Atypical glandular cells

Clin Lab Med 23 (2003) 633–657

Atypical glandular cells David C. Chhieng, MDa,*, Joan F. Cangiarella, MDb a

Department of Pathology, University of Alabama at Birmingham, 619 19th Street South, KB 627, Birmingham, AL 35249-6823, USA b Department of Pathology, New York University Medical Center, 530 First Avenue, Suite 7S, New York, NY 10016, USA

The diagnostic category of ‘‘atypical glandular cells’’ (AGC) remains a challenge for cytopathologists. The classification of AGC has been radically altered since its inception in the first edition of the Bethesda system for reporting of cervicovaginal cytology [1]. The lack of uniformity in the cytologic criteria for diagnosis, the high degree of interobserver variability, and the lack of standardization in patient management can cause a diagnosis of AGC on cervicovaginal cytology to create havoc for clinicians and their patients. In the 2001 Bethesda System, terminology for reporting results of cervical cytology, glandular abnormalities are classified into one of three categories (Box 1). This article reviews the classification of the diagnostic category of AGC, describes the cytomorphologic features and the differential diagnosis, discusses the reproducibility of this interpretation, reports on the incidence and clinical significance, and presents management options for patients. Classification The diagnostic category of ‘‘atypical glandular cells of undetermined significance’’ (AGUS) has been significantly altered since its inception in 1988 in The Bethesda System for the reporting of cervicovaginal cytological diagnoses [1]. The AGUS category, as originally proposed, was characterized by the presence of glandular cells that demonstrated changes beyond those typical of benign reactive processes, yet were insufficient for an interpretation of adenocarcinoma. This category was further subclassified into a ‘‘favor reactive’’ and a ‘‘favor neoplastic’’ category in 1991 [2]. The International Academy of Cytology Task Force subsequently advocated * Corresponding author. E-mail address: [email protected] (D.C. Chheing). 0272-2712/03/$ - see front matter Ó 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0272-2712(03)00057-X

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Box 1. The 2001 Bethesda System for reporting of glandular cell lesions Epithelial cell abnormalities Glandular cell Atypical glandular cells (specify endocervical, endometrial, or not otherwise specified) Atypical glandular cells, favor neoplastic (specify endocervical or not otherwise specified) Endocervical adenocarcinoma in situ (AIS) Adenocarcinoma (specify endocervical, endometrial, extrauterine, or not otherwise specified)

separating AIS from AGUS when sufficient cytologic criteria were present [3]. In 2001, the classification of glandular abnormalities was radically revised based on the consensus of The Third Bethesda Workshop for the reporting of cervicovaginal cytology [4]. The qualifying term ‘‘of undetermined significance’’ was eliminated to avoid confusion with ‘‘atypical squamous cells of undetermined significance’’ (ASC-US) and was changed to AGC. This distinction is clinically important because the risk for the development of cervical neoplasia is much greater with an interpretation of AGC than with atypical squamous cells or even with low-grade squamous intraepithelial lesion (LSIL) [5]. Further difficulty with the category of AGC has been the high rate of misinterpretation of squamous intraepithelial lesions that involve endocervical glands as a neoplastic glandular lesion on cervicovaginal smears [6,7]. The 2001 Bethesda conference eliminated the qualifier ‘‘favor reactive’’ from the AGC diagnosis because it was shown that a significant proportion of cases (10% to 30%) that are interpreted as ‘‘favor reactive’’ at histologic follow-up are proven to be high-grade squamous or glandular lesions [6,8]. Most of the studies that examined the correlation of the subcategories of AGC (ie, favor a reactive process [FR], not otherwise specified [NOS], and favor a neoplastic process [FN]) with the histologic diagnosis, showed that although statistically more significant lesions are noted in patients who have a diagnosis of AGC-FN compared with patients who have a diagnosis of AGC-FR, a substantial number (5% to 39%) of high grade lesions, including invasive carcinomas, are noted in patients who have AGC-FR on follow-up [9]. These studies also showed that the incidence of high-grade lesions is similar between patients who have AGC-FR (5% to 39%) and patients who have AGC-NOS (9% to 41%). As a result, the AGC-FR category was eliminated in 2001 because it was believed to be misleading to clinicians and could lead to inadequate treatment of some patients. Because histologically-confirmed high-grade

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lesions have been noted in 9% to 41% of women who have AGC-NOS versus 27% to 96% of women who have AGC-FN, the separation of AGCNOS from AGC-FN in the 2001 Bethesda System is warranted [10]. The AGC-FN category thus denotes a population of patients who are at significant risk of having high-grade lesions, and, thus, requires more aggressive follow-up. AGC, favor endometrial origin (or atypical endometrial cells) is an uncommonly-used category that accounts for only 5% of all smears that are classified as AGC [11]. About one-third of women who have this interpretation have a significant uterine lesion on follow-up. More than 80% of patients with a significant uterine lesion are endometrial in origin and include endometrial hyperplasia and adenocarcinoma, and, thus, require different management from endocervical lesions. These observations support the qualification of AGC as endocervical or endometrial origin whenever possible. The category ‘‘AGUS, probably neoplastic’’ in the 1991 Bethesda System included AIS. AIS is broken out as a separate category in the 2001 Bethesda System because numerous studies reported reliable and reproducible cytologic criteria for this interpretation [12–14]. Cytologic features Atypical endocervical cells, not otherwise specified The cytologic features that are characteristic of atypical endocervical cells, not otherwise specified (AEC, NOS) include cells that occur in sheets or strips with minimal nuclear overlap, slight nuclear hyperchromasia, mild variation in size and shape, abundant cytoplasm, and distinct cell borders (Fig. 1). Nucleoli are often present and there is nuclear enlargement, in a range of three to five times that of a normal endocervical cell nucleus

Fig. 1. Atypical endocervical cells, not otherwise specified. A cluster of endocervical cells with mild nuclear crowding and overlapping. Individual cells show nuclear enlargement, slight nuclear hyperchromasia, and mild anisonucleosis. Follow-up revealed that the patient had an endocervical polyp. (Conventional, high magnification)

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[2,15]. Cytologic features that are useful in distinguishing AEC, NOS from endocervical adenocarcinoma are the absence of the following: necrosis, bare atypical cells, papillary groupings, anisonucleosis, irregular chromatin pattern, and hyperchromasia [16]. The differential diagnosis of AEC, NOS includes many benign conditions, including tubal metaplasia, Arias-Stella reaction, pregnancy-induced changes, microglandular hyperplasia, inflammatory changes, endocervical polyps, cervical endometriosis, and reparative changes that are associated with previous cervical conization [17–23]. In many of the follow-up studies, the categories of AEC, NOS and AGC, NOS have not been separated [24]; some investigators imply that if a lesion is not interpreted as favor endometrial, an endocervical lesion is favored [25]. In pregnancy, abundant hyperplastic endocervical cells show nuclear enlargement, multinucleation, and prominent nucleoli, yet the cytologic features of abundant vacuolated cytoplasm, normal nuclear to cytoplasmic ratios, and minimal nuclear crowding favor a reactive process [18,26]. The Arias-Stella reaction represents an exaggerated physiologic response of the glandular epithelium to the increased hormonal levels of pregnancy. The glandular cells of the Arias-Stella reaction are rarely noted on Papanicolaou smear, but when present, are characterized by single cells or groups of cells with nuclear crowding and overlap, nuclear enlargement with smudgy chromatin, prominent nucleoli, intranuclear inclusions, and nuclear grooves (Fig. 2) [18]. Obtaining the history of pregnancy is critical to avoid a misinterpretation of adenocarcinoma. Atypical endocervical cells, favor neoplastic The cytologic criteria for atypical endocervical cells, favor neoplastic (AEC-N) includes cells that are arranged in sheets, strips, and rosettes with nuclear crowding and overlap (Fig. 3) [15]. The cells have increased nuclear

Fig. 2. Atypical endocervical cells, not otherwise specified. A small group of endocervical cells show nuclear enlargement, smudgy chromatin, and markedly vacuolated cytoplasm. The biopsy showed Arias Stella reaction. The patient had a missed abortion. (Conventional, high magnification)

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Fig. 3. Atypical endocervical cells, favor neoplastic. A hyperchromatic crowded group with haphazard arrangement of the endocervical cells. Individual cells are markedly hyperchromatic and have high nuclear to cytoplasmic ratio. Endocervical curettage showed adenocarcinoma in situ. (Conventional, high magnification)

to cytoplasmic ratios, diminished cytoplasm, and ill-defined cell borders. Variation in size and shape, nuclear elongation and stratification, and hyperchromasia with finely to moderately granular chromatin are generally noted. Nucleoli are small to inconspicuous and mitotic figures may be identified. Studies that used logistic regression analysis to define criteria to separate AEC-N from AEC, NOS found that the presence of atypical single cells, irregular nuclear membranes, and diminished cytoplasm are features that are indicative of a preneoplastic or neoplastic lesion [27]. Comparison of the cytologic features of benign/reactive conditions with neoplastic lesions that cause AEC reveals that neoplastic glandular lesions contain glandular rosettes, increased nuclear to cytoplasmic ratios, and hyperchromasia [14]. The presence of nucleoli and abundant cytoplasm, and of the so-called ‘‘taffy pull’’ appearance are more commonly noted in benign/ reactive lesions [14]. Other investigators showed that the presence of feathering, rosettes, crowded nuclei, and scant cytoplasm are helpful features in distinguishing AIS from benign conditions [17]. Nuclear chromatin pattern also can aid in this distinction; AIS shows smudged or coarsely granular chromatin in contrast with reactive conditions that have finely granular chromatin [28]. Atypical endometrial cells The cytologic criteria that were established in The Bethesda System for the diagnosis of AGC, favor endometrial or atypical endometrial cells (AMC) include the presence of cells that occur in small groups, with slight nuclear enlargement, slight hyperchromasia, inconspicuous or small nucleoli, ill-defined cell borders, and scant cytoplasm that is sometimes vacuolated (Fig. 4) [2,15]. Studies showed that there are no cytologic criteria that reliably separate cases that are interpreted as AMC into benign and malignant categories [29]. Thus, these abnormalities are all grouped as

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Fig. 4. Atypical endometrial cells. A tightly cohesive, three-dimensional group of small endometrial cells with nuclear enlargement and scant vacuolated cytoplasm. Endometrial biopsy showed a well-differentiated endometrial adenocarcinoma. (Conventional, high magnification)

AMC in the 2001 Bethesda System. Histologic follow-up of cases that are interpreted as AMC on Papanicolaou smears has shown a variety of lesions, including atrophic endometrium, endometrial polyps, chronic endometritis, tubal metaplasia, endometrial hyperplasia, and adenocarcinoma; most of the lesions are benign (see references [11,30–34]). Key cytologic criteria, found in one series, that are helpful for the separation of AMC of benign nature from a malignant include: the presence of an atrophic smear background, the presence of cells with a nuclear size that is greater than twice that of an intermediate squamous nucleus, and the absence of clusters with irregular borders [29]. Adenocarcinoma in situ The cytologic features of AIS have been well-described [35,36]. Box 2 summarizes the cytologic features of AIS. Common cytologic findings in AIS smears are crowded groups of cells that are arranged in sheets or rosettes, or strips of cells with polarity or feathered edges (Figs. 5, 6) [37]. High nuclear to cytoplasmic ratios and round to ovoid nuclei with distinct, thin, nuclear membranes are commonly seen. Chromatin granules are uniformly dispersed and coarse rather than finely granular. Nucleoli are usually small and mitotic activity and apoptoses are noted in many cases [37]. Most reports of AIS indicate that nuclei are often fairly uniform in size [38] yet a recent report describes a much greater degree of nuclear irregularity [37]. The cytologic findings in microinvasive adenocarcinoma are not distinguishable from those of AIS; thus, a percentage of cases that are interpreted as AIS on cervicovaginal cytology will represent invasive adenocarcinoma on histologic evaluation [12]. The cells of AIS have larger nuclei compared with normal endocervical cells [36]. The nuclear and

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Box 2. Cytologic features of endocervical adenocarcinoma in situa Architectural pattern Sheets and groups of glandular cells with overcrowding and overlapping Nuclear and cytoplasmic feathering (group marginal protrusions) Rosette/gland formation Strips with pseudostratification Cellular features Columnar cells Nuclear enlargement (at least three times that of a normal endocervical cells) Increased nuclear to cytoplasmic ratio Hyperchromasia Fine to coarse granular chromatin, evenly distributed Presence of micronucleoli Presence of mitotic figures or apoptotic bodies a

Not all cases of AIS will demonstrate all of these features.

cellular sizes of AIS and microinvasive adenocarcinoma are similar to those of squamous carcinoma in situ, microinvasive squamous carcinoma, nonkeratinizing invasive squamous carcinoma, and endocervical adenocarcinoma [39,40]. AIS cells show an increase in the size and coarseness of the chromatin granules; however, the chromatin granules are not as large as

Fig. 5. Adenocarcinoma in situ. A hyperchromatic crowded group of endocervical cells with feathering. Biopsy showed adenocarcinoma in situ. (Conventional, high magnification)

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Fig. 6. Adenocarcinoma in situ. A small group of endocervical cells showing rosette formation and feathering. Biopsy showed adenocarcinoma in situ. (Conventional, high magnification)

those that are seen in squamous cell carcinoma in situ. Thus, the presence of nucleoli in AIS and the increase in the size and coarseness of the chromatin granules can be used to distinguish these cells from those of squamous cell carcinoma in situ [36]. The frequency of some cytologic features of AIS varies widely from study to study. For example, in one study, feathering is noted in 88% of AIS [13], whereas in another study, it is present in only 4% [14]. Nucleoli are noted in 24% to 76% of AIS. Moreover, these features, when present, may be confined to only a few cell groups [17]. It is not surprising that all cases of AIS do not contain all of the described cytologic features. Therefore, cases that show some, but not all features, of AIS should be designated as AEC-N to convey to clinicians the high level of concern, but emphasizing the fact that benign mimics may also show some of these features, as well. There are rare variants of AIS that do not conform to the typical patterns of AIS that were described earlier. For example, Lee and Flynn [41] described an endometrioid variant of AIS that is composed of small groups of crowded, minimally atypical, glandular cells that mimic benign endometrial cells. They are easy to underinterpret unless close attention is paid to the subtle endocervical cell differentiation, nuclear crowding, and hyperchromasia. False positives cases of AIS have been reported [42,43]. The differential diagnosis includes high-grade squamous intraepithelial lesion (HSIL), reactive endocervical cells, tubal metaplasia, microglandular endocervical hyperplasia, and directly sampled endometrial cells (see references [19,21– 23,37,44,45]). The features that are common to these mimicking entities are the groups of tightly crowded, variably atypical glandular cells that can be mistaken for AIS. HSIL with endocervical glandular involvement should be differentiated from AIS [46]. Most cases of HSIL have a syncytial arrangement, rather than a glandular pattern with nuclei that have a more coarse chromatin pattern (Figs. 7, 8). Table 1 summarizes the features that are helpful in distinguishing AIS from HSIL. As we become more familiar

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Fig. 7. Atypical endocervical cells, favor neoplastic. A hyperchromatic crowded group of glandular cells. Some spindling of the cells is noted. Biopsy showed a CIN 3 with endocervical gland involvement. (Conventional, medium magnification)

with the cytology of HSIL with endocervical gland involvement, our recognition of such cases is improving. In some instances, however, squamous lesions can be difficult to differentiate from an endocervical process; this results in the inevitable classification of a small number of HSIL cases as glandular lesions [47]. In one study, 21% of smears with a cytologic diagnosis of AIS had HSIL on biopsy [8]. Squamous intraepithelial lesion (SIL) and AIS may coexist which further complicates the issue. The cytologic features of AIS and HSIL with gland involvement in ThinPrep liquid-based preparation (Cytyc Corporation, Boxborough, MA) are similar to those that are described for conventional preparations, except for enhanced nuclear details, such as the consistent presence of nucleoli and thickened irregular nuclear membranes. In addition, mitotic figures and apoptotic bodies are more frequently present in liquid-based, ThinPrep preparations (Figs. 9, 10) [48,49].

Fig. 8. Atypical endocervical cells, favor neoplastic. A hyperchromatic crowded group of glandular cells with coarse chromatin and inconspicuous nucleoli. Biopsy showed CIN 3 with endocervical gland involvement. (Conventional, high magnification)

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Table 1 Differential diagnosis between HSIL involving endocervical gland and endocervical adenocarcinoma in situ Cytologic features

Endocranial (EC) AIS

HSIL with EC gland involvement

Architectural patterns

Syncytial tissue fragments and cell groups with nuclear overlapping and crowding Variable Absent Sometimes Variable

Syncytial tissue fragments and cell groups with nuclear overlapping and crowding Variable Present Occasional Rare

Sometimes Irregular

Absent Smooth on one edge in some occasions

Round and columnar Round to oval to cigar-shaped Hyperchromatic Fine to coarsely granular Variable Delicate +/ÿ vacuolation Absent

Round and spindle Round to oval to elongated

Single cells Spindling Feathering Rosette/gland formation Strips Contours of cell groups Cellular features Cells Nuclei Chromatin Nucleoli Cytoplasm Dysplastic squamous cells

Hyperchromatic Coarsely granular Absent Dense Variable

+/ÿ, with or without.

Benign mimics of adenocarcinoma in situ Reactive and reparative endocervical cells may have enlarged nuclei and prominent nucleoli, and, can therefore, mimic AIS [50], These reactive/ reparative atypical glandular cells are uniform in size and shape with smallto medium-sized regular nucleoli and abundant cytoplasm. They are typically arranged in groups, rather than singly, and often have the classic ‘‘taffy pull’’ cytoplasmic morphology [48]. Tubal metaplasia can mimic AIS because of nuclear crowding, nuclear overlap, and nuclear palisading, but mitotic figures and apoptoses are rare, rosettes are uncommon, and, most importantly, the nuclear chromatin is finely granular (Fig. 11) (see references [22,23,51]). The identification of terminal bars and cilia is the most helpful cytologic finding, but these features may not be present in some cases [3,22]. On liquid-based preparations, although the identification of cilia is the most reliable feature to distinguish these cases from neoplastic glandular lesions, the presence of fine chromatin, uniformity of the cell groups, and the absence of true nuclear overlap and disorganization are also useful cytologic features [48]. Microglandular endocervical hyperplasia is a localized proliferation of endocervical cells that can be mistaken for adenocarcinoma [21]. The most

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Fig. 9. Adenocarcinoma in situ. A hyperchromatic crowded group of endocervical cells with feathering. Biopsy showed adenocarcinoma in situ. (ThinPrep, high magnification)

common cytologic findings are nuclear enlargement, nuclear hyperchromasia with fine nuclear chromatin, and nuclear overlap [22,45]. The absence of chromatin heterogeniety, macronucleolus formation, and tumor diathesis are the best discriminators to avoid an erroneous interpretation of adenocarcinoma (Fig. 12). Directly-sampled endometrial tissue may mimic AGC or glandular neoplasia. Sampling of the lower uterine segment (LUS) following conization is the result of endocervical brush or broom sampling of the endometrial cavity secondary to the shortened endocervical canal that may occur following a conization procedure [43]. Vigorous use of endocervical brushes in patients who have not undergone conization also may cause LUS sampling [3]. Smears from the LUS show cellular two- or threedimensional fragments with branching tubular glands that are embedded in a stroma that is composed of round to spindled-shaped cells (Fig. 13) [52].

Fig. 10. Adenocarcinoma in situ. A strip of hyperchromatic endocervical cells with pseudostratification. Biopsy showed adenocarcinoma in situ. (ThinPrep, high magnification)

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Fig. 11. Atypical endocervical cells, not otherwise specified. A strip of endocervical cells shows mild overcrowding and overlapping, and nuclear enlargement. Cilia are not apparent in this example. The biopsy showed tubal metaplasia. (Conventional, high magnification)

Cytologic differences between AIS and LUS sampling AGC smears show more prominent nuclear rather than architectural features [37]. When compared with AIS smears, LUS sampling smears show smaller nuclei with less distinct nuclear membranes; densely dispersed, but finely granular chromatin; less frequent mitotic figures; and abundant endometrial type stromal cells in the background [37]. The presence of endometrial-type stromal cells is significant and is absent from the background of all cases of AIS [37]. Most false-positive interpretations are secondary to the presence of groups of nonciliated small glandular cells from either the upper endocervical canal or lower uterine segment of the endometrium [8,17]. These tightly crowded groups differ from AIS by having smaller, less hyperchromatic nuclei with finer chromatin, and by being intermixed with benign epithelial cells, and, occasionally, endometrial stromal cells [8]. On liquid-based preparations, sampling of the lower uterine segment shows large, dark, three-dimensional groups of cells; however, these cells were uniform with bland chromatin and uniform nuclei [48].

Fig. 12. Atypical endocervical cells, not otherwise specified. A small cluster of loosely cohesive endocervical cells with anionucleosis and vacuolated cytoplasm. Endocervical curettage showed microglandular hyperplasia. (Conventional, high magnification)

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Fig. 13. Lower uterine segment. Large tissue fragment with branching. Individual cells have uniform round to oval nuclei and scant cytoplasm. (Conventional, low magnification)

Interobserver variability and reproducibility in the diagnosis of AGC The level of interobserver variability with interpretations of AGC is poor [53,54]. The interobserver agreement on predicting the site of origin of glandular lesions on cervicovaginal cytology is also poor (unpublished data, 2002). Even expert cytopathologists have difficulty identifying cytologic features that are important in distinguishing benign AGC smears from clinically significant ones [53,54]. In one study, reclassifying AGC smears by expert cytopathologists led to some interpretations being upgraded to cancer [54]. In addition, 25% of cases that had HSIL or glandular neoplasia on follow-up were downgraded to benign. In this study on the reclassification of AGC smears, more clinically-significant lesions were missed by the expert cytopathologists than by the original pathologists [54]. Some studies have shown a higher degree of accuracy in reclassifying cases that were originally diagnosed as AGC when specific criteria, which include irregular nuclear membranes, atypical single cells, and decreased cytoplasm, are used [27]. These criteria, when used in combination, had a sensitivity of 29% and a specificity of 94%, but when used singly, had a sensitivity of 100% with a specificity of only 28% for clinically-significant lesions. Although most neoplastic lesions can be distinguished from mimics of AGC by experienced cytopathologists, improved specificity of AGC interpretations may, in turn, decrease sensitivity for detection of an underlying highgrade lesion [53]. The false-negative rate for AIS is high for cervicovaginal cytology because only approximately 50% of the cases are detected by the Papanicolaou smears [55,56]. Although some studies attribute the high false negative rate to sampling error [57], others disclosed a significant number (55%) of screening errors [42]. Small, ‘‘endometrioid-looking’’ cells and AIS cells that resemble reactive endocervical cells can be misinterpreted as benign, thus diminishing the sensitivity [42]. Attention to the presence of large, branching groups with nuclear hyperchromasia and small or absent

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nucleoli may help in distinguishing these abnormal cells from reactive endocervical cells [42]. Groups of cells with small nuclei and an endometrioid appearance can be difficult to distinguish from normal, but the cytologic features of nuclear crowding, nuclear hyperchromasia with mild chromatin coarseness, and the lack of benign endocervical or lower segment endometrial cells may be helpful. Lee et al [42] reported a sensitivity for the detection of adenocarcinoma in situ of 40% to 68%, with increased sensitivity upon rescreening. The literature has contradictory reports that compared conventional smears with liquid-based samples for the detection of AIS. In one study of 30 paired cytologic samples, AIS was predicted in 67% of conventional smears and 47% of liquid-based samples, whereas other studies showed that the liquid-based method may be more accurate for the detection of glandular disease [58,59]. Interobserver agreement is better in liquid-based samples than for conventional smears [53,54].

Prevalence of AGC Table 2 summarizes the prevalence rate of AGC as reported in the literature. The prevalence rate of AGC varies from 0.11% to 2.10% with a mean and median of 0.48% and 0.27%, respectively. In most of the reports, the rate of AGC was less than 1%. The proportion of AGC smears with concomitant squamous abnormalities (either ASCUS or SIL) ranged from 10% to 67% with a mean of 34% [7,60–65]. The mean and median AGUS rates that were obtained during a survey by the College of American Pathology (CAP) were 0.35% and 0.3%, respectively [66]. The lower mean AGUS rate that was reported by CAP when compared with that in the literature may be attributed to the fact that the institutions where most studies were conducted are tertiary referral centers, and, therefore, have a higher proportion of high-risk patients. It is generally agreed that the rate of ASCUS should not exceed 5% of all Pap smears that are examined or two to three times the frequency of the diagnosis of SIL [2]. The optimal rate of AGC is still undetermined. Several investigators have observed a steady increase in the annual incidence of AGC, despite the fact that the incidence of ASCUS and SIL, as well as the ratio of ASCUS to SIL remained relatively constant [62,78]. These investigators attributed the steady increase in AGC to a long ‘‘learning curve’’ as cytologists became familiar with the entity and refined their morphologic criteria for the assessment of glandular atypia. In a study that compared the AGC rate among three different patient populations, the highest AGC rate was noted among the patient population that had the highest incidence of ASCUS and SIL [78]. The second highest AGC rate was noted in a patient population that had the highest proportion of postmenopausal patients, despite the fact that this group had the lowest

0.46% 1.83% NS (54) 0.26% 0.74% 0.20% 0.12% 0.63% 0.27% 0.17% 0.27% 0.53% 2.10% 0.24% 0.08% 0.20% 0.50% 0.29% 0.11% (NS) 492 0.50% 0.20%

Reference

Goff et al, 1992 [67] Nasu et al, 1993 [68] Bose et al, 1994 [28] Lee et al, 1995 [8] Raab et al, 1995 [27] Kennedy et al, 1996 [69] Schindler et al, 1998 [70] Eddy et al, 1997 [62] Zweizig et al, 1997 [66] Duska et al, 1998 [60] Korn et al, 1998 [64] Veljovich et al, 1998 [71] Burja et al, 1999 [61] Cheng et al, 1999 [6] Kim et al, 1999 [72] Manetta et al, 1999 [73] Chhieng et al, 2000 [7] Chin et al, 2000 [74] Soofer et al, 2000 [75] Geier et al, 2001 [63] Valdini et al, 2001 [76] Nasuti et al, 2002 [77]

Abbreviation: NS, not specified. a Adenocarcinoma, not otherwise specified. b Including cases with cytologic follow up. c Included cases of in situ adenocarcinoma.

AGC rate number of cases)

56.0% 86.4% 81.0% 35.2% 49.0% 56.6% 71.0%b 47.5% 66.9% 36.3% 87.2% 57.7% 17.0% 82.7% 82.2%b 60.0% 59.5% 45.4% 75.0%b 71.7% 88.5% 59.9%

Biopsy rate 60.7% 38.8% 79.5% 58.1% 52.0% 17.0% 30.2% 34.4% 48.3% 34.2% 34.0% 32.0% 59.4% 37.0% 25.0% 42.5% 24.8% 50.0% 25.0% 36.0% 58.7% 33.9%

(3.6%) (1.7%) (22.7%c) (2.7%) (9.5%) (4.0%) (0.0%) (6.4%) (10.6%) (4.1%) (12.0%) (4.0%) (1.6%) (7.0%) (7.4%) (5.0%) (5.3%) (7.8%) (4.3%) (0.8%) (4.3%) (5.4%)

Rate of significant lesions (rate of invasive carcinoma)

Table 2 Incidence and cytohistologic correlation of AGUS reported in the literature

44.6% (25.0%) 9.1% (NS) 79.5% (40.5%) 44.6% (43.2%) 39.4% (11.0%) 9.0% (5.2%) 11.7% (9.3%) 27% (NS) 21.2% (7.1%) 28.8% (23.3%) 19.0% (13%) 23.6% (15.1%) 54.7% (21.9%) 19.0% (NS) 10.4% (9.0%) 28.8% (7.5%) 19.5% (13.5%) 39.1% (32.8%) 14.5% (11.6%) 31.0% (16.6%) 54.3% (13.4%) 26.8% (9.8%)

Rate of SIL/ SCC (rate of HSIL/SCC) 34.1% 0.0% 13.5% 3.9% 7.0% 5.2% 2.1% 8.6% 5.5% 6.0% 2.5% 4.7% 5.0% 7.4% 6.3% 0.0% 3.1% 2.9% 2.5% 0.0% 3.6%

16.0%

a

Rate of endocervical dysplasia/AIS/ACA 4.5% 0.0% 0.0% 8.7% 1.0% 0.0% 5.3% 17.7% 4.1% 4.0% 2.7% 0.0% 11.0% 7.1% 5.0% 5.3% 6.3% 7.2% 2.5% 4.3% 3.6%

Rate of endometrial hyperplasia/ACA

0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 1.1% 2.7% 2.0% 1.5% 0.0% 2.0% 0.4% 2.5% 0.0% 1.6% 0.0% 0.0% 0.0% 0.0%

Others

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rates of ASCUS and SIL. A possible explanation is that the incidence of ASCUS and SIL reflects only the prevalence of squamous, and not glandular, lesions. Endometrial lesions are more frequent in older, postmenopausal women. The investigators pointed out that there were a significantly higher proportion of smears that were classified as AMC and a higher incidence of endometrial adenocarcinoma on subsequent histologic follow-up among this patient population. The investigators concluded that the incidence of AGC varies with the incidence of squamous abnormalities and with the menopausal status of the patient population. Only a few studies examined the rate of AGC in different subgroups of patients, namely, postmenopausal and pregnant/postpartum patients. Within a 3-year study period, AGC rates of 0.51% and 0.26% were observed for postmenopausal and pregnant/postpartum patients, respectively [18,79]. The AGC rate among postmenopausal patients was similar to that of the general population during the study period. The AGC rate among the pregnant/postpartum patients, however, was significantly lower than that of general population. Michael and Esfahani [26] identified only 26 (9%) AGC cases in their review of 278 abnormal Papanicolaou smears from pregnant/postpartum patients [26]. Significance of AGC The rate of finding a significant uterine lesion on subsequent follow-up in patients varies from 17% to 80%, with a mean of 41% (see Table 2). One possible explanation for this wide variance is that most of the studies are retrospective and the number of patients who had AGC and underwent histologic evaluation also varied widely from 17% to 89% (mean of 64%). In addition, patients were not evaluated in a systematic fashion. Another possible reason is that different criteria are used to define ‘‘significant lesions.’’ For example, some authors exclude cervical intraepithelial lesion (CIN) 1 and condyloma from their list of significant uterine lesions [74,76]. Significant glandular lesions are noted in 0% to 30% (average 11%) of patients who have an interpretation of AGC. Patients who have AGC may have premalignant or malignant endometrial lesions that account, on average, for 5% of all significant uterine lesions; however, the rate can vary from 0% to 17%. The lack of endometrial lesions in some series may be explained by the fact that the investigators only included AGC of endocervical origin in their series [8,28]. The presence of symptoms, such as vaginal bleeding, does not predict the presence of significant endometrial pathology [7,65]. Moreover, a substantial number of patients who have AGC and endometrial diseases on follow-up are asymptomatic. Endocervical neoplastic lesions, including invasive and in situ adenocarcinoma, as well as glandular dysplasia, account for an average of 6% of all significant uterine lesions. The incidence of significant endocervical lesions, however, can be as high as 34% [68].

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Despite the fact that the atypical cells that are found on the Papanicolaou specimen are designated as glandular, squamous lesions account for an average of 30% of all significant uterine lesions. The incidence can reach as high as 80%, however [28]. Among these squamous lesions, about 60% (range: 25% to 100%) are high-grade dysplasia. Because SIL often arises or involves the transformation zone, the dysplastic squamous cells often retain some features of glandular epithelium and mimic atypical glandular cells. Because most of these significant lesions are of squamous origin, some investigators have argued that the category of AGC should be combined with ASC to form a single category of ‘‘atypical epithelial cells.’’ Because of the presence of a substantial proportion of preneoplastic and neoplastic glandular lesions in patients who have AGC, which is not seen in patients who have ASC, it is believed that this distinction is clinically warranted. In contrast with patients who have ASC, patients who have AGC carry a small, but definitive, risk of invasive disease. The incidence of invasive carcinomas following interpretations of AGC ranges from 0% to 22.7%. Most of these carcinomas are endocervical or endometrial in origin. This observation implies that patients who have AGC should be managed aggressively. Several studies have examined the significance of AGC among various patient subgroups. Twenty-six percent to 53% of postmenopausal patients who have AGC are reported to have a significant uterine lesion on follow-up (see references [61,79,80]). There is no difference in the rates of clinicallysignificant lesions in postmenopausal patients (33%) who have AGC compared with that of the general population (29%) [79]. Postmenopausal women who have AGC have significantly more glandular lesions on followup when compared with the general population who have AGC [79]. In one study, more than 50% of the clinically-significant lesions in postmenopausal women who had AGC were glandular and included 15 endometrial adenocarcinomas, 2 endocervical adenocarcinomas, 1 endocervical AIS, and 1 endometrial hyperplasia with atypia [79]. Some investigators failed to observe any difference in the incidence of significant lesions that were associated with an interpretation of AGC, considering the hormonal status of the patients [65,81]. For pregnant/postpartum patients who had AGC, all clinically-significant lesions were squamous in origin; no glandular lesions were encountered [18,26]. Liquid-based preparation and AGC Many investigators have shown that the use of liquid-based preparation significantly reduces the rate of ASCUS in screening populations [82–86]. A few studies examined the rate of AGC using liquid-based preparation; all were based on the ThinPrep Pap test (Table 3) (see references [59,87–90]). The results are conflicting, however. One study observed that the AGC rate using liquid-based preparation is significantly lower than in conventional

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Table 3 Comparison of the incidence and rate of significant lesions of AGUS using conventional and liquid-based (ThinPrep) preparation reported in the literature AGUS rate

Rate of significant lesions

Reference

Conventional ThinPrep P-value Conventional ThinPrep P-value

Ashfaq et al, 1999 [59] Bai et al, 2000 [88] Eltabbakh et al, 2000 [87]b Hecht et al, 2002 [89] Wang et al, 2002 [90]

0.11% 0.14% — 0.19% 0.77%

a b

0.14% 0.07% 0.65% 0.15% 0.59%

NS \0.01 — NSa NS

71% 32% — 15% 21%

68% 40% 23% 22% 28%

NSa NSa — NSa NS

Calculated from the data provided in the manuscripts. The authors included only ThinPrep preparation.

specimens [88]. Other studies do not observe any difference in the AGC rate based on the type of preparation (see references [59,89,90]). None of the studies showed a statistically significant difference in the rate of significant lesions (defined as squamous or glandular preneoplastic/ neoplastic lesions) after an interpretation of AGC using either preparation. Ashfaq et al [59] noted that when a glandular cytologic interpretation was rendered, liquid-based preparation seemed to be more specific for glandular disease. Thirty percent of patients who had AGC on conventional preparations had squamous abnormalities compared with 11% of those who had AGC on liquid-based preparations [59]. These investigators also observed that there was a reduction in false-negative cases when using the liquidbased preparation; 44% of all AIS/adenocarcinoma cases interpreted as negative on conventional preparation versus only 15% on liquid-based preparations. Bai et al [88] also noted that liquid-based preparations identified more dysplastic glandular lesions/AIS than did conventional preparations. These investigators suggested that liquid-based preparation may be more sensitive and specific in the detection of preneoplastic and neoplastic endocervical glandular lesions than is the conventional preparation. Guidelines for managing women who have AGC or AIS Fig. 14 summarizes the algorithm for the management of women who have AGC or AIS as proposed by the American Society for Colposcopy and Cervical Pathology (ASCCP)-sponsored consensus conference held in Bethesda, Maryland in September of 2001 [10]. Because of the lack of sensitivity of repeat cytology examination for the detection of HSIL and c Fig. 14. Algorithm of management of women who have atypical glandular cells. The Consensus Guidelines algorithms originally appeared in and are reprinted from The Journal of Lower Genital Tract Disease Vol. 6 Issue 2 and are reprinted with the permission of ASCCP Ó American Society for Colposcopy and Cervical Pathology 2002. No copies of the algorithms may be made without prior consent of ASCCP.

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neoplastic glandular lesions in women who have AGC [72] and the increased risk of high-grade preneoplastic and neoplastic uterine lesions, it is recommended that the initial evaluation of women who have any subcategories of AGC or AIS should include colposcopy and endocervical sampling. The latter, which can be either curettage or brushing, is included in the initial management because HSIL and AIS may occur as isolated foci within the endocervical canal and can be missed by colposcopic examination alone (see references [42,55,72,91,92]). The exception to this recommendation is women who have AMC who should initially be evaluated by endometrial sampling. Women who are older than 35 who have AGC, and those who have unexplained vaginal bleeding and AMC, regardless of age, should undergo endometrial sampling along with colposcopy and endocervical sampling. If a biopsy-confirmed preneoplastic or neoplastic lesion is identified, the patient should be managed accordingly. If a preneoplastic or neoplastic lesion is not identified during the initial work-up, patients who have either AEC, NOS or AGC, NOS should be followed up with repeat cytologic examination at 6-month intervals until four consecutive ‘‘negative’’ results are obtained, after which the patient can be returned to routine screening. Any repeat abnormal cytologic findings require evaluation accordingly. If neoplasia is not found in patients who have a diagnosis of AEC-N, AGC-N, or AIS during the initial work-up, a diagnostic excisional procedure, such as conization, should be considered. Reflex testing for high-risk types of HPV is widely accepted as one of the alternative methods for managing patients who have ASCUS, particularly when liquid-based preparation is used [10]. Currently, there are not enough data to support the use of HPV testing to triage women who have AGC. Some preliminary observations suggest that HPV testing may improve the management of women who have AGC, however. Using the Hybrid Capture method for high risk HPV, Ronnett et al [5] identified 92% (11/12) of biopsy-confirmed HSILs and 100% (5/5) of AIS in women who had an initial cytologic diagnosis of AGC. The investigators concluded that a negative HPV DNA test provides reassurance that a patient who has AGC does not have HSIL or AIS. HPV testing would not detect any endometrial lesions or non-HPV related malignancies. Some investigators have shown variable success in using other ancillary methods, such as detection of oncoprotein expression, image analysis, and neural network slide scanning, to triage women wwho have AGC [93,94]. Additional prospective studies are warranted to establish the efficacy of HPV testing and other modalities in managing patients who have AGC. Summary The 2001 Bethesda System has radically altered the classification of glandular abnormalities. The recognition of the cytologic features of atypical glandular cells on cervicovaginal smears is important because

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a significant number of patients will be found to have an underlying cancerous or dysplastic lesion of the exocervix, endocervix, or endometrium. The differential diagnosis of AGC on cytology is diverse and accurate classification is necessary because the most appropriate form of follow-up depends on the specific subcategorization of the atypical glandular cells. Because the level of interobserver agreement in the diagnosis of AGC is poor, effective communication between cytopathologists and clinicians is essential to accurately triage these patients. This article should help the cytology practitioner by providing a comprehensive review of the approach to the interpretation, clinical significance, histopathologic correlation, and management of patients who have atypical glandular cells on gynecologic cytology specimens. References [1] Anonymous. The 1988 Bethesda System for reporting cervical/vaginal cytological diagnoses. National Cancer Institute Workshop. JAMA 1989;262:931–4. [2] Kurman R, Solomon D. The Bethesda System for reporting cervical/vaginal cytologic diagnoses: definitions, criteria and explanatory notes for terminology and specimen adequacy. New York: Springer-Verlag; 1994. [3] Solomon D, Frable WJ, Vooijs GP, et al. ASCUS and AGUS criteria. International Academy of Cytology Task Force summary. Diagnostic cytology towards the 21st century: an international expert conference and tutorial. Acta Cytol 1998;42:16–24. [4] Solomon D, Davey D, Kurman R, et al. The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA 2002;287:2114–9. [5] Ronnett BM, Manos MM, Ransley JE, et al. Atypical glandular cells of undetermined significance (AGUS): cytopathologic features, histopathologic results, and human papillomavirus DNA detection. Hum Pathol 1999;30:816–25. [6] Cheng RF, Hernandez E, Anderson LL, et al. Clinical significance of a cytologic diagnosis of atypical glandular cells of undetermined significance. J Reprod Med 1999;44:922–8. [7] Chhieng DC, Elgert PA, Cangiarella JF, et al. Clinical significance of atypical glandular cells of undetermined significance. A follow-up study from an academic medical center. Acta Cytol 2000;44:557–66. [8] Lee KR, Manna EA, St John T. Atypical endocervical glandular cells: accuracy of cytologic diagnosis. Diagn Cytopathol 1995;13:202–8. [9] Wilbur D, Chhieng D, Cox JT, et al. AGUS draft recommendations Bethesda 2001 Workshop. 2001. [10] Wright TC Jr. Cox JT, Massad LS, et al. Conference ASCCP. 2001 Consensus Guidelines for the management of women with cervical cytological abnormalities. JAMA 2002; 287:2120–9. [11] Chhieng DC, Elgert P, Cohen JM, et al. Clinical implications of atypical glandular cells of undetermined significance, favor endometrial origin. Cancer 2001;93:351–6. [12] Betsill WL Jr. Clark AH. Early endocervical glandular neoplasia. I. Histomorphology and cytomorphology. Acta Cytol 1986;30:115–26. [13] Biscotti CV, Gero MA, Toddy SM, et al. Endocervical adenocarcinoma in situ: an analysis of cellular features. Diagn Cytopathol 1997;17:326–32. [14] Siziopikou KP, Wang HH, Abu-Jawdeh G. Cytologic features of neoplastic lesions in endocervical glands. Diagn Cytopathol 1997;17:1–7. [15] Anonymous. The Bethesda System for reporting cervical/vaginal cytologic diagnoses: revised after the second National Cancer Institute Workshop, April 29–30, 1991. Acta Cytol 1993;37:115–24.

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