Fig. 4.1
ASC-US (LBP, ThinPrep). A 32-year-old woman. Atypical intermediate squamous cells with a nucleus 2−3× the area of a normal intermediate squamous cell nucleus and mild irregularity of nuclear contour. This isolated cell has some features suggestive of HPV infection. hrHPV was positive. Follow-up biopsy revealed LSIL (CIN1)
Fig. 4.2
ASC-US (LBP, ThinPrep). A 28-year-old woman. An intermediate squamous cell with an enlarged nucleus and slight nuclear membrane irregularity. The atypical features do not meet the criteria for LSIL. hrHPV was positive. Follow-up biopsy revealed LSIL (CIN1)
Fig. 4.3
ASC-US (LBP, SurePath). Routine screen from a 32-year-old woman. Single atypical squamous cell with ill-defined cytoplasmic halo in a background of inflammation. Adjacent squamous cell shows adherent lactobacilli. HPV testing was not performed on this sample
Fig. 4.4
ASC-US (LBP, ThinPrep). A 28-year-old female. An atypical binucleated intermediate cell with molded nuclei and orangeophilic cytoplasm suggestive but not diagnostic of LSIL. hrHPV was positive. Follow-up biopsy revealed LSIL (CIN1)
Fig. 4.5
Negative for intraepithelial lesion or malignancy (NILM) versus atypical squamous cells – undetermined significance (ASC-US) (CP). Perimenopausal woman. Mature squamous cells show mild nuclear enlargement, binucleation, and even chromatin distribution. Note benign endocervical cells at bottom of field
Fig. 4.6
ASC-US (CP). Cells with multinucleation, nuclear enlargement, and air-drying artifact, possibly representing LSIL (CIN1)
Fig. 4.7
ASC-US (LBP, SurePath). A 21-year-old woman. Thick cohesive sheet of cells with focal nuclear enlargement, orangeophilic cytoplasm, poorly formed cytoplasmic vacuoles, and binucleation. Follow-up biopsy was LSIL (CIN1)
Fig. 4.8
ASC-US (LBP, ThinPrep). A 35-year-old woman. A group of cells featuring mild nuclear enlargement, slight nuclear membrane irregularity and mild hyperchromasia in a clean background. The cytologic features do not meet the criteria for LSIL. hrHPV was positive. Follow-up biopsy revealed LSIL (CIN1)
Fig. 4.9
ASC-US (LBP, ThinPrep). A 25-year-old woman. Intermediate cells with nuclear enlargement ×2−3 that of normal intermediate squamous cell nucleus. There are rare binucleated cells. Slight nuclear irregularity and hyperchromasia are present that do not meet the diagnostic criteria for LSIL. A repeat cervical cytology showed similar findings. Follow-up biopsy revealed LSIL (CIN1)
Fig. 4.10
ASC-US (LBP, ThinPrep). A 40-year-old woman. Binucleated atypical intermediate squamous cell with slightly enlarged irregular nuclei in an inflammatory background. hrHPV was positive. Follow-up biopsy showed LSIL (CIN1)
Fig. 4.11
ASC-US (LBP, ThinPrep). A 40-year-old woman. A single atypical intermediate squamous cell with a nucleus that is 2 to 3 times the area of a normal intermediate squamous nucleus and an irregular nuclear contour. The background shows acute inflammation. The cytologic features do not meet the criteria for LSIL
Fig. 4.12
ASC-US (LBP, SurePath). Routine screening in a perimenopausal woman. Several cells showing slightly increased nuclear hyperchromasia and nuclear to cytoplasmic ratios. Occasional bi-nucleation and cytoplasmic halos are seen. These features may be seen in a reactive/infectious process; however, given the absence of organisms and lack of history, an interpretation of ASC-US was rendered. Repeat cervical cytology was negative; hrHPV testing was also negative
Fig. 4.13
ASC-US (LBP, ThinPrep). A 23-year-old woman. An atypical intermediate squamous cell with a mildly enlarged nucleus and a poorly-formed perinuclear halo. The atypical features are suggestive but not diagnostic of LSIL. hrHPV was positive. Follow-up biopsy revealed LSIL (CIN1)
Fig. 4.14
ASC-US (LBP, ThinPrep). A 30-year-old woman. A metaplastic cell with dense cytoplasm, slightly enlarged nucleus and mild nuclear membrane irregularity is seen in the center. Below it is a binucleated intermediate squamous cell with irregular nuclear contour. The cytologic features are suggestive but do not meet the criteria for LSIL. hrHPV was positive. Follow-up biopsy revealed LSIL (CIN1)
Fig. 4.15
ASC-US – atypical keratinized cells (LBP, ThinPrep). A 25-year-old woman. A cohesive sheet of spindled keratotic cells with nuclear enlargement, hyperchromasia and orangeophilic cytoplasm. hrHPV was positive. Follow-up biopsy revealed LSIL with prominent keratinization
Fig. 4.16
ASC-US – atypical keratinized cells (LBP, ThinPrep). A 32-year-old woman. Cohesive sheet of atypical squamous cells with orangeophilic cytoplasm and elongated, hyperchromatic crowded nuclei. hrHPV was positive. Follow-up biopsy revealed HSIL (CIN 2) with prominent keratinization
Fig. 4.17
ASC-US – atypical repair (CP). In this image, cells are arranged in two-dimensional sheet with abundant cytoplasm showing a “pulled-out” or streaming effect. Nuclei show pleomorphism of size and shape with some cells having multiple nuclei. Most nuclei show prominent nucleoli. These changes, while indicative of a reparative reaction, may be classified as ASC-US because of the nuclear pleomorphism noted. In favor of a reactive process is the generally fine granularity of the chromatin pattern
Fig. 4.18
ASC-US – atypical repair (CP). Group of cells with features of repair; however, the presence of irregular chromatin distribution and the increased nucleus to cytoplasmic ratio are not typical (see Figs. 2.38 and 2.39). Atypical reparative squamous cells may be classified as ASC-US, or sometimes as ASC-H if invasive carcinoma is a morphologic consideration
Fig. 4.19
Postmenopausal atypia (LBP, SurePath). Postmenopausal woman with an atrophic cell pattern, predominantly comprised of parabasal cells. The presence of occasional enlarged nuclei is a characteristic feature of postmenopausal atypia and is often overcalled as ASC-US. hrHPV testing is usually negative in such cases
4.4.1 Definition
ASC-US refers to changes that are suggestive of LSIL.
4.4.2 Criteria
Nuclei are approximately two and one half to three times the area of the nucleus of a normal intermediate squamous cell (approximately 35 mm2) or twice the size of a squamous metaplastic cell nucleus (approximately 50 μm2) [12] (Fig. 4.1).
Slightly increased ratio of nuclear to cytoplasmic area (N/C) (Fig. 4.2).
Minimal nuclear hyperchromasia and irregularity in chromatin distribution or nuclear shape.
Nuclear abnormalities associated with dense orangeophilic cytoplasm (“atypical parakeratosis”), cytoplasmic changes that suggest HPV cytopathic effect (incomplete koilocytosis) – including poorly defined cytoplasmic halos or cytoplasmic vacuoles resembling koilocytes but with absent or minimal concurrent nuclear changes (Figs. 4.3 and 4.4).
Preparation Specific Criteria
Conventional Preparations:
Liquid-Based Preparations:
Cells may appear smaller and have higher nuclear to cytoplasmic ratios in two-dimensional views due to fixation in liquid media (which leads to rounding up of cells) and lack of flattening on the slide (Fig. 4.7).
4.4.3 Explanatory Notes
The normal-appearing intermediate cells that are present on a slide provide an appropriate source of comparison for assessing whether nuclear size and appearance meet criteria for ASC-US or SIL. Cells which might lead to an ASC-US designation for the slide typically have the overall size and shape of superficial or intermediate squamous cells. Round or ovoid cells that are approximately one-third the size of superficial cells and therefore resemble large metaplastic or small intermediate cells may also be classified as ASC-US. Criteria for ASC-US may differ subtly among laboratories, reflecting differences in stains and techniques for slide preparation (Figs. 4.8 and 4.9).
Determining whether to classify a specimen as NILM or ASC-US may be difficult in cases showing mild diffuse nuclear enlargement, the presence of reactive/reparative or degenerative changes, organisms, air-drying with artifactual nuclear enlargement, atrophic patterns, and in the presence of other artifacts (Figs. 4.10–4.13). In such specimens, the patient’s age and history should be considered, and previous specimens should be reviewed microscopically, if deemed relevant, to interpreting the current case. Generally, when the current cytologic findings favor a reactive process over an SIL and the patient has a history of multiple prior negative specimens-particularly if there is a recent negative hrHPV result-the interpretation of NILM should be favored. Most specimens classified as ASC demonstrate a numerically minor subpopulation of atypical cells that are either isolated or occur in small sheets or groupings (Fig. 4.14).
The prevalence of ASC-US declines with increasing age in the screening population, as does the prevalence of hrHPV DNA (including genotypes 16 and 18) [13]. ASC-US cytology in younger women is more prevalent and more often refelective of an HPV-related lesion than in older women [13]. Regardless of age, the knowledge of a patient’s concurrent hrHPV result could potentially bias the perspective of the cytotechnologist or cytopathologist when making an interpretation of NILM vs. ASC-US, especially in specimens with minimal cytologic changes [14–16]. Hence, care should be taken when reviewing specimens with a priori knowledge of HPV status.
4.5 Common Patterns Classified as ASC-US (Figs. 4.15–4.19)
4.5.1 Atypical Parakeratosis (APK) (Figs. 4.15 and 4.16)
Cells with dense orangeophilic or eosinophilic cytoplasm and small pyknotic nuclei (“parakeratosis”) should be classified as NILM if the nuclei appear normal (see Figs. 2.15 and 2.16). However, if the nuclei are enlarged, hyperchromatic, or irregular in contour or if the cells occur in three-dimensional clusters (referred to by some as “atypical parakeratosis”), an interpretation of ASC-US, ASC-H, or SIL should be considered depending on the degree of the abnormality [10, 17] (Figs. 4.15 and 4.16; see Figs. 5.8, 5.9, 5.26, 5.43, and 5.44).
4.5.2 Atypical Repair (Figs. 4.17 and 4.18)
Reparative changes that manifest some degrees of cellular overlap, dyscohesion, anisonucleosis, and/or loss of nuclear polarity may be designated as “atypical repair” which can be classified under the ASC-US category. The incidence of subsequent SIL among women with atypical repair has been reported to range from 25 to 43 % in high-risk population groups; however, the incidence of SIL in a more diverse population has been shown to be much lower (5.2 %) [18]. The differential diagnosis of atypical repair is wide. Changes that are at the lower end of the spectrum of atypia are generally designated as ASC-US (Figs. 4.17 and 4.18), while those that are concerning for the possibility of invasive carcinoma, especially in high-risk patients, should be placed in the ASC-H category.
4.5.3 Atypia in Postmenopausal Women and in Atrophy (Fig. 4.19)
Atrophic samples showing nuclear enlargement with hyperchromasia that fall short of a definitive interpretation of SIL may also be designated as ASC-US. Occasionally, and especially in the case of a high-risk patient, the atypia in atrophy may warrant an interpretation of ASC-H, if it raises concern for HSIL (see Fig. 4.29). The interpretation of HSIL may be difficult to make in an atrophic background because of the lack of maturity (and hence high nuclear to cytoplasmic ratio) of the parabasal cells. In low-risk scenarios, it may be prudent to categorize such atypias as ASC-US rather than ASC-H and allow adjunctive hrHPV testing to determine downstream management which may avoid overtreatment.
In peri- and postmenopausal women, mild bland nuclear enlargement is a common cause for ASC over utilization. Changes of mild nuclear enlargement without significant hyperchromasia or nuclear irregularity have sometimes been termed “postmenopausal atypia” and are not generally associated with HPV-related disease (Fig. 4.19). In the absence of definitive abnormalities, such cases are preferably interpreted as NILM, especially in women who have no prior history of squamous cell abnormalities or do not have a prior positive hrHPV test [19, 20].
4.5.4 Other Patterns
Rarely, the difficult distinction between SIL and decidual and trophoblastic cells may also prompt an interpretation of ASC-US (see Figs. 2.28, 2.29, and 5.53).
ASC may also be an appropriate designation for some specimens that contain abnormal-appearing naked nuclei without associated cytoplasm, since isolated nuclei may be associated with SIL in some cases (see Fig. 5.39).
4.6 Atypical Squamous Cells – Cannot Exclude an HSIL (ASC-H) (Figs. 4.20–4.33)
Fig. 4.20
ASC-H (LBP, ThinPrep). A 27-year-old woman. (a) On the left are isolated small cells with variable N/C ratios and some cells displaying prominent nuclear irregularity. (b) On the right is a high-magnification view of six small cells with enlarged and irregular, but degenerated, nuclei. Follow-up was HSIL (CIN 3)
Fig. 4.21
ASC-H (LBP, SurePath). Routine cytology for a 30-year-old woman. Rare metaplastic cells with dense cytoplasm and nuclear enlargement with hyperchromasia are present in a background of scattered acute inflammation. An interpretation of ASC-H was rendered. Follow-up cervical biopsies revealed immature squamous metaplasia. Immature squamous metaplasia is one of the most common mimics of HSIL. An interpretation of ASC-H is appropriate, especially when only rare abnormal cells with “metaplastic” cytoplasm and high nuclear to cytoplasmic ratio are present
Fig. 4.22
ASC-H (LBP, SurePath). Perimenopausal woman with history of LSIL. Unremarkable slide with only a single large atypical cell in a clean background. The nuclear irregularity and hyperchromasia were worrisome but not definitive for SIL. Cervical biopsies were performed and showed tubal metaplasia but no intraepithelial neoplasia. A solitary cell of this nature is difficult to classify. Cyto-histologic correlation favored this to be a reactive endocervical cell, although a terminal bar and cilia were not conclusively identified
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