We reviewed potential clinical correlates of abnormal cytology. Patients treated with radiation therapy had more abnormal Pap test results (391/2,646, 14.8%) compared with those treated with surgery alone (133/1,521, 8.7%); however, the type of treatment, surgery, or radiation or chemoradiation was not associated with colposcopy for abnormal Pap test results (P=.49). When stratified by stage and institution, patients treated with surgery were less likely to have abnormal results (OR 0.41, 95% CI 0.29–0.59, P<.001). The majority of patients with stage II or higher cancers were treated with radiation or chemoradiation and the majority of patients with stage IA1 or IA2 cancers were treated with surgery. The stage IB1 and IB2 group was more evenly divided between those patients treated with radiation and those patients treated with surgery. In this group, controlling for stage and institution, those patients treated with radiation had more abnormal Pap test results (17% compared with 9.4%, P<.001) (Table 5).
We attempted to determine the association between cancer recurrence and abnormal cytology. Cancer recurrence was documented in 147 (15.8%) women, with 12 cases (8.1% of recurrences) detected by Pap test. All the recurrences detected by Pap test were in the first 5 years after treatment. The latest recurrence detected by Pap test was 3.6 years after diagnosis. Most (8/12) were detected in the first 2 years. All except one of the women with recurrences had Pap test results of ASC-H or worse. One patient with AS-CUS+HPV had a visible lesion when called back for assessment 2 months after Pap testing. Colposcopy for cytology less than HSIL without a visible lesion on examination did not detect any recurrence or CIN 3. Of the six cases of recurrence detected on Pap test at Washington University in St. Louis, all were assessed by positron emission tomography. Five had distant disease on positron emission tomographic scan, all opted for chemotherapy, and all ultimately died of disease. One had disease limited to the pelvis, but this included positron emission tomography 5-fluoro-deoxyglucose avid pelvic lymph nodes. She was offered an exenteration but declined and underwent Syed needle radiotherapy and chemotherapy. She died of her disease 11 months later. Of the two cases of recurrence detected by Pap test at the University of Alabama Birmingham, one patient had disease limited to the pelvis and underwent a total pelvic exenteration; she remains without evidence of disease after 2 years of follow-up. The second patient had metastatic disease in the chest on positron emission tomographic scan and elected to be treated elsewhere. Four cases of recurrence were detected by Pap test at the University of Kentucky. Two patients had been treated initially with radical hysterectomy and received chemoradiation for recurrence and are without evidence of disease after 3 and 7 years of follow-up, respectively. One patient had local recurrence treated with chemotherapy, and she died of disease. The last patient had distant disease on computed tomographic scan and failed treatment with combination platinum-taxane therapy. She was alive with disease after 15 months of observation. Thus, Pap surveillance appears to have led to salvage for recurrence in 3 of 929 (0.3%) cervical cancer survivors. Assuming this was a representative sample of the population, 810 Pap tests would be required to detect at least one cancer with 90% probability.
Abnormal cervicovaginal cytology is a common problem among cervical cancer survivors, with nearly one-third of cervical cancer survivors having at least one abnormal Pap test result during the first years after treatment. This presents a significant survivorship burden. Despite the frequency of abnormality, clinicians at leading academic centers lack consensus on appropriate follow-up. Only 31% of abnormal Pap test results were evaluated by colposcopy in this group, and rates were lower for those women with lesser cytologic abnormalities. On the other hand, 20% of women with ASC-H, 25% of women with atypical glandular cells, 43% of women with HSIL, and 67% of women with Pap test results read as favor neoplasia who underwent colposcopy had CIN 2 or worse. For women without distant disease or limiting comorbidity, colposcopy is indicated for cervical cancer survivors with these grades of cytologic abnormality.
On the other hand, most abnormalities in our series did not reflect a cervical or vaginal recurrence of their cancer, or a significant new premalignant change. In the absence of symptoms or visible lesions, cervical cancer survivors with ASC-US and LSIL cytology can be followed without colposcopy.
Our data build on those of others. Larson et al3 evaluated 249 patients treated with radical hysterectomy and pelvic lymphadenectomy followed with a standard protocol of clinical history, physical examination, and vaginal cytology every 3 months for the first postoperative year, every 4 months for the second postoperative year, and then every 6 months for 3 years. In this study, five women (18% of recurrences) were diagnosed with vaginal cytology, and all except one patient had either symptoms or physical examination findings. This study reported vaginal cytology as either malignant or negative, so comparisons to our study are limited.
Likewise, Soisson et al4 reviewed the records of 203 patients treated for cervical cancer with radical hysterectomy and lymphadenectomy who had 2 years of follow up or more. Patients had the same surveillance protocol as the Larson et al study, with clinical history, physical examination, and Pap testing as previously described. In this study, 119 patients were treated with postoperative radiation for high-risk disease. Vaginal cytology was considered positive only if malignant cells were identified. Four patients with recurrence were noted to have malignant cytology. Two of these patients had no symptoms or examination findings and Pap testing was the only abnormality in their screening. Subsequently, both received radiation for central recurrence and were cured. The authors noted that in their population, 2,639 Pap tests were required to detect two cancers amenable to treatment. In our study, 812 Pap tests were required to detect one cancer, and of those cancers detected only three were a central recurrence treated with apparent cure. In contrast, Bodurka-Bevers et al6 reviewed 1,026 cervical cancer patient records from 1983 to 1993 and found that traditional Pap testing did not detect a single asymptomatic recurrence. Without data on colposcopy from previous studies, we cannot make a direct comparison in detection rates between traditional Pap testing and liquid-based cytology; however, given the poor detection rate of liquid-based cytology in our study, it seems there was no obvious improvement.
The strengths of this review are its large number of patients from multiple institutions, the completeness of the data, and the length of follow-up. It is limited, however, by its retrospective nature and by limited use of colposcopy and long interval of data collection, during which time practices may have changed. In particular, we cannot exclude the possibility that women with ASC-US or LSIL could have developed local recurrence over further surveillance. For this reason, colposcopy may be indicated for cervical cancer survivors with persistent ASC-US or LSIL.
Persistence of carcinogenic HPV in women treated for cervical cancer is a sensitive indicator of risk for recurrence.10 Our data show that carcinogenic HPV is common in women with cervical cancer, as reflected by HPV DNA positivity in women with ASC-US and by LSIL results. Prospective studies are needed to explore the specificity, negative predictive value, and cost-effectiveness of HPV testing as a surveillance strategy for cervical cancer before it can be adopted clinically.
Our data suggest that Pap testing has limited utility in the detection of recurrences, with only 8% of recurrences detected by Pap and only three patients salvaged. The cost of cytologic surveillance, including colposcopy when necessary, may outweigh the benefit of detection. The reality of limited resources and need for cost containment suggests that continued cervical cytology surveillance should be questioned. Cost-effectiveness analysis comparing surveillance strategies including liquid-based cytology, clinical examination, patient education regarding symptoms, and positron emission or computed tomographic imaging or both, is needed. Prospective surveillance trials are also needed to examine new strategies for earlier detection of recurrence.
Despite the lack of data on this subject, cytology should remain a component of surveillance.2 In patients treated for cervical cancer, regardless of stage or treatment modality, the low yield of colposcopy and biopsy for cytology less than ASC-H in our data suggests that in the absence of a visible lesion, patients with ASC-US or LSIL can be followed without colposcopy unless abnormalities persist. Women with ASC-H, HSIL, and other severe abnormalities deserve further evaluation with colposcopy and biopsy.
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© 2011 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.
10. Song YJ, Kim JY, Lee SK, Lim HS, Lim MC, Seo SS, et al.. Persistent human papilloma virus DNA is associated with local recurrence after radiotherapy of uterine cervical cancer. Int J Cancer 2010 [Epub ahead of print].