benign changes and mimics of malignant and premalignant

Benign Changes and Mimics of Malignant and Premalignant Epithelial Lesions

Camilla J. Cobb, MD

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General FeaturesThe recognition of benign changes, organisms, and arti-facts in cervical/vaginal cytologic samples is importantfor all cytology practitioners. Many benign conditionsobserved in Pap slides are notorious for their ability tomimic malignant and premalignant epithelial lesions.Awareness of these entities and recognition of their uniquecytomorphology are important to avoid misdiagnosis and,

especially, overdiagnosis. The observation of variousorganisms may be useful in the treatment of diseases relat-ed to their presence. Recognition of various artifacts is alsoimportant for proper interpretation. The cytomorphologyof common and uncommon benign conditions is discussedin this chapter, with emphasis on the features that are mostuseful in distinguishing them from malignant and prema-lignant epithelial lesions.

Benign Inflammatory Conditions

Figure 4-1. Reactive and inflammatoryepithelial cell changes.Inflammatory epithelial cell changes include nonspecificreactive features such as nuclear enlargement, prominentnucleoli, fine and evenly distributed chromatin, binucle-ation and multinucleation, and smooth nuclear borders (Athrough D). These changes may be seen in either squamousor endocervical cells. A benign finding that may be con-fused with low-grade squamous intraepithelial lesion(LSIL) is that of small perinuclear vacuoles, which are dis-tinguished from koilocytes by their small diameter, lack ofa sharp “cookie-cutter” edge, and absence of associateddysplastic nuclear changes (see Figure 7-17). These shallowvacuoles can also be found with specific infections, such asCandida and Trichomonas (E and F). Degenerative change(eg, dark clumpy or smudgy chromatin, karyopyknosis,karyorrhexis) is common in association with these process-es (H). Distinction from dysplasia is sometimes difficult.However, dysplasia is associated with greater nuclearenlargement (greater than three times the size of a normal

intermediate nucleus); darker, more coarsely granular,irregularly distributed chromatin; and frequent irregulari-ty of the nuclear borders (I). Background inflammation ispredominantly acute in nature, but remember that anacute inflammatory background can be seen with dysplasiaas well.

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College of American Pathologists Practical Guide to Gynecologic Cytopathology

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Figure 4-2. Parabasal and squamous metaplastic cells.These two cell types are morphologically similar, and theirpresence in Pap specimens reflects sampling from a rela-tively thin, immature, squamous mucosal surface predis-posed to conditions (eg, infection, irritation, erosion, ulcer-ation) that lead to reactive/reparative and degenerativechanges. Parabasal-like cells often dominate during thepostpartum and postmenopausal periods and are also seenin some cyclic women taking Depo-Provera or other prog-estational drugs (C). These cells reflect the lack of matura-tion of the squamous epithelium due to low estrogen lev-els. Squamous metaplasia occurs at the transformation

zone of cyclic women and may yield large numbers ofimmature squamous cells. Reactive/reparative change(prominent nucleoli, mild hyperchromasia, nuclearenlargement, mitotic activity) and degenerative changes(dark clumpy or smudgy chromatin) in these small squa-mous cells are sometimes confused with dysplasia or carci-noma (E and H). Cytologic features that support an accu-rate benign interpretation include nuclear uniformity,smooth nuclear borders, polarity in cell groups, and finelygranular and evenly distributed chromatin (see Figure 7-19). In conventional Pap smears, these cells most oftenappear in two-dimensional sheets (D), but they can formmore rounded groups in liquid-based preparations (F).

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Figure 4-3. Anucleated squamous cells.Anucleated squamous cells (ANSC) are indicative of super-ficial epithelial keratosis and, when present in small num-bers, may represent contamination from skin and can beignored, as this does not represent a significant clinical find-ing (A). ANSC, especially in larger numbers, may representkeratosis involving the cervix or vagina, where the cause ischronic irritation due to an infection or uterine prolapse.ANSC may also overlie squamous intraepithelial lesionsand even, on occasion, squamous cell carcinoma (B).Therefore, careful review of the slide for an underlyingepithelial lesion is warranted whenever abundantANSC arepresent, especially when in large plaque-like aggregates (C).

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Figure 4-4. Atrophic vaginitis.Atrophic vaginitis (AV) is usually observed in post-menopausal women or, uncommonly, in postpartumpatients. Pap slides with AV show variable inflammation,marked background necrosis (simulating a tumor diathe-sis), and degeneration of the small, parabasal squamouscells. “Blue blobs,” which are degenerating parabasal cells,resemble large, abnormal, bare nuclei (B, arrow). Thesefindings can be confused with malignancy, especially whenthe atrophic changes include background necrosis or adegenerative pseudo-parakeratotic change (F, G, and H).Close examination of the viable cells and noting the

absence of significant atypia in these cells help to avoidoverinterpretation. In benign atrophy, there is most often aspectrum of atrophy ranging from obvious benign changesto the more atypical groups. Occasionally a diagnosis ofatypical squamous cells of undetermined significance(ASC-US) or atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H) is warrant-ed (see Figure 5-8), in which case follow-up testing forhigh-risk human papillomavirus (HPV) and/or col-poscopy would be warranted, according to the latestAmerican Society for Colposcopy and Cervical Pathology(ASCCP) guidelines.

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Figure 4-5. Degenerative changes in benign cells.Degenerative changes include cytoplasmic and nuclearvacuolization, cellular and nuclear enlargement, chromatinclumping, karyopyknosis (very dense chromatin that lacksdetail), karyorrhexis (the breaking up of nuclear chromatinfollowing rupture of the nuclear membrane), and karyoly-sis (dissolution of the nuclear chromatin) (A, B, and C). Thedegenerative finding that is perhaps most worrisome forcancer or dysplasia is chromatin clumping. However,degenerative chromatin clumps are more smoothly con-toured and regular in size, shape, and distribution than arethose found in dysplasia or carcinoma (D and E). Exercise

caution when evaluating for dysplasia or malignancy ingroups of cells showing obvious degenerative changes.

HSIL

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Figure 4-6. Chronic follicular cervicitis.Chronic follicular (ie, germinal center) cervicitis (CFC) islimited to the cervical submucosa. Therefore, Pap slidesmay show evidence of CFC only when there is erosion orulceration of the overlying mucosa or if the mucosa is verythin, as in markedly atrophic squamous conditions. CFC ischaracterized by focal collections of polymorphous lym-phocytes with scattered intermixed tingible bodymacrophages. The differential diagnosis can include HSIL,small cell carcinoma and lymphoma/leukemia. Most help-ful for interpretation is the appreciation of the characteris-tic dark, clumped chromatin of the small mature lympho-cytes and the recognition of the larger, phagocytic tingiblebody macrophages (A, arrow). In HSIL, the chromatin isnot as coarsely granular, and cells are overall larger andmore pleomorphic, with some cells showing obvious squa-mous differentiation. In HSIL, abnormal epithelial clustersare also usually present elsewhere on the slide. Pap slidesinvolved with a small cell malignancy (eg, primary ormetastatic small cell carcinoma, leukemia/lymphoma) aretypically dominated by the malignant cells and show atumor diathesis and significant nuclear abnormalities. Incontrast, CFC is a focal and minor component of the slide

and is not associated with necrosis or a diathesis. Whenlymphoma or leukemia presents in Pap slides, there is usu-ally a history of such, as primary lymphoma of the cervi-covaginal area is extremely rare. With regard to CFC, thereare differences between conventional smears and liquid-based preparations. In conventional smears, CFC presentsas dispersed cells in localized areas (A and B), whereas inliquid-based preparations, the cells of CFC usually formloose clusters, with scattered isolated small lymphocytespresent in the slide background (C, D, and E).

benign changes and mimics of malignant and premalignant

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