Journal of Cytology
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ORIGINAL ARTICLE  
Year : 2017  |  Volume : 34  |  Issue : 4  |  Page : 203-207
Histological follow-up in patients with atypical glandular cells on Pap smears


1 Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Hacettpe University, Faculty of Medicine, Ankara, Turkey
2 Department of Pathology, Division of Cytology Hacettpe University, Faculty of Medicine, Ankara, Turkey

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Date of Web Publication6-Oct-2017
 

   Abstract 

Context: Atypical glandular cells (AGCs) result in the Papanicolaou (Pap) smear may be associated with significant genital and nongenital neoplastic processes. Aims: To evaluate the underlying histopathology in women who had AGCs on Pap smears. Settings and Design: Retrospective cross-sectional study. Patients and Methods: Clinicopathological data of patients who had AGC on Pap smears and underwent histological workup between January 2004 and December 2014 were retrieved from the computerized database of a tertiary care center. Patients with a prior history of cervical intraepithelial neoplasia or gynecological cancer were excluded. Statistical Analysis Used: Chi-square test or Fisher's exact tests were used as appropriate. Results: Cytological examination of the uterine cervix was carried out in 117,560 patients. We identified 107 patients (0.09%) with AGC and 80 of those with histological follow-up were included in the study. The median age at diagnosis was 47 years (range, 18–79), and 32 women (40%) were postmenopausal, while 56 (70%) had gynecological symptoms. Significant preinvasive or invasive lesions on pathological examination were detected in 27 (33.8%) patients, including 12 endometrial adenocarcinomas (15%), 8 cervical carcinomas (10%), 3 cervical intraepithelial neoplasia II/III (3.75%), 2 ovarian adenocarcinomas (2.5%), and 2 metastatic tumors (2.5%). Univariate analysis showed that postmenopausal status (P < 0.001), age >50 years old (P < 0.001), having symptoms at the time of admission (P = 0.041), and AGC “favor neoplasia” smear results (P = 0.041) were the clinical factors associated with significant pathological outcome. Conclusions: Patients with AGC on Pap smears should be evaluated vigilantly with histological workup, especially if they are postmenopausal or symptomatic.

Keywords: Atypical glandular cells, carcinoma in situ, cervical intraepithelial neoplasia, neoplasms

How to cite this article:
Boyraz G, Basaran D, Salman MC, Ibrahimov A, Onder S, Akman O, Ozgul N, Yuce K. Histological follow-up in patients with atypical glandular cells on Pap smears. J Cytol 2017;34:203-7

How to cite this URL:
Boyraz G, Basaran D, Salman MC, Ibrahimov A, Onder S, Akman O, Ozgul N, Yuce K. Histological follow-up in patients with atypical glandular cells on Pap smears. J Cytol [serial online] 2017 [cited 2019 Jun 18];34:203-7. Available from: http://www.jcytol.org/text.asp?2017/34/4/203/216128



   Introduction Top


Cervical cytological evaluation with Papanicolaou (Pap) smear is the standard screening test for cervical malignant and premalignant lesions. Positive screening may reveal either squamous or glandular cell abnormalities. Glandular cell abnormalities are found far less commonly than squamous cell abnormalities.[1] According to the literature, glandular cell abnormalities are found in <1% of cervical cytology samples and atypical glandular cell (AGC) incidence varies from 0.1 to 2.1% in the literature.[2],[3] AGCs are defined as cells that demonstrate changes beyond those encountered in benign reactive processes, still are not sufficient for the diagnosis of adenocarcinoma.[4] Although these cells usually originate from the glandular epithelium of the endocervix or endometrium, they may originate from various locations such as salpinges, ovary, or other intraperitoneal organs.[5] According to the Bethesda 2001 system, glandular cell abnormalities are subclassified into: (i) AGCs either endocervical (EC), endometrial (EM), or not otherwise specified (AGC–NOS); (ii) AGCs favor neoplastic (AGC-FN), either EC or not otherwise specified; (iii) EC adenocarcinoma in situ (AIS); and (iv) adenocarcinoma.[6],[7]

The identification of AGCs in a  Pap smear More Details is clinically important due to its close association with premalignant and malignant diseases. In the literature, 9–38% of the women with AGC have cervical intraepithelial neoplasia (CIN) 2, CIN 3, and AIS; 3–17% have invasive carcinomas.[2] The commonly detected malignancies in patients with AGC cytology is EM adenocarcinoma, EC adenocarcinoma, and squamous cell cervical carcinoma. Occasionally, ovarian or  Fallopian tube More Details malignancy could be detected. Ovarian cancer has been reported in 0.1–0.6% of women with AGC in the literature.[8],[9] Thus, patients with AGC require further aggressive diagnostic evaluation for premalignant or malignant conditions of the cervix, endometrium, ovary, and fallopian tube. Colposcopic examination, cervical biopsy, EC curettage, EM biopsy, and gynecologic ultrasonography should be considered for women with AGC smear results to detect possible malignant or premalignant diseases.[5],[10],[11] Although a number of studies have addressed the incidence, clinical implications, and management of patients with AGC, the results have varied significantly. Therefore, this study was conducted to evaluate the significance of AGC by analyzing the final histologic diagnosis results attained via histologic follow-up.


   Patients and Methods Top


Clinicopathological data of patients who had AGC on Pap smears between January 2004 and December 2014 were retrieved from the computerized database of a tertiary care center. Liquid-based cytology (ThinPrep or SurePath systems) system was used for liquid-based cytological analysis. Patients with AGC on cervical cytology who underwent histopathological workup at our Department of Obstetrics and Gynecology were included. Patients with previous personal history of CIN or any gynecological cancer were excluded. Relevant study flowchart is presented in [Figure 1]. Following AGC result, cervical colposcopy with directed cervical biopsies and sampling of the EC canal was performed by gynecologic oncologists in our department. We performed EM sampling for all patients aged 35 years or older. For younger patients EM sampling was done if they had risk factors for EM cancer, including abnormal uterine bleeding, obesity, or polycystic ovarian syndrome. The clinical and pathological characteristics including patient's age, symptoms, menopausal status, Pap test findings and subclassifications, EM, EC, or cervical biopsy results were evaluated.
Figure 1: Study flowchart

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The Institutional Ethical Committee approval was not sought as this study represented a retrospective database review.

Statistical Package for the Social Sciences, version 17 (SPSS Inc., Chicago, IL, USA) was used for the data record and statistical analyses. P value <0.05 was considered significant. Chi-square test or Fisher's exact tests were used, as appropriate.


   Results Top


Cytological examination of the uterine cervix was carried out in 117,560 patients between January 2004 and January 2015. Of these patients, 107 were diagnosed with AGC at a detection rate of 0.1%. After exclusion of cases with previous history of gynecological cancer or cervical preinvasive disease and those without proper follow-up, 80 patients were included in the study with a median age at diagnosis as 47 years (range: 18–79 years). Of these women, 32 (40%) were postmenopausal and 56 (70.0%) had gynecological symptoms. The most frequent symptom was postmenopausal bleeding, which was found in 35% of study population. Menorrhagia was present in 22 patients (27.5%). Two patients (2.5%) had post coital bleeding and four (5.0%) had chronic pelvic pain. The remaining 24 (30%) AGC cases were detected on routine follow-up in asymptomatic women.

Among the 80 patients with AGC, 39 (48.8%) had AGC-NOS (not otherwise specified), 18 (22.5%) had AGC-EC (of endocervical origin), 14 (17.5%) had AGC-EM (of endometrial origin), 4 (5.0%) had AGC-FN, 3 (3.7%) had AGC-EX (from extragenital origin), 2 (2.5%) had AGC and atypical squamous cells of undetermined significance (ASC-US) [Figure 2].
Figure 2: Glandular cell abnormalities

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Histopathologic evaluation confirmed a clinically significant pathology in 27 patients with AGC (33.8%) [Table 1]. Of these, endometrium was the most common (15%) site for significant pathology, including 10 cases with endometrioid EM adenocarcinoma, 1 with serous EM adenocarcinoma, and 1 with EM carcinosarcoma. A total of seven cases had cervical squamous lesions, which were squamous cell cervical carcinoma in four and CIN 2/3 in three patients. Four cases (5.0%) had invasive cervical adenocarcinoma.
Table 1: Histopathologic results in patients with AGC

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When the association with significant pathology was evaluated according to different AGC subgroups, a diagnosis of AGC-FN was the most serious one that was associated with invasive disease in all cases (P = 0.04). It was followed by AGC-EX (AGC of extragenitalial origin) which was associated with invasive malignancy in 2 out of 3 patients (66.7%) [Table 2].
Table 2: Significant pathological diagnoses according to AGC subgroups

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In an attempt to demonstrate the risk factors for significant pathology in patients with AGC, univariate analysis was performed [Table 3]. Being postmenopausal, being aged 50 years or older, and having a gynecologic symptoms during initial presentation were found to be statistically significant risk factors for having such pathologies [P< 0.001, P < 0.001, and P = 0.04, respectively).
Table 3: Risk factors for significant pathology in patients with AGC

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   Discussion Top


The frequency of AGC according to the Bethesda system is reported to range from 0.1 to 2.1% in the literature.[2],[3],[12] In accordance with the literature, AGC was detected in approximately 0.1% of all cervical cytologies in our study. Although rarely reported, AGC diagnosis should raise the clinician's suspicion for significant pathologies either in the genital tract or in extragenital structures. In the literature, the rates of malignant or premalignant lesions ranged from 22 to 53% in patients with AGC.[13] Kim et al. reported that malignant diseases were found in 24 patients (28.9%) during histological follow-up among 83 patients with AGC on Pap smear. In their study group, cervical adenocarcinoma (8/24 patients, 33.3%) was the most frequently observed malignant disease, followed by EM cancer (6/24 patients, 25%), ovarian cancer (4/24 patients, 16.6%), breast cancer (3/24 patients, 12.5%), and stomach cancer (3/24 patients, 12.5%).[14] Krane et al. detected malignant or premalignant lesions in 34.3% of 108 patients with AGC. In their study, 24 patients had cervical neoplasia, while 13 had other neoplasia consisting of five EM adenocarcinoma, 4 EM hyperplasia, 2 ovarian carcinoma, and 2 fallopian tube adenocarcinoma.[15] Mood et al. reported that neoplastic or preneoplastic diseases were detected in 22 of 44 patients (55.3%). Of those, 15 (68.1%) had cervical premalignant disease and 2 (9%) had cervical adenocarcinoma. Other diseases included EM adenocarcinoma, metastatic lobular breast carcinoma, vaginal adenocarcinoma, simple EM hyperplasia, and nonvillous trophoblastic tissue in that series.[16] In the study from Zhao et al., clinically significant pathology was reported to be 22.8% in women with AGC, which mostly consisted of EM lesions (in 51%) followed by cervical squamous and glandular lesions (in 43%).[17]

In the present study, 27 of 80 patients (33.8%) were diagnosed to have either malignant or premalignant disease. The most common origin of significant pathology was endometrium followed by cervix and ovary. Of patients in our study group, 10 (12.5%) had endometrioid type EM adenocarcinoma, which was the most common invasive pathology. In addition, serous adenocarcinoma was detected in one patient and carcinosarcoma of the endometrium was seen in another. Cervical pathologies included invasive squamous cell carcinoma in four patients, invasive adenocarcinoma of cervix in four, and preinvasive cervical disease in three women. Although the most commonly reported pathologies in patients with AGC are preinvasive and invasive cervical lesions and EM diseases are less likely according to the literature,[9],[16] the highest incidence of EM malignancies in the current series may be attributed to the relatively low incidence cervical neoplasms in Turkey compared to EM neoplasia.[18]

On rare occasions, ovarian cancer may also be diagnosed during the further evaluation of women with AGC cytology. The ovarian cancers in this patient population may be primary or metastatic and the metastases mostly originate from the gastrointestinal system.[8] The rates of ovarian pathology in patients with AGC were reported to be <1%.[7],[9] However, Tam et al. reported that five (3.6%) had ovarian cancer and two (1.4%) had extragenital malignancies among 138 women with AGC.[19] In the present study, ovarian cancer was detected in two patients (2.5%) and extragenital malignancies metastatic to the ovaries were detected in two (2.5%). This high rate of ovarian origin in this series could be a result of relatively small sample size. Nevertheless, in cases without any malignancy detected by pathological evaluation of the cervix and endometrium, abdominal and pelvic imaging modalities as well as serum tumor markers should be used to reveal the ovarian or abdominal origin of malignant glandular cells.

It is apparent that patients with AGC result on cervical cytology carry a significant risk for having a diagnosis of genital or less commonly extragenital invasive or preinvasive neoplasia. The question is whether some women with AGC have more risk of having these neoplasia than others. Several predictive factors were reported on this issue. Tam et al.[19] reported that while 67.6% of the 34 patients with AGC-FN had significant pathology, only 19.2% of patients with AGC-NOS had significant pathology. Similarly, Sawangsang et al.[20] found that the rate of significant lesions in women with AGC-FN was significantly higher than in women with AGC-NOS. In accordance with the literature, while 38.5% of patients with AGC-NOS had significant pathology, all patients with AGC-FN had significant pathology in our study. In addition, among patients with AGC cytology, age was reported to be a predictor for significant pathology in several studies.[7],[9],[16],[21] Cheng et al.[7] showed that women who are aged over 60 years have a higher possibility of having gynecological cancer. The role of age was mentioned by another study where no EM cancers were detected if patients with AGC were younger than 35 years of age.[22] Current study also confirmed the importance of age because the rate of significant pathology was higher if the patient with AGC was aged 50 years or older. The other risk factors for significant pathology in the current series were being in the postmenopausal state and having gynecological complaints during initial presentation.

In conclusion, AGC result on cervical cytology is associated with significant pathology in a considerable proportion of patients. Therefore, such a result should trigger the clinician to thoroughly evaluate the patient with special attention on endometrium and cervix. Ovaries, tubes, and abdominal structures should also be investigated in detail when endometrium and cervix are free of malignancy. It should also be kept in mind that especially older and postmenopausal patients with AGC may carry a higher risk for having premalignant and malignant disease, which may warrant a more aggressive diagnostic workup in those women.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
   References Top

1.
Chummun K, Fitzpatrick M, Lenehan P, Boylan P, Mooney E, Flannelly G. Diagnostic and therapeutic dilemma associated with atypical glandular cells on liquid-based cervical cytology. Cytopathology 2012;23:378-82.  Back to cited text no. 1
    
2.
Marques JP, Costa LB, Pinto AP, Lima AF, Duarte ME, Barbosa AP, et al. Atypical glandular cells and cervical cancer: Systematic review. Rev Assoc Med Bras 2011;57:234-8.  Back to cited text no. 2
    
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Jeng CJ, Liang HS, Wang TY, Shen J, Yang YC, Tzeng CR. Cytologic and histologic review of atypical glandular cells (AGC) detected during cervical cytology screening. Int J Gynecol Cancer 2003;13:518-21.  Back to cited text no. 3
    
4.
The Bethesda System for reporting cervical/vaginal cytologic diagnoses: Revised after the second National Cancer Institute Workshop, 1991. Acta Cytol 1993;37:115-24.  Back to cited text no. 4
    
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Solomon D, Davey D, Kurman R, Moriarty A, O'Connor D, Prey M, et al. The 2001 Bethesda System: Terminology for reporting results of cervical cytology. JAMA 2002;287:2114-9.  Back to cited text no. 6
    
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Cheng WF, Chen YL, You SL, Chen CJ, Chen YC, Hsieh CY, et al. Risk of gynaecological malignancies in cytologically atypical glandular cells: Follow-up study of a nationwide screening population. BJOG 2011;118:34-41.  Back to cited text no. 7
    
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Schnatz PF, Guile M, O'Sullivan DM, Sorosky JI. Clinical significance of atypical glandular cells on cervical cytology. Obstet Gynecol 2006;107:701-8.  Back to cited text no. 8
    
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Zhao C, Florea A, Onisko A, Austin RM. Histologic follow-up results in 662 patients with Pap test findings of atypical glandular cells: Results from a large academic women's hospital laboratory employing sensitive screening methods. Gynecol Oncol 2009;114:383-9.  Back to cited text no. 9
    
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Eltabbakh GH, Lipman JN, Mount SL, Morgan A. Significance of atypical glandular cells of undetermined significance on ThinPrep Papanicolaou smears. Gynecol Oncol 2000;78:245-50.  Back to cited text no. 10
    
11.
Chin AB1, Bristow RE, Korst LM, Walts A, Lagasse LD. The significance of atypical glandular cells on routine cervical cytologic testing in a community-based population. Am J Obstet Gynecol 2000;182:1278-82.  Back to cited text no. 11
    
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Lee CY, Ng WK. Follow-up study of atypical glandular cells in gynecologic cytology using conventional Pap smears and liquid-based preparations: Impact of the Bethesda System 2001. Acta Cytol 2008;52:159-68.  Back to cited text no. 12
    
13.
Westin MC, Derchain SF, Rabelo-Santos SH, Angelo-Andrade LA, Sarian LO, Oliveira E, et al. Atypical glandular cells and adenocarcinoma in situ according to the Bethesda 2001 classification: Cytohistological correlation and clinical implications. Eur J Obstet Gynecol Reprod Biol 2008;139:79-85.  Back to cited text no. 13
    
14.
Kim SS, Suh DS, Kim KH, Yoon MS, Choi KU. Clinicopathological significance of atypical glandular cells on Pap smear. Obstet Gynecol Sci 2013;56:76-83.  Back to cited text no. 14
    
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Krane JF, Lee KR, Sun D, Yuan L, Crum CP. Atypical glandular cells of undetermined significance. Outcome predictions based on human papillomavirus testing. Am J Clin Pathol 2004;121:87-92.  Back to cited text no. 15
    
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Mood NI, Eftekhar Z, Haratian A, Saeedi L, Moghaddam PR, Yarandi F. A cytohistologic study of atypical glandular cells detected in cervical smears during cervical screening tests in Iran. Int J Gynecol Cancer 2006;16:257-61.  Back to cited text no. 16
    
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Zhao C, Austin RM, Pan J, Barr N, Martin SE, Raza A, et al. Clinical significance of atypical glandular cells in conventional pap smears in a large, high-risk U.S. west coast minority population. Acta Cytol 2009;53:153-9.  Back to cited text no. 17
    
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Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136:E359-86.  Back to cited text no. 18
    
19.
Tam KF, Cheung AN, Liu KL, Ng TY, Pun TC, Chan YM, et al. A retrospective review on atypical glandular cells of undetermined significance (AGUS) using the Bethesda 2001 classification. Gynecol Oncol 2003;91:603-7.  Back to cited text no. 19
    
20.
Sawangsang P, Sae-Teng C, Suprasert P, Srisomboon J, Khunamornpong S, Kietpeerakool C. Clinical significance of atypical glandular cells on Pap smears: Experience from a region with a high incidence of cervical cancer. J Obstet Gynaecol Res 2011;37:496-500.  Back to cited text no. 20
    
21.
DeSimone CP, Day ME, Tovar MM, Dietrich CS 3rd, Eastham ML, Modesitt SC. Rate of pathology from atypical glandular cell Pap tests classified by the Bethesda 2001 nomenclature. Obstet Gynecol 2006;107:1285-91.  Back to cited text no. 21
    
22.
Sharpless KE, Schnatz PF, Mandavilli S, Greene JF, Sorosky JI. Dysplasia associated with atypical glandular cells on cervical cytology. Obstet Gynecol 2005;105:494-500.  Back to cited text no. 22
    

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Correspondence Address:
Gokhan Boyraz
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Faculty of Medicine, Hacettepe University, Ankara
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JOC.JOC_209_16

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