear polarity, nuclear hyperchromasia, prominent nucleoli, scant vacuolated cytoplasm, intracytoplasmic neutrophils and watery tumor diathesis. In contrast, endocervical adenocarcinoma cells may present as pseudostratified strips of cells with crowding, nuclear enlargement and peripheral feathering. Block positive p16 staining can help differentiate endocervical adenocarcinoma in situ (or invasive) from endometrial adenocarcinoma. Extrauterine adenocarcinoma will often present in a clean background as opposed to endometrial adenocarcinoma with tumor diathesis.

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Reference: Bethesda system