Hellmuth Pickel

Prognostic factors and operative treatment of stages IB to IIB cervical cancer

Between 1971 and 1985, a total of 325 cases of cervical cancer, Stages IB to IIB, in which operation was performed were evaluated with a view toward prognostic factors and survival rates. In radical abdominal operations, a complete resection of parametrial tissue was the goal. Extensive lymphadenectomy of the pelvis was performed. Operative specimens were processed by giant sections comprising cervix, lateral parametria, and vaginal cuff. Lymph nodes were cut by step-serial sections. Exact measurements of tumor sizes were done along with investigations of parametrium and lymph nodes. Tumors were classified according to a ratio of tumor size to size of cervix. Incidence of lymph node involvement increased with tumor size, reaching a maximum of 68.3% in the group with a ratio from 70% to 80%. Direct spread into the parametrium was rarely found, even in larger tumors occupying the entire cervix. parametrial lymph nodes were most often involved; these were scattered over the entire ligament. Five-year survival rates reached 88.1% in patients with no nodal involvement and 60.9% with nodal involvement. In the latter, the results depended on the number of nodal groups involved and the diameter of metastases. Parametrial involvement alone had no influence on healing rates, but when pelvic nodes were simultaneously involved, the results were less satisfactory. Survival rates based on tumor size differed only between the group with a ratio up to 20% and the large-tumor groups, with rates ranging from 97.5% to 70.9%. There was no statistical difference between Stages IB (31.1% positive nodes) and IIB (44.1% positive nodes) with regard to survival rates (82.2% and 76.9%, respectively).

Pelvic lymphadenectomy in operative treatment of ovarian cancer

From the end of 1979 to September, 1985, radical pelvic lymphadenectomy was performed at the Graz Clinic in 123 cases of Stages IA to IV ovarian cancer following maximum debulking procedure. In 97 patients lymphadenectomy was done primarily. In 26 it was performed during a follow-up operation to chemotherapy. The frequency of pelvic node involvement was 61.8% in the total material and 78.0% in 82 cases of Stage III disease only; 75.0% positive nodes were found in Stage III after chemotherapy. Aortic nodes were positive in 41.4%, but only when pelvic nodes were also positive. The 5-year actuarial survival rate for Stage III disease was 53.0% after pelvic lymphadenectomy compared with 13.0% without. In cases with negative nodes the survival rate was 74.7%; with positive nodes the survival rate was 45.9%.

Microinvasive carcinoma of the uterine cervix (International Federation of Gynecology and Obstetrics Stage IA).

In 1985 the International Federation of Gynecology and Obstetrics (FIGO) subdivided Stage IA cervical cancer and specified metric criteria to demarcate Stage IA from Stage IB. Early stromal invasion (Stage IA1) denotes the first invasive protrusions of a carcinoma in situ into the stroma. Microcarcinomas (Stage IA2) are small cancers a number of orders of magnitude larger than Stage IA1 lesions and with a maximum depth of invasion of 5 mm and a maximum horizontal spread of 7 mm; larger lesions are classified as Stage IB. This study reviews 486 patients previously classified as having Stage IA disease. This yielded 344 Stage IA1 and 101 Stage IA2 lesions; 41 cancers were reclassified as Stage IB. Three hundred nine, 89, and 38 patients were followed for ± 5 years. One (0.3%) patient with Stage IA1 disease re‐presented with Stage IIB disease 12 years after conization. Five (5.6%) patients with Stage IA2 lesions developed invasive recurrences; three died. None of the 38 patients reclassified as having a Stage IB lesion, including 16 who were treated conservatively, developed a recurrence. The FIGO classification is not a guideline for treatment. Stage IA1 lesions can be treated conservatively, but treatment in Stage IA2 must be individualized. Risk factors such as vascular space involvement and confluency are of high sensitivity but low specificity.

Cervical intraepithelial neoplasia III: long-term follow-up after cold-knife conization with involved margins.

OBJECTIVE To evaluate the long‐term outcome of patients with severe cervical intraepithelial neoplasia (CIN) III or squamous carcinoma in situ after cold‐knife conization with involved margins. METHODS A total of 390 patients (median age 39 years, range 20–69) with positive margins after cold‐knife conization for CIN III were followed expectantly for a mean of 19 (range 6–30) years. Follow‐up consisted of colposcopy, cytology, histology, and pelvic examination. RESULTS Overall, 306 (78%) patients remained free of CIN III, and 84 (22%) had persisting or recurrent CIN III (n = 78) or developed invasive carcinoma (n = 6). Fifty‐three patients had persisting CIN III (diagnosed within 1 year of conization), 25 developed recurrent CIN III after a median of 3 (range 2–28) years, five developed microinvasive carcinomas (at 3, 6, 7, 12, and 23 years), and one developed a stage IB carcinoma at 8 years. Persisting or recurrent disease was more common in patients in whom both the endocervical and the ectocervical cone margins were involved than in those in whom only the ectocervical or the endocervical margin was positive (52% versus 17% and 21%, respectively, P < .001). CONCLUSION Expectant management is reasonable for patients with CIN III and positive margins after cold‐knife conization. However, these patients require careful follow‐up, particularly during the first year.

Carcinoma of the cervix: analysis of complications after primary external beam radiation and Ir-192 HDR brachytherapy.

BACKGROUND AND PURPOSE There is still a concern that the use of HDR brachytherapy might result in an increase of late tissue damage. This restrospective study evaluates the incidence and severity of late complications in patients with carcinoma of the cervix who underwent combined external beam radiation (EBR) and Ir-192 HDR brachytherapy and attempts to identify pretreatment and treatment parameters correlating with late complications. MATERIAL AND METHODS Between 1985 and 1992, 161 patients with carcinoma of the cervix (FIGO stages IB-IVB) received EBR to the pelvis (ave, max. dose 48.8 Gy) followed by 1-6 Ir-192 HDR placements (median 2). Doses to point A ranged from 8.5 to 38.7 Gy (median 17 Gy). Parameters examined included age, diabetes, obesity, history of inflammatory bowel disease or diverticulitis, prior surgery, hemoglobin level, FIGO stage, EBR dose, technique and daily dose fraction, number of HDR treatments and total dose to point A, maximum doses to bladder and rectum delivered by brachytherapy and cumulative dose to point A. Median follow-up for all patients was 37 months. Complications were rated using an in-house scoring system and according to the French-Italian Glossary (FIG). RESULTS Actuarial 5-year survival was 93%, 57%, 46%, and 0% for stages IB, II, IIIB, and IV, respectively. Of 161 patients, 11% developed moderate and 3.7% severe sequelae (FIG: 2.5%, 3.7%). Since some patients experienced more than one complication, the overall incidence was 13.6% and 4.9% (FIG: 3.1%, 4.9%) with respective 5-year actuarial rates of 14% and 5% for moderate, and 2% and 8% for severe bowel and genitourinary tract complications (FIG: 3.5%, 0, and 2%, 8%). All severe bowel complications occurred within 1.5 years whereas urinary tract sequelae continued to develop throughout the follow-up period. FIGO stage was associated with a significant increase in late sequelae (P = 0.015). Analysis of the remaining pretreatment and treatment parameters failed to reveal any statistically significant correlation with moderate or severe sequelae. CONCLUSION In our series using HDR brachytherapy, complication and survival rates were comparable with other series employing either LDR or HDR procedures. Of all parameters analysed, stage of disease was the only parameter significantly correlated with complications in univariate and multivariate analysis.

Pelvic and paraaortic lymphocysts after radical surgery because of cervical and ovarian cancer

To determine the incidence and clinical import of lymphocysts after radical gynecologic surgery including lymphadenectomy, we reviewed the records of 173 patients with cervical cancer and 135 patients with ovarian cancer who were followed up by computed tomography. Lymphocysts were found in 35 (20%) and 43 (32%) of the patients, respectively. Patients with cervical cancer and positive lymph nodes had a significantly higher rate of lymphocyst formation than did those with negative nodes (29% versus 14%, respectively, p less than 0.02). Age, type of lymphadenectomy, volume of fluid furthered by postoperative drains, disease stage, and tumor histology were not related to lymphocyst development. We saw no complications strictly attributable to lymphocysts. The clinical import and treatment possibilities are discussed.

Cervical intraepithelial neoplasia III: long-term outcome after cold-knife conization with clear margins

Objective To evaluate the long-term outcome of patients with severe cervical intraepithelial neoplasia or squamous cell carcinoma in situ (CIN III) after cold-knife conization with clear margins. Methods A total of 4417 women (mean age 36, range 18–72 years) with histologically confirmed CIN III had cold-knife conization with clear margins at our institution between 1970 and 1994. All patients were followed up with colpos-copy, cytology, and pelvic examination for a mean of 18 years (range 5–30years). Results New high-grade squamous intraepithelial lesions (SILs) (CIN II and III) developed in 15 (0.35%) patients (mean age 35, range 25–65 years) after a median of 107 (range 40–201) months. A total of 4402 (99.65%) patients (mean age 36, range 18–72 years) were free of high-grade SILs after a mean follow-up of 18 (range 5–30) years. High-grade glandular intraepithelial lesions developed in two (0.05%) patients 14 and 17 years after conization. Twelve (0.3%) patients had metachronous vulvar intraepithelial neoplasia (VIN) grade III or vaginal intraepithelial neoplasia (VAIN) grade III, and one (0.02%) patient had invasive vaginal carcinoma 10 years after conization. Conclusion Cold-knife conization with clear margins was an adequate method to definitively treat CIN III.

The predictive value of a combination of tumor markers in monitoring patients with ovarian cancer

To evaluate the predictive value of the serial determination of various tumor markers, we measured carcinoembryonic antigen, ferritin, cancer antigen 125, and tissue polypeptide antigen in 109 patients with ovarian cancer before surgery, during postoperative chemotherapy, and follow‐up. From these patients two groups were randomly selected. Group 1 (30 patients) had a favorable course, and Group 2 (30 patients) had an unfavorable course. Using the discriminant analysis we calculated a linear discriminant function and a cut‐off score. The two groups were thereby separated according to their scores (characteristic values) from their marker values. The scores accurately reflected the clinical course in 55 of the 60 patients (91.7%). This discriminant function was then used to make a prognosis in 49 patients. In 21 patients an elevated characteristic value (⩽ cut‐off score) indicated disease progression 5 months before clinical confirmation was possible. The remaining 28 patients scored below the cut‐off point. From six to 65 months (mean, 26.2) after surgery all are free of recurrence. It is concluded that invasive procedures, second‐look laparotomy, for instance, may not be necessary in following up ovarian cancer patients with normal tumor marker profiles.

Microinvasive carcinoma of the cervix: site of first focus of invasion

Objective To evaluate the topography of the first invasive focus in microinvasive squamous cell carcinoma of the uterine cervix. Methods We studied 120 formalin-fixed and paraffin-embedded cold-knife conization specimens processed as step-serial sections. Four types of microinvasion were distinguished according to site: type I (ectocervical outside the last cervical gland), type II (ectocervical between the external os and the last gland and in connection with the surface epithelium), type III (ectocervical between the external os and the last gland but deep in cervical glands), and type IV (intracervical and in connection with the surface epithelium). Results A total of 142 early invasive foci were seen in the 120 cones. A single focus was seen in 106 (88%) specimens, whereas 14 (12%) had more than one focus. The foci were classified as type I in 16 (11%), type II in 31 (22%), type III in 70 (49%), and type IV in 25 (18%) cases. Conclusion One half of the early invasive foci originated at the surface epithelium (types I, II, IV), either at the ectocervix (types I, II) or in the endocervix (type IV).

Chemotherapy for advanced and/or recurrent cervical cancer

SummaryA combination of bleomycin, vincristine, mitomycin-C, and cisplatin was used to treat 39 patients with advanced and/or recurrent cervical cancer. Twenty patients showed an objective response (complete or partial) with a mean duration of 14.8 months. The overall response rate was 58.8%. Twelve patients are still alive and in remission 7–36 months after the start of chemotherapy. Toxicity was acceptable.