66_00d epidemiology

Epidemiology
The American Cancer Society estimated that in 2007 there were 11,150 new cases of invasive carcinoma of the cervix in the United States and about 3,500 deaths, in addition to over 60,000 cases of carcinoma in situ (279). However, cervical cancer is highly prevalent in developing nations; it is estimated that close to 500,000 women worldwide develop this tumor and 233,000 die of the disease (262). Cervical cancer is more common in Latin America and less frequent in Jewish and European women and Fiji Islanders (250). Although some researchers have attributed the low frequency of cervical carcinoma in Jewish women to the circumcision of Jewish men (602), this low incidence has not been demonstrated in sexual partners of non-Jewish circumcised men. Lynch et al. (390) noted that although Ashkenazi women have an overall cancer risk comparable to other ethnic groups, it is still lower for carcinoma of the cervix, which occurs infrequently in Jewish women.
Carcinoma of the uterine cervix can be induced in experimental animals by application of hormonal or other chemical
P.1533


P.1534

carcinogens (287). However, no definite evidence exists linking the use of oral contraceptives with carcinoma of the uterine cervix (127,188). The association of prenatal exposure to diethylstilbestrol (DES) and development of clear-cell adenocarcinoma of the cervix or vagina in young women has been reported; the overall incidence is thought to be small (0.14 to 1.4 per 1,000 DES-exposed women) (243). Clear cell adenocarcinoma of the cervix unrelated to DES exposure has been described (293).

A large proportion of cervix cancer can be characterized as a sexually transmitted disease, with early age of first intercourse, history of multiple sexual partners, and large number of pregnancies as risk factors (85,309). Epidemiological studies relating genital herpetic infection to cervical cancer have been reported (432). The role of human papilloma virus (HPV) as a causative agent of cervical cancer is well established (50,665), and the detection of HPV types 16 and 18, predominantly, carries prognostic importance in some studies (509,668). Bosch et al. (51) noted that HPV 16 predominated in squamous-cell carcinoma, whereas in adenocarcinoma and adenosquamous carcinoma HPV 18 predominated.
The male partner's role as a potential carrier of HPV is evidenced by the higher incidence of cervical cancer among women whose spouses are known or suspected to have had higher exposure to HPV (6) or whose partner has a history of penile carcinoma (274). Boon et al. (47) characterized the male partner as potential “vector and victim” of HPV, especially in countries where the rate of male circumcision is low.
In June 2006, the U.S. Food and Drug Administration approved the quadrivalent human papillomavirus recombinant vaccine for women 9 to 26 years for prevention of gynecological disease caused by HPV types 6, 11, 16, and 18. This is an exciting development and a landmark decision, heralded as a major advance in the prevention of cervical cancer that may have a worldwide impact on the incidence of this malignancy.
Other risk factors among HIV-positive women included racial/ethnic background (African American vs. white, relative risk [RR] = 1.64), current smoking (yes vs. no, RR = 1.55), and younger age (younger than 30 years vs. 40 years or older, RR = 1.75) (457).
An association between cigarette smoking and development of cervical cancer has been reported (32,187). A review of over 50 studies concluded that smoking was a cofactor for HPV infection and induction of cervical cancer (594). However, in the study by Agarwal et al. (6), cigarette smoking was not a risk factor.
Natural History and Patterns of Spread
Squamous-cell carcinoma of the uterine cervix usually originates at the squamous columnar junction (transformation zone) of the endocervical canal and the portio of the cervix. The lesion is frequently associated with severe cervical dysplasia and carcinoma in situ, usually progressing to invasive carcinoma over 10 to 20 years in the majority of patients (30,84).
The malignant process breaks through the basement membrane of the epithelium and invades the cervical stroma. Formerly, if the invasion was <3 mm, the lesion was classified as microinvasive or superficially invasive (84), a term not used in the International Federation of Gynecologists and Obstetricians (FIGO) staging, which classifies this tumor as Ia1. Invasion may progress, and in a modification of the FIGO staging schema (272), if a tumor is not grossly visible but has a depth of penetration of <5 mm and breadth of 7 mm or less, it is classified as stage IA2 invasive carcinoma; the incidence of metastatic pelvic lymph nodes is related to the depth of invasion, with an overall incidence of 3% to 8% (42,84).
The lesion may eventually be manifested by superficial ulceration, exophytic tumor in the ectocervix, or extensive infiltration of the endocervix. The tumor, if untreated, may spread to the adjacent vaginal fornices or to the paracervical and parametrial tissues (270), with eventual direct invasion of the bladder, the rectum, or both. Landoni et al. (352), in operative specimens of 230 radical hysterectomies with pelvic lymphadenectomy of patients with clinical stage IB and IIA, noted the tumor spreads endocervically equally in all directions; tumor extension into the vesicocervical ligament (anterior para-metrium) was noted in 23% of cases, into the uterosacral ligaments (posterior parametrium) and the rectovaginal septum in approximately 15%, and into the parametria in 28% to 34% of cases. Paracervical extension was related to the depth of stromal invasion, tumor size, lymphatic invasion, and presence of lymph node metastasis.
Carcinoma of the uterine cervix has been found to extend into the lower uterine segment and the endometrial cavity in 10% to 30% of patients (470). Perez et al. (470) and Chao et al. (73) noted decreased survival and a greater incidence of distant metastases in patients with stromal endometrial invasion or replacement of normal endometrium by cervical carcinoma. Regional lymphatic or hematogenous spread occurs, depending on the stage of the tumor, but dissemination does not always follow an orderly sequence, and occasionally a small carcinoma may be seen infiltrating the pelvic lymph nodes, invading the bladder or rectum, or producing distant metastasis.
In addition to the frequently described pelvic lymph nodes, Girardi et al. (178), in 359 specimens of radical hysterectomies, found parametrial nodes in 280 patients (78%); the incidence of positive nodes was 11.4% in stage IB and 21.5% in stage IIB disease. With negative parametrial nodes, only 26% of patients had positive iliac lymph nodes, whereas 81% of patients with positive parametrial lymph nodes also had metastatic pelvic nodes. These data underscore the need to irradiate the parametrial tissues or carry out a complete bilateral pelvic lymphadenectomy in patients with invasive cervical carcinoma.
Carcinoma of the cervix may spread to the obturator lymph nodes (considered a medial group of the external iliac), to other external iliac nodes, and to the hypogastric lymph nodes. From these, there may be tumor metastases to the common iliac or para-aortic lymph nodes (242). The incidence of metastasis to pelvic or para-aortic lymph nodes for various stages of the disease is listed in Tables 66.1 and 66.2.
In 225 patients with carcinoma of the cervix treated with radical hysterectomy and pelvic lymphadenectomy, 13/91 (14.2%) with stage IB and IIA, 16/81 (19.8%) with stage IIB, and 11/40 (28%) with stage IIIB disease had positive pelvic lymph nodes (34). The most commonly involved groups were the parametrial, obturator, external iliac, and common iliac nodes (Fig. 66.3). Para-aortic lymph nodes were involved in
P.1535

3/91 (3.3%) patients with stage IB and IIA tumors 4 cm or less and in 5/38 patients (13.1%) with stage IIB and III disease.

Hematogenous dissemination through the venous plexus and the paracervical veins occurs less frequently but is relatively common with more advanced stages. In an analysis of 322 patients in whom distant metastases developed, the most frequently observed metastatic sites were the lung (21%), para-aortic lymph nodes (11%), abdominal cavity (8%), and supraclavicular lymph nodes (7%) (151). Bone metastases occurred in 16% of patients, most commonly to the lumbar and thoracic spine (Table 66.3). Spinal epidural compression from metastatic tumor, often involving lumbar segments, can occur rarely (15), and metastasis to the brain and the heart have been reported (372,394).
Clinical Presentation
Intraepithelial or early invasive carcinoma of the cervix can be detected before it becomes symptomatic by cytologic smears; Papanicolaou (Pap) smear, colposcopy and biopsies, and HPV testing have high specificity and sensitivity (94.5%)
Frequently, the first manifestation of abnormality is postcoital spotting, which may increase to metrorrhagia (intermenstrual bleeding) or more prominent menstrual bleeding (menorrhagia). Serosanguineous or yellowish, foul-smelling vaginal discharge may be noted in patients with advanced invasive carcinoma. If chronic bleeding occurs, the patient may complain of fatigue or other symptoms related to anemia.
Pain in the pelvis or hypogastrium may be caused by tumor necrosis or associated pelvic inflammatory disease. In patients with pain in the lumbosacral area, the possibility of para-aortic lymph node involvement with extension into the lumbosacral roots or hydronephrosis should be considered.
Urinary and rectal symptoms (hematuria, rectal bleeding) may appear in advanced stages as a consequence of invasion of the bladder or rectum by the neoplasm.
Diagnostic Work-Up
Every patient should be jointly evaluated by the radiation and gynecologic oncologists. After careful clinical history a general physical examination with attention to the supraclavicular (nodal) areas, abdomen, and liver, a careful pelvic examination should be carried out with as little discomfort to the patient as possible, without compromising the thoroughness of the evaluation (447). Pelvic examination should include inspection of external genitalia, vagina, and uterine cervix, rectal examination, and bimanual palpation of the pelvis. Pelvic examination under anesthesia is very important in the evaluation and clinical staging of these patients. Cystoscopy or rectosigmoidoscopy should be performed in all patients with stage IIB, III, and IVA disease or those with earlier stages who have a history of urinary or lower gastrointestinal tract disturbances. The diagnostic procedures for carcinoma of the cervix are presented in Table 66.4.
Screening
The American Cancer Society has recommended that asymptomatic women 20 years of age and older or sexually active younger than 20 years have annual Pap smears for 2 consecutive years and at least one every 3 years until the age of 65 years. The American College of Obstetricians and Gynecologists has strongly recommended that that Pap smears be obtained on an annual basis.
When obtaining the Pap smear, special attention should be directed to not using a lubricating agent (warm water on the speculum will suffice), to obtaining good “scrapings” from the cervix and vaginal posterior fornix (without blood), and to using a small brush to obtain an endocervical sample. The patient should be instructed not to cleanse with a douche before the examination, and specimens should be obtained for studies of
P.1536

trichomonas. If the cytologic smear shows atypia or mild dysplasia (class II), the smear should be repeated no sooner than after 2 weeks, to allow representative cellular exfoliation.

Guidelines for reporting results of cervical and vaginal cytology were promulgated in 1988. The Bethesda system eliminated the classes of Pap cytology. The correlation between the cytologic diagnosis and subsequent histologic examination is over 90% (334). This system was modified in 1991 and in 2001 (565).
If the cytologic smear shows dysplasia or malignant cells, directed biopsies at colposcopy should be carried out immediately. Endocervical curettage must always be performed except in pregnant women. If the biopsy results are negative, the procedure should be repeated and, if necessary, a conization should be performed.

Conization/Loop Excision
Conization must be performed when no gross lesion of the cervix is noted and an endocervical tumor is suspected; the entire lesion cannot be seen with the colposcope; diagnosis of microinvasive carcinoma is made on biopsy; discrepancies are found between the cytologic and the histologic appearances of the lesion; or the patient is not reliable for continuous follow-up.
Conization involves a conical removal of a large portion of the ectocervix and endocervix. Cold biopsy specimens should always be obtained with a scalpel or other appropriate instrument. At least 50% of the endocervical canal should be removed without compromising the internal sphincter. Curettage of the remaining endocervical canal should be carried out.
Laser conization and loop diathermy excision have achieved some popularity in recent years. Loop excision or laser conization is frequently done in an office setting as an alternative to conization; loop excision is less expensive and more reliable than laser conization (505).
Biopsy
When a gross lesion of the cervix is present, multiple punch biopsies should be adequate to confirm the diagnosis of invasive carcinoma. Specimens should be obtained from any suspect area as well as in all four quadrants of the cervix and from any suspect areas in the vagina. It is important to obtain tissue from the periphery of the lesion with some adjoining normal tissue; biopsy specimens from central ulcerated or necrotic areas may not be adequate for diagnosis.
Dilatation and Curettage
Because possible upper extension of the tumor may modify the plan of therapy, fractional curettage of the endocervical canal and the endometrium is recommended at the time of initial evaluation, or during the first intracavitary radioisotope insertion if the patient is treated with radiation therapy.
Laboratory Studies
For invasive carcinoma, patients should have the following laboratory studies: complete peripheral blood evaluation, including hemogram, white blood cell count, differential and platelet count; blood chemistry profile, with particular attention to blood urea nitrogen, creatinine, and uric acid; liver function values; and urinalysis.
Imaging Studies
Traditionally, chest radiographs and intravenous pyelograms (IVP) were obtained in all patients for staging purposes. The IVP in many countries has been replaced by CT scan of the pelvis and abdomen with contrast material. A colon barium enema should be performed in patients with stage IIB, III, and IVA disease as well as those with earlier stages who have symptoms referable to the colon and rectum.
Pedal lymphangiography was used to assess lymph node involvement in the pelvic or para-aortic nodes. Unfortunately, not all of the lymph nodes to which carcinoma of the cervix may metastasize are opacified (i.e., obturator or hypogastric nodes), small metastatic lesions do not modify the architecture of the lymph node apparent on the lymphangiogram, and at times the metastatic tumor completely obliterates the lymph node or obstructs lymphatics, preventing visualization of the involved lymph nodes (478). Lagasse et al. (346) found the lymphangiogram to be unreliable as a basis for treatment decisions. This procedure has been replaced by CT scanning or MRI.
P.1537


If performed with intravenous (IV) contrast, CT scans substitute for IVP. The cervical tumor may be seen as an enlarged, irregular, hypoechoic cervix or as a mass with ill-defined margins. The overall accuracy of CT scanning in staging cervical cancer ranges from 63% to 88% (321). In the detection of lymph node abnormalities, the overall accuracy of conventional CT scanning is 77% to 85%, with a sensitivity of 44% and specificity of 93% (264).
Camilien et al. (67) reported on 61 patients with carcinoma of the cervix who had both preoperative CT scans and exploratory laparotomy; correlation of radiographic and surgical/pathologic findings showed that 75% of the enlarged pelvic lymph nodes on CT contained metastases and 97% of patients with negative nodes on CT scan were pathologically negative (specificity of 97%). However, histologically positive pelvic nodes were often missed on CT scan (sensitivity of 25%). The CT scan is more valuable in evaluation of the para-aortic lymph nodes (specificity of 100% and sensitivity of 67%; Table 66.5).
Shepherd et al. (554), in a retrospective study of CT scans in 56 patients with carcinoma of the cervix treated with irradiation, noted that tumor depth was correlated with lymph node involvement (p <0.01) and risk of death.
Heller et al. (239) reported a prospective evaluation of 320 patients with stage IIB to IVA carcinoma of the cervix entered into a Gynecologic Oncology Group (GOG) protocol in which preoperative CT scan, lymphangiography, and ultrasonography of the aortic area were performed. Para-aortic node dissection was done in patients with negative staging studies. Lymphangiography, CT scan, and ultrasonography had false-negative frequencies for pelvic lymph node evaluation of 14.2%, 25%, and 30%, respectively. The sensitivity was 79% for lymphangiography, 34% for CT scan, and 19% for ultrasonography and the specificity ratings were 73%, 96%, and 99%, respectively. Ultrasonography, therefore, is not reliable in preoperative detection of lymph node metastases, but it has limited value in evaluating extrauterine tumor involvement and may be used to detect uterine perforation, which can occur during intracavitary insertion (661).
MRI is being used more frequently for assessment of extracervical tumor extension (265), although it is somewhat more expensive. MRI is very useful in patients allergic to iodinated contrast material or impaired renal function. It is contraindicated in patients with pacemakers, cochlear implants, metallic prostheses, or large vascular clips. On T2-weighted images, a cervical cancer may be seen as a mass of intermediate signal intensity, usually of greater intensity than the fibrocervical stroma. On T1-weighted images, tumors are usually isointense with the normal cervix and may not be seen (24). Abnormal, irregular cervix margins, prominent parametrial strands, exocentric parametrial enlargement, and loss of parametrial fat planes on T1-weighted images or high signal in the parametria or cardinal/uterosacral ligaments on T2-weighted images are indicative of more extensive tumors (264,321,561). Parametrial tumor is easily identified on T2-weighted images from the low-intensity cervix and uterine ligaments.
Hawnaur et al. (236) compared pretreatment tumor staging and volume assessment by examination under anesthesia (EUA), transrectal ultrasonography (TRUS), and MRI in 60 patients with invasive carcinoma of the cervix. TRUS and MRI assigned the same tumor stage in only 30% of patients, and EUA and MRI agreed on tumor stage in an additional 27%. In cases of disagreement, the MRI staging correlated better with outcome than TRUS or EUA. Sixty-two percent of patients with enlarged lymph nodes on pretreatment MRI either died or had tumor recurrence or metastases. MRI was superior in assessing the full extent of bulky tumors and lymph node enlargement over both TRUS and EUA.
Hatano et al. (235) also evaluated MRI in 42 patients with advanced cervical cancer treated with external irradiation and high–dose-rate (HDR) brachytherapy. In biopsies performed immediately after radiation therapy (RT), no residual tumors were found in 36 patients (86%). The simultaneous MRI study demonstrated no high-signal intensity on T2-weighted images in 28 patients (75%). A high–signal-intensity area was observed in 14 patients, and this disappeared 3 months after RT in eight patients with a negative histologic study. The sensitivity, specificity, and accuracy of MRI tumor response studies at 3 months after radiation therapy were 100%. MRI studies performed at 30 Gy of external irradiation and 3 months after radiation therapy were predictive for local tumor control.
Postema et al. (494) compared MRI with pelvic examination (including under general anesthesia in selected patients) in 103 patients with invasive cervical carcinoma. The gold standard for comparing treatment decisions was based on surgicopathologic data available in 91 patients. MRI was better at identifying extracervical tumor spread, but it had more false-positive results. The pelvic examination led to correct treatment decisions in 89% of patients, with MRI not leading to an overall improvement in treatment decisions.
Also, in a study by Hansen et al. (230), clinical assessment was superior to low-field MRI in staging cervical cancer in 95 women on whom MRI examinations and clinical staging according to the FIGO recommendations were performed within 2 weeks after clinical diagnosis; the clinical staging correctly classified 57 patients (accuracy, 92%), compared with 52 patients with MRI using contrast enhancement (accuracy, 84%).
MRI dynamic enhancement during the first 2 weeks of radiation therapy may provide early prediction of tumor regression rate. In seven patients, tumor regression rates ranged from 2% to 15.2% per day and correlated positively with changes in both peak and mean tumor enhancement (p <0.01). A similar study was published by Gong et al. (181) and van de Bunt et al. (627). MRI also was found to be useful in providing accurate target volume definition in brachytherapy treatment planning (122).
P.1538


Haider et al. (218) evaluated 56 patients with adenocarcinoma involving the cervix using MRI and noted that 42 (75%) had a visible mass. Findings were more prevalent in patients with primary adenocarcinoma of the endometrium, as characterized by a endometrial thickening (11 [73%] vs. 3 [13%]) endometrial cavity expansion by a mass (9 [60%] and 2 [9%] respectively) (p = 0.003).
Kodaira et al. (331) reviewed 84 patients with stage II cancer evaluated by MRI; all patients received intracavitary brachytherapy with (83) or without (1) external-beam radiation therapy (EBRT). The 5-year disease-free survival (DFS) of patients with maximal tumor size (Dmax ≥50 mm) was significantly lower (46.2%) than that for patients with Dmax <50 mm (88%; p <0.0001).
Ebner et al. (136) reported that, in comparing MRI findings in 12 women with recurrent pelvic tumors and 10 with fibrotic mass (confirmed by laparotomy or biopsy in 21 patients), they were able to differentiate the two processes accurately in most instances. However, it is highly desirable to confirm abnormal or suspect lymph node radiographic findings with CT-guided fine-needle aspiration biopsies.
Corn et al. (96) evaluated endorectal coil MRI in 18 patients with cervical carcinoma (stages IB to IIIB); in seven patients, tumors were determined to be in a higher stage by endorectal coil MRI because of proximal vaginal involvement or the combination of proximal vaginal involvement and parametrial extension). Patients were treated with EBRT and low–dose rate (LDR) brachytherapy. Compared with those who had dark or intermediate signal, patients with bright signal characteristics tended to present with earlier stages, were less likely to have anemia, and more likely to have complete response to external irradiation.
Positron Emission Tomography
Positron emission tomography (PET) scanning is increasingly used in the evaluation of patients with malignant neoplasia, including invasive cervical cancer, using 2-[18F]-fluoro-2-deoxy-D-glucose (FDG). Rose et al. (521), in 32 patients with locally advanced carcinoma of the cervix, observed uptake in 91% of the primary tumors. Compared with surgical staging, PET scanning had a sensitivity of 72% and a specificity of 92% in detecting para-aortic metastasis.
Grigsby et al. (207) compared CT and FDG-PET scanning for lymph node staging in 101 patients with carcinoma of the cervix. CT demonstrated abnormally enlarged pelvic lymph nodes in 20 and para-aortic lymph nodes in seven patients, whereas PET demonstrated abnormal FDG uptake in pelvic lymph nodes in 67, in para-aortic lymph nodes in 21 and in supraclavicular lymph node in eight. The 2-year progression-free survival rate, based solely on para-aortic lymph node status, was 64% in CT-negative and PET-negative patients, 18% in CT-negative and PET-positive patients, and 14% in CT-positive and PET-positive patients (p <0.0001). The most significant prognostic factor for progression-free survival was the presence of positive para-aortic lymph nodes on PET imaging (p = 0.025). The authors noted in 76 patients with no abnormal FDG uptake, 2-year survival was 86%, with persistent abnormal uptake 40% and no survivors in patients who developed new sites of abnormal uptake (206). In a follow-up study of 152 patients, the authors reported 5-year cause-specific survival (CSS) of 80% in 114 patients without abnormalities on posttherapy FDG-PET versus 32% in 20 with persistent uptake and no survivors in 18 with new sites of abnormal uptake (205). In another study on 208 patients, Grigsby et al. (208) noted a close correlation between doses of irradiation and number and size of positive lymph nodes with treatment failures and survival (Fig. 66.4).

Hope and Grigsby (257) performed FDG-PET scans in 58 patients with cervical carcinoma who had endometrial biopsy or dilatation and curettage; 36 (64%) had pathologic endometrial invasion (EI). Pelvic lymph node metastasis was more commonly detected in this group than in patients without EI (70% vs. 23%, respectively; p <0.001) as were para-aortic node and supraclavicular node metastasis (30% vs. 0%; p = 0.006). Further, 2-year survival was 78% versus 58% and overall survival 92% versus 65%, respectively (p = 0.047).
Lin et al. (377) described the use of FDG-PET for brachytherapy treatment planning in 24 patients with cervical carcinoma, improving tumor coverage dose distribution, lowering dose to pelvic normal tissues, and improving outcome. Lin et al. (378), using FDG-PET in 32 patients with cervix carcinoma, observed a reduction in physiologic tumor volume of 50% occurring within 20 days from the initiation of radiation therapy.
Staging
The staging recommendations were last revised in 1995. Stage TIB includes all invasive tumors limited to the cervix larger than IA2. Stage TIB occult is no longer used. In 1995, FIGO modified the staging of stage IB lesions (confined to the cervix) into IB1, clinical lesions no >4 cm in size, and IB2, lesions >4 cm in size. There were no changes in the other stages, including the 1987 definitions of stages IA, IA1, and IA2 (553,621).
A parallel TNM staging system has been proposed by the American Joint Committee on Cancer (191). All histologic types should be included. When there is a disagreement regarding the staging, the earlier stage should be recorded (Table 66.6 and Fig. 66.5).
Kolstad (333) reviewed results of therapy in 643 patients with microinvasive carcinoma reclassified as stage IA1 or IA2.
P.1539

Three of 232 patients with stage IA1 disease (1.3%) and 12/411 with stage IA2 (2.9%) had local recurrence in addition to four pelvic recurrences, confirming the validity of the staging modification.

The FIGO staging system is based on clinical evaluation (inspection, palpation, colposcopy); roentgenographic examination of the chest, kidneys, and skeleton and endocervical curettage and biopsies. Lymphangiograms, arteriograms, imaging findings, and laparoscopy or laparotomy findings should not be used for clinical staging.
Suspected invasion of the bladder or rectum should be confirmed by biopsy. Bullous edema of the bladder and swelling of the mucosa of the rectum are not accepted as definitive criteria for staging.
For a lesion to be classified as stage IIIB, the tumor should definitely extend to the lateral pelvic wall, although fixation is not required.
Patients with hydronephrosis or nonfunction of the kidney ascribed to extension of the tumor are classified as stage IIIB regardless of the pelvic findings. The currently used staging systems could be modified to accommodate some prognostic factors that have been reported, such as the significance of endometrial extension of cervical carcinoma, stromal invasion, and tumor volume in stage I and IIA carcinoma (barrel-shaped in the cervical or bulky tumor presentations), lymphatic/vascular permeation, and involvement of the lateral parametrium in stage IIB as opposed to the medial parametrium (478,489).
Surgical Staging
Some gynecologists have advocated the use of pretherapy laparotomy, particularly to evaluate the involvement of para-aortic lymph nodes. Recently, sentinel node biopsy in patients with cervical cancer has been used with encouraging results (120). The GOG prospectively evaluated 290 patients with carcinoma of the cervix (346); para-aortic node metastases were found in 19/58 (32.8%) patients with clinical stage IIB and 19/61 (31.1%) with stage IIIB disease.
A number of studies have compared the significance of para-aortic nodal metastases with other clinical and surgical findings with regard to progression-free survival and survival (578). In 626 patients treated on GOG randomized studies, the relative risk associated with positive para-aortic nodes was 11.0 for time to recurrence and 6.2 for survival time. In addition to the significant increase in risk of regional relapses, patients with para-aortic nodal metastasis are more likely to have extrapelvic failure (36).
Ketcham et al. (310) reported positive scalene fat pad biopsies in 7/36 (19%) patients with stage II, III, and IV carcinoma of the cervix and in 4/22 patients with postirradiation recurrences. However, this procedure is no longer routinely carried out at most institutions because of the low yield of positive specimens. Perez-Mesa and Spratt (479) found no supraclavicular node metastasis in 73 consecutive patients with various stages of cervical carcinoma. Manetta et al. (397) also did not detect scalene node metastasis in 24 patients with recurrent
P.1540

carcinoma of the cervix evaluated for exploration and possible pelvic exenteration.

Follow-Up
After treatment, patients should be regularly followed by both the radiation and the gynecologic oncologists. Careful history taking and a complete physical and pelvic/rectal examination usually is performed every month for the first 3 months after completion of irradiation, every 3 months for the remaining of the first year, every 4 months the second year, every 6 months during the third through fifth year, and yearly thereafter. The use of Pap smears for cervical and vaginal cytology as a follow-up study is controversial because of bizarre postirradiation cellular morphology that renders it difficult to distinguish postirradiation changes from residual or recurrent malignant cells (400,564). DNA analysis of postirradiation cytologic smears demonstrating atypia or dysplasia may provide ancillary information (109).
Rintala et al. (511) evaluated the reliability of cytologic analysis and atypia after radiation therapy in 89 patients treated for cervical carcinoma. A total of 697 Pap smears were taken; during the follow-up, 44 patients had recurrent disease, which was local in 17 (39%) cases. The rate of false-positive samples was only 3%. Radiation-induced atypia was detected in 28% of the Pap smears taken during the first 4 months after radiation therapy, and its incidence decreased thereafter. In 1,000 patients treated with either surgery or radiation therapy at the M.D. Anderson Cancer Center for stage IB cervical cancer posttreatment, Pap smears did not detect a single asymptomatic recurrence among 133 patients with recurrent disease (41).
The presence of apparently viable tumor cells in the cytologic smear 3 months after irradiation should be evaluated with cervical biopsies, dilation and curettage, and careful examination under anesthesia, as indicated.
Complete blood counts and chemistry profile tests are obtained as clinically indicated. Chest radiography is commonly obtained on a yearly basis, usually for the first 5 years posttreatment, although its value to detect curable lung metastasis is not proven. If radiographs are consistently negative, obtaining them every other year thereafter may be sufficient.
Other imaging studies, such as CT, MRI, PET scanning, or bone scans, are obtained when clinically warranted. When persistent or recurrent tumor is suspected, biopsies should be obtained for histologic confirmation. If a biopsy is positive, immediate treatment should be instituted, as is discussed later.
Usually, hematometra after radiation therapy for cervical carcinoma is related to recurrent disease but occasionally may be related to estrogen replacement therapy, endometrial activity, and fibrosis and obliteration of the endocervix (634).
Pathologic Classification
Over 90% of tumors are squamous-cell carcinoma. Approximately 7% to 10% are classified as adenocarcinoma, and 1% to 2% are the clear-cell, mesonephric type.
Squamous-cell or epidermoid carcinoma is composed of cores and nests of epithelial cells arranged randomly; cells show central keratinization with cornified pearls and sometimes necrosis. Nonkeratinizing tumors may be seen. Electron microscopy may show desmosomes and tonofilaments. Squamous-cell carcinomas are divided into three types: large-cell keratinizing and nonkeratinizing and small-cell type, and they are subdivided according to the degree of differentiation into well, moderately, or poorly differentiated.
Verrucous carcinoma is a variant of a very well-differentiated squamous-cell carcinoma that characteristically has a tendency to recur locally but not to metastasize (338). Mitotic activity is very low. It may be difficult to discriminate from a giant condyloma with cytologic atypia or from a well-differentiated invasive squamous carcinoma. Microscopically, verrucous carcinoma is exophytic, with an undulating, hyperkeratotic surface; the deep margin of a verrucous carcinoma is composed of large, bulbous masses that invade along a wide front in a “pushing” fashion.
Adenocarcinoma arises from the cylindrical mucosa of the endocervix or the mucus-secreting endocervical glands. Mucinous is the most common substage of adenocarcinoma. The endocervical adenocarcinoma may form mucosal glands lined by high columnar cells and produce tubular folds oriented in many directions. In another subtype, cells resemble those of the intestines; the epithelium tends to be pseudostratified and may contain goblet cells. The third variant is the signet-ring cell, which is rare and usually mixed with the endocervical or intestinal patterns.
Endometrioid carcinoma is the most common cell type of endocervical adenocarcinoma; the cells resemble those of the endometrium, and the presence of intracytoplasmic mucin in some cells may be seen in a substantial proportion of tumors. The World Health Organization recommends that endometrioid or endocervical types of adenocarcinoma be graded according to their architecture, based on the degree of gland formation (385).
P.1541


Sometimes it is difficult to differentiate a primary endocervical adenocarcinoma from an endometrial tumor. Drescher et al. (126) described a higher incidence of involvement of the uterine corpus and the regional lymph nodes in 21 patients with adenocarcinoma compared with a similar number of patients with squamous-cell carcinoma. Chao et al. (71) and Contag et al. (93) described the use of microarray analysis for gene profiling (cDNA/RNA) to understand the molecular features of these tumors, which could aid in their classification. HPV has been identified in some subtypes of adenocarcinoma of the cervix (16).
A well-differentiated cervical adenocarcinoma has been improperly designated as adenoma malignum when it is truly a malignant tumor that invades adjacent tissues and may produce distant metastasis (559).
Adenosquamous carcinoma is relatively rare (2% to 5%) and consists of intermingled epithelial cell cores with squamous features and glandular structures. The squamous component is frequently nonkeratinizing. If the squamous component is benign metaplasia, the tumor is called adenoacanthoma.
Glassy cell carcinoma (1% to 2%) is considered a poorly differentiated adenosquamous tumor; it is rare and highly malignant. Survival is poor after surgery or irradiation. Ulbright and Gersell (622), in five cases of glassy cell carcinoma evaluated by light and electron microscopy, described both glandular and squamous differentiation. Littman et al. (379) reported only 4/13 patients, the majority with stage II disease, surviving 5 years (six had extrapelvic failures). Piura et al. (485) reported on five patients with cervical glassy cell carcinoma, three with stage IB1. All three patients were alive without disease 4, 12, and 18 months after diagnosis.
Adenoid cystic carcinoma is a rare variant of adenocarcinoma of the cervix (<1%) with an appearance similar to its counterparts in the salivary gland or the bronchial tree (184). The tumor is composed of nests and nodules of small carcinoma cells with a few characteristic cribriform patterns. Immunohistochemical findings for type IV collagen and laminin reveal intercellular cylinders composed of basement membrane material in the solid area without a cribriform pattern. They are locally aggressive and prone to metastasize (444).
Clear-cell carcinoma (mesonephric), not related to DES exposure, comprises approximately 2% of primary cervical adenocarcinomas and is thought to arise in mesonephric remnants (243). These tumors are submucosal, composed of clear and “hobnail” cells, and may grow in a tubular, glandular, papillary, or solid pattern. They appear at any age, with one-third occurring in women younger than 30 years of age. The clear cell is characterized by a voluminous cytoplasm filled with glycogen and the hobnail cell by single-cell apical projections into the neoplastic lumina. These tumors tend to be deeply positioned, with the bulk of the lesion on the stroma forming tubular structures, diffusely infiltrating the cervical stroma.
Clement et al. (89) described the clinicopathologic features in nine patients. Gross examination revealed polypoid or pedunculated masses that invaded the cervical wall in 50% of the hysterectomy specimens. On microscopic examination, five tumors contained basaloid carcinoma or squamous-cell carcinoma and four adenocarcinoma. In seven tumors, the sarcomatous component was homologous, usually resembling fibrosarcoma or endometrial stromal sarcoma, and two tumors contained heterologous sarcomatous elements. Cervical malignant müllerian mixed tumors, compared with their counterparts in the corpus, are more commonly confined at presentation and may have a better prognosis.
Small-cell carcinoma of the cervix, according to some authors, arises from endocervical argyrophilic cells or their precursors, multipotential neuroendocrine cells; however, some small-cell tumors do not contain morphologic evidence of neuroendocrine origin. Nuclear molding, absence of nucleoli, cell necrosis, and high mitotic activity are common. One-third to one-half stain positively for neuroendocrine markers such as chromogranin, serotonin, synaptophysin, or somatostatin. In the majority of patients, the cervical stroma is extensively infiltrated by single small round cells (2). Lymphatic and vascular invasion are significantly more common in small-cell carcinomas (noted in 58% of patients with stage IB disease; 40% of these patients had lymph node metastases at the time of radical surgery) (177). HPV 18 has been detected in the majority of these tumors (273).
Gersell et al. (177) described 15 patients with small-cell carcinoma; 13 showed cytokeratin on immunohistochemical studies, and at least one neuroendocrine marker was found in all 13 tumors (neuron-specific enolase, Leu-7, chromogranin, and synaptophysin). Invasion of vascular spaces was a prominent feature in seven tumors. Only three patients were alive 5, 11, and 78 months after treatment. In contrast, Van Nagell et al. (629), in an analysis of 25 patients, noted a 5-year survival rate of 54% for all stages of small-cell carcinoma, compared with 68% for matched large-cell nonkeratinizing squamous-cell and 74% for keratinizing squamous-cell carcinomas.
Basaloid carcinoma or adenoid-basal carcinoma, an extremely uncommon tumor, is characterized by nests or cords of small basaloid cells, prominent peripheral palisading of cells in the tumor nests, no significant stromal reaction or capillary space invasion, and an infiltrating growth pattern. Some authors have suggested a slow growth pattern with limited local invasiveness and low probability of lymph node metastases (107). Prognosis is excellent (358).
Primary sarcomas of the cervix have been occasionally described (e.g., leiomyosarcoma, rhabdomyosarcoma, stromal sarcoma, carcinosarcoma) (615).
Malignant lymphomas, primary or secondary in the cervix, have been sporadically reported. They behave, are classified, and should be treated as other lymphomas (148).
Metastasis of distant tumors to the uterine cervix are rare (about 4% of all tumors) and should be considered in the differential diagnosis. Metastasis from the breast, ovary, and kidney have been reported (53,464,557).
Prognostic Factors
Patient Factors
Age
According to some reports, age is not a prognostic factor in carcinoma of the cervix (116). Other authors have noted decreased survival in women younger than 35 or 40 years (108), who have a greater frequency of poorly differentiated tumors. In contrast, two European studies showed improved outcome for younger patients (407). This apparent contradiction may be explained by an analysis by Rutledge et al. (537), who showed an interaction between age and stage in the relative hazard plots for 250 patients younger than 35 years of age and matched control subjects. Mitchell et al. (413) evaluated 398 patients with stage I to III cervical carcinoma treated with radiation therapy. Patients were divided into nonelderly (35 to 69 years of age; n = 338) and elderly (≥70 years of age; n = 60) groups. Comorbid conditions in the elderly resulted in diminished ability to undergo intracavitary brachytherapy. Although the 5-year actuarial disease-free and CSS rates were comparable in the two groups, tumor recurrence and death from cervical cancer were more common beyond 5 years in the elderly group.
Race/Socioeconomic Status
Several authors have noted a correlation between racial or socioeconomic characteristics of patients and outcome of
P.1542

therapy (78,648). Mundt et al. (427) examined factors affecting outcome in 316 African American and 94 white patients undergoing RT for cervical cancer. With a median follow-up of 72.4 months, African Americans had a trend toward poorer 8-year cause-specific survival rates (47.9% vs. 60.6%; p = 0.10) compared with white patients. Factors correlating with poor outcome, present in the African American group, included lower hemoglobin (Hb) levels during RT (p = 0.001), lower median income (p = 0.001), and less frequent intracavitary brachytherapy (p = 0.09). Multivariate analysis demonstrated that race was not an independent prognostic factor after controlling for difference in patient, tumor, and treatment factors. Grigsby et al. (195), in 452 white and 124 African American women with stage II or III cancer of the cervix treated with RT alone, observed 5-year CSS rates for stage II of 66% and 61% (p = 0.56) and for stage III 38% and 47% (p = 0.34), respectively. Overall survival rates for stage II for the two racial groups were different (60% and 51%, respectively; p = 0.02) and may be related to non–cancer-related comorbidity factors.
Brooks et al. (56) evaluated 1,009 patients with invasive carcinoma of the cervix; 606 white, 354 African American, and 5% “other” races. African Americans were more likely to have Medicaid or to be uninsured (44% vs. 23%; p = 0.001) and were more likely to be admitted for an emergency or for a cancer-related complication (p = 0.036), to have comorbid illness (p = 0.001), to be admitted for a transfusion (p = 0.01), or to be treated with irradiation rather than surgery (p = 0.001). Racial differences existed in patterns of admission, type of therapy, and severity of illness.
Moreover, in an analysis of the 1994 Patterns of Care study of 471 cases of squamous-cell carcinoma treated in the United States and a randomly selected 215 additional cases from 17 institutions that admitted more than 40% minority patients, women who lived in low-income neighborhoods, who had only Medicaid coverage, or who were treated at large academic or minority-rich institutions tended to have a poorer initial performance status, higher-stage or bulky central tumor, and a lower pretreatment hemoglobin level (303).
General Medical Factors
Anemia and Tumor Hypoxia
Although stage, tumor volume, histologic type of the lesion, and vascular or lymphatic invasion are known to affect the prognosis of patients with cervical carcinoma, hemoglobin levels have also been the subject of extensive investigation in this regard.
Reviewing experimental data, Hirst (249) emphasized that in animal tumor models the opportunity to affect radiosensitivity by blood transfusion is transient. Blood transfusion is in general beneficial to the anemic patient with cancer, but it must be given as soon as possible before the first radiation dose to maximize its effects. Accounting for both the normal pulmonary and peripheral circulation and parallel flow through tumor tissue, Kavanagh et al. (308) calculated that decreasing hemoglobin–oxygen affinity should render a quantitatively greater decrease in radiobiologically hypoxic regions than what has been measured after the use of transfusions alone (586).
Using polarographic needle electrodes for direct tumor tissue oxygen measurements, investigators have reported worse outcomes for patients whose tumors have either a median partial pressure of oxygen (PO2) level below 10 mm Hg (251) or a high percentage of PO2 measurements below 5 mm Hg (330,518). Comparisons of intratumoral oxygen measurements before and after external-beam radiation therapy have usually indicated a trend toward improved oxygenation after radiation therapy (94,129), but the significance of posttreatment measurements is unclear (169). Hypoxic tumors are more likely to recur locoregionally than well-oxygenated tumors regardless of whether surgery or radiation therapy is the primary local treatment (251).
Höckel et al. (251) reported higher 5-year disease-free survival rates in 21 patients in whom median oxygenation measured with polarographic needle electrodes was at least 10 mm Hg, in contrast to only 40% in 23 patients with a PO2 <10 mm Hg.
Hypoxia-mediated genetic alterations such as inactivation or mutation of p53 are suspected to impart biologically aggressive traits (186).
Haensgen et al. (217), in 70 patients with stage IIB to IVA cervical cancer treated with EBRT and brachytherapy, analyzed biopsies for p53 transformed with a functionally inactive mutation (tp53) and DNA index measured by flow cytometry. In vivo oxygenation was measured with an Eppendorf probe, and patient hemoglobin levels were recorded. Patients with hemoglobin <11 g/dL had a 3-year survival rate of 27%, compared with 62% in those with hemoglobin ≥11 g/dL (p = 0.006). Of 70 tumors, 49 showed evidence of hypoxia (any reading of PO2 <5 mm Hg) and a trend toward poorer survival compared with nonhypoxic tumors (48% vs. 70%; p = 0.07). Sixty of 70 tumors showed tp53 expression, which alone had no impact on survival (tp53 = 50% vs. wtp53 = 79%; p = 0.11). Hypoxic tumors had a significantly higher expression of tp53 (p = 0.012), whereas FIGO stage and anemia had no impact on p53 expression. Combining hypoxia and tp53 allowed stratification of subgroups with differing 3-year survival rates: tp53 (n = 10), 79%, and tp53 without hypoxia (n = 44), 47%. Flow cytometry demonstrated no effect of ploidy on survival. Advanced stage and pretreatment hemoglobin are independent prognostic factors in cervical carcinoma. Mutated or transformed tp53 was found more often in hypoxic tumors.
Notwithstanding the uncertain association between hypoxia and anemia, a randomized trial reported by Bush (64) 20 years ago remains an influential study; 132 patients with stage IIB to III cervical cancer were randomized to a control arm in which transfusions were given only if the hemoglobin level dropped below 10 g/dL, or an experimental arm in which transfusions were given to maintain the hemoglobin level at or above 12.5 g/dL. The results in the initial report suggested an improved outcome for patients in the experimental arm who received transfusion, but Bush underscored the need to interpret the study results with caution in view of certain inherent biases in the analysis. As noted by Fyles et al. (168), there was not a statistically significant difference in outcome between treatment arms when compared by an intent-to-treat analysis. Second, the randomization was not stratified according to the potentially confounding influence of tumor size, and records of individual patients' tumor dimensions are not available. Finally, and perhaps most important, the thresholds for transfusion were based on anemia during therapy, not the initial hemoglobin. Although the subgroup analysis indicated a difference between patients in the control arm who received transfusion and patients in the experimental arm who received transfusion, only the least responsive patients in the control arm would likely continue to bleed during treatment and require a transfusion for a hemoglobin decrease below 10 g/dL, whereas the higher threshold for transfusion in the experimental group would have captured more patients already beginning to respond early in the course of treatment. Subsequently, Thomas (606) reviewed the Canadian experience and found that in 605 eligible patients with cervical cancer, 25% received blood transfusions, most frequently when Hb was below 100 g/L. On multivariate analysis baseline Hb was not a significant prognostic factor, but average weekly nadir during radiation therapy was significant (those with values higher than 120 g/L had lower incidence of local relapses and distant metastasis and better 5-year survival than patients with lower Hb levels).
P.1543


Dunst et al. (130) studied 87 patients with squamous-cell cervical carcinoma treated with EBRT and HDR brachytherapy. Tumor oxygenation was measured with Eppendorf PO2 before RT and at 19.8 Gy and angiogenesis was determined by microvessel density on biopsies. Pretreatment anemia had a significant impact on relapse rate (at 3 years, 6% in 20 patients with Hb >13 g/dL, 15% in 47 with Hb between 11to 13 g/dL and 67% in 20 with Hb <11 g/dL). The 3-year overall survival was 79%, 64%, and 32%, respectively). Twenty-three tumors were poorly oxygenated (median PO2 <15 mm Hg before RT and at 19.8 Gy) and 3-year survival was 38%, compared to 68% in patients with higher PO2 (p = 0.02).
On the other hand, Eifel et al. (139), in a retrospective review of 2,997 patients with cervical cancer stage I or II treated with RT, found no impact of any Hb parameter on central, pelvic, or distant failures. Only tumor size and lymph node status were independent predictors of central recurrence (p <0.0001) and tumor size, FIGO stage, lymph node status, and marginally transfusion during RT (p = 0.04) were correlated with disease-specific survival.
Munstedt et al. (426), in 183 patients who received adjuvant postradical surgery RT, noted that those with Hb <11 g/dL had lower recurrence-free and overall survival. Noteworthy, the difference was present mainly in a subgroup of women who had inadequate surgery.
The issue of whether blood transfusions to hemoglobin levels above 12 to 12.5 g/dL improve prognosis remains unsettled, but there are additional data to support that giving transfusions to maintain the average hemoglobin level during treatment at that level is beneficial. In a retrospective review of over 600 patients treated at seven different cancer centers in Canada, Grogan et al. (212) observed that the patients who maintained an average weekly hemoglobin level above 12 g/dL with or without transfusions had a significantly higher 5-year survival rate than patients with lower average weekly hemoglobin levels, regardless of the hemoglobin at presentation.
Many radiation oncologists routinely administer red blood cell transfusions (RBCT) to correct anemia before treatment with radiation therapy for cervical cancer, hoping at least for a generally favorable effect on the patient's sense of well-being and energy level if not also an impact on tumor radiosensitivity. Kapp et al. (297) reported on 204 patients who received red cell transfusion during RT when Hb level was <11 g/dL. Patients whose Hb was corrected (18.5%) had outcome similar to nontransfused patients. However, patient nonresponders to RBCT had decreased tumor control and survival.
Vaupel et al. (633), in a review of published data, concluded that maximum oxygenation of tumors is expected with Hb in the range of 12 to 14 g/dL for women and that higher Hb levels may not be better. This has implications for transfusions or administration of epoetin.
During the past decade, it has been established that recombinant human erythropoietin (EPO) provides an alternative means of sustaining or raising hemoglobin levels during radiation therapy. Typically, a dose of 200 U/kg per day 5 days per week would be expected to elevate hemoglobin by an average of 1 to 3 g/dL (133,356,637).
Dusenbery et al. (133), in 20 patients with carcinoma of the cervix with anemia, noted that EPO induced a prompt reticulocyte response (from 2.4% to 4.9%) by the beginning of radiation therapy. In the EPO group, the mean baseline hemoglobin level was 10.3 g/dL; by the second week it had increased to 12.2 g/dL, and by completion of radiation therapy, to 13.2 g/dL. Mean baseline hemoglobin level in concurrent control patients was 10.7 g/dL; at the completion of radiation therapy it was 10.4 g/dL.
Although it is clear that EPO can reduce the need for transfusions for anemic patients with cancer in a variety of settings, its effect on quality of life is less certain (547). Furthermore, there is currently no proof that the use of EPO is in any way superior to transfusions with respect to impact on clinical outcome for patients receiving radiation therapy in particular, and transfusions are a less expensive option in most cases (305).
Other Medical Factors
Jenkin and Stryker (280) observed a higher incidence of pelvic recurrences and complications in patients with arterial hypertension (diastolic pressure >110 mm Hg).
Kapp and Lawrence (296) reported on 398 patients; patients with temperatures over 101°F had a higher incidence of distant metastases and a lower survival rate.
Tumor Factors
Tumor Volume
There is a close correlation between depth of stromal invasion, tumor size, and incidence of parametrial and pelvic node metastases and survival in patients with cervical cancer (12,117). In a study of women treated with radical hysterectomy, the 5-year disease-free survival rate was 90% in 181 patients stage IB1 (≤4 cm) and 72.8% in 48 patients with stage IB2 disease (p = 0.02) (155).
Toita et al. (614), in a review of 70 patients with stage IIB and IIIB carcinoma of the uterine cervix treated with RT alone, reported no significant correlation of 5-year DFS with size of the cervical tumor <60 mm (70% to 85%); however, in patients with tumor >60 mm, the 5-year DFS was 28.6%.
Piver and Chung (488) showed a greater incidence of lymphatic and distant metastasis and lower survival rates in patients with bulky and barrel-shaped stage IB and IIA tumors treated by radical hysterectomy (Table 66.7). Also, a higher incidence of pelvic recurrences and distant metastases and a decreased survival rate were reported by Fletcher (161), Eifel et al. (142), and Perez et al. (476) in patients with larger tumors treated with irradiation. In stages IB and IIA, higher radiation doses or combination with an extrafascial hysterectomy improved local tumor control (144,474).
Further, Leveque et al. (375), in patients with stage I to II adenocarcinoma of the cervix treated with RT alone or combined with radical surgery, noted that FIGO stage and pelvic node involvement were the most important parameters influencing overall survival. Silver et al. (558), in 93 patients with stage I adenocarcinoma of the cervix, described patient age and tumor grade as significant prognostic variables for survival (p <0.01 and 0.01, respectively); tumor size was significant (p <0.01) for survival and progression-free survival.
In contrast, Grigsby et al. (198), in patients with stage IB and IIA carcinoma of the cervix treated with preoperative irradiation and radical or conservative hysterectomy, observed no correlation of tumor volume with outcome. The 5-year pelvic failure rates for stage IB were 16% for tumors smaller than 3 cm and 9% for larger tumors (p = 0.90) and for stage IIA 22% for tumors both smaller or larger than 3 cm (p = 0.75).
Several retrospective studies have demonstrated decreased survival and a greater incidence of distant metastases in patients with endometrial extension of a primary cervical carcinoma (endometrial stromal invasion or replacement of the endometrium by tumor only) (470). Grimard et al. (211), on the other hand, confirmed these findings only in patients with stage IB tumors, but not in more advanced stages. Similar findings were noted by Noguchi et al. (445). Patients without uterine body invasion had a 5-year survival rate of 92.4% compared with 53.8% in patients with invasion.

P.1544


Histology
Most reports have shown no significant correlation of survival or tumor behavior with the degree of differentiation of squamous-cell carcinoma or adenocarcinoma of the cervix (10,79,640).
Alfsen et al. (10) analyzed 417 adenocarcinomas and 88 other nonsquamous-cell carcinomas of the cervix; in patients with stage I, histological type, extension to the vagina or corpus uteri, tumor volume (>3,000 mm3), infiltration depth (in thirds of the cervical wall), vascular invasion, lymph node metastases, treatment, and patient age were significant prognostic variables.
Although Reagan and Fu (507) demonstrated prognostic value of histologic differentiation in patients treated with irradiation, Crissman et al. (101) failed to observe a correlation between histologic parameters and patient survival.
Angiogenesis and Tumor Vascularity
Microvessel count is higher in patients with cervical neoplasia than in control patients and higher in patients who experience posttreatment recurrences. Obermair et al. (448), in 166 patients with stage IB cervical cancer, observed a 5-year survival rate of 89.7% in 102 patients whose tumors had a microvessel density of 20/field or less and 63% in 64 patients whose tumors had a microvessel density of >20/field (log rank p <0.0001). Similar findings were reported by Cooper et al. (95).
Loncaster et al. (383), in a retrospective study of 100 patients, found that vascular endothelial growth factor (VEGF) expression in tumor biopsies in advanced carcinoma of the cervix was associated with a poor prognosis.
Flow Cytometry Studies on DNA and Growth Fraction
Some authors have noted no significant difference in recurrence rates between patients with diploid or aneuploid tumors. Kristensen et al. (339), in a study 465 patients with invasive carcinoma of the uterine cervix on whom DNA index and S-phase fraction studies were performed, observed that neither ploidy level nor S-phase fraction had prognostic significance. On the contrary, Strang et al. (582) noted more relapses in tumors with an S-phase rate of 20% or greater.
Apoptosis and Radiation Response Markers
Wheeler et al. (652) evaluated levels of apoptosis as “predictors for tumor response” in 44 patients with stage IB adenocarcinoma of the cervix. Patients whose tumors had a baseline apoptosis level above the median value (2%) had better overall survival than those with lower than median levels (p = 0.056). Chung et al. (86), in pretreatment biopsy specimens of 48 patients with stage IIB squamous-cell carcinoma of the uterine cervix treated with RT, found that those tumors with an apoptotic index above the median had better tumor control (p = 0.0062) and overall survival (p = 0.0053) than those whose tumors had a lower apoptotic index. Sheridan et al. (555), in a study of 39 patients with adenocarcinoma of the cervix, also noted that when the apoptotic index was quantified, the 5-year survival rates for women with tumors whose apoptotic index/mitotic index was greater or less than the median were 81% and 25%, respectively.
On the other hand, Paxton et al. (465) examined the percentage of apoptotic cells in 146 carcinomas of the cervix from patients scheduled to receive RT. The median apoptotic level was 0.73%. Patients were divided into two groups around the median. There was no statistically significant difference in outcome between the two groups.
Cerciello et al. (69), in 40 patients with stage IIA-IIIB cervix cancer treated with RT without chemotherapy, obtained biopsies before and after five fractions of RT. They observed significant changes in the cell cycle of cervical cancer, indicating intact G2/M checkpoint function, leading to the expectation that targeting compounds interfering with G2/M transition may enhance the effect of irradiation on cervix cancer.
Tsang et al. (619), in patients with carcinoma of the uterine cervix treated with irradiation, observed that the most significant factors for disease-free survival were large tumor size (p = 0.01), low hemoglobin (p = 0.01), labeling index (LI) flow cytom-etry (disease-free survival 67% for LI lower than 7%, 33% for LI of 7% or higher; p = 0.03), and potential doubling time (T(pot)) (66% for T(pot) longer than 5 days, 35% for T(pot) of 5 days or less; p = 0.04). For small tumors (<6 cm in diameter), either a high LI (>7%) or a high apoptotic index (>1%) were associated with poorer disease-free survival.
West et al. (650) evaluated the intrinsic radiosensitivity of 145 tumor biopsies from patients with cervical carcinoma (in vitro survival fraction at 2 Gy using a clonogenic assay). Diploid tumors tended to be more radioresistant than aneuploid tumors (p = 0.07).
Bax, Bcl-2, c-erbB-2, p53
Bax protein serves as a positive regulator of apoptosis by forming heterodimers with bcl-2 protein, promoting cell survival; c-erbB-2 is a cell growth factor, and p53 a tumor suppressor gene. Ohno et al. (452) assessed the relation between apoptosis and the expression of Bax and Bcl-2 protein during RT for cervical carcinoma in 20 patients before and after administration of 9 Gy. The apoptotic cell index in tumor cells was 0.22% before irradiation and 1.20% after 9 Gy (p = 0.0004). The positive rate of Bax protein increased from 15% (in 3/20 patients) before irradiation to 60% (in 12/20 patients) after 9 Gy (p = 0.0126), suggesting that Bax protein is associated with apoptosis induced
P.1545

by fractionated radiation therapy. Wootipoom et al. (663), in 174 patients with cervical cancer, noted Bax, Bcl-2, and p53 expression in 68.4%, 25.9%, and 77.6% of the cases, respectively. Bax expression was associated with better survival, whereas Bcl-2 expression was associated with poor survival. Jain et al. (277) also found that neither Bcl-2 nor p53 expression were independent predictors of outcome in locally advanced cervical cancer.
Grace et al. (185), in a study of 105 patients with cervical cancer and 20 age-matched controls, noted a highly significant correlation between p53 and Bcl-2 expressions and HPV infection (p = 0.00001) and with various stages from dysplasia to invasive carcinoma.
Harima et al. (233), in 37 patients with stage IIIB cervical carcinoma treated with irradiation alone or combined with hyperthermia, noted that pelvic tumor control was associated with increased Bax expression: 10.5% (2/19) in the RT group versus 44.4% (8/18) in the thermoirradiation group (p = 0.02).
Mukherjee et al. (425) retrospectively analyzed 78 cases of stage II or IIB carcinoma of the cervix treated with RT followed by surgery 4 to 6 weeks later. On histologic examination of the surgical specimens, 40 cases (51%) showed a complete response to therapy. In the radioresistant cases, 15% (six cases) had positivity for Bcl-2 and p21 proteins, respectively, and 34% (13 cases) showed mutant p53 protein. None of the radiosensitive tumors were positive for these proteins. Seventy-five percent of the radiosensitive tumors (30 cases) were positive for the Bax antibody, whereas 81% of the radioresistant tumors (31 cases) were negative for Bax (p < 0.01). The presence of Bcl-2, p21, and p53 proteins could also be related to radioresistance of the tumors.
Altered expression of c-ercB-2 protein was shown to have prognostic significance in adenocarcinoma but not in squamous-cell carcinoma of the cervix (396).
The p53 gene controls entry into the S-phase of the cell cycle. Kainz et al. (292), in a study of 109 surgically treated patients, and Ebara et al. (135), in 46 patients with stage IIIB squamous-cell carcinoma of the cervix treated with RT alone, noted no significant difference in outcome, when correlated with p53 protein expression.
Cellular Oncogenes
Alterations in either the expression or function of cellular genes that control cell growth and differentiation have been investigated as prognostic markers in cervical cancer, but, as yet, the data based on small studies show no clear-cut useful marker.
The p27/Kip1 gene inhibits a variety of cyclin-dependent kinase complexes and regulates cell growth. Oka et al. (453) studied 202 biopsy specimens obtained from 77 patients with squamous-cell carcinoma of the cervix before and during RT for expression of p27 and p53 proteins. A high p27 LI before radiation therapy was associated significantly with good disease-free and metastasis-free survival rates. A high p53 LI before irradiation was associated with poor overall survival.
Both specific point mutations and amplification of ras genes have been noted, and overexpression of the ras gene p21 product is associated with a poor prognosis and increased frequency of lymph node involvement (237). Although loss of heterozygosity of the c-Ha-ras gene in squamous-cell carcinomas was not associated with advanced-stage disease, mutations were associated with a poor prognosis. In contrast, mutations of the Ki-ras gene have been detected in a small percentage of cervical adenocarcinomas, but have not been significantly associated with stage, grade, or survival (335,365).
The c-myc oncogene is amplified from three to 30 times in approximately 20% of squamous-cell carcinomas and is more frequent in high-stage compared with low-stage tumors. Overexpression of c-myc has been associated with a worse clinical outcome (275,512).
Gadd45 belongs to the class II family of DNA damage-inducible genes, and its role in DNA repair has been proved in many experimental models. Santucci et al. (543), in 14 patients with cervical cancer, found a correlation between the lack of gadd45 induction and a clinical response to irradiation (both local tumor control and disease-free survival) when a dose ranging from 18 to 25 Gy was delivered to the pelvis.
CD 34 is an antigen present in hemopoietic progenitor cells and is a sensitive marker for endothelial cells. In 62 patients with cervical cancer evaluated by Vieira et al. (636), CD 34 reactivity and higher microvessel density was associated with squamous-cell carcinoma.
CD 109 is a cell surface protein that was found to be expressed in cervical cancer more than in endometrial adenocarcinoma (669), which may have implications for development of new targeted therapy for cervical cancer.
Preoperative elevated CA 125 levels (cutoff value, 26 U/mL) were associated with depth of stromal invasion, lymphovascular invasion, and nodal metastasis in 116 patients with adenocarcinoma of the cervix. In patients with negative nodes, high CA 125 levels determined poor histopathological prognostic factors (618).
Carcinoembryonic Antigen
Tsai et al. (617) in 117 patients with adenocarcinoma of the cervix, 28 of whom had preoperative carcinoembryonic antigen (CEA) levels >5 ng/mL, noted a correlation with larger tumor size, deeper cervical invasion, and lymphovascular invasion (p <0.001). A Spanish study of 96 patients with invasive carcinoma of the cervix and seven with intraepithelial neoplasia showed elevated CEA levels in 33%, CA 19.9 in 32%, and CA 125 in 21.5% of patients (48). Specificity for each tumor maker was 98%. Increased CEA and CA 19.9 levels were found with more advanced stages of the disease and in patients with adenocarcinoma compared with squamous-cell carcinoma. At follow-up, all cases of progressive tumor or recurrence were detected by elevation of one of the three antigens. Specificity during follow-up was 92% for CEA and CA 125 and 92.6% for CA 19.9.
Cytokeratin Markers
In 80 patients with carcinoma of the cervix, expression of cytokeratin 10 and 13 and involucrin was found in 24%, 64%, and 53%, respectively (626). There was no difference in the expression of cytokeratin or involucrin between patients with positive or negative lymph nodes, although in the lymph node–positive group, survival was higher in patients lacking cytokeratin 13 expression (p = 0.02).
In another study of 272 patients with invasive carcinoma of the cervix with 1,053 samples, Bolli et al. (44) noted an elevation of squamous-cell carcinoma antigen (SCC-Ag) before treatment in 53% of 103 patients, increasing with advancing tumor stage at diagnosis. In 70 patients with recurrent tumor, 81% had elevated SCC-Ag. Ngan et al. (442) also identified elevation of serum SCC-Ag in 62% of 308 women with carcinoma of the cervix. Posttreatment SCC levels were raised in 69 patients (22.4%), and this was associated with a <5% 5-year survival rate, in contrast to 87% in women with normal SCC-Ag levels.
Hong et al. (254), in 401 patients with stage I to IV squamous-cell carcinoma of the cervix treated with RT, noted that the preirradiation SCC-Ag level strongly correlated with disease stage. A persistently elevated SCC-Ag level 3 months after RT was a stronger predictor for treatment failure than residual induration by pelvic examination, and it was associated with a higher incidence of distant metastasis.
Likewise, Micke et al. (409), in 141 patients with cervical cancer treated with RT, noted the pretherapy serum level of SCC-Ag was elevated in 72% (>2 ng/mL). Patients with a SCC
P.1546

below 7.2 U/mL had better tumor response than those with higher levels. After RT, 98% of patients in complete remission and 87% of those in partial remission had a serum level below the cutoff. In recurrent tumors, 82% of patients had a significant increase in serum levels before clinical manifestation of relapse (≤0.001). Hong et al. (256), in 1,031 patients with squamous-cell cervical cancer treated with RT with or without chemotherapy, noted that independent risk factors for local relapse were advanced stage and age <45 years; 5-year local relapse-free survival was higher (90%) if squamous-cell carcinomas antigen was less than two. This antigen may be a useful marker in the prognosis of patients with carcinoma of the uterine cervix.
Epstein-Barr, Transforming Growth Factor, β-Integrin, and Other Markers
Activity of Epstein-Barr virus antigen–specific killer T cells and shedding of Epstein-Barr virus were evaluated in 55 patients with carcinoma of the cervix (326). Activity was decreased in patients with cervical carcinoma compared with control patients; it became increasingly lower as the clinical stage of the disease advanced, and activity after treatment was clearly related to patient survival. These data may indicate an imbalance in local immunity against viral infection and impairment of T-cell immunity in patients with advanced cervical carcinoma.
In 79 patients undergoing radiation therapy for carcinoma of the cervix, pretreatment transforming growth factor-β1 (TGF-β1) levels were a significant prognostic factor for survival and local tumor control. There were weak significant correlations of TGF-β1 levels with disease stage and the levels of circulating tumor markers (CA 125) (121). Hazelbag et al. (238) also assessed TGF-β1 and plasminogen activator inhibitor (PAI-1) expression in 108 specimens of cervical carcinoma and noted that TGF was not associated with worse prognosis, whereas PAI-1 was.
Gruber et al. (213), in biopsies of 82 patients with cervical cancer, found that β3-integrin was expressed in 50 (61%) and correlated it with higher incidence of locoregional recurrences and decreased survival.
Cyclooxigenases
Gaffney et al. (172), in 24 patients with carcinoma of the cervix treated with RT, observed that 5-year overall survival rates for tumors with low versus high COX-2 values were 75% and 35%, respectively (p = 0.021). COX-2 staining intensity was found to correlate positively with tumor size (p = 0.022).
Kim et al. (322) screened 84 patients with stage IIB squamous-cell and 21 with adenocarcinoma cervical cancer and found COX-2 expression more frequently in the adenocarcinoma group (57% vs. 24%; p = 0.007). The 5-year survival rate was 83% for COX-2 negative and 57% for COX-2 positive patients, regardless of histological subtype (p = 0.001). Pyo et al. (503) also showed that expression of COX-2 and coexpression of COX-2 and thymidine phosphorylase (TP) were correlated with high locoregional recurrence and lower survival. Moreover, Kang et al. (294), in 84 patients with cervix adenocarcinoma, observed a higher incidence of lymph node metastasis and decreased survival with elevated expression of COX-2
Hormonal Receptors
Suzuki et al. (590) investigated the expression of estrogen receptors and progesterone receptors (PgR) in biopsy specimens from cervical tumors before RT in 44 patients with cervical adenocarcinoma and 22 with adenosquamous-cell carcinomas treated. Staining for estrogen receptors or PgR was positive in 12 patients (19%). The estrogen receptor status did not correlate with the local tumor control, disease-free, or cause-specific survival. Disease-free survival rate of PgR-positive patients was significantly higher than that of PgR-negative patients (p = 0.044), but it was not statistically significant in relation to 5-year cause-specific survival or local tumor control.
HIV
In 120 patients with cervical cancer screened for HIV and treated with RT, Campbell et al. (68) observed a 4.2% positive HIV. These patients had more advanced tumors and duration of remission was shorter than in the HIV negative group. RT had no effect on the HIV titers. Women who are HIV positive or have acquired immunodeficiency syndrome associated with in situ or invasive carcinoma of the cervix are at a higher risk for tumor recurrence after treatment and death as a consequence of the malignant process (328,665).