Chemoradiation for primary invasive squamous carcinoma of the vagina.

OBJECTIVE: To report outcomes for patients with primary, invasive, squamous carcinoma of the vagina treated with chemoradiation. METHODS: Between 1986 and 1996, 14 patients were treated with primary therapy consisting of synchronous radiation and chemotherapy. Patients were judged not to be surgical candidates based on tumor size, location, and concerns related to urinary, bowel, or sexual function. Three patients were FIGO stage I, ten patients stage II, and one patient stage III. Radiation consisted of teletherapy alone (six patients) or in combination with intravaginal brachytherapy (eight patients). Total radiation dose ranged from 5700 to 7080 cGy (median 6300 cGy). Chemotherapy consisted of 5-fluorouracil alone (seven patients), or with cisplatin (six patients) or mitomycin-C (one patient). RESULTS: One patient failed locally at 7 months and died of disease at 11 months. Four patients died of intercurrent illness (46, 92, 104, 109 months) and nine are alive and cancer-free 74-168 months after treatment (median 100 months). There were no vesicovaginal or enterovaginal fistulae. CONCLUSIONS: Radiation with synchronous chemotherapy is an effective treatment for squamous carcinoma of the vagina. Cancer control outcomes compare favorably with previously published results employing higher dose radiation as monotherapy.

Atypical glandular cells of undetermined significance (AGUS): cytopathologic features, histopathologic results, and human papillomavirus DNA detection.

We intensively reviewed 137 smears initially classified as atypical glandular cells of undetermined significance (AGUS) to refine cytological criteria for evaluating these cases, evaluate histological outcomes, and assess the value of human papillomavirus (HPV) DNA testing in management. Consenting, nonpregnant study participants were identified from a cohort of 46,009 women receiving routine Pap smear screening in a managed care setting. Colposcopy was performed on all women, and at least one histological sample was obtained from each. Review diagnoses were assigned to smears and biopsy specimens by two separate panels of pathologists. DNA testing for cancer-associated HPV types was performed on rinses of cytological samplers after a smear and thin-layer slide had been made. On review, 47 (34%) smears were reclassified as negative, 44 (32%) as AGUS, 30 (22%) as atypical squamous cells of undetermined significance (ASCUS), and 16 (12%) as squamous intraepithelial lesions (SIL). The 19 smears interpreted as high-grade intraepithelial lesions on review included 13 high-grade SIL (HSIL), two HSIL with AGUS, favor neoplastic (endocervical adenocarcinoma in situ [AIS]), and four AGUS, favor neoplastic (AIS). Review histological diagnoses were negative in 105 (77%), squamous or glandular atypia in four (3%), low-grade SIL (LSIL) in nine (7%), HSIL in 12 (9%), AIS in five (4%, including two with concurrent HSIL), and endometrial carcinoma in one (1%). HPV testing identified 11 (92%) of 12 women with histologically confirmed HSIL and all five with AIS (100%). A high-grade intraepithelial lesion or carcinoma is detected in approximately 14% of women with community-based diagnoses of AGUS who are referred for immediate evaluation. Use of refined cytological criteria and HPV DNA testing may permit improved management of women with AGUS.

Identifying women with cervical neoplasia: using human papillomavirus DNA testing for equivocal Papanicolaou results.

CONTEXT: A Papanicolaou (Pap) test result of atypical squamous cells of undetermined significance (ASCUS) presents a clinical challenge. Only 5% to 10% of women with ASCUS harbor serious cervical disease, but more than one third of the high-grade squamous intraepithelial lesions (HSILs) in screening populations are identified from ASCUS Pap test results. OBJECTIVE: To determine whether human papillomavirus (HPV) DNA testing of residual material from liquid-based Pap tests and referral of cases found to be HPV-positive directly to colposcopy could provide sensitive detection of underlying HSILs in women with ASCUS Pap results, compared with repeat Pap testing. DESIGN AND SETTING: Natural history of women with ASCUS Pap smear results, all of whom had liquid-based cytology, HPV testing, and subsequent repeat Pap tests and colposcopy with histologic evaluation, conducted at 12 gynecology clinics in a large managed care organization between October 1995 and June 1996. PARTICIPANTS: From a cohort of 46009 women who had routine cervical examinations, 995 women with Pap test results of ASCUS who consented to participate were identified. MAIN OUTCOME MEASURES: Cervical histology, HPV test results, and repeat Pap smear results, and sensitivity of HPV testing to identify patients found to have HSIL+ histology. RESULTS: Of 995 participants with ASCUS Pap test results, 973 had both a definitive histologic diagnosis and HPV result. Sixty-five (6.7%) had histologic HSIL or cancer. For women with histologic HSIL+, the HPV test was positive in 89.2% (95% confidence interval [CI], 78.4%-95.2%), and the specificity was 64.1 % (95% CI, 60.9%-67.2%). The repeat Pap smear result was abnormal in 76.2% (95% CI, 63.5%-85.7%). Triage based on HPV testing only or on repeat Pap testing only would refer similar proportions (approximately 39%) to colposcopy. The sensitivity of HPV DNA testing for HSIL was equivalent to, if not greater than, that of the repeat Pap test. We further estimated that an HPV-based algorithm including the immediate colposcopy of HPV-positive women, and then repeat Pap testing of all others, would provide an overall sensitivity of 96.9% (95% CI, 88.3%-99.5%). CONCLUSIONS: For women with ASCUS Pap tests, HPV DNA testing of residual specimens collected for routine cervical cytology can help identify those who have underlying HSIL. By testing the specimen collected at initial screening, the majority of high-risk cases can be identified and referred for colposcopy based on a single screening.

Where's the high-grade cervical neoplasia? The importance of minimally abnormal Papanicolaou diagnoses.

OBJECTIVE: To characterize the relative contributions of the different abnormal Papanicolaou smear cytologic diagnoses in the Bethesda System to the subsequent histologic diagnosis of high-grade cervical neoplasia. METHODS: A total of 46,009 nonpregnant female members of the Kaiser Permanente Health Plan, Northern California Region, were studied prospectively. The main outcome measures included routine Papanicolaou smear diagnoses and subsequent histologic diagnosis of colposcopically directed cervical tissue specimens. RESULTS: Atypical squamous cells of undetermined significance (ASCUS) was the most common abnormal Papanicolaou diagnosis, representing 3.6% of the total number of smears. Of the total number of cases of histologically confirmed high-grade cervical neoplasia present in the population, the largest proportion (38.8%) was in women with smears showing ASCUS. Minimal abnormalities combined (ASCUS, atypical glandular cells of undetermined significance, and low-grade squamous intraepithelial lesion) were coincident with 68.6% of the cases of histologic high-grade cervical neoplasia diagnosed in this routine screening population. CONCLUSION: Recognition of the importance of equivocal and mild Papanicolaou test abnormalities in the subsequent diagnosis of high-grade cervical neoplasia emphasizes the need for accurate and cost-effective triage of the large population of women with minimally abnormal Papanicolaou diagnoses.

Prophylactic chemoradiation of inguinofemoral lymph nodes in patients with locally extensive vulvar cancer.

OBJECTIVE: Primary surgical resection of locally advanced squamous cancer of the vulva may compromise the integrity of important midline structures such as the anus, clitoris, urethra, and vagina. Chemoradiation (synchronous radiation and cytotoxic chemotherapy) has been used as alternative initial treatment which may serve as definitive management for some patients, or may reduce the scope and functional sequelae of subsequent surgery in others. Inguinofemoral node dissection is associated with substantial risk of both acute and late morbidity, prompting consideration of elective inclusion of groin nodes within the irradiated volume and deletion of subsequent groin surgery. Concern that disease relapse in the groins is potentially fatal suggested the prudence of formal outcome assessment of our recent experience with prophylactic treatment of clinically uninvolved groin nodes in the context of concurrent chemoradiation for locally advanced primary vulvar cancer. METHODS: A review was conducted of 23 previously untreated patients with locally advanced squamous cancer of the vulva (2 T2, 20 T3, 1 T4) and clinically uninvolved groin nodes (1969 FIGO stages 14 N0, 4 N1, and 5 N2 with negative node biopsies) who were treated since 1987 with chemoradiation administered to a volume electively including bilateral inguinofemoral nodes. These patients did not undergo subsequent groin surgery. RESULTS: With follow-up from 6 to 98 months (mean, 45.3 months; median, 42 months), no patient has failed in the prophylactically irradiated inguinofemoral nodes. No patient has developed lymphedema, vascular insufficiency, or neurological injury in a lower extremity, and no patient has experienced aseptic necrosis of a femur. CONCLUSIONS: Elective irradiation of the groin nodes in the context of initial chemoradiation for locally advanced vulvar cancer is an effective therapy associated with acceptable acute toxicity and minimal late sequelae. It constitutes a sensible alternative to groin dissection in this patient population.

Treatment of recurrent adenocarcinoma of the endometrium with pelvic exenteration.

Women with recurrent endometrial carcinoma are usually not considered candidates for pelvic exenteration. To assess the efficacy of this procedure, the records of all patients undergoing pelvic exenteration for adenocarcinoma of the endometrium at four institutions from 1955 through 1988 were reviewed. Of the 31 procedures performed, 7 were for primary therapy and 4 were judged to be palliative in nature and were excluded from analysis. Of the 20 patients with recurrent endometrial cancer who underwent exenteration with curative intent, all had previously received pelvic radiotherapy, 14 as part of their primary treatment and 6 as part of the treatment of recurrent disease. Six of 20 patients also received chemotherapy or hormonal therapy prior to exenteration. The median patient age was 65 years (range 44-79 years). At most recent follow-up, 8 patients were alive and disease free, 2 were alive with disease, 6 had died of disease, and 4 had died of other causes. The median follow-up of living patients is 89 months. Twelve of 20 patients experienced major complications, the most common of which was neovaginal flap necrosis. Of the 20 patients, 1 patient (5%) died in 1963 of surgical complications. The Kaplan-Meier estimate of 5-year disease-free survival is 45%. Pelvic exenteration can produce an acceptable rate of disease-free survival in highly selected patients with local recurrence of endometrial adenocarcinoma who have exhausted other treatment modalities.

Surgical treatment of patients with stages IB and IIA carcinoma of the cervix and palpably positive pelvic lymph nodes.

Review of the records of all patients undergoing radical hysterectomy for cervical cancer at our institution between 1956 and 1985 revealed 121 patients with stage IB or IIA lesions and metastasis to pelvic lymph nodes. A uniform part of our surgical practice is to record the findings from visual and palpatory examinations of the intra-abdominal and retroperitoneal structures at the beginning of the operative report. This information was available for 117 of 121 patients. Of these 117 patients, 51 (44%) had pelvic lymph nodes palpably involved with metastatic malignant disease at the time of exploration. The Kaplan-Meier estimate of 5-year disease-free survival for this group was 40% (median follow-up of disease-free patients was 20.5 years). Adjuvant pelvic radiotherapy was received by 29 of the 51 patients. The remaining 22 patients received no adjuvant treatment. Information on the sites of recurrence was available for 30 of 32 patients who had recurrence. The site of first recurrence included an extrapelvic component in 22 of the 30 (73%). Disease-free survival rates for these patients reflect the advanced nature of their tumors. In light of our experience and our current understanding of the relationship between radiotherapy dose, tumor volume, and efficacy, we regard the assertion that primary radiotherapy is preferable to surgery in this population to be counterintuitive, and we await with interest data demonstrating that disease-free survival with approaches that involve leaving macroscopic tumor on the pelvic sidewall is superior to that noted above.

Identification of a low-risk subset of patients with stage IB invasive squamous cancer of the cervix possibly suited to less radical surgical treatment.

Because of the well-documented morbidity of radical hysterectomy, it would appear desirable to isolate a subset of patients at low risk of parametrial spread or disease recurrence who might thereby be candidates for less radical surgical therapy. To this end, the records of all patients undergoing radical hysterectomy for cervical carcinoma at our institution between 1956 and 1985 were reviewed. Of the 387 patients treated for squamous carcinoma clinically confined to the cervix, 83 (21.4%) had tumors with depth of invasion greater than 3 mm (stage IB) but volume of tumor less than or equal to that of a sphere 2 cm in diameter (4.19 cm3) and no tumor in angiolymphatic spaces. Of the 83 patients, none had parametrial nodal metastasis. Median follow-up of this subgroup was 9.8 years, and the Kaplan-Meier estimate of 5-year disease-free survival was 97.6% (95% confidence interval, 94.3-100%). We consider patients in the subset described above to be candidates for modified radical hysterectomy and pelvic lymphadenectomy, with a decrease in morbidity associated with the less radical dissection, a low risk of failure to excise occult parametrial tumor, and the expectation of an excellent chance of long-term disease-free survival.

A matched study of surgically treated stage IB adenosquamous carcinoma and adenocarcinoma of the uterine cervix.

Thirty-eight patients with surgically treated stage IB adenosquamous carcinoma of the uterine cervix (AS) have been matched with patients with other histologic subtypes of adenocarcinoma (A) for stage, lesion size, node status, grade of adenocarcinoma and age at diagnosis. An additional six patients with AS were unable to be matched. Overall 5-year survival and disease-free survival for the matched AS and A were not significantly different, 83 vs. 90%, and 78 vs. 81% nor were the number of recurrences, 8/38 AS vs. 6/38 A, but the mean time to recurrence was significantly shorter in the AS group: 11 vs. 32 months (P = 0.003). A subgroup of AS with a high risk of a poor outcome can be identified based on either lesion size >/= 4 cm, depth of invasion >/= 10 mm or plevic lymph node metastasis. These patients may be suitable candidates for adjuvant therapy before or after surgical treatment.

Condylomata acuminata. Roles of different techniques of laser vaporization.

Eighty-four women with acuminate warts of the external genital tract were treated with two methods of laser vaporization. Patients were classified by lesion number and volume (1+, 2+, 3+). Thirty-three patients had only the lesions vaporized, whereas 51 had individual lesions vaporized followed by the "brushing" technique applied to the surrounding mucosa. Postoperative discomfort and pain were worse in those patients who had the brushing technique. The results were assessed colposcopically six to eight weeks postoperatively. Regardless of the method of laser vaporization, the majority of patients with extensive disease (2+ or 3+) had persistent lesions, although reduced in number in most instances. Patients with relatively few lesions (1+) had complete elimination of the warts whether or not brushing was employed. Based upon this study, reducing the burden of acuminate warts before laser vaporization is recommended.

Second-look operation in ovarian cancer.

BACKGROUND: Although second-look laparotomy (SLL) remains the hallmark method for determining disease status after completion of adjuvant therapy, the inclusion of reassessment surgery in the treatment scheme of ovarian carcinoma has been challenged. Given the absence of prospective analyses addressing this issue, justification for continued use of SLL must demonstrate benefits regardless of the outcome of the procedure. RESULTS: In the absence of residual disease, either the recurrence rate after SLL should be acceptably low or the outcome should permit identification of specific groups that would benefit from consolidation therapy. The characteristics associated with a significant risk for recurrence after a negative SLL include patient age, histologic grade, and the amount of residual disease after the primary cytoreduction operation. The postoperative benefits of positive SLL findings must be manifested in enhanced survival rates after secondary cytoreduction surgery, salvage therapy, or both. Recent evidence suggests that tumor reduction during SLL and contemporary salvage methods favorably influence specific subgroups of patients. CONCLUSIONS: The criteria for continued use of SLL in advanced epithelial ovarian cancer should include the availability of (and preferably prospective clinical trials for) both consolidation and salvage therapy to which all patients with ovarian cancer optimally would be afforded access.

Synchronous radiation and cytotoxic chemotherapy for locally advanced or recurrent squamous cancer of the vulva.

Between July 1987 and September 1991 a program of external beam radiation and synchronous, radiopotentiating chemotherapy was employed to treat 25 women with locoregionally advanced or locoregionally recurrent squamous cancer of the vulva. Of 18 previously untreated patients, 1 was Stage II, 10 were Stage III, 6 were Stage IVA, and 1 was Stage IVB. Reasons for patient referral for nonsurgical management included the presence of initially unresectable disease (5 patients), disease extent which would have necessitated partial or total exenteration if treated surgically (9 patients), disease extent predictive of inadequate surgical margins (less than 1 cm gross margin) if treated by less than exenterative surgery (8 patients), and severe comorbid illness precluding surgical management (3 patients). Complete clinical response was obtained in 16 of 18 previously untreated patients (89%) and in 4 of 7 patients with recurrent disease following vulvar surgery (57%). Of 20 patients achieving a complete clinical response, 3 patients have relapsed within the irradiated volume at 11, 38, and 48 months following completion of treatment. Fourteen patients remain alive and continuously cancer free from 2-52 months after completion of treatment (median follow-up 24 months). This experience suggests that initial management with radiation and chemotherapy may offer some patients with locally advanced squamous cancer of the vulva an alternative to exenterative surgery and may hold curative potential for some patients with surgically unresectable or medically inoperable disease.

Flow-cytometric DNA analysis of stages IB and IIA cervical carcinoma.

The prognostic significance of flow-cytometric DNA analysis was assessed in 375 stages IB and IIA squamous cell carcinoma patients treated with radical hysterectomy and lymphadenectomy at the Mayo Clinic between 1956 and 1985. Paraffin-embedded samples containing at least 20% tumor were dewaxed, rehydrated, stained with propidium iodide, and analyzed. Among 344 assessable samples, 136 (40%) were diploid and 208 (60%) were nondiploid (26 tetraploid, 158 aneuploid, and 24 polyploid). Diploid cases were further subclassified: 25 high proliferative phase (HPP) (S+G2M greater than 20%) and 111 low proliferative phase. No significant correlation was noted between DNA diploid patterns and stage, tumor size, grade, or histotype, but HPP diploid tumors had a significantly higher risk of nodal metastasis. With a mean follow-up period of 150 months, 62 patients died of disease. No significant difference was observed in survival rates (SR) between diploid and nondiploid tumors, but the subset of HPP diploid tumors had a prognosis significantly worse than that of any other group (P less than 0.01). Other significant variables included nodal metastases, parametrial extension, age, and clinical stage. While ploidy patterns did not assign additional risk to node-positive lesions, HPP diploid tumors in node-negative patients were associated with a significantly lower SR. Multivariate analyses in node-negative patients demonstrated that stage, histologic subtype, and HPP diploid patterns retained prognostic independence.

Long-term survival and sequelae after surgical management of invasive cervical carcinoma diagnosed at the time of simple hysterectomy.

From 1956 to 1988, 27 women (median age, 60 years) found to have occult invasive carcinoma of the cervix at total hysterectomy underwent radical reoperation consisting of radical parametriectomy, upper vaginectomy, and pelvic lymphadenectomy. Residual disease was present at reexploration in 4 (15%) of the 27 patients: in the pelvic lymph nodes in 2, in the parametrium in 1, and in the vagina and a para-aortic node in 1. All patients were followed a minimum of 18 months; there were no deaths within 3 months of operation. However, 2 (7%) of the 27 patients developed ureterovaginal fistulas. Recurrent disease was observed in 6 (22%) of the patients: 2 had successful salvage procedures, and 4 died of disease, all within 4 years of reoperation. Recurrence correlated with the presence of residual disease at reoperation and with nonsquamous histologic findings. At a median follow-up of 8.4 years, 23 of the 27 patients were alive and disease-free. The 5-year absolute survival estimate (Kaplan-Meier) was 82%. Radical reoperation can be performed safely in selected patients who have early-stage invasive carcinoma of the cervix at the time of total hysterectomy with the expectation of an acceptable rate of long-term disease-free survival.

Identification of prognostic factors and risk groups in patients found to have nodal metastasis at the time of radical hysterectomy for early-stage squamous carcinoma of the cervix.

In a retrospective study conducted at the University of Alabama at Birmingham, the University of Michigan, and the Mayo Clinic, 185 patients with previously untreated FIGO stage IB and IIA squamous cell carcinoma of the cervix were found to have nodal metastasis at the time of radical hysterectomy and pelvic lymphadenectomy. Of these patients, 103 received adjuvant pelvic irradiation. Cancer recurred in 76 patients; the median time to recurrence was 3.1 years. The prognostic significance of patient age, clinical stage, lesion diameter, number and location of nodal metastases, and use of adjuvant radiation therapy was determined by multivariate analysis. Only patient age (P = 0.0006), lesion diameter (P less than 0.0001), and number of nodal metastases (P = 0.0004) were noted to be significant factors in determining overall survival. Rates of recurrence were also related to these factors. Employment of these significant variables led to identification of four risk groups. In general, patients with small cervical lesions (diameter less than 1 cm) and no more than two nodes with metastases fell into the low-risk category; those patients with large cervical lesions (diameter greater than 4 cm) and more than two involved nodes fell into the high-risk category. All other patients were categorized into intermediate-risk groups. Ten-year survival was 92% in the low-risk group (n = 13), 70% in the low-intermediate-risk group (n = 66), 56% in the high-intermediate-risk group (n = 66), and 13% in the high-risk group (n = 20). This risk group classification identifies subgroups of early-stage cervical carcinoma patients found to have nodal metastasis at the time of radical hysterectomy that warrant appropriately selected adjuvant therapy.

Value of adjuvant whole-pelvis irradiation after Wertheim hysterectomy for early-stage squamous carcinoma of the cervix with pelvic nodal metastasis: a matched-control study.

In a retrospective study, 185 patients with previously untreated stage IB or IIA (International Federation of Gynecology and Obstetrics) squamous cell carcinoma of the cervix were found to have pelvic nodal metastasis at the time of Wertheim hysterectomy and bilateral pelvic lymphadenectomy. Of these patients, 103 received adjuvant whole-pelvis irradiation and 82 received no adjuvant therapy. Median dose of pelvic irradiation was 5000 cGy. Among the irradiated patients, in 75% the dose was 5000 cGy or greater. Matching irradiated and nonirradiated patients according to stage, tumor size, and number and location of positive nodes yielded 60 pairs. Mean length of follow-up was 3.9 years for the 60 irradiated patients and 5.8 years for the non-irradiated patients. Kaplan-Meier overall and cancer-specific survival estimates for the two groups were not significantly different (P greater than 0.30). During the follow-up period, 21 surgery-only patients and 22 patients treated with adjuvant radiotherapy had recurrence, but adjuvant radiotherapy decreased the proportion of recurrences occurring in the pelvis alone--27% compared with 67% in the surgery-only group (P = 0.01).

Wertheim hysterectomy in the geriatric population.

A series of 38 patients 65 years of age or older who underwent Wertheim hysterectomy for primary treatment of stages IB and IIA (FIGO) carcinoma of the cervix is reported. There were no ureteral fistulas and no perioperative mortality, but 4 of the patients required reoperation. A control population of 320 patients less than age 65 was identified who had been treated in the same fashion and who resembled the older group in regard to stage, histologic features, grade, and incidence of pelvic nodal metastasis. Transfusion requirements and incidence of postoperative lower extremity edema were similar between groups. Febrile morbidity was less frequent in the geriatric group (P = 0.03) but postoperative small bowel obstruction (P = 0.01), bladder dysfunction (P = 0.06), and pulmonary emboli were more frequent (P = 0.11). Five-year cancer-specific Kaplan-Meier survival estimates were 84 and 85% for the geriatric and younger patient populations, respectively.