Clinical implications of atypical glandular cells of undetermined significance, favor endometrial origin.

BACKGROUND: The Bethesda System recommends qualifying atypical glandular cells with regard to their possible origin: endocervical versus endometrial. This study was undertaken to determine the clinical significance of atypical glandular cells of undetermined significance that favor an endometrial origin (AGUS-EM). METHODS: A computer search identified 62 cervicovaginal smears (5.25% of all smears classified as AGUS) with a diagnosis of AGUS-EM in the files of Shared Cytopathology Laboratory of New York University Medical Center/Bellevue Hospital Medical Center between January 1995 and December 1999. The patients ranged in age from 29 years to 88 years (mean age, 53 years). Thirty-four patients were postmenopausal (55%), and 5 patients were on hormonal replacement therapy. Follow-up was available for 56 patients (90%); 45 patients (73%) underwent biopsy, and 11 patients (17%) had repeat cervicovaginal smears. Six patients were lost to follow-up. RESULTS: Among patients who underwent biopsy, 14 patients (31%) had a clinically significant uterine lesions, including 6 (13%) endometrial adenocarcinomas, 5 (11%) endometrial hyperplasias, and 3 (7%) squamous lesions (2 high-grade squamous intraepithelial lesions and 1 squamous cell carcinoma). Ten of 11 patients with significant endometrial pathology findings were postmenopausal. The remaining 31 patients had benign pathology results, which included chronic cervicitis, endometritis, endometrial polyps, microglandular hyperplasia, and tubal metaplasia. Among the patients with repeat cervicovaginal smears, one patient had atypical squamous cells of undetermined significance; the remaining patients were within normal limits. CONCLUSIONS: Approximately one-third of women with a diagnosis of AGUS-EM had a significant uterine lesion on subsequent biopsy; the majority of these lesions were endometrial in origin. Patients with a diagnosis of AGUS-EM on cervicovaginal smears should be followed closely, and endometrial curettage or biopsy should be included in their initial work-up.

Variation in the incidence of AGUS between different patient populations.

OBJECTIVE: To determine the frequency of atypical glandular cells of undetermined significance (AGUS) for three consecutive calendar years from three different referral sources. STUDY DESIGN: Cervicovaginal smears with a diagnosis of AGUS were identified from January 1995 through December 1997. The smears were submitted from three different sources: two were city government hospital clinics, one with predominantly African American and Hispanic patients and the other with predominantly Asian and Hispanic patients. The third referral source was private practitioners' offices with predominantly Caucasian patients. RESULTS: A diagnosis of AGUS was made in 707 cases, accounting for 0.56% of all smears examined. This was in contrast to 6,872 smears reported as atypical squamous cells of undetermined significance (ASCUS) (5.4%) and 3,347 reported as squamous intraepithelial lesions (SIL) or above (2.7%). The incidence of AGUS ranged from 0.16% to 1.00% among different patient populations. This difference was also noted in the rate of ASCUS and SIL in the same patient population. There was a steady increase in the rate of AGUS for each referral source during the study period. The overall rate of patients who underwent histologic evaluation and the incidence of biopsy-proven preinvasive and invasive lesions were 62.4% and 23%, respectively. There was no significant difference in the rate of significant lesions after a diagnosis of AGUS during the study period or between the three referral sources. CONCLUSION: The AGUS rate in our laboratory was low and within the range (0.17-1.83%) reported in the literature. The AGUS rate varies with different patient populations, particularly with the incidence of SIL and age distribution.

Significance of AGUS Pap smears in pregnant and postpartum women.

OBJECTIVE: To study the clinical significance of atypical glandular cells of undertermined significance (AGUS) in pregnant and postpartum women. STUDY DESIGN: We evaluated 35 women who were pregnant (30) or within three months postpartum (5) and had a cytologic diagnosis of AGUS. Twenty-seven (77%) patients had follow-up: 17 (63%) patients underwent colposcopic examination and biopsy, and 10 (37%) had repeat Pap smears. Eight patients were lost to follow-up. RESULTS: Five (29.4%) patients had a squamous intraepithelial lesion (SIL), including three high grade and two low grade, on subsequent biopsy. The remaining (70.6%) patients had benign pathology, which included 5 chronic cervicitis, 4 endocervical and/or endometrial polyps, 2 Arias-Stella reaction and 1 microglandular hyperplasia. Among the patients with repeat Pap smears, two had persistent AGUS/atypical squamous cells of undetermined significance, the remaining cases were within normal limits. CONCLUSION: Pregnancy-related changes may present with glandular atypia. In addition, about one-third of pregnant and postpartum women with a diagnosis of AGUS had SIL on subsequent biopsy; that rate is similar to that in nonpregnant women. Therefore, pregnant women with a cytologic diagnosis of AGUS should be followed closely.

Clinical significance of atypical glandular cells of undetermined significance in postmenopausal women.

BACKGROUND: Glandular atypia in Papanicolaou (Pap) smears from postmenopausal women is encountered frequently. This finding can be the result of artifactual alterations such as drying artifacts and inflammatory changes or may represent a squamous or glandular, preneoplastic or neoplastic process. Therefore, it is important to determine the clinical implication of a diagnosis of atypical glandular cells of undetermined significance (AGUS) in postmenopausal patients. METHODS: A total of 30,036 Pap smears were obtained from postmenopausal women between 1995 and 1997. Among these smears, 154 (0.51%) had a diagnosis of AGUS. Follow-up was available for 133 patients (86.4%); 110 patients (82.7%) had histologic follow-up (including cervical biopsy, endocervical [EC] curettage, and/or endometrial [EM] biopsy) and 23 patients (17.3%) had repeat smears. RESULTS: Thirty-six of 110 patients (32.7%) were found to have a clinically significant lesion (defined as a preneoplastic or neoplastic, glandular or squamous lesion) on subsequent histologic follow-up. Nineteen patients (53%) had glandular lesions (15 EM adenocarcinoma [ACA] cases, 2 EC ACA cases, 1 EC adenocarcinoma is situ case, and 1 EM hyperplasia case). Seventeen patients (47%) had a squamous intraepithelial lesion (SIL) (6 cases of low-grade SIL, 9 cases of high-grade [HGIL], and 2 cases of squamous cell carcinoma). Among those patients with repeat Pap smears, five patients had persistent AGUS/atypical squamous cells of undetermined significance and one patient had an SIL. CONCLUSIONS: The incidence of AGUS among postmenopausal patients was similar to that of the general population (0.51% vs. 0.56%; P > 0.05). A significant percentage of these patients were found to have a clinically significant lesion on subsequent follow-up. Furthermore, a majority of these lesions were ACA (53%) or HGSIL (26%). The findings of the current study strongly suggest the need for the close follow-up of postmenopausal patients with a diagnosis of AGUS. Cancer (Cancer Cytopathol)

Use of computer-assisted rescreening as an ancillary tool to subclassify AGUS cervical smears.

A substantial percentage of women with a diagnosis of atypical glandular cells of undetermined significance (AGUS) on cervical smears harbor a significant squamous or glandular, preneoplastic or neoplastic lesion on subsequent follow-up. Attempts to subclassify AGUS smears by conventional methods have had mixed results. To determine whether subclassification of AGUS cervical smears using computer-assisted rescreening based on the neural network would improve correlation with subsequent histologic follow-up, 91 cervical smears, conventionally diagnosed as AGUS without concomitant squamous lesions, were subjected to analysis by a computer-assisted automated screening system. Computer-generated images were evaluated by a cytotechnologist without the knowledge of the histologic outcomes. Prior to manual review, each case was classified as either within normal limits, no review required; or abnormal, review required. Based on the degree of abnormality, the latter category was further subclassified into either low probability or high probability of abnormality. The results of the computer-assisted reclassification were then compared with the histologic follow-up of all patients. Thirty-three cases (38.8%) had a significant lesion on histologic follow-up. The lesions included 4 CIN I, 7 CIN II/III, 12 endocervical adenocarcinomas (ACA), and 10 endometrial ACA. Based on computer-generated images, 65% of the smears that were triaged as high probability of abnormality, 11.5% that were triaged as low probability of abnormality, and 10.5% that were triaged as within normal limits had a significant lesion on subsequent follow-up. We conclude that computer-assisted rescreening aids in the triage of AGUS smears and that computer-assisted rescreening based on the neural network or other algorithms may be a useful ancillary tool for subclassifying AGUS cervical smears.

Clinical significance of atypical glandular cells of undetermined significance. A follow-up study from an academic medical center.

OBJECTIVE: To determine the rate of atypical glandular cells of undetermined significance (AGUS) and the incidence of subsequent clinically significant lesions. STUDY DESIGN: A computer-based search of our cytology laboratory files was performed for cervicovaginal smears diagnosed as AGUS from January 1996 to December 1996. RESULTS: In 43,456 cervicovaginal smears examined during the 12-month period, AGUS was reported in 222 (0.5%) cases, with follow-up in 191 (86.0%) (133 [59.9%] biopsies and 58 [26.1%] repeat cervicovaginal smears). Among the patients with repeat cervicovaginal smears, 1 (1.7%) had a high grade squamous intraepithelial lesion, and 10 (17.2%) had persistent AGUS/atypical squamous cells of undetermined significance; the remainder were within normal limits. Thirty-three (24.8%) patients had preneoplastic or neoplastic, squamous or glandular lesions on biopsy (8 [6.0%] cervical intraepithelial neoplasia [CIN] 1, 18 [13.5%] CIN 2/3 and 7 [5.3%] endometrial adenocarcinomas). Half the patients with CIN 2/3 also had evidence of endocervical gland involvement. Squamous lesions were seen more commonly in premenopausal women, while glandular lesions were noted predominantly in postmenopausal women. Patients with a prior abnormal gynecologic history or a concomitant diagnosis of squamous intraepithelial lesion (SIL) had a higher incidence of significant lesions on subsequent biopsy. CONCLUSION: Our incidence of AGUS was 0.5%, similar to that in other published reports. AGUS is associated with a significant number of squamous or glandular, premalignant or malignant lesions. A majority of these lesions are high grade SIL, often with endocervical gland involvement. A small but significant number of patients had a glandular malignancy. Our results justify close and persistent follow-up for patients with a diagnosis of AGUS on cervicovaginal smears.

Cytology of polypoid adenomyomas: a report of two cases.

Uterine polypoid adenomyomas, both typical and atypical variants, often arise in the lower uterine segment or endocervical canal as pedunculated polypoid masses that may be accessible for cytologic sampling. However, their cytologic findings have rarely been described in the literature. Two women in their reproductive age presented with abnormal vaginal bleeding. The cervicovaginal smear of the first patient contained sheets and strips of reactive endocervical cells in an inflammatory background. In addition, loose aggregates of spindle-shaped smooth muscle cells were also noted. The findings were consistent with those of a typical polypoid adenomyoma. The cervicovaginal smears of the second patient consisted of tightly packed, crowded clusters of glandular cells which were initially interpreted as atypical glandular cells, suspicious of adenocarcinoma. In retrospect, loose aggregates of smooth muscle stromal cells were noted. Subsequent curettage revealed an atypical polypoid adenomyoma. The cytologic findings of typical polypoid adenomyoma were nonspecific except for the presence of loose aggregates of smooth muscle cells. The cytologic features of an atypical polypoid adenomyoma may mimic that of a neoplastic glandular process. The findings of tightly packed clusters of glandular cells and loose aggregate of bland-appearing smooth muscle cells in premenopausal patients may suggest the diagnosis of atypical polypoid adenomyoma. Diagn. Cytopathol. 2000;22:176-180.

Evaluation of PAPNET testing as an ancillary tool to clarify the status of the "atypical" cervical smear.

To assess the utility of the PAPNET system (Neuromedical Systems Inc., Suffern, NY) in clarifying the status of cervical smears showing borderline abnormalities, we analyzed the results of five cytotechnologists who reclassified 200 "atypical" smears by evaluating PAPNET images only. The interobserver agreement (reliability) of the PAPNET reviewers was computed, and their readings were compared with three standards: the consensus diagnosis of five pathologists who used light microscopy, the detection of cancer-associated human papillomavirus DNA by Southern analysis, and the correlation with diagnoses of biopsy specimens obtained during passive follow-up. The PAPNET reviewers classified 18 to 65% of cases as normal, 25 to 42% as equivocal, and 10 to 55% as abnormal. Unanimous interobserver agreement was achieved in only 24 (13%) cases. Four of the five PAPNET reviewers agreed moderately well with the results of the pathology reference panel. In four of the five PAPNET reviews, classification of cases as abnormal was strongly correlated with the detection of cancer-associated types of human papillomavirus. Consensus PAPNET results of abnormal were predictive of abnormal histologic findings at follow-up. Theoretically, if colposcopy had been performed on all of the women with equivocal or abnormal PAPNET results (based on the consensus of the panel), as much as 95% of biopsy-confirmed lesions could have been detected, but 79% of women would have been referred. Restriction of colposcopy referral to women with definitely abnormal PAPNET readings would have reduced referrals to 31%, but the sensitivity of the triage would have dropped to 51% of biopsy-confirmed lesions.

Fine needle aspiration cytology of orbital masses.

OBJECTIVE: To review our experience with fine needle aspiration of orbital lesions. STUDY DESIGN: Over an eight-year period, 24 orbital fine needle aspiration (FNA) samples were recorded, 22 of them adequate for interpretation. RESULTS: There were two benign tumors. There were 14 malignant tumors, 5 primary, 8 metastatic and 1 malignant and originating in the nasal cavity, invading the orbit. In two cases the original tissue diagnosis was incorrect and was revised by the fine needle aspirate. There were six nonneoplastic cases. In one case an infectious agent was identified, and another showed atypical lymphoid cells. Of the two nondiagnostic cases, one was compatible clinically with an orbital pseudotumor, and the other had no available follow-up. A specific diagnosis was achieved in 18 of 24 instances, or 75% of the cases. CONCLUSION: FNA is useful in the workup of an orbital lesion, leading to prompt diagnosis and treatment.

Evaluation of the PAPNET cytologic screening system for quality control of cervical smears.

The PAPNET system is an automated interactive instrument for analysis of conventional (Papanicolaou) cervical smears. The instrument, described in this paper, introduces several important innovations to cytology automation. The cell selection system is composed of two stages: an algorithmic classifier, followed by a trained neural network allowing for great flexibility and precision in recognition of abnormal cell images. Contrary to other attempts at cytology automation, this machine does not attempt to diagnose cell abnormalities. Instead, it is interactive, leaving the assessment of the cells displayed on a high-resolution video screen to trained human observers. The slides judged to contain abnormal cells or to be inadequate are referred for a second microscopic review. Two versions of the instrument (Alpha and Beta) were evaluated in several modes. Initial testing was performed on archival smears with known, histologically confirmed neoplastic lesions of the uterine cervix. These lesions comprised the entire spectrum of abnormalities, from low-grade lesions to invasive cancers of several types. The Alpha machine displayed recognizable abnormal cells in 97% of the 201 cases, and the Beta machine displayed such cells in 97.2% of 176 cases. The Beta instrument was subsequently tested on 500 sequential archival cervical smears that had been previously subjected to a rigorous quality control. One hundred forty smears (28%), which either displayed atypical cells or were considered "inadequate," were referred for further rescreening. Fifteen of 16 previously diagnosed neoplastic smears were appropriately identified with the help of the machine. The one missed case contained a single cluster of vacuolated cancer cells from an endometrial carcinoma. As a result of PAPNET-triggered review, three new cases of low-grade squamous intraepithelial lesions view, three new cases of low-grade squamous intraepithelial lesions (SIL) came to light in previously negative smears; three additional cases, previously classified as atypical, were also reclassified as SIL, for a net gain of six neoplastic abnormalities. In two additional atypical cases, colposcopic follow-up was recommended, even though the diagnosis was not modified. Two cases of cervical intraepithelial neoplasia, represented by tiny single clusters of abnormal cells missed on original screening, quality control, and on machine rescreening, came to light on second review of the residual 360 cases. The initial experience with the PAPNET system suggests that the instrument may be valuable in quality control and may assist in significantly reducing false-negative cervical smears in an efficient and timely manner. Further testing of the instrument on a much larger number of cervical smears is in progress.