Cervical cancer is the third most common gynecologic cancer in the United States (US) with more than 13,000 new diagnoses and 4,000 cancer deaths annually.1 Cervical cancer disparately affects women of black race (8.4/100,000) or those of Latinx (8.9/100,000) and/or native American (8.1/100,000) ethnicity more than white and Asian females (7.4 and 6.9/100,000, respectively).1 The rate of new cervical cancer is highest in Mississippi, Louisiana, and Oklahoma at 10.2, 9.6, and 9.4 per 100,000 women, respectively.2 The humanpapilloma virus (HPV) is implicated in nearly 99% of all cervical cancers of all the following 3 major histologies: squamous cell, adenocarcinoma, and small cell neuroendocrine carcinoma.3 The natural history of HPV infections and subsequent progression from intracellular changes to invasive cervical cancer is well described with many opportunities for primary and secondary prevention along the disease pathway.
Once high-grade cervical intraepithelial neoplasia is identified, the standard of care is to proceed with an excisional procedure. The findings of invasive cancer on colposcopic or excisional biopsy warrant referral to a gynecologic oncologist for further staging and treatment planning. Treatment for invasive cervical cancer includes radical hysterectomy with pelvic lymphadenectomy for locally contained disease; stages Ia2, Ib1, or rarely even IIa1 with postoperative radiation therapy-based risk stratification related to intraoperative findings. Simple hysterectomy is a treatment option for those women with very early disease (stage Ia1: no visible lesion, tumor depth ≤ 3 mm and width ≤ 7 mm and no lymph vascular space invasion). Outside of this indication, simple hysterectomy is not the standard of care for surgical management of cervical cancer. Chemoradiation is indicated for all bulky and locoregionally advanced cervical cancer (LACC), typically stage IB2 or greater.
Simple hysterectomy is the most common gynecologic surgery in the US, and the most common benign indications for hysterectomy include uterine fibroids (51%), abnormal uterine bleeding (AUB) (42%), pelvic pain/endometriosis (30%), and pelvic organ prolapse (18%).4 Preoperative evaluation for benign hysterectomy includes a thorough history and physical, including previous cervical cancer screening. Although most providers caring for women understand the basics of cervical cancer screening, it has been shown that there are serious gaps in patient understanding. Studies have demonstrated that most women cannot distinguish a Pap from a routine pelvic examination and this lack of understanding is more prevalent among younger women.5 Thus, it is paramount that a cervical cancer screening history is corroborated by medical records rather than relying on the memory of the patient.
Failure to identify invasive cancer in the preoperative work-up for a simple hysterectomy may result in incidental invasive cervical cancer. Because of the lack of standardized terminology, we have defined “incidental invasive cervical cancer” as any invasive cervical carcinoma found after simple hysterectomy. We view that incidentally found invasive cervical cancer can present as 2 clinically distinct entities: either “occult invasive cervical carcinoma” (OICC) or cancer that is microscopic, contained within in the hysterectomy specimen and likely not apparent on routine examination or as a “cut-through hysterectomy” (CTH). Cut-through hysterectomy refers to the performance of a simple hysterectomy in the setting of a large bulky cervical cancer that has spread to the parametria or pelvic side wall and is therefore “cut through” at time of surgery. Cut-through hysterectomy implies a higher-stage disease with positive surgical margins and potentially gross residual disease. Although finding incidental invasive cervical cancer can be associated with a significant failure of the cervical cancer screening itself or a failure of the surgeon/clinician in using appropriate preoperative evaluation, it is not an absolute negligent act in an otherwise asymptomatic patient. For any stage greater than IA1, simple hysterectomy is an inadequate treatment and reoperation, and salvage chemoradiation or a combination of the two may be required. Moreover, evidence shows that those with LACC, who undergo a CTH with gross and/or bulky residual disease, are at greater risk for bladder and bowel toxicity due to required postsurgical radiation therapy.6 Chemoradiation for LACC is curative in intent and comprises external beam radiation to shrink the bulky tumor followed by high-dose brachytherapy to sterilize the cervical tumor bed and parametria. Without the uterus and active tumor in place, external beam radiation is more likely to be administered with the aid of interstitial implants resulting in increased procedural invasiveness, bladder and bowel toxicity, and potential for reduced survival given distorted anatomy and parametrial retraction to the pelvic side wall.6
MATERIALS AND METHODS
Our study was proposed as a retrospective study and approved by the institutional review board of University of Oklahoma and Stephenson Cancer Center, Oklahoma City, Oklahoma, Institutional Review Board Number 8445. A search of historical tumor board minutes and departmental databases from January 1987 to May 2018 was performed to identify patients who either underwent radical parametrectomy and bilateral pelvic lymphadenectomy or received radiation therapy using perineal (interstitial) implants with a diagnosis of invasive cervical cancer after simple hysterectomy. Inclusion criteria were women older than 18 years with a documented cervical cancer screening history on referral records that had subsequently undergone simple hysterectomy and were found to have incidental invasive cervical cancer on surgical pathology. All histologies were included. Medical records were reviewed and the following data were obtained: demographics, tumor histology and grade, surgical margin status, stage, referring surgeon, indications for initial surgery, preoperative evaluations including Pap smears, and cervical biopsies if applicable. A generally acceptable cervical cancer screening pathway was devised based on the updated 2012 guidelines7 and applied to each patient (see Figure 1). Because of the large time interval from which subjects were collected (1987–2018) and variations in screening recommendations, having not received a Pap screening was defined as no documented Pap smear in 5 or more years preceding hysterectomy for those women 70 years and younger. Low-grade cytology or pathology changes were considered inappropriately managed if no follow-up was obtained within 1 year of antecedent screening test. Humanpapilloma virus status was not collected for the purposes of this study because it was not consistently collected and/or reported. Subjects were classified as either having had (A) appropriate cervical cancer screening, or no deviations from our generalized screening pathway, resulting in a failure of the cervical cancer screening pathway, or (B) a deviation from recommended screening guidelines resulting in provider failure of proper execution of screening guidelines (see Figure 1). If patients were found to have a deviation in cervical cancer screening, the step at which the deviation occurred was further defined and tested against clinicopathologic variables for significance.
All statistical analyses were performed using SAS Version 9.4 (SAS Institute, Cary, NC). Two-group comparisons of continuous variables were performed using the 2-sample t test. Two-group comparisons of binary variables were performed using the χ2 test (or Fisher's exact test in the presence of sparse cell count). A 2-sided p value of <.05 defines statistical significance.
We identified 59 eligible subjects referred to the University of Oklahoma after simple hysterectomy from 1987 to 2018. The patient ages ranged from 30 to 82 years with a median age of 43 years. The median body mass index was 25 with a range from 18 to 47. Fifty-four (92%) of the women were white. Reported indications for surgery included AUB in 36 patients (61%), pain in 14 patients (24%), pelvic mass in 10 patients (17%), and fibroids in 6 patients (10%). For 25 patients (42%), cervical dysplasia was listed as at least 1 of the indications for hysterectomy. Most subjects (n = 44, 75%) were operated on by a general gynecologist, and a majority were insured (n = 43, 78%). Abdominal hysterectomy was the most commonly performed surgery (n = 36, 61%), followed by transvaginal (n = 15, 25%), total laparoscopic (n = 7, 12%), and 1 supracervical hysterectomy was completed. Regarding histology, approximately two-thirds (n = 37) of the cases were squamous cell carcinoma, 19 (32%) were cervical adenocarcinoma, and 3 (5%) were undifferentiated or neuroendocrine. Sixty-four percent (n = 38) of the women were stage Ia1 to Ib1; however, we also identified a large proportion, 24% (n = 14) of women with advanced stage carcinoma: stage Ib2 to IV (see Table 1). For those with OICC or CTH, 45 patients (76%) were found to have had inappropriate execution of screening guidelines, whereas a false negative or failure in the screening process itself was found in only 14 patients (24%). For those with inappropriate screening, 38% (n = 17) had not received a routine screening Pap, 22% (n = 10) had a Pap that was not triaged appropriately with colposcopy, 18% (n = 8) received colposcopy and biopsy but did not receive indicated excision, and lastly 22% (n = 10) had an excisional procedure with biopsy results that would have warranted further sampling or referral to gynecologic oncology. To determine whether there were any identifiable risk factors for inappropriate screening, we tested the following independent variables against each deviation along the screening process: (1) failure to obtain Pap, (2) failure to obtain colposcopy/cervical biopsy; (3) failure to perform excisional procedure; and (4) failure to re-excise or refer to gynecologic oncology (see Figure 1). For each step (1–4) along the screening pathway, we found no statistically significant independent risk factors associated with having had a deviation including patient age, body mass index (BMI), cervical histology, or insurance status (see Table 2). For the subset of patients who had appropriate but false-negative screening, we also found no statistically significant risk factors including age, BMI, histology, and insurance status (see Table 3). Interestingly, for 14 patients with stage Ib2 or greater disease after a true CTH, we found that dysplasia was significantly less likely to be listed as an indication for surgery (p = .001), whereas AUB (p = .003) or pelvic mass (p = .03) is significantly more likely to be listed as an indication for hysterectomy (see Table 4). Conversely, there was no statistically significant relationship between higher-stage and risk of a deviation from the screening pathway, histology, or surgical approach.
The incidence and risk factors for OICC/CTH in the US are not well described. Current published literature is composed largely of small retrospective studies of Asian populations where cervical cancer is more prevalent and resources are limited.6,8–10 Most US literature regarding incidentally found that invasive cervical cancer is focused on the challenges of treatment planning. Significant attention has been paid to the safety and utility of radical parametrectomy versus observation versus chemoradiation after simple hysterectomy for invasive cancer; however, these studies are largely based on early-stage disease with negative surgical margins.11–16 In contrast, we present a study of OICC/CTH of all stages hoping to emphasize that the best management strategy is prevention and identification of risk factors associated with incidental invasive carcinoma. Our study is limited by the small single institution sample size because of the relative rarity of this outcome and lacks sufficient statistical power to detect significant risk factors. In addition, the population of Oklahoma, while socioeconomically diverse is relatively racially and ethnically homogenous, limits investigation into the roles of disparate care along racial and ethnic lines. Despite these challenges, when compared with similar studies, we are able to present a relatively large US cohort of women and a large proportion of true CTHs, a truly preventable condition. Similar to previously published Chinese reports, we found that most early stage and OICC are likely a result of inappropriate screening execution rather than a failure of the screening test itself.6,10 Although our study was not designed or powered to evaluate this question specifically, we noted that for those with a true CTH, AUB and/or pelvic mass were significantly more likely be noted as an indication for hysterectomy. This finding lends to our hypothesis that women presenting with bleeding and/or masses are more likely to undergo urgent or emergent hysterectomies resulting in a suboptimal preoperative assessment, which includes collecting cervical cancer screening history. In a review of the 44 patients with deviation from screening guidelines, we found 4 cases in which hysterectomy was rushed, urgently referred from emergency department and scheduled for surgery within 7 days of referral to gynecology or emergently performed at time of presentation. All 4 of these cases were cases in which a Pap smear was indicated but not obtained. However, because of reliance on complete and clear operative documentation for each referral, no significant conclusions could be drawn. However, as gynecologic oncologists practicing at a large tertiary referral center, we find that there is rarely a case of vaginal bleeding so persistent or severe that it cannot be temporized, including use of intraoperative vaginal packing and Foley catheter placement. Simple hysterectomy performed for a large bleeding cervical mass with no previous work-up should be avoided and rather biopsies obtained if feasible and prompt referral or transfer should be requested. The consequences of a true CTH are great; a patient who is potentially curable with chemoradiation alone has become decidedly less so because of disrupted anatomy and decreased ability to direct radiation to the tumor. Retracted tumor at the pelvic side wall remains difficult to isolate and target with radiation and thus incurs a higher risk of bowel and bladder toxicity resulting in decreased dosing and effectiveness. Thus, we strongly encourage all surgeons performing hysterectomy to elicit and obtain cervical cancer screening before any elective surgery. For a history of dysplasia, extra care must be taken to ensure that complete work-up, including colposcopy, biopsy, and excision procedures, was completed if indicated. Women older than 70 years with a history of high-grade dysplasia should continue to be screened according to American Society for Colposcopy and Cervical Pathology guidelines7 and postmenopausal bleeding should be thoroughly worked up for any potential malignant causes. In the instance in which uterine versus cervical origin of bleeding or abnormal cells cannot be determined, consider the addition of HPV testing for additional clinical information. In the setting of acute bleeding, particularly with known pelvic mass, care should be taken to delay surgery until cervical cancer screening history can be elucidated or updated. If complete records are not known to the patient and supporting documentation is not available, then any urgent hysterectomy should be preceded by a thorough examination, under anesthesia if necessary, with biopsies of any abnormality for frozen and permanent pathological evaluation. For emergent hysterectomy in the setting of acute hemorrhage, we recommend immediate transfusion, placement a Foley catheter, attempting vaginal packing, and expedited transfer to a tertiary referral medical center where gynecologic oncology services are readily available.
Future directions following this study include continuing patient and provider education regarding adherence to preoperative cervical cancer screening and early referral for suspected invasive cervical cancer. In addition, we continue to collect data on management and survival outcomes of incidentally found cervical cancer, especially in cases of true CTH.
The most common cause of incidental invasive cervical cancer at the time of simple hysterectomy was failure of providers to adhere to cervical cancer screening guidelines. Less frequently, false-negative screening was the cause. No statistically significant independent risk factor in either group was identified in this single institution study. The indication for hysterectomy may be related to the risk of finding bulky or OICC after simple hysterectomy. Illustrated is the importance of continuing patient and provider education regarding adherence to cervical cancer screening and its role in preoperative evaluation for benign hysterectomy, especially for those women with a history of cervical dysplasia, AUB, and/or a pelvic mass.
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Keywords:Copyright © 2019 by the American Society for Colposcopy and Cervical Pathology
cervical cancer; occult cervix cancer; incidental cervical cancer; cut through hysterectomy; simple hysterectomy