Vulvar sarcoma: clinical implications.

This is a review of the histories of 47 patients with vulvar sarcoma, consisting of leiomyosarcoma (25), malignant fibrous histiocytoma (5), epithelioid sarcoma (8), dermatofibrosarcoma protuberans (9), including 7 from our own institute. When compared to the biological behaviour of sarcomas from other anatomic sites of the body, no essential differences were found. The prognosis after the appearance of regional or distant recurrence was poor and prevention of local recurrence by wide excision was the best way to improve the prognosis of leiomyosarcoma and dermatofibrosarcoma protuberans. However, the poor prognosis of epitheloid sarcoma did not change. Elective treatment of regional lymph nodes was not indicated in the four tumor types discussed and dissection of metastatic inguinal nodes was rarely beneficial. However, distressing local problems were prevented in a patient with epithelioid sarcoma and lasting benefit was seen in a patient with malignant fibrous histiocytoma who developed an inguinal metastasis after a 3-year disease-free interval. The beneficial effect of resection of pulmonary metastasis needs more attention.

Squamous cell carcinoma of the vagina in a male pseudohermaphrodite with 5alpha-reductase deficiency.

A 50-year-old Spanish male pseudohermaphrodite (karyotype 46, XY) is described, who had a squamous cell carcinoma of the vagina, FIGO stage IV B. He was reared as a girl and changed gender at puberty. The phenotype was typical for 5alpha-reductase deficiency, as were the laboratory findings. A radical vulvectomy and dissection of the groins revealed inadequate resection near the urethra. Postoperative external irradiation was given. Human papillomavirus 16 DNA sequences were found in the tumor and in a groin metastasis. He died 3.5 years postoperation because of a tumor of the lung, probably a metastasis, without signs of local recurrence. Some 60 male pseudohermaphrodites due to 5alpha-reductase deficiency have been described. Many of them had to cope with the traumatic experience of a change of gender at puberty, because early gonadectomy was seldom done. The sex-life and family-life of our patient were unsatisfactory. We recommend early gonadectomy to prevent virilization at puberty. Psychologic care, genetic counseling and corrective surgery of the genitalia are necessary. Although there are predisposing factors, testicular malignancies have not been reported. This is the first report of squamous cell carcinoma of the vagina in a male pseudohermaphrodite with 5alpha-reductase deficiency and human papillomavirus 16 DNA sequences.

Phase I/II study of intraperitoneal mitoxantrone in refractory ovarian cancer.

BACKGROUND: Mitoxantrone has demonstrable clinical activity when administered intravenously in a wide range of malignancies. The feasibility and toxicity of intra-peritoneal administration was established in a phase I study. The optimal dose from the phase I was subsequently evaluated in a phase II study. PATIENTS AND METHODS: 19 patients with refractory malignancies and extensive abdominal disease (13 ovarian cancer, 4 breast cancer, 2 mesothelioma) were entered in a phase I study. The dose of intraperitoneal mitoxantrone was escalated from 10 mg/m2, administered in 21 of fluid via a Tenckhoff catheter, to 55 mg/m2, in increments of 5 mg/m2. Cycles were repeated every three weeks. Sixty-seven cycles of mitoxantrone were administered, the maximum tolerable dose being 25 mg/m2. A phase II study at this dose was conducted in 14 patients with refractory ovarian cancer, all of whom had previously received systemic platinum based therapy. Five of the 14 had also previously been treated with intraperitoneal carboplatin. Fifty-one cycles were administered. RESULTS: The dose limiting toxicity in the phase I study was peritoneal irritation and pain. Leucopenia was frequent at doses equal or greater than 30 mg/m2. Three complete remissions were documented in the phase I study (2 breast cancer and 1 ovarian cancer). There was no significant haematological toxicity in the phase II assessment, though local toxicity precluded further therapy in 2 patients. No objective responses were seen in the phase II evaluation. CONCLUSIONS: These studies demonstrate the feasibility of intra-peritoneal mitoxantrone therapy in patients with peritoneal disease, but do not support its routine use in ovarian cancer.

Endodermal sinus tumor of the vagina: radiation therapy and progeny.

BACKGROUND: Extraovarian endodermal sinus tumor generally originates in the vagina or cervix of young girls. Some 50 cases are known, all younger than 3 years of age. Many were treated with outdated regimens, and there are 5-year survival data on only nine of them. We describe a curative outcome of primary radiation only. CASE: A 40-year-old woman had a history of localized endodermal sinus tumor of the vagina, stage I, treated by brachytherapy at the age of 6 months. Radiation had a severe impact upon the later functioning of her pelvic organs, with marked deformity of the pelvic floor, vagina, urethra, and bones of the pelvic outlet. She conceived by homologous insemination at the age of 34. Delivery was by cesarean at 31.5 weeks' gestation. CONCLUSION: Current forms of management give preference to limited excisional surgery and multi-agent chemotherapy, analogous to that used for the treatment of endodermal sinus tumor of the ovary. This is the first report of a patient treated by radium needles and the only known patient who had a subsequent pregnancy.

Human papillomavirus type 16 in tumor tissue of low-stage squamous carcinoma of the uterine cervix in relation to ploidy grade and prognosis.

BACKGROUND: The relationship among the presence of human papillomavirus (HPV) in tumor cells, DNA ploidy, and the prognosis of squamous cell carcinoma of the uterine cervix was studied. METHODS: HPV 16 was detected using the polymerase chain reaction on paraffin-embedded material from 69 patients with Stage IB and IIA carcinoma of the uterine cervix. The presence or absence of HPV was related to age, survival, and ploidy status as measured by DNA flow cytometry. All patients were treated by radical surgery. RESULTS: Thirty-four patients had HPV 16, and 35 did not. The mean age of the patients differed statistically significantly between the HPV-positive group (51.1 years) and the HPV-negative group (45.1 years, P = 0.015). No difference was found in the mean DNA index (1.21 versus 1.22, P = 0.85) or 5-year survival rate (85% versus 86%, P = 0.87) between the two groups. CONCLUSIONS: The high prevalence of HPV 16 in cervical cancer, which appeared to be correlated with age (in combination with its presence in diploid and aneuploid tumors), indicated the important role of HPV 16 in the evolution of cervical cancer. However, using stepwise Cox regression analysis, the presence of HPV 16 had no additional prognostic value over lymph node metastases findings.

A clinicopathological study of 30 melanomas of the vulva.

Thirty cases of malignant melanomas of the vulva were studied for prognostic factors. Ulceration, tumor thickness, and positive inguinal lymph nodes were the most important prognostic factors. Morphometry did not demonstrate any prognostic meaning. Traditionally a radical vulvectomy and bilateral inguinal lymph node dissection were the therapy of choice, but this treatment modality did not show a better survival than less radical treatment. A low-risk and a high-risk group of patients have been identified for recurrence. The low-risk patient has a nonulcerative tumor, less than 3 mm thick, without clinical evidence of inguinal lymph node metastases, and should be treated by local excision with a 2- to 3-cm margin. The high-risk patient has a tumor which is ulcerative and/or more than 3 mm thick and should also be treated by local excision without elective inguinal node dissection. If clinical suspicion of inguinal lymph node metastases exists, an inguinal node dissection is advocated for better local control of the disease.

Outcome, complications and follow-up in surgically treated squamous cell carcinoma of the vulva 1956-1982.

Between 1956 and 1982, 139 patients were surgically treated in the Netherlands Cancer Institute because of a squamous cell carcinoma of the vulva. Eighty-nine of these patients underwent radical vulvectomy and inguinal lymph-node dissection. Five-year survival rates were 91% for stage I, 85% for stage II, 64% for stage III and 33% in stage IV cases. The fact that 5 year survival rates between the group of patients with a more extensive surgical treatment (i.e., inguinal lymph node dissection) and the group of patients only being treated by a vulvar operation were equal, is a remarkable result. Postoperative complication rates were, in conformity with results found elsewhere, high. Only 25% of the patients did not have any early complication at all. The most important early complication was found to be wound infection (52%). Late complications were mostly miction problems (24%) and pelvic relaxation, resulting in cystocele, rectocele and/or descensus uteri (26%). Patients who were treated only by a vulvar operation had significantly less late complications (P = 0.027). The majority of recurrences were observed in the first 2 postoperative years. Patients with a pelvic relapse or with distant metastases could in no case be treated successfully. Inguinal relapses, however, could only be treated with success when primary treatment of the groin had not been given before. Complete remissions were very often accomplished in case of vulvar relapse and second, third, or fourth relapses on the vulva. Ten percent of all the patients still alive 5 years after primary treatment had a relapse as yet, or more likely, a second vulvar carcinoma.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term survival in ovarian cancer. Mature data from The Netherlands Joint Study Group for Ovarian Cancer.

In two studies initiated in 1979 and 1981, 377 patients were treated for advanced epithelial ovarian cancer. In the first study patients were randomly assigned to receive Hexa-CAF (hexamethylmelamine, cyclophosphamide, methotrexate, 5-fluorouracil) or CHAP-5 (cyclophosphamide, hexamethylmelamine, doxorubicin, cisplatin for 5 days) and in the second study to receive CHAP-5 or CP (cyclophosphamide, cisplatin on 1 day). Patients who did not respond to Hexa-CAF were offered subsequent treatment that included cisplatin. Median follow-up of patients in the first study was 9.5 years and in the second study 7.7 years. At 10 years 9% of the patients initially treated with Hexa-CAF and 21% of patients assigned to CHAP-5 were alive. Among the 10-year survivors treated with Hexa-CAF, 50% had experienced progressive disease but were alive as a result of retreatment with a cisplatin regimen. The survival curves of both studies revealed that approximately 60% of the patients who reached a complete remission were alive at 5 years and 40% at 10 years. Patients with microscopic disease at second-look had a less favourable outlook: 35% survived 5 years. Not recognised at first publication of both studies was the influence of tumour grade on survival. Before 5 years of follow-up, the good prognosis of grade 1 tumours (well differentiated) could not be detected. About 50% of patients with grade 1 tumours were alive at 5 and 30% at 10 years while these survival rates were halved for the other grades. Combination chemotherapy with cisplatin can enhance survival by more than 10% at 5 and 10 years compared with the best treatment of the precisplatin era: Hexa-CAF.

DNA ploidy level as prognostic factor in low stage carcinoma of the uterine cervix.

Flow cytometry was used to measure DNA content of tumor cells in paraffin-embedded archival material from 89 patients with squamous cell carcinoma of the cervix uteri stages IB and IIA. Patients were all treated with radical hysterectomy and transperitoneal lymphadenectomy. Twenty-four percent received radiotherapy postoperatively because of tumor spread into parametria or positive lymph nodes. Ploidy grade was compared to other prognostic factors. DNA-aneuploidy was seen in 44 (49%), DNA-diploidy in 16 (18%) and 29 (33%) of the tumors were DNA-periploid. Sixty-nine (78%) patients were in FIGO stage IB, 20 (22%) in IIA. In 19 (21%) lymph node metastases were found, vasoinvasion in 25 (28%). Overall disease-specific 5-year survival was 80%. There was a significant effect of positive lymph nodes (90% vs 47%) and vasoinvasion (87% vs 64%) on the 5-year survival (resp. P less than 0.01 and P = 0.02). No correlation was found between stage (81% for IB vs 80% for IIA) or DNA-ploidy grade (81% for aneuploidy, 82% for periploidy, 79% for diploidy) and survival (resp. P = 0.9 and P = 0.8). Ploidy grade was equally divided over other prognostic factors. In stepwise Cox regression analysis DNA-ploidy grade showed no independent effect on survival. We conclude that DNA flow cytometry in this material was of no additional prognostic value.

Fluid detection in the uterus during and after irradiation for carcinoma of the cervix--clinical implications.

The records of 16 patients with an obstructed, fluid-filled uterus due to carcinoma of the uterus or to its treatment by radiation therapy were analysed. In 12 uteri the presence of malignant tumor was simultaneously established, e.g. primary cervical carcinoma (1), recurrence of cervical (4), endometrial Stage II or III carcinoma (2), second primary tumors, MMT (2), and endometrial carcinoma (3). The uterine fluid consisted of blood (8), pus (3) or was serous (3). Twice the fluid could not be analysed. In our series the prognosis of patients with recurrent cervical cancer or a second primary tumor was poor. Improvement of the prognosis can result by intensifying the follow-up examinations with CT and/or ultrasound in the first 2 years, and not by prolongation of the follow-up period. Estrogen therapy was believed to be the causal factor in three cases of hemotometra. In the near future an increase of this complication is possible as a consequence of hormonal replacement therapy given to prevent osteoporosis after pelvic irradiation.

Carcinoma of the uterine cervix stage I and IIA: results of surgical treatment: complications, recurrence and survival.

Between 1967 and 1981, 213 patients with carcinoma of the uterine cervix Stage I and IIA underwent an abdominovaginal radical hysterectomy with transperitoneal lymphadenectomy. In 1987 the overall 5-year survival rate was 87.5% and the 10-year survival 85%. Recurrences were seen in 29 patients (13.7%). Lymph node metastases occurred in 39 patients (18%). Five-year survival decreased from 94% without positive nodes to 65% with positive nodes. The median blood loss was 2100 cc. Fistulas were seen in 6.7% of the patients. Long-term voiding problems were encountered in 40.8%. In 25% of the women intercourse was impeded postoperatively because of shortening of the vagina. The results obtained with this type of radical surgery in cervical cancer Stages I-IIA are good and do not differ from other methods reported in the literature. However this also means that this more difficult and time-consuming approach does not improve survival rates. For this reason there are no reasons to change from the Wertheim operation to this combined approach.

Repair of the radiation induced rectovaginal fistulas without or with interposition of the bulbocavernosus muscle (Martius procedure).

Two local repair procedures, one without (9) and the other with (14) a bulbocavernosus muscle graft were performed on 20 patients with a radiation induced rectovaginal fistula. Four patients had two procedures successively. The initial success rate of both procedures was 7/9 and 14/14 respectively. Though the initial result of the bulbocavernosus graft was obviously better, in many of the local repair procedures, subclinical radiation damage progressed, resulting in recurrence of rectovaginal fistula (5), rectovesical fistula (4), pararectal abscess (2) etc. After a mean follow up of around 10 years, the success rate of fistula repair decreased to 5/9 and 13/14 and only 2/9 and 6/14 finally remained without a colostomy. A local repair operation should be restricted to carefully selected cases. The musculus gracilis is proposed as a better vascular graft. If the general condition of the patient does not allow more aggressive reconstructive procedures, fistula repair is better cancelled because there is a high risk of subsequent radiation damage.

Surgical repair of radiation damage of the rectum: a systematic approach to a difficult problem.

Twenty-three patients with serious irradiation damage of the rectum underwent surgical treatment. Patients were classified according to the level of the lesion and the presence of stenosis. Patients with high lesions (Type I) (n = 5), were treated by resection with end to end anastomosis. Patients with low lesions, with stenosis (Type II) (n = 6), were treated by resection with descending colon flap repair. Patients with low lesions, without stenosis (Type III) (n = 7) were treated by gracilis muscle repair. The remaining patients (n = 5) with miscellaneous, often complex problems (Type IV) were treated by a variety of techniques. Results in Type I, II, and III patients were encouraging with 80% of the reconstructed patients obtaining normal faecal continence.

Low stage invasive carcinoma of the uterine cervix stage I-IIA morphological prognostic factors.

Histological material was reviewed from the 213 patients who had undergone radical surgery for carcinoma of the uterine cervix stage I and IIA between 1967 and 1981. Squamous carcinoma was found in 179 patients (84.7%). In 39 patients (18%) there were lymph node metastases and in nine (4.2%) tumor spread into the parametrium. Vaso-invasion was present in 49 patients (22%). Prognostic factors were studied by Cox's regression analysis. Lymph node metastases and vaso-invasion were both found to be significantly related to survival rate (P = 0.0001 and P = 0.0008). Stage, cell type, differentiation and invasion depth were of no prognostic importance.

Complications of Tenckhoff catheter implantation in patients with multiple previous intraabdominal procedures for ovarian carcinoma.

In patients with minimal residual ovarian carcinoma after aggressive surgical and chemotherapeutic treatment, nephrotoxicity and/or peripheral neuropathy often prohibit continued treatment with intravenous combination cisplatin-based chemotherapy. It is attractive to continue treatment of these patients with intraperitoneal (ip) delivered chemotherapy. From 1981 through 1984 a Tenckhoff catheter was implanted in 59 women for ip chemotherapy after a staging laparoscopy or laparotomy. Minor complications occurred in 8 patients and could be treated conservatively. Ten patients suffered major complications, leading to three (re)laparotomies and catheter extraction in 7 of 10 patients. No patient died of complications, but mean hospitalization time of patients with major complications was 25 days as compared to 11 days for patients without complications. An analysis of nine factors that could lead to postoperative complications failed to reveal a statistically significant risk factor. From this study no profile of a typical high-risk patient emerges.

Experimental and clinical results with intraperitoneal cisplatin.

Up to 30% of ovarian cancer patients with minimal residual disease may achieve a complete remission with intraperitoneal cisplatin therapy. This mode of therapy, however, is toxic and cumbersome. Sodium thiosulfate was shown to protect renal function, as well as lessen hematologic complications of cisplatin therapy. A major problem with cisplatin in terms of achieving maximal therapeutic dosages is neurotoxicity. Different platinum chemotherapeutic agents, pharmacodynamics, and pharmacokinetics of intraperitoneal administration, and rescue agents other than sodium thiosulfate are presently being investigated by The Netherlands Cancer Institute.