Cervical Intraepithelial Neoplasia Grade 1
The recommended management of women with a histologic diagnosis of CIN1 preceded by an ASC-US, ASC-H, or LSIL cytology is follow-up with either HPV DNA testing every 12 months or repeat cervical cytology every 6 to 12 months. If the HPV DNA test is positive or if repeat cytology shows ASC-US or greater, colposcopy is recommended. If the HPV test is negative or two consecutive repeat cytology tests are negative, return to routine cytologic screening is recommended. If CIN1 persists for at least 2 years, either continued follow-up or treatment with excision or ablation can be performed. Hysterectomy as the primary and principal treatment for histologically diagnosed CIN1 is not recommended. For CIN1 preceded by HSIL or AGC not otherwise specified cytology, either a diagnostic excisional procedure or observation with colposcopy and cytology at 6-month intervals for 1 year is acceptable. If observation with cytology and colposcopy is elected, a diagnostic excisional procedure is recommended for women with repeat HSIL or AGC not otherwise specified cytologic results at either the 6- or 12-month visit. The recommended management of pregnant women with a histologic diagnosis of CIN1 is follow-up without treatment.
Cervical Intraepithelial Neoplasia Grades 2 and 3
Both excision and ablation are acceptable treatment modalities for women with a histologic diagnosis of CIN2/3 and satisfactory colposcopy. If the colposcopy is unsatisfactory or the lesion is large, excision should be performed with ablation not recommended.
For women <25 years of age with a histologic diagnosis of CIN2, either treatment or observation for up to 24 months using both colposcopy and cytology at 6-month intervals is acceptable, provided colposcopy is satisfactory. Treatment is recommended if CIN3 is subsequently identified or if CIN2/3 persists for 24 months.
In the absence of invasive disease, additional colposcopic and cytologic examinations are acceptable in pregnant women with a histologic diagnosis of CIN2/3 at intervals no more frequent than every 12 weeks. Repeat biopsy is recommended only if the appearance of the lesion worsens or if cytology suggests invasive cancer. Reevaluation with cytology and colposcopy is recommended 6 weeks postpartum.
Treatment of Adenocarcinoma In Situ
Hysterectomy is preferred for women who have completed childbearing and have a histologic diagnosis of AIS. Conservative management with cervical conization is acceptable if future fertility is desired. If the margins of the specimen are involved or endocervical sampling obtained above the cone bed contains CIN or AIS, reexcision to increase the likelihood of complete excision is recommended. Long-term follow-up is recommended for women who do not undergo hysterectomy.
Treatment of Invasive Cervical Carcinoma
Treatment of invasive cervical cancer depends on many factors, including disease stage, patient age, performance status, fertility of the patient, and skill and resources of the care providers. The treatment of cervical cancer is described by stage of disease in the following sections.
Hysterectomy Classification According to Piver et al
In 1974, Piver et al (37) categorized hysterectomy into five classes according to the extent of tissue resection.
Simple hysterectomy is removal of the uterus along with the cervix in an extrafascial manner without incision into the cervical or uterine tissue.
Modified radical hysterectomy is removal of the uterus with part of the paracervical and parametrial tissue in the lateral aspect of the cervix after dissecting the ureters away. Half of the cardinal ligament (lateral aspect), the uterosacral ligament (posterior aspect), and one-third of the upper vagina are all removed. This is usually performed in cases of stage IA2 or persistent or local recurrent cervical cancer after radiation therapy.
Radical hysterectomy is removal of the uterus in a manner similar to that of class II hysterectomy, but the tissue structure is removed to a greater extent, generally close to the pelvic side wall laterally and sacrum posteriorly; the upper half of the vagina is also removed. Conventionally, this class of hysterectomy is done for cases of stage IB to IIA disease. However, it can be performed for persistent or recurrent cervical cancer after primary radiation therapy as an alternative procedure to exenteration in highly selected patients. These include patients with stage IB to IIA disease at primary diagnosis, no clinical parametrial involvement, and a tumor diameter of ≤4 cm at the time of recurrence.
Extended radical hysterectomy is complete removal of the cervix, uterus, parametrial tissue, cardinal, and uterosacral ligaments. In addition, the ureter is completely dissected from the vesicouterine ligament, and the superior vesical artery is sacrificed. This is a possible procedure for central locoregional recurrence.
Partial exenteration is partial excision of the involved organs. In addition to the above procedures, this encompasses the removal of the distal ureter and urinary bladder. This procedure is performed in cases of central recurrence.
Hysterectomy Classification According to Cibula et al
A more recent classification has been introduced by Cibula et al (38).
Type A: Minimum Resection of Paracervix
This resection is an extrafascial hysterectomy, in which the position of the ureters is determined by palpation or direct vision (after opening of the ureteral tunnels) without freeing the ureters from their beds. The paracervix is transected medial to the ureter but lateral to the cervix. The uterosacral and vesicouterine ligaments are not transected at a distance from the uterus. Vaginal resection is generally at a minimum, routinely less than 10 mm, without removal of the vaginal part of the paracervix (paracolpos).
Type B: Transection of Paracervix at the Ureter
Partial resection of the uterosacral and vesicouterine ligaments is a standard part of this category. The ureter is unroofed and rolled laterally, permitting transection of the paracervix at the level of the ureteral tunnel. The caudal (posterior, deep) neural component of the paracervix caudal to the deep uterine vein is not resected. At least 10 mm of the vagina from the cervix or tumor is resected.
Type C: Transection of Paracervix at Junction With Internal Iliac Vascular System
The Q–M classification system distinguishes between a type C1 procedure, which corresponds to the nerve-sparing modification, and the type C2 procedure, which aims for a complete parametrial resection. Type C1 requires separation of two parts of the dorsal parametria; the medial part, which entails rectouterine and rectovaginal ligaments, and the lateral laminar structure, also called mesoureter, which contains the hypogastric plexus. Furthermore, type C1 requires only a partial dissection of the ureter from the ventral parametria, which is usually asymmetric towards more extensive resection of the medial leaf of the cranial (above the ureter) part of the ventral parametria. In the C2 type, the ureter is completely dissected from the ventral parametria up to the urinary bladder wall. Defining the resection limits on the longitudinal (deep parametrial or vertical) plane is crucial for distinguishing between types C1 and C2.
Type D: Laterally Extended Resection
This type differs from type C2 only in the lateral extent of the lateral parametria resection. Ureteral dissection and resection of both dorsal and ventral parametria is identical to the type C2. Laterally, however, it requires ligation and removal of the internal iliac artery and vein, together with their branches, including the gluteal, internal pudendal, and obturator vessels.
Treatment by Stage of Disease
Stage IA1 cervical cancer should be diagnosed using a conization specimen, because small tissue biopsy study may not be accurate enough to rule out other areas of a more extensive lesion. The treatment depends on the need for fertility preservation.
In a recent study, He et al (39) evaluated the value of cold knife conization (CKC) as a conservative management in patients with microinvasive cervical SCC. A total of 108 patients with stage IA1 were enrolled. Eighty-three patients (76.9%) underwent further hysterectomy, out of which 48 (57.8%) underwent extrafascial hysterectomy, 30 (36.1%) underwent extensive hysterectomy, and 5 (6.1%) underwent radical hysterectomy. All patients were followed up for 1 year. The 18 patients with positive resection margins had greater likelihood of cervical residual lesions (CIN1-3) than the 65 patients with clear resection margins, but there were no significant differences (P = .917). Twenty-five patients who underwent CKC as final therapy were followed up for 1 year. Two patients with positive resection margins had a second CKC surgery; one patient was diagnosed with CIN1, and the other was diagnosed with cervicitis by pathology. Twenty-three patients had clear resection margins; two patients underwent a second CKC 3 months after the first CKC because of the abnormal ThinPrep Cytologic Test (TCT) result, and they were both diagnosed with microinvasive cervical SCC (stage IA1) by pathology with clear resection margins. No one enrolled in this study presented with metastasis or progression within 1 year of follow-up. This provided the clinical evidence for the possibility of fertility-sparing treatments, especially CKC, as conservative treatment for microinvasive cervical SCC.
Simple hysterectomy may be performed in women with stage IA1 cervical cancer in whom preservation of fertility function is not required. However, in patients with LVSI, a modified radical hysterectomy may be the procedure of choice.
The incidence of LNI in patients with this stage of cervical cancer is as high as 7% with a recurrence rate of 3% to 5%, and these patients should be treated with a radical hysterectomy with pelvic lymph node dissection. In women who want to conserve fertility, another approach that has been reported to have a successful outcome is radical trachelectomy with laparoscopic pelvic lymphadenectomy, in which the body of uterus is preserved for fertility function (40). Individualization of therapy based on findings from extensive pathologic review of an adequate cone biopsy specimen is important for treatment planning.
The standard surgical treatment for FIGO stage IB1 cervical cancer consists of a radical hysterectomy or trachelectomy and systematic pelvic lymphadenectomy.
Traditionally, surgery for stage IB disease consists of radical hysterectomy performed in conjunction with pelvic lymphadenectomy. Lately, some have recommended class II hysterectomy rather than conventional class III hysterectomy in stages IB and IIA disease with a tumor size <2 cm due to fewer complications from the former and no difference in the 5-year survival (41) (Figs. 33-7 and 33-8).
Gross specimen from a radical hysterectomy with lymph nodes dissected.
A radical hysterectomy specimen with a portion of upper vagina. Note that the ovaries need not be removed unless indicated by the associated pathology.
Sentinel Lymph Node Mapping
The concept of the sentinel node (SN) was first clinically developed by Cabanas in association with penile carcinoma (42). It is based on the principle that if the SN or the first node receiving drainage from tumor is negative, more extensive lymphadenectomy may be exempted to avoid the morbidity of the procedure.
Generally, the techniques used to map SNs involve identification of the lymphatic duct by injecting isosulfan blue dye or lymphoscintigraphy, using gamma probe detection of technetium 99m–labeled colloid, which is injected into the cervix. This can be done either before or during the operation. A number of studies of SN mapping for cervical cancer have been published; in these instances, the investigators used either blue dye, lymphoscintigraphy, or both with varying degrees of success. The introduction of indocyanine green (ICG) as another tool for SN mapping may be revolutionizing the field because it is now being used in patients undergoing minimally invasive surgery, both by the laparoscopic and robotics approach. Indocyanine green is a dye that fluoresces in the near-infrared (NIR) spectrum when illuminated with 806-nm light. When a laser emitted from the NIR imager excites ICG, it produces a wavelength that is converted to a fluorescent image. The emitted fluorescence is captured with a video camera device that allows for the ICG to be displayed in the visible light spectrum (43).
Jewell et al (44) assessed the detection rate of SNs using ICG in patients with uterine and cervical cancer. A total of 227 cases were performed. The median SN count was 3 (range, 1-23). An SN was identified in 216 cases (95%), with bilateral pelvic mapping in 179 cases (79%). The authors found that there was no difference in the detection rate when ICG alone was used versus the combination of both dyes (ICG and isosulfan blue). The authors concluded that combined use of ICG and blue dye appears unnecessary.
In the SENTICOL study by Lécuru et al (45), the authors aimed to determine if bilateral negative SNs accurately predict absence of lymph node metastasis in early cervical cancer patients with stage IA1 disease with LVSI to stage IB1. One hundred forty-five patients were enrolled, and 139 were included in a modified intent-to-diagnose analysis. Intraoperative radioisotope-blue dye mapping detected at least one SN in 136 patients (97.8%; 95% CI, 93.8%-99.6%), 23 of whom had true-positive results and two of whom had false-negative results, yielding 92.0% sensitivity (23 of 25 patients; 95% CI, 74.0%-99.0%) and 98.2% negative predictive value (111 of 113 patients; 95% CI, 74.0%-99.0%) for node metastasis detection. No false-negative results were observed in the 104 patients (76.5%) in whom SNs were identified bilaterally. Therefore, the authors concluded that SN biopsy was fully reliable only when SNs were detected bilaterally.
Radical trachelectomy (RT) is resection of the cervix together with paracervical and parametrial tissue, with retention of the corpus uteri. The procedure is indicated in reproductive-age women with disease stage IA1 (with LVSI), IA2, or IB1 (<2 cm) disease who wish to preserve fertility (46).
Abu-Rustum and Sonoda (40) analyzed a prospectively maintained database of all patients with FIGO stage IA1 to IB1 cervical cancer admitted to the operating room for planned fertility-sparing abdominal RT. Sentinel node mapping was performed through cervical injection. Between November 2001 and May 2010, 98 consecutive patients with FIGO stage IA1 to IB1 cervical cancer and a median age of 32 years (range, 6-45 years) underwent a fertility-sparing RT. The most common histology was adenocarcinoma in 54 patients (55%) and squamous carcinoma in 42 patients (43%). Lymphovascular invasion was seen in 38 patients (39%). The FIGO stages included IA1 (with lymphovascular invasion) in 10 patients (10%), IA2 in 9 patients (9%), and IB1 in 79 patients (81%). Only 15 patients (15%) needed immediate completion radical hysterectomy because of intraoperative findings. Median number of nodes evaluated was 22 (range, 3-54), and 16 patients (16%) had positive pelvic nodes on final pathology. Final trachelectomy pathology showed no residual disease in 44 patients (45%), dysplasia in 5 patients (5%), and AIS in 3 patients (3%). Overall, 27 patients (27%) needed hysterectomy or adjuvant pelvic radiation postoperatively. One documented recurrence (1%) was fatal at the time of this report. It was thus concluded that cervical adenocarcinoma and lymphovascular invasion are common features of patients selected for RT, and most patients can undergo the operation successfully, with approximately 65% having no residual invasive disease; however, nearly 27% of all selected cases will require hysterectomy or postoperative chemoradiation for oncologic reasons.
Diaz et al (47) compared the oncologic outcomes of women who underwent a fertility-sparing RT to those who underwent a radical hysterectomy for stage IB1 cervical carcinoma. Forty stage IB1 patients underwent an RT, and 110 patients underwent a radical hysterectomy. There were no statistical differences between the two groups for the following prognostic variables: histology, median number of lymph nodes removed, node-positive rate, LVSI, or deep stromal invasion. The median follow-up time for the entire group was 44 months. The 5-year recurrence-free survival rate was 96% for the RT group compared with 86% for the radical hysterectomy group (P value not significant). On multivariate analysis in this group of stage IB1 lesions, tumor size <2 cm was not an independent predictor of outcome, but both LVSI and deep stromal invasion retained independent predictive value (P = .033 and P = .005, respectively). The authors concluded that for selected patients with stage IB1 cervical cancer, fertility-sparing RT appears to have a similar oncologic outcome to radical hysterectomy. Lymphovascular space invasion and deep stromal invasion appear to be more valuable predictors of outcome than tumor diameter in this subgroup of patients.
In 2013, Pareja et al (48) published a systematic literature review of patients with early-stage cervical cancer who underwent abdominal RT. A total of 485 patients age 6 to 44 years were identified. The most common stage was IB1 (71%), and the most common histologic subtype was SCC (70%). Operative times ranged from 110 to 586 minutes. Blood loss ranged from 50 to 5568 mL. Forty-seven patients (10%) had conversion to radical hysterectomy. One hundred fifty-five patients (35%) had a postoperative complication. The most frequent postoperative complication was cervical stenosis (n = 42; 9.5%). The median follow-up time was 31.6 months (range, 1-124 months). Sixteen patients (3.8%) had disease recurrence. Two patients (0.4%) died of disease. A total of 413 patients (85%) were able to maintain their fertility. A total of 113 patients (38%) attempted to get pregnant, and 67 of these patients (59.3%) were able to conceive. Therefore, the authors concluded that abdominal RT is a safe treatment option in patients with early-stage cervical cancer interested in preserving fertility.
The possibility of less radical surgery may be appropriate not only for patients desiring to preserve fertility but also for all patients with low-risk early-stage cervical cancer. Recently, a number of studies have explored less radical surgical options for early-stage cervical cancer, including simple hysterectomy, simple trachelectomy, and cervical conization with or without SN biopsy and pelvic lymph node dissection. Criteria that define this low-risk group include squamous carcinoma, adenocarcinoma, or adenosquamous carcinoma, tumor size <2 cm, stromal invasion <10 mm, and no LVSI (49).
The ConCerv study is one of the several prospective studies evaluating the role of conservative surgery in women with newly diagnosed, early-stage cervical cancer.
Retrospective data have shown that low-risk cervical cancer may not require radical hysterectomy because the risk for parametrial involvement is less than 1% in these patients. In this study, eligible women undergo CKC or simple hysterectomy and pelvic lymphadenectomy with SN based on their desire for future fertility. The primary outcome of this study is the safety and feasibility of a conservative approach (49).
More recently, a Gynecologic Cancer Intergroup (GCIG) trial was led by the National Cancer Institute of Canada Clinical Trials Group, called the SHAPE trial. In this trial, patients with stage IA2 to IB1 cervical cancer with low-risk qualities (early-stage cervical cancer [IA2, IB1 <2 cm], limited stromal invasion <10 mm on loop electrosurgical excision procedure/cone biopsy, <50% stromal invasion on pelvic MRI) are randomized to either simple or radical hysterectomy. The study is currently ongoing and is aiming to accrue a total of 700 patients (50).
In 1999, the US National Cancer Institute announced its support of concurrent cisplatin-based chemotherapy and radiation therapy in women who require radiation therapy for the management of cervical cancer. This was based on data from five randomized controlled trials that showed a significant benefit of concurrent chemoradiation either as postoperative adjuvant therapy in patients with high-risk factors or primary therapy in patients with locally advanced cervical cancer. All five trials sed concurrent cisplatin either alone or in combination with 5-fluorouracil (5-FU) or 5-FU and hydroxyurea. Peters et al (51) applied concurrent chemoradiation as postoperative adjuvant therapy in patients with risk factors found from radical hysterectomy in stage IA2 to IIA disease and indicated that it was superior to radiation therapy alone. Keys et al (52) compared chemoradiation and radiation with adjuvant hysterectomy as the definitive treatment in patients with stage IB2 disease. Significant improvement of 3-year survival was found in the chemoradiation group (83% vs 74%). Pathologic examination of the hysterectomy specimens demonstrated a significant decrease in persistent disease with chemoradiation.
Three other studies comprised patients with more advanced disease (53,54,55). The Radiation Therapy Oncology Group trial (RTOG) 9001 by Morris et al randomized stage IB-IVA patients to concurrent chemoradiation with cisplatin and 5-FU versus extended-field radiation (53). Chemoradiation was superior, with an increase in overall survival of 73%, compared with 58% for radiation alone. Acute toxicity was more common with chemoradiation, but the rates of late complications (>60 days after treatment) were similar. A trial by Rose et al (54) studied the optimal chemoradiation regimen by randomizing patients with stage IIB-IVA disease to receive radiation therapy concurrent with one of the following chemotherapy regimens: cisplatin alone; cisplatin, 5-FU, and hydroxyurea; or hydroxyurea alone. With a median follow-up time of 35 months, the results demonstrated superior survival rates for both concurrent cisplatin regimens (66% and 64%, respectively) compared with concurrent hydroxyurea alone (39%). The toxicity of treatment was least with the single-agent cisplatin regimen. Another Gynecologic Oncology Group trial in stage IIB to IVA cervical cancer by Whitney et al (55) compared the efficacy of a chemotherapy regimen in the concurrent chemoradiation setting. The results showed superiority of cisplatin and 5-FU over hydroxyurea; survival rates at a median follow-up of 8.7 years were 55% and 43%, respectively. Leukopenia occurred less often in the group receiving cisplatin and 5-FU than in those receiving hydroxyurea.
A summary of these five trials is presented in Table 33-4.
Table 33-4Five Randomized Control Trials of Concurrent Chemoradiation for Cervical Cancer ||Download (.pdf) Table 33-4 Five Randomized Control Trials of Concurrent Chemoradiation for Cervical Cancer
|Study (Protocol) ||Setting ||No. of Patients ||Treatment ||Outcomea ||Remarks |
|Keys et al (52), 1999 (GOG 123) ||IB2 ||369 || |
RT + weekly C
RT (followed by TAH in both groups)
|RR of progression and death, 0.51 and 0.54 in CRT arm ||Higher severe hematologic and GIT toxicity in CRT arm (21% vs 4% and 14% vs 5%) |
|Peters et al (51), 2000 (SWOG 8797/GOG 109) ||PO IA2-IIA with risk factors ||243 || |
RT + CF
4-year PFS and SVR, 80% and 81% in group 1
4-year PFS and SVR, 63% and 71% in group 2
|ACA had similar outcomes as SCC in CRT arm; ACA did worse in RT arm |
|Whitney et al (55), 1999 (GOG 85) ||IIB-IVA ||368 || |
RT + CF
RT + HU
RR of progression and death, 0.79 and 0.74 of group 1 compared to group 2
(21% and 26% decreased risk of progression and death)
|Severe leukopenia more common in HU arm (24% vs 4%) |
|Morris et al (53), 1999 (RTOG 9001) ||IB-IVA ||388 || |
RT + CF
RT + extended-field radiation
5-year OS and DFS, 73% and 67%
5-year OS and DFS, 58% and 40%
|Higher reversible hematologic side effects in CRT arm |
|Rose et al (54), 1999 (GOG 120) ||IIB-IVA ||526 || |
RT + weekly C
RT + CF + HU
RT + HU
2-year PFS, 67% and 64% in groups 1 and 2 and 47% in group 3
RR of death, 0.61 and 0.58 in groups 1 and 2 compared with group 3
|Group 1 least toxic |
A review by the Neoadjuvant Chemotherapy for Locally Advanced Cervical Cancer Meta-Analysis Collaboration group discovered seven randomized controlled trials available for analysis, comprising 872 patients (56). The overall analysis and analysis of each individual trial showed significant improvement of all outcomes with neoadjuvant chemotherapy: hazard ratio of 0.65 for survival, with 14% absolute improvement in 5-year survival rate (50% to 64%); hazard ratio of 0.68 for disease-free survival, with 13% absolute improvement of disease-free survival (45% to 58%); and hazard ratio of 0.63 for metastasis-free survival, with 15% absolute improvement in metastasis-free survival (45% to 60%). However, many confounding factors were inherent and unavoidable in this systematic analysis: these factors were that a number of patients, ranging from 28% to 90% in each trial, also received postoperative adjuvant radiation therapy or triple-modality treatment compared with radiation therapy, the route of cisplatin administration differed (intra-arterial in one trial), and patients recruited to each trial had different stages of disease.
Eddy et al (57) published a phase III trial from the Gynecologic Oncology Group to determine whether neoadjuvant chemotherapy (NACT) prior to radical hysterectomy and pelvic/para-aortic lymphadenectomy (RHPPL) could improve progression-free survival and overall survival, as well as operability, with acceptable levels of toxicity. Two hundred eighty-eight eligible patients with bulky FIGO stage IB cervical cancer, tumor diameter ≥4 cm, adequate bone marrow, renal, and hepatic function, and performance status ≤2 were randomly allocated to RHPPL (n = 143) or NACT + RHPPL (n = 145). The NACT + RHPPL group had a similar recurrence rate (relative risk, 0.998) and death rate (relative risk, 1.008) compared with the RHPPL group. Seventy-nine percent of patients had surgery in the RHPPL group compared to 78% in the NACT + RHPPL group. Fifty-two percent of patients received postoperative RT in the RHPPL group compared to 45% in the NACT + RHPPL group (not statistically significant). The authors concluded that NACT offered no additional objective benefit to patients undergoing RHPPL for stage IB cervical cancer.
Another phase III trial was conducted by Katsumata et al (58) to determine whether NACT before radical surgery improved overall survival. A total of 134 patients with stage IB2, IIA2, or IIB SCC of the uterine cervix were randomly assigned to receive either BOMP (bleomycin, vincristine, mitomycin, cisplatin) plus radical surgery (NACT group) or radical surgery alone (radical surgery group). Patients with pathologic high-risk factors received postoperative radiotherapy. This study was prematurely terminated at the first planned interim analysis because overall survival in the NACT group was inferior to that in the radical surgery group. The 5-year overall survival was 70.0% in the NACT group and 74.4% in the radical surgery group (P = .85). Hence, it was concluded that NACT with BOMP regimen before radical surgery did not improve overall survival but reduced the number of patients who received postoperative radiotherapy.
In patients with stage IVB cervical cancer, which implies systemic disease, treatment is palliative rather than curative. Radiation therapy has a role for local primary disease to alleviate symptoms such as bleeding and pain. In patients who have distant metastasis, symptoms such as bone pain can be relieved with high-dose radiation. Chemotherapy is also an option for patients with stage IVB disease, but the response is modest because of factors like poor vascular supply and bone marrow reserve.