A case-matched molecular comparison of extraovarian versus primary ovarian adenocarcinoma.

BACKGROUND: Extraovarian müllerian adenocarcinoma (EOM) resembles primary ovarian carcinoma (POC) both histologically and clinically, yet little is known regarding the molecular genetic characteristics of this entity. The objective of this study was to compare the expression of three molecular markers of tumor behavior in EOMs and POCs. METHODS: Forty-four patients meeting strict criteria for EOM were identified and matched to POC controls for age, stage, tumor histology and grade, cytoreductive surgery, and survival. Immunohistochemistry was used to determine overexpression of p53 and HER-2/neu. DNA content was evaluated by flow cytometry. Direct DNA sequencing of exons 5-8 of the p53 gene was performed in nine EOM tumors. Statistical comparisons were made using chi-square, Kaplan-Meier, and Mantel-Cox log rank methods. RESULTS: Overexpression of HER-2/neu was demonstrated in 59% (26 of 44) of the EOM group versus 36% overexpression (16 of 44) in the POC controls (P = 0.05). Overexpression of p53 was noted in 48% of the EOM cases, similar to the 59% incidence observed in the control group (P = 0.29). Missense mutations were found in 9 of 9 EOM tumors showing strong p53 nuclear immunostaining. No significant difference in the incidence of aneuploidy was observed when EOM cases were compared with POC controls (65% vs. 63%). High tumor grade was strongly associated with HER-2/neu overexpression in the EOM group (P = 0.002). None of the parameters studied were predictive of prognosis within the EOM and POC groups. CONCLUSIONS: Although overexpression of p53 protein, p53 gene mutations, and abnormal DNA content were similar between EOMs and POCs, EOMs demonstrated almost twice the rate of HER-2/neu overexpression. This result suggests that distinct genetic events may be responsible for malignant transformation in EOMs versus POCs.

Vaginal evisceration: presentation and management in postmenopausal women.

BACKGROUND: Vaginal evisceration is a rare event, often associated with previous vaginal surgery in postmenopausal women. To date, 57 cases have been described in the world literature since 1901. STUDY DESIGN: We report three cases of vaginal evisceration and review risk factors and management described in the current literature. RESULTS: Of 60 reported cases of vaginal evisceration, 41 occurred in postmenopausal women. A common triad of previous vaginal surgery (73 percent), postmenopausal status (68 percent), and the presence of an enterocele (63 percent) was identified. Histopathologic evaluation of one case revealed a chronic vaginal-peritoneal fistula, and immunohistochemistry highlighted migration of squamous cells to multiple peritoneal serosal surfaces. This finding emphasizes the chronic nature of factors that predispose to the acute evisceration of abdominal contents. Most eviscerations were managed by primary repair of the vaginal disruption and the accompanying disorder of the pelvic floor, after assessing the viability of the prolapsed bowel and resecting any compromised segments. However, most surgeons agreed that delayed vaginal repair was preferable if the vaginal tissues appeared acutely inflamed or nonviable. CONCLUSIONS: Vaginal evisceration is primarily seen with obstetrical or postcoital trauma, but in postmenopausal women it is most often associated with a history of vaginal surgery and a pelvic support disorder. Hypoestrogenism, atrophy, and devascularization from previous surgery seem to play a significant role. Management is directed toward resecting any compromised bowel, repairing the vaginal defect, and correcting the contributing defect in the pelvic floor.

Adenoid cystic carcinoma of Bartholin gland.

Five cases of adenoid cystic carcinoma of the Bartholin gland, a rare vulvar tumor, are reviewed with respect to clinical and pathological characteristics. Histologic transition from normal Bartholin gland to adenoid cystic carcinoma was evident in two cases. Two patients developed the tumor in association with pregnancy. Local recurrences are common and may precede distant metastases, pulmonary being the most common. Patients with repetitive local recurrence or pulmonary metastases may have slowly progressive disease and survive for many years. This is reflected in the disparity between the progression-free interval and survival curves. The recommended primary treatment is wide local excision, obtaining clear margins, and an ipsilateral inguinal lymphadenectomy.

Surgical management of irradiation-induced small bowel damage.

Seventy-seven patients, presenting with radiation small bowel injuries at the University of Texas M. D. Anderson Hospital and Tumor Institute at Houston between 1962 and 1978, were analyzed retrospectively. The patients were divided into two categories: bowel bypass without resection, and resection of irradiated bowel. Each group was then analyzed for its short- and long-term complications. Ileocolectomy with end-to-end anastomosis was the surgical procedure of choice in those people undergoing resection. There was no difference in short-term complications noted between the two groups. The long-term complications of fistula formation and continued small bowel necrosis could be prevented by resection, as a primary procedure. The surgical details of ileocolectomy with end-to-end anastomosis are presented, along with an analysis of the complications encountered in both groups.

Role of "third-look" laparotomy in the guidance of ovarian cancer treatment.

Twenty-seven patients with Stage III epithelial ovarian carcinoma received a "third-look" celiotomy. Each patient received a minimum of an additional 12 courses of chemotherapy after persistent tumor had been documented at a "second-look" procedure. Twelve of the twenty-seven patients have died. No tumor-associated deaths occurred in patients with grade 1 neoplasms. Of the patients with microscopic disease at the second-look procedure who came to third-look laparotomy, none had died secondary to tumor growth. The survival time of patients with microscopic disease at third-look is greater than that of patients with macroscopic disease (P = 0.0009). In patients who had effective tumor reductive surgery performed at second-look, the third-look findings were highly predictive as to survival. Long-term chemotherapy had a significant incidence of related mortality. Four of the twenty-seven patients died as a direct result of the chemotherapeutic toxicity. The patients receiving melphalan for at least 24 courses appeared to be at greatest risk, with 23% dying from either aplastic bone marrow changes or leukemia. The morbidity associated with third-look laparotomy was not excessive. Many factors need careful review prior to planning a third-look laparotomy. This retrospective study demonstrates that patients with either a grade 1 neoplasm or only microscopic disease at the second-look procedure do well regardless of the third-look findings.

Measurement of progesterone receptor in human renal cell carcinoma and normal renal tissue.

Progesterone receptor was measured in eight samples of renal cell carcinoma, nine samples of normal renal tissue, and one sample of melanoma tissue. Progesterone receptor was identified in all samples, with the exception of one renal cell carcinoma. Three patients, all with receptor-positive tumors, were treated with medroxyprogesterone acetate for metastatic disease. In one of these patients there was a partial objective response to treatment. Further research regarding progesterone receptor in renal cell carcinoma is indicated.

Cisplatin chemotherapy for disseminated endometrial cancer.

Twenty-six women with advanced or recurrent endometrial cancer were treated with cisplatin at a dose of 50, 70, or 100 mg/m2 every 4 weeks. An objective response was obtained in 11 of 26 patients (42%), with 10 partial responses and 1 complete response. The median duration of remission was 5 months, with a range of 2 to 11 months. The complete response lasted 8 months. Five patients had stable disease lasting an average of 5 months. One of 6 patients (16.6%) responded to cisplatin at a dose of 50 mg/m2, 4 of 7 (57%) responded to the dose of 70 mg/m2, and 6 of 13 (46%) responded to the dose of 100 mg/m2, but the differences were not statistically significant (P = .2). In 8 of 26 cases (31%) cisplatin was discontinued because of toxicity. Three patients developed a peripheral neuropathy, 1 patient refused further therapy because of vomiting, 2 patients had nephrotoxicity, and 2 others had both nephrotoxicity and neurotoxicity. The average total cumulative dose of cisplatin administered when renal deterioration and neuropathy occurred was approximately 500 mg/m2. Cisplatin is definitely active against endometrial cancer, but toxicity precludes its prolonged administration in high doses on an outpatient basis. By maintaining a forced diuresis, toxicity can probably be decreased, thereby permitting continued administration of cisplatin. The drug may also be more useful when used at a lower dose in combination with other active agents against endometrial cancer.

Hexamethylmelamine chemotherapy for disseminated endometrial cancer.

To evaluate the role of hexamethylmelamine (HMM) in the treatment of endometrial cancer, 20 women with metastatic or recurrent endometrial carcinoma received HMM orally at a dose of 8 mg/kg/day. Six patients (30%) showed a partial response, with a median duration of response of 3.5 months and a range of 1 to 7 months. Two patients responded to HMM as a second-line agent following previous treatment with nonhormonal chemotherapy. There were no complete responses. The major toxicities noted with HMM therapy were nausea, vomiting, and neurotoxicity. In 6 patients (30%), therapy with HMM was discontinued because of toxicity. Although HMM is active against endometrial cancer when given at a dose of 8 mg/kg/day, it appears to have limited usefulness because toxicity precludes its prolonged administration.

Doxorubicin and cyclophosphamide chemotherapy for disseminated endometrial cancer.

Twenty-six cases of metastatic adenocarcinoma of the endometrium treated with doxorubicin hydrochloride (Adriamycin) and cyclophosphamide at M. D. Anderson Hospital and Tumor Institute were retrospectively analyzed. Thirteen patients were treated initially for disseminated disease and 13 for a recurrence. Eight of 26 patients, or 31%, showed a partial response. There were no complete responses. The median duration of remission was 4 months, with a range of 2 to 12 months. Previous exposure to progestins did not significantly affect subsequent response to doxorubicin and cyclophosphamide. Toxicity from chemotherapy was moderate. Four patients (15%) developed serious myelosuppression, 2 developed cardiac arrhythmia, and 1 developed a doxorubicin extravasation. No deaths were attributable to chemotherapy. The combination of doxorubicin and cyclophosphamide has demonstrable, albeit limited, activity against metastatic endometrial cancer.

Progressive chromosome changes associated with different sites of one ovarian carcinoma.

Karyotype analyses were done on cells from the primary and metastatic sites, as well as on the ascitic fluid, from 1 patient with serous carcinoma of the ovary. An increase in the proportion of near-tetraploid cells occurred in the following order: cells from the primary site less than cells from the metastatic site less than cells from ascitic fluid. In addition, two new marker chromosomes appeared among the polyploid cells of ascitic fluid.

Progesterone binding by human endometrial tissue during the proliferative and secretory phases of the menstrual cycle and by hyperplastic and carcinomatous endometrium.

Cytosol receptors for progesterone were assayed in human endometrial tissue during the proliferative and secretory phases of the menstrual cycle and in the hyperplastic and carcinomatous endometrium. The assays were performed utilizing a technique involving prior treatment of the cytosol extract with dextran-coated charcoal to remove endogenous progesterone. The results showed that the progesterone receptor activity was higher during the later proliferative and early secretory phases of the menstrual cycle. Hyperplastic and carcinomatous endometrium also contained specific cytosol receptor for progesterone, and the binding activity of the hyperplastic endometria and endometrial polyps was comparable to that found during the later proliferative phase of the menstrual cycle. No apparent correlation between the progesterone receptor level and the morphologic degree of differentiation in Grades 1 and 2 adenocarcinomas of the endometrium was observed.

Abnormalities of lymphocyte transformations in women with intraepithelial carcinoma of the vulva.

Cellular immunity of the delayed type in women with intraepithelial carcinoma (carcinoma is situ) of the vulva was investigated by an in vitro assay of mitogen-induced lymphocyte transformations. Test results from 9 patients were compared to those of 23 age-matched control subjects. Lymphocyte transformation responses in counts per minute were significantly lower for women with carcinoma in situ of the vulva than for control subjects for phytohemagglutinin-P (at 50 microgram/ml) 6238 and 28,102 (P less than 0.0001); for phytohemagglutinin-P (at 165 microgram/ml 7222 and 21,417 (P less than 0.001); for concanavallin A, 14,988 and 41,888 (P less than 0.0001); and pokeweed mitogen, 20,861 and 49,601 (P less than 0.001). No significant differences in lymphocyte transformations were noted between these two groups to the specific antigens, Candida or streptokinase-streptodornase. Four patients with carcinoma in situ of the vulva were also found to have intraepithelial carcinoma of the cervix and/or vegina. The occurrence and clinical course of carcinoma in situ of the vulva in some women may be related to an underlying defect in cellular immunity. Immunosuppression may also explain the frequent association noted between carcinoma of the vulva and the development of other malignant neoplasms.

Abnormalities of lymphocyte transformations in women with condylomata acuminata.

The cellular immunity of 16 women with recalcitrant condylomata acuminata was investigated with an in vitro assay of antigen-induced lymphocyte transformations. Results were compared to those of 24 age-matched controls. Lymphocyte transformation responses (in counts per minute) for women with condylomata were much lower than controls for phytohemagglutinin-P, 32,285 and 60,015, (P less than .001); for concanavallin A, 28,664 and 58,605, (P less than .001); and for pokeweed mitogen, 34,941 and 73,394 (P less than .0001). No significant differences in lymphocyte transformations were noted between the 2 groups to Candida or streptokinase-streptodornase antigens. Immunosuppressive diseases, recurrent infections, and intraepithelial neoplasms of the genital tract were more frequent in the group of women with condylomata, and this seems to clinically substantiate the depressions noted in their in vitro cellular immunity. A refractory course of condyloma acuminatum in some women may be a reflection of an underlying state of immunosuppression.

Microinvasive squamous carcinoma of the cervix: definition, histologic analysis, late results of treatment.

The surgical tissues and clinical records of 54 surgically treated patients with microinvasive carcinoma of the cervix were retrospectively analyzed. Utilizing a definition that limited microinvasion to a depth of 3 mm, and excluded lymphatic and blood vascular involvement, the incidence of regional metastases in 37 patients for whom lymph nodes were available for study was 0%. Confluence of microinvasion did not imply a greater potential for metastatic spread or a worse prognosis. Lymphatic and blood vascular permeations were associated with nodal metastasis in one of four lesions which otherwise were microinvasive. Random cervical biopsy alone was inadequate for the diagnosis of microinvasion. Cone biopsy demonstrated an accuracy of 83% in diagnoses, but failed to eliminate intraepithelial or microinvasive carcinoma in 78% of the hysterectomy specimens. It is concluded that microinvasive carcinoma, as defined in this study, can be effectively treated by conservative rather than radical means.

Bladder dysfunction after radical abdominal hysterectomy.

Bladder dysfunction is a common occurrence following radical hysterectomy. We studied bladder function prospectively in 10 patients before and after radical hysterectomy. Results suggest that the hypertonic phase observed immediately postoperatively is the result of an increase in myogenic tonicity of the detrusor muscle secondary to the trauma of operation and prolonged catheter drainage. The inability of patients to urinate effectively is due to partial detrusor denervation. Combined cystometry and electromyography confirmed the presence of normal sphincter function and the absence of detrusor sphincter dyssynergia. Prevention of postoperative bladder atony includes a careful preoperative urologic evaluation, including cystometry. Postoperative bladder care should emphasize the prevention of overdistention. Inability to empty the bladder after operation may be managed effectively by intermittent self-catheterization, Urecholine, or prolonged catheter drainage. Patients should be evaluated periodically to uncover delayed bladder decompensation.

Radical pelvic surgery versus radiation therapy for stage I carcinoma of the cervix (exclusive of microinvasion).

During the period from January 1, 1945, through December 31, 1975, 446 patients with Stage I infiltrative carcinoma of the cervix (exclusive of microinvasion) were evaluated at the University of Michigan Medical Center. Four different study groups with treatment comparisons between radical hysterectomy with pelvic lymph node dissection and full-course radiation therapy are analyzed. The over-all uncorrected five-year survival rate when each form of therapy is evaluated approximates 85 per cent; the corrected five-year survival rate is approximately 90 per cent. When the regional lymph nodes were negative, the five-year survival rate was 96 per cent; when they were positive, the five-year survival rate was 55 per cent. Pathologic variations are evaluated, and basic vital statistics are reported. Thirteen per cent of the patients developed a recurrence within five years, 70 per cent occurring within the first three years. The therapeutic morbidity experienced in both groups of patients is essentially comparable, and the advantages of each form of therapy are presented.