Clinical Utility of Adjunctive High-Risk Human Papillomavirus DNA Testing in Women With Papanicolaou Test Findings of Atypical Glandular Cells

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1 Clinical Utility of Adjunctive High-Risk Human Papillomavirus DNA Testing in Women With Papanicolaou Test Findings of Atypical Glandular Cells Chengquan Zhao, MD; Anca Florea, MD; R. Marshall Austin, MD, PhD N Context. Atypical glandular cell (AGC) Papanicolaou (Pap) test interpretations are challenging. Most biopsy findings are benign, but AGC results may also reflect highly significant noninvasive neoplastic and malignant histologic outcomes. High-risk human papillomavirus (hrhpv) test use with AGC Pap test results is evolving. Objective. To further evaluate the utility and limitations of hrhpv testing with AGC Pap tests. Design. Hospital records were searched for AGC Pap tests results from June 1, 2005, to August 31, Cases of AGC with hrhpv tests and histopathologic follow-up were included. Results. Of the 662 women with AGC Pap test results and follow-up analyzed, hrhpv results were available for 309 (46.7%) and were positive in 75 cases (24.3%). Among the 75 cases with hr AGC results, 13 (17.3%) had cervical intraepithelial neoplasia grades 2/3, 10 (13.3%) had adenocarcinoma in situ, and 3 (4.0%) had cervical invasive adenocarcinoma, whereas for 234 women with hrhpv 2 results, 1 (0.4%) had cervical intraepithelial neoplasia grades 2/3, 1 (0.4%) had adenocarcinoma in situ, 1 each (0.4%) had cervical adenocarcinoma and ovarian carcinoma, and 8 (3.4%) had endometrial carcinoma. Conclusions. Positive hrhpv AGC results were most strongly associated with cervical intraepithelial neoplasia grades 2/3 and adenocarcinoma in situ in women younger than 50 years. Positive hrhpv AGC results were also present in all 3 cases of invasive cervical adenocarcinoma in women younger than 50 years. Of note, hrhpv 2 AGC results were present in 10 of 13 carcinomas (76.9%) detected after AGC Pap tests, all in women 40 years or older with endometrial adenocarcinomas (n = 8), ovarian carcinoma (n = 1), and cervical adenosquamous carcinoma in a woman (n = 1) in her 50s. Testing for hrhpv after AGC Pap testing was most helpful in the detection of cervical intraepithelial neoplasia grades 2/3, adenocarcinoma in situ, and invasive cervical adenocarcinomas in women younger than 50 years. (Arch Pathol Lab Med. 2010;134: ) Accepted for publication April 10, From the Department of Pathology, Magee-Womens Hospital, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. The authors have no relevant financial interest in the products or companies described in this article. Presented in part at the annual meeting of the United States and Canadian Academy of Pathology, Denver, Colorado, March 1 7, Reprints: Chengquan Zhao, MD, Department of Pathology, Magee- Womens Hospital of University of Pittsburgh Medical Center, 300 Halket St, Pittsburgh, PA ( zhaoc@upmc.edu). Atypical glandular cell (AGC) interpretations 1 2 and screening for glandular cervical neoplasia 3 7 remain some of the major challenges in gynecologic cytopathology. Even though most Papanicolaou (Pap) tests with AGC findings turn out to reflect a variety of underlying benign conditions, 8 10 a significant subset of AGC cases reflect underlying cervical intraepithelial neoplasia (CIN) grades 2/3 and/or endocervical adenocarcinoma in situ (AIS) as well as occasional cases of invasive cervical and noncervical carcinoma Cervical glandular cancers remain a major challenge to cervical cancer prevention efforts in the United States because cervical glandular cancers continue to increase even as squamous carcinomas have experienced an accelerated decline since the advent of liquid-based cytology. 21,22 The low incidence of AGC Pap test results 23 to date has limited our understanding of how best to integrate highrisk human papillomavirus (hrhpv) testing into AGC follow-up algorithms. Nevertheless, several series examining possible roles for hrhpv testing in patients with AGC Pap test results are accumulating Accordingly, we sought to analyze our histologic follow-up results for women with AGC Pap test findings and available hrhpv test results in a large, integrated, academic health system that was a participant in the atypical squamous cells of undetermined significance (ASC-US)/low-grade squamous intraepithelial lesion triage study 38 and an early adopter of widespread adjunctive hrhpv testing. MATERIALS AND METHODS Case Selection A retrospective study was approved by the institutional review board at the University of Pittsburgh Medical Center (Pittsburgh, Pennsylvania). The computerized records at Magee-Womens Hospital, University of Pittsburgh Medical Center, from June 1, 2005, to August 31, 2007, were searched for cases with AGC cytology. The final diagnoses of AGC were made by staff cytopathologists, based on categories defined by the 2001 Bethesda System 39 : AGC, either endocervical (AGC- EC), endometrial (AGC-EM), glandular cells not otherwise specified (AGC-NOS), and AGC favor neoplasia, either endocervical (AGC-EC-FN) or not otherwise specified (AGC- NOS-FN). Cases with cytologic interpretations of endocervical AIS and adenocarcinoma were not included in this study. Arch Pathol Lab Med Vol 134, January 2010 HPV Testing in AGC Pap Zhao et al 103

2 Table 1. Correlation of the Atypical Glandular Cell (AGC) Subcategories for 309 Cases With High-Risk Human Papillomavirus (hrhpv) DNA Testing and Histologic Diagnoses of Neoplastic or Malignant Lesions on Surgical Pathology Follow-up AGC/ASC-US (n = 97), AGC/ASC-H (n = 29), AGC/HSIL (n = 4), Cytologic Result HPV HPV HPV Age, y (range) 45.1 (19 84) 41.5 (21 76) 34.4 (24 45) Histologic diagnosis, % Squamous cell CIN 10 (58.8) 10 (12.5) 4 (33.3) 5 (29.4) 3 (100) 1 (100) CIN 2/3, No. 3 a 2 a 2 a 1 CIN 1, No Glandular cell cervical neoplasia 1 (5.9) 0 2 (16.7) 1 (5.9) 1 (33.3) 0 Invasive cervical carcinoma, No. 1 c AIS, No. 1 a 2 a 1 a Endometrial neoplasia 0 6 (7.5) Endometrial carcinoma 3 Endometrial hyperplasia 3 Ovarian neoplasia Serous carcinoma Abbreviations: AGC-EC, AGC-endocervical; AGC-EM, AGC-endometrial cells; AGC-NOS, AGC, not otherwise specified; AIS, adenocarcinoma in situ; ASC-H, atypical squamous cells, cannot exclude high-grade squamous lesion; ASC-US, atypical squamous cells of undetermined significance; CIN, cervical intraepithelial neoplasia (grades 1 and 2/3); HSIL, high-grade squamous intraepithelial lesion. a One case with CIN 2, CIN 3, and AIS; 4 cases with both CIN 2/3 and AIS. b Including 7 cases of endometrioid cancer and 1 case of papillary carcinoma. c Adenosquamous carcinoma (older patient, HPV 2 ). Some women with AGC Pap tests had coexisting squamous abnormalities, such as ASC-US; atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H); and high-grade squamous intraepithelial lesion (HSIL). These subsets of cases were separated from other cases with AGC and no coexisting squamous cell abnormalities. Papanicolaou tests with findings of AGC and coexisting squamous abnormalities were included in the study as well-defined AGC subsets: AGC and ASC-US, AGC and ASC-H, AGC and HSIL. For the purposes of this study, all AGC cases were divided into 1 of the 6 following diagnostic categories: AGC and ASC-US, AGC and ASC-H, AGC and HSIL, AGC-EC, AGC-EM, and AGC-NOS. Intentionally, AGC favor neoplasia is a rarely used designation at this facility. Available literature and extensive personal experience in Pap-related litigation and other retrospective reviews indicate that this AGC subtype is poorly reproducible. We prefer to emphasize to clinicians that all AGC subtypes reflect significant risk for underlying consequential disease and the need for recommended, but often neglected, initial follow-up tissue examinations. Surgical Pathology Follow-up Follow-up included review and recording of surgical pathology results, including cervical biopsies, endocervical curettages, cone excisions, loop electrosurgical excision procedures, endometrial biopsies and curettages, and hysterectomies. For patients undergoing 2 or more procedures during the follow-up period, only the histologic diagnosis most out of reference range was recorded. Findings of abnormal histopathologic lesions were categorized into 4 large groups: (1) cervical squamous lesions, including (CIN 1) and CIN 2/3; (2) cervical glandular lesions, including AIS and invasive adenocarcinoma; (3) endometrial lesions, including endometrial hyperplasia, complex atypical hyperplasia (CAH), and endometrial carcinoma; and (4) metastatic malignancy. In this article, CIN terminology is used exclusively for histologic diagnoses. Low-grade squamous intraepithelial lesion and HSIL terminology refers exclusively to cytologic results. Benign lesions, including endometrial polyps, endometritis, endocervical polyps, endocervical tubal metaplasia, and endocervical microglandular hyperplasia, were recorded. Each patient s age at time of AGC diagnosis, time elapsed from Pap test until colposcopic examination and cervical biopsy, follow-up procedures, and histologic findings were abstracted from the records. Papanicolaou Test Methods Papanicolaou tests specimens were collected by a highly diverse group of clinical providers, which included gynecologists, family physicians, internists, nurse practitioners, physician assistants, and trainees. All cytology specimens were processed and evaluated in the large, academic cytopathology laboratory at Magee-Womens Hospital and reported using current 2001 Bethesda System terminology. The Magee-Womens Hospital/ University of Pittsburgh Medical Center cytopathology laboratory is a large, subspecialized, academic hospital laboratory, which consistently reports more than Pap tests per year from a large integrated hospital health system and which serves a metropolitan area with a significantly older age profile than the national average. 47 Approximately 98% of Pap tests in this hospital are ThinPrep Pap tests prepared according to manufacturer s specifications from PreservCyt samples using an automated processor (ThinPrep 3000; Cytyc Corporation, Marlborough, Massachusetts). Staining of slides was done on a Sakura Tissue Tek Automated Slide Stainer (Cytyc) according to a US Food and Drug Administration approved manufacturer s protocol. Location-guided, computer-assisted screening of ThinPrep Pap tests slides was accomplished using the ThinPrep Imaging System (Cytyc). 48 The cytology laboratory at Magee-Womens Hospital employs conservative workload policies (mean 8.0; range, Pap tests per cytotechnologist screening hour) and has a continuous, quality improvement program that focuses on staff education through multiple slide-blinded reviews of abnormal and questionably abnormal, internal and external consultation, Pap test results that precede later tissue-documented cases of CIN 2/3, AIS, cervical carcinoma, and noncervical uterine carcinoma. Human Papillomavirus Testing Testing for hrhpv DNA was ordered by clinicians according to several ordering options: reflex testing, triggered by indeterminate abnormal atypical squamous cell Pap test results; routine cotesting with Pap testing in women 30 years and older; and hrhpv DNA cotesting, regardless of age or Pap test result. Detection of hrhpv DNA was performed using the commercially available US Food and Drug Administration approved Hybrid Capture 2 system 49 (Digene Corporation, Gaithersburg, Maryland). 104 Arch Pathol Lab Med Vol 134, January 2010 HPV Testing in AGC Pap Zhao et al

3 Table 1. Extended AGC-EM (n = 19), AGC-EC (n = 75), AGC-NOS (n = 85), Total (n = 309), HPV HPV HPV HPV 52.2 (42 77) 38.7 (19 72) 46.3 (27 84) 43.9 (19 84) (5.6) 15 (53.6) 12 (25.5) 7 (50.0) 3 (4.2) 39 (52.0) 32 (13.7) 4 a (25.0) 0 2 (14.3) 0 13 (17.3) 1 (0.4) a (22.2) 0 1 (2.1) 0 4 (5.6) 0 15 (6.4) b (2.1) (0.4) 1 1 Statistical Analysis Statistical analysis included a x 2 test and a Fisher exact test for small numbers using the SAS software system, Version 9.1 (SAS Inc, Cary, North Carolina). P,.05 was considered statistically significant. RESULTS AGC Subcategories and Histopathologic Outcomes During the June 1, 2005, to August 31, 2007, 27-month study period, Pap tests were reported. The number of AGC results reported in this period was 1021 (0.41%). Test results for hrhpv from residual-vial fluid were available in 309 of 662 cases (46.7%) of AGC that also had available tissue follow-up results. The 309 cases of AGC were subclassified as AGC and ASC-US (n 5 97; 31.4%), AGC and ASC-H (n 5 29; 9.4%), AGC and HSIL (n 5 4; 1.3%), AGC-EM (n 5 19; 6.1%), AGC-EC (n 5 75; 24.3%), and AGC-NOS (n 5 85; 27.5%). The ages of women who had AGC ThinPrep Pap and reflex Hybrid Capture 2 hrhpv DNA test results ranged from 19 to 84 years, with a mean age of 44 years. The ages in different groups are listed in Table 1. The mean histologic followup period was 2.7 months, with a range of 10 days to 22 months. Of the 309 cases of AGC, 97 women (31.4%) had neoplastic histologic follow-up results, including 71 cases with CIN (23.0%); 14 cases with cervical glandular neoplasia (4.5%), which included 4 cases with both AIS and CIN 2/3; 15 cases with endometrial neoplasias (4.9%), and 1 case with metastatic ovarian carcinoma (1%). The incidence of CIN was significantly higher than that of cervical glandular neoplastic lesions and endometrial neoplasias (both P,.001). The incidences of cervical glandular and endometrial neoplasias showed no statistical difference (P 5.85). A positive hrhpv DNA result was obtained in 75 of the 309 women (24.3%) with AGC Pap test results and available histologic follow-up. The hr rates were highest in women with AGC and HSIL (75.0%), AGC and ASC-H (41.4%), and AGC-EC (37.3%) and were lowest in the AGC-EM group (5.3%). Women with AGC results had a higher risk for detection of CIN (52.0%) and glandular neoplasia (17.3%) than women with HPV 2 AGC results (13.7% for CIN and 0.4% for endocervical glandular lesions). The differences were statistically significant (P,.001). When the histologic results were analyzed with respect to the initial Pap test interpretive subgroups and the hrhpv test results, an interpretation of AGC-EM was most often (22.2%) associated with a significant endometrial lesion and a negative HPV result. Negative hrhpv DNA results were present in all women with AGC Pap tests who, on histologic follow-up, had endometrial hyperplasia or endometrial cancer. Of the neoplastic lesions in the AGC-EM follow-up group, 80.0% (4 of 5) were endometrial in origin. In both AGC-EC and AGC-NOS groups, the incidence of CIN was higher than for cervical glandular lesions (AGC-EC, 27 versus 7; AGC- NOS, 10 versus 2). Of the hr AGC-EC and AGC-NOS cases, 25.0% and 14.3%, respectively, had cervical glandular lesions. One HPV 2, AGC 2, ASC-H case had followup findings of an endocervical adenosquamous carcinoma, but no cases of AGC-EC or AGC-NOS with negative hrhpv showed cervical glandular neoplasia. In the summarized initial group of Pap test results with AGC and abnormal squamous cells, CIN was found in 52.0% and 13.7% of women who were hr and hrhpv 2, respectively (P,.001). Cervical intraepithelial neoplasia associated with an HPV 2 AGC result was CIN 1 in 31 of 32 cases (96.9%). Histologic cervical glandular neoplasias were found in 17.3% and 0.4% of women who were hr and hrhpv 2, respectively (P,.001). Table 1 summarizes the follow-up test with abnormal histologic results based on the initial Pap test subgroups and hrhpv test results in details. Age and Histopathologic Outcomes When age, hrhpv test results, and precancerous (CIN 2/3, AIS, CAH) and malignant (carcinoma) histologic outcomes alone were analyzed (refer to Table 2), CIN 2/3 was strongly related to hr AGC results in women younger than 40 years. All AIS patients were younger than 50 years. Six of 10 AIS cases (60%) were detected in women aged 40 to 49 years, and all 10 cases (100%) followed AGC results. Endometrial neoplasias (CAH and carcinomas) predominated in women 50 years and older. In total, 13 of 14 cervical glandular neoplasias cases (92.9%), 10 of 10 AIS cases (100%), and 3 of 4 cervical adenocarcinoma cases (75%) followed hr AGC results. The positive predictive value, negative predictive value, sensitivity, and specificity for reflex hrhpv DNA testing with AGC to detect cervical glandular neoplasia were 17.3%, 99.6%, 92.9%, and 79.0%, respectively. Arch Pathol Lab Med Vol 134, January 2010 HPV Testing in AGC Pap Zhao et al 105

4 Table 2. Age and Subsequent Significant Histologic Diagnoses in Women With Atypical Glandular Cell Papanicolaou Tests and High-Risk Human Papillomavirus (hrhpv) Test Results,40 y $40 y to,50 y $50 y Total Histologic Diagnoses (n = 41) HPV (n = 64) (n = 19) HPV 2 (n = 108) (n = 15) HPV (n = 62) (n = 75) HPV (n = 234) CIN 2/3 10 a (24.4) 1 (1.6) 2 b (10.5) 0 1 (6.7) 0 13 (17.3) 1 (0.4) Invasive cervical adenocarcinoma 2 (4.9) 0 1 (5.3) (1.6) 3 (4.0) 1 (0.4) AIS 4 a (9.8) 0 6 b (31.6) (13.3) Endometrial carcinoma (1.9) 0 6 (9.7) 0 8 (3.4) CAH (1.9) 0 3 (4.8) 0 5 (2.1) Metastatic carcinoma (0.9) (0.4) Total 13 (31.7) 1 (1.6) 8 (42.1) 5 (4.6) 1 (6.7) 10 (16.1) 22 (29.3) 16 (6.8) Abbreviations: AIS, adenocarcinoma in situ; CAH, complex atypical endometrial hyperplasia; CIN 2/3 indicates cervical intraepithelial neoplasia grades 2/3. a There were 3 cases with both AIS and CIN 2/3. b There was 1 case with both AIS and CIN 2/3 for a total of 4 cases with AIS and CIN 2/3, all. However, HPV 2 AGC results were present in 10 of 13 carcinomas (76.9%) detected after AGC Pap test findings in this series, all in women 40 years or older, including endometrial adenocarcinomas (n 5 8), ovarian carcinoma (n 5 1), and cervical adenosquamous carcinoma (n 5 1) in a woman in her 50s. Benign Histopathologic Outcomes Benign histologic follow-up results of endometrial and endocervical polyps, endometritis, endocervical tubal metaplasia, and endocervical microglandular hyperplasia are summarized in Table 3. COMMENT This study from a large, integrated, academic health system supports accumulating data that adjunctive hrhpv testing has substantial clinical utility in women with AGC Pap test findings As noted in previous studies, the largest group of clinically significant (precancerous) lesions or malignant lesions detected after AGC Pap test results were noninvasive high-grade CIN, CIN 2/ 3 and/or AIS. 24,29,30,32,33 A positive HPV test result with an AGC Pap test result significantly increases the positive predictive value for high-grade CIN and AIS. Age, in our data set, was strongly associated with different patterns of histologic outcome. Of 20 diagnosed cases of high-grade cervical intraepithelial neoplasia (CIN 2/3, AIS), 19 cases (95%) were in women younger than 50 years. None of 10 cases of AIS were detected in women 50 years or older. All 3 carcinomas detected in women younger than 50 years with AGC results were cervical adenocarcinomas. The only cervical carcinoma detected in a woman 50 years or older was an adenosquamous cervical carcinoma with an HPV 2 AGC/ASC-H Pap test result. In particular, 10 of 13 carcinomas (77%) detected after AGC Pap test findings in this series were in women 40 years and older with HPV 2 AGC Pap test results. Several recent clinical trials have proposed the possibility of using HPV testing as a primary screening test in older women, with cytology reserved for women with positive HPV test results. 50,51 This approach would have yielded negative screening test results for 10 of 13 carcinomas (77%) detected with AGC Pap test results in this study, including 1 of 4 cervical carcinomas (25%). In the largest reported age-stratified series of cervical adenocarcinomas, 49 of 132 cervical adenocarcinomas (37.1%) in women 40 years and older and 39 of 78 cervical adenocarcinomas (50.0%) in women 50 years and older tested negative for HPV. 52 The absence of HPV has been significantly associated with high age at diagnosis for cervical adenocarcinoma. 53 It would be unfortunate if some of the complementary benefits of cytologic screening and adjunctive HPV cotesting were to be lost in proposed algorithms employing primary HPV screening Whether or not cytologic screening for endometrial adenocarcinoma is a realistic benefit of cytologic screening remains a matter of some debate In this study, the largest group of AGC-detected carcinomas were endometrial carcinomas, all detected in women 40 years and older. Atypical glandular cell Pap test results also detected 5 cases of precancerous complex atypical endometrial hyperplasia. Similar results have been reported, especially in studies of AGCs favored to be endometrial in origin 60,61 or of AGCs in postmenopausal women. 62 Several investigators have noted that precise discrimination as to the likely site of origin of AGCs is often uncertain, 1,63 precluding clinical algorithms based solely on cytologicsuspected site of origin. Our results are consistent with, Table 3. Significant Benign Histologic Diagnoses and High-Risk Human Papillomavirus (hrhpv) Results Reported in 212 Cases of Atypical Glandular Cells With Nonneoplastic Follow-up Histologic Diagnoses hr (n = 27), hrhpv (n = 185), Total (n = 212), Endometrial polyp 1 (3.7) 23 (12.4) 24 (11.3) Endometritis 0 2 (1.1) 2 (0.9) Endocervical polyp 1 (3.7) 7 (3.8) 8 (3.8) Endocervical tubal metaplasia 1 (3.7) 13 (7.0) 14 (6.6) Microglandular hyperplasia 1 (3.7) 6 (3.2) 7 (3.3) Benign, other 23 (85.2) 137 a (74.1) 160 a (75.5) a A total of 3 cases had 2 benign lesions. 106 Arch Pathol Lab Med Vol 134, January 2010 HPV Testing in AGC Pap Zhao et al

5 and support, the most recent 2006 consensus guidelines for the management of women with AGCs, not otherwise specified. 64 A hoped for, but as yet undocumented, benefit of HPV testing in screening for developing cervical glandular neoplasia would be detection of glandular neoplasias at earlier and more prognostically favorable stages. 6 As noted previously, the effect of screening to prevent endocervical adenocarcinoma has been far less than for squamous cancers in population studies. 3 7 For most women with HPV-associated endocervical carcinoma, 52,65 more widespread HPV cotesting could offer an additional test to potentially offset sampling, screening, or interpretive false-negative cytology results, 66 particularly in women younger than 50 years. The benefits of HPV testing in screening for glandular cervical neoplasia may also supplement reported benefits associated with liquidbased cytology and computer-assisted screening. 2,67 69 References 1. 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