Surgical management of vulvar cancer.

Vulvar cancer is an uncommon disease, marked by typical long delays in diagnosis due to lack of awareness by doctors and patients. The most common histology is squamous, although melanoma, sarcoma and adenocarcinoma occur less frequently. The predictable spread pattern of vulvar cancer to regional then distant lymphatics has allowed for improvements in survival largely due to radical surgical intervention. However, the significant morbidity from radical surgery has led to the search for better prognostic indicators and complementary therapeutic modalities to modify the extent of surgery in both early and advanced disease. En bloc radical vulvectomy and bilateral inguinal-femoral lymphadenectomy are rarely performed today: an early invasive stage has been defined where only limited excision is required. The extent of and the indications for inguinal lymphadenectomy for various clinical tumors and role of separate incisions have been clarified. When disease has spread to more than one inguinal node, adjuvant radiotherapy has replaced pelvic lymphadenectomy as the standard. Inguinal radiotherapy without groin dissection does not appear to be adequate therapy for most patients. The use of chemotherapy and radiation to shrink large tumors to allow surgical resection continues to be evaluated but has demonstrated excellent results to date. The utility of newer techniques of sentinel node mapping is also being evaluated in squamous cancers and melanoma to limit the extent of lymphadenectomy in patients with clinically normally lymph nodes.

Effect of surgical debulking on survival in stage IV ovarian cancer.

In order to determine whether optimal surgical debulking in Stage IV epithelial ovarian cancer impacts survival, a retrospective review of patients treated at the University of Pennsylvania Cancer Center (UPCC) from 1984 to 1995 diagnosed with Stage IV epithelial ovarian cancer was performed. Data were collected regarding grade, histology, reason for allocation to Stage IV, extent of surgery performed and residual disease at initial staging procedure, major perioperative complications, first-line chemotherapy regimen, length of inpatient hospital stay, outcome at second-look laparotomy, follow-up, and survival. For the purposes of this study, optimal cytoreduction was defined as a residual disease of 2 cm or less. Forty-seven patients with Stage IV epithelial ovarian cancer identified in the Society of Gynecologic Oncologists (SGO) Database at UPCC are included. Fourteen of 47 (30%) were optimally cytoreduced at the time of their staging procedure. Twenty-six of 47 (55%) were deemed Stage IV by virtue of positive pleural effusion cytology only. Twenty-one of 47 (45%) had intraparenchymal liver involvement or metastatic disease outside of the abdomen. The median survival of the suboptimally debulked group was 17 months, while median survival in the optimal group was 37 months (P = 0.0295). These data suggest that Stage IV epithelial ovarian cancer patients with less than 2 cm residual disease have a survival advantage over patients with greater than 2 cm residual.

Mutations of the BRCA2 gene in ovarian carcinomas.

Inherited mutations in the recently discovered BRCA2 gene are believed to be responsible for a significant fraction of early-onset hereditary breast cancers. Unlike BRCA1, however, which confers a high risk to both breast and ovarian cancer, the incidence of ovarian cancer appears to be much lower In BRCA2-linked families, causing uncertainty as to the relevance of BRCA2 to hereditary ovarian cancer. Numerous allelotype studies indicate that allelic deletions Including the BRCA2 locus on chromosome 13q are common in ovarian cancers in general, suggesting that somatic mutations of this gene may be involved in sporadic ovarian tumorigenesis. The purpose of this study was to test the hypothesis that germline or somatic mutations of BRCA2 are associated with hereditary and/or sporadic ovarian cancers, respectively. The entire 10.2-kb coding region of BRCA2 was screened for mutations in 130 consecutive ovarian tumors, the only selection criterion being a pathological diagnosis of epithelial ovarian carcinoma. Loss of heterozygosity at markers flanking BRCA2 was observed in 56% of the tumors. Four germline mutations and two somatic mutations were identified; two of the germline mutations are recurrent, having been previously described. Remarkably, the patients with germline mutations were late-onset cases with no medical or family histories suggestive of hereditary cancer. These data suggest that mutations of BRCA2 are rare in sporadic ovarian cancers, and that the proportion of ovarian cancers resulting from hereditary predisposition may be higher than previously suspected based on estimates derived from studies of highly penetrant genetic loci.

Preoperative evaluation and staging of endometrial cancer.

Preoperative examination of a patient for whom a diagnosis of endometrial cancer has been made by office biopsy or dilatation and curettage includes careful history taking and physical examination, with emphasis on the pelvic examination, blood tests, and imaging evaluations of the pelvis, abdomen and chest, and other specific studies related to medical operability. The primary approach to endometrial cancer is surgery, which has been used for staging and treatment since the adoption of the Federation of Obstetrics and Gynecology system in 1988. Pilot studies and the Gynecologic Oncology Group have researched this system extensively and have emphasized the findings that could be defined only by pathologic study of the uterus, adnexa, retroperitoneal lymph nodes, and peritoneal cytologic findings. Preoperative endocervical evaluation is no longer necessary unless gross invasion of the cervix is suspected. However, initial histologic findings can identify patients at high risk, that is, those with high grade adenocarcinomas, clear cell carcinomas, adenosquamous carcinomas, and papillary serous adenocarcinomas. Intraoperative pathologic evaluation of the uterus by frozen section, which reveals depth of invasion into the myometrium and correlation with tumor grade, can identify patients for whom lymph node sampling should be performed.

Recurrent squamous cell carcinoma of the cervix with pulmonary lymphangitic metastasis.

A case report and review of the world literature are presented to examine all the reported cases of cervical carcinoma manifesting as pulmonary lymphangitic carcinomatosis in order to better understand this rare condition. The clinical and pathologic features of this disease process are reviewed, as are potential treatment options. We present the first reported case of an immunocompromised patient with cervical carcinoma and pulmonary lymphangitic metastasis with a prospective diagnosis made by transbronchial biopsy. Given that this condition carries a uniformly fatal prognosis, unwanted therapy may result from a missed diagnosis. A prospective pathologic diagnosis by transbronchial biopsy may guide appropriate therapy in these patients.

Metastatic cervical cancer and pelvic inflammatory disease in an AIDS patient.

The Center for Disease Control (CDC) recently added invasive cervical cancer to its list of surveillance case-defining diseases, and also included cervical dysplasia, carcinoma in situ, and pelvic inflammatory disease (PID) in the classification system. There are several reported cases of cervical cancer in AIDS patients that behaved in an unusually aggressive fashion and responded poorly to therapy. In light of the above-reported cases, it may be expected that cervical cancer may manifest itself in unusual ways in HIV-positive women. A case of aggressive cervical cancer in an AIDS patient with PID is reported. She was admitted with PID and newly diagnosed cervical cancer with recurrent fever spikes despite adequate antibiotic coverage. An aspiration of a presumed psoas abscess revealed metastatic squamous cell carcinoma. These data suggest that not only are HIV-infected women at risk for aggressive and unusual presentations of cervical cancer, but also that coexistent pelvic infection may contribute to development and spread of the disease. Immunosuppression from the virus may increase the incidence and severity of neoplasia. Data suggest that cervical cancer in HIV-infected women is often of advanced stage and responds poorly to treatment. Unique treatment approaches may need to be developed as conventional strategies do not seem to be adequate. More research is required to determine what these strategies should be. Lastly, universal HIV screening of women with either PID or cervical cancer seems prudent.

Endometriosis and tamoxifen therapy.

Tamoxifen is an estrogen antagonist/agonist often associated with antiestrogenic effects such as hot flushes and vaginal dryness in premenopausal women. Estrogenic side-effects, such as thromboembolic phenomena and endometrial proliferation has been reported in postmenopausal women. Paradoxically, tamoxifen has also been shown to be capable of increasing estrogen levels in premenopausal women. Since tamoxifen is being used more frequently in this group of women, potential adverse effects are only now being recognized. Two cases of premenopausal women who developed symptomatic endometriomas while on tamoxifen for breast cancer, are reported. Stimulation of endometriosis should be considered when pain and an ovarian mass develops in a woman on tamoxifen. The unique effects of tamoxifen in premenopausal women may contribute to this even in the presence of regular ovulation.

International Federation of Gynecology and Obstetrics staging of endometrial cancer 1988.

In 1988, the International Federation of Gynecology and Obstetrics (FIGO) Cancer Committee changed the staging of endometrial carcinoma from a clinical one to a surgicopathologic one. The emphasis in the new FIGO system was changed to the pathologic findings in the uterus, cervix, adnexa, and pelvic and/or periaortic nodes, and peritoneal cytologic findings. The major changes in this staging system were (1) the use of the depth of myometrial invasion and (2) the identification of tumor cells in peritoneal cytologic examination and of invasion in the retroperitoneal lymph nodes. Preoperative endocervical curettage was no longer necessary. Currently, the high level of operability of patients with endometrial carcinoma makes this staging system a viable one, which will provide information about the need for additional treatment. The use of the grading system for the tumor also was refined to upgrade nuclear changes that were inappropriate for the architectural grade. In serous adenocarcinomas, clear cell adenocarcinomas, and squamous cell carcinomas, nuclear grading took precedence. Adenocarcinomas with squamous differentiation were graded according to the nuclear grade of the glandular component.

A formula for predicting the risk of a positive second-look laparotomy in epithelial ovarian cancer: implications for a randomized trial.

OBJECTIVE: To develop a formula to predict the risk of a positive second-look laparotomy. METHODS: A retrospective review was performed on 89 patients who underwent second-look surgery following a complete clinical remission after cis-platin- or carboplatin-based chemotherapy. Logistic regression was used to develop a formula to predict the probability of a positive second look based on age, stage, grade of tumor, residual disease after initial surgery, and histologic type. RESULTS: We identified three groups based on estimated probabilities: low probability (0.25 or less), intermediate probability (0.26-0.74), and high probability (0.75 or more). The low-probability group had an 8% chance of a positive second look, the high-probability group had an 82% chance of a positive second look, and the intermediate-probability group had the correct outcome predicted only 61% of the time. Survival curves paralleled these results and were significantly different for each group. CONCLUSIONS: Using known prognostic factors, a formula can aid in implementation of a randomized clinical trial to test the efficacy of second-look laparotomy. This formula could exclude patients not suitable for randomization and give the investigator a better idea of the expected survival of various subgroups.

Extended-field radiation therapy in early-stage cervical carcinoma: survival and complications.

Four hundred fifteen patients with early-stage cervical carcinoma were explored via a transperitoneal approach for radical hysterectomy at the Hospital of the University of Pennsylvania between January 1, 1960, and December 31, 1985. Twenty-four of these patients were found to have histologic documentation of para-aortic lymph node metastases. Twenty-one patients (88%) were treated primarily with extended-field radiotherapy. Forty-eight percent of these patients have survived greater than 5 years from diagnosis. Six patients have been followed more than 10 years after initial treatment. All six are alive although one patient has recurrent disease that was diagnosed at 164 months. Patients with adenocarcinoma or adenosquamous carcinoma had a survival significantly lower than that of those with squamous cell cancers (p = 0.022). Complications included one treatment-related death from multiple fistulas and sepsis, one vesicovaginal fistula, two enteric fistulas, and two small bowel obstructions. The major morbidity rate was 19%. Extended-field radiation is effective therapy for para-aortic nodal metastasis associated with early-stage squamous cell carcinomas of the cervix but carries a considerable morbidity rate. Other modalities such as combined chemotherapy and radiation may be necessary for adenocarcinoma.

Treatment of advanced and recurrent endometrial cancer with cisplatin, doxorubicin, and cyclophosphamide.

Twenty-five patients with recurrent or advanced-stage endometrial cancer were treated with cisplatin, doxorubicin, and cyclophosphamide (PAC) from May 1982 to November 1987. A retrospective chart analysis was performed to evaluate the effect of treatment on survival and progression-free interval. Toxicity was moderate. Neutropenia was the most common side effect. Age, performance status, and tumor cytoreduction were statistically significant predictors of survival time (P less than 0.03). In the 17 evaluable patients, the response rate was 47%. PAC is an active regimen in the treatment of endometrial cancer. Larger prospective studies are needed to evaluate whether tumor cytoreduction is important in the treatment of this disease.

Database management for a gynecologic oncology service.

With the ready availability of powerful desktop computers, the ability to manage large clinical databases has become practical. A computer can enhance the capability of a gynecologic oncology service to catalog, recall, and analyze data about patients, tumors, and therapies. While commercially available database packages can be used for this purpose, we have developed a custom database for tracking the clinical activity of a busy gynecologic oncology service. The system catalogs data about patients, admissions, tumors, and therapeutic modalities and uses this information to generate several useful reports. The reports are used for daily patient care, fellow and resident case statistics, and clinical research. What is unique about the system is that it is optimized for ease of use. The development of this tumor registry, its user friendliness, and advantages over a manual recordkeeping system are described. Unlike other tumor registries, our system is utilized on a daily basis for patient care. Therefore, the data being entered have an immediate usefulness in addition to being simultaneously added to the tumor register for retrospective clinical research. One may hypothesize that it would be useful if all gynecologic oncology services used a common computerized tumor registry that could allow for the sharing of information on a national or global scale.

Single application treatment of human papillomavirus infection of the cervix and vagina with trichloroacetic acid: a randomized trial.

Treatment of human papillomavirus (HPV) infection of the lower genital tract with trichloroacetic acid was evaluated in a randomized, double-blind fashion at the Hospital of the University of Pennsylvania. Thirty-four patients who had colposcopic and histologic evidence of HPV without dysplasia were entered into the study and randomly placed into either a treatment or placebo group. The treatment group received a single topical application of 50% trichloroacetic acid to the vagina and cervix on day 1. The placebo group was treated in the same manner using saline. The patients were evaluated at 4 and 16 weeks post-treatment for cytologic and histologic evidence of HPV. No differences between the treatment and placebo groups were found. Only one of 16 patients in the treatment group and three of 18 in the placebo group were free of HPV infection at the 4- and 16-week evaluations. Our data suggest that treatment of subclinical HPV infection with trichloroacetic acid is ineffective at this concentration.

Low-grade stromal sarcoma: DNA flow cytometric analysis and estrogen progesterone receptor data.

DNA flow cytometry (FCM) data and estrogen receptor (ER) and progesterone receptor (PR) status were studied in three cases of low-grade stromal sarcoma (LGSS). One case was a primary presentation and the remaining two were recurrent tumors. DNA FCM showed a DNA index (DI) equal to 1.00, consistent with a diploid cell population, for four of the six specimens studied. The other two showed near-diploid populations. Proliferation indices (PI) were low in two of the patients' tumors (8.0 and 12.7%). These findings are consistent with the clinical history of LGSS and its propensity for indolent growth, long intervals between recurrences, and generally favorable prognosis. In case 2, a patient with several recurrences, the PI was increased to 20.3% in a specimen from the first recurrence. She subsequently recurred within 1 year with a more aggressive tumor, characterized by a mitotic index of greater than 10 mitoses/10 high-power fields (HPF), absence of ER and PR, and an aneuploid population (DI = 1.19). Receptor data, obtained by dextran-coated charcoal assay, showed that all tumors except the aggressive recurrence in case 2 had high ER (average 316 fmole/mg protein) and high PR (average 753 fmole/mg protein) levels. These ER and PR data are similar to the two other reports in the literature and the usual clinical response to progestational therapy was demonstrated. Further studies will help define the possible role of FCM and ER and PR determinations in patients with LGSS. These preliminary data suggest that they may be of prognostic significance.

Cytologic smears of peritoneal surfaces as a sampling technique in epithelial ovarian carcinoma.

Ovarian carcinoma disseminates primarily through the shedding of cells into the peritoneal cavity and subsequent implantation onto peritoneal surfaces. Accurate evaluation of the extent of disease is important both at initial surgical evaluation for staging and at second-look operations to determine the necessity of further therapy. Techniques used for such assessment include node sampling, peritoneal washings, and random biopsies of peritoneal surfaces. Although random biopsies are used by some, others have found them to be of negligible value in the absence of gross disease. The use of cytologic smears of peritoneal surfaces offers a simple method by which cells from a large surface area may be evaluated, and uses equipment readily available to the gynecologist. We compared results of 125 cytologic smears with washings and biopsy specimens obtained during 33 laparotomies for ovarian carcinoma. Cytologic smears identified disease in 48 of 125 sites, whereas biopsy identified only 29 areas of disease. Thirteen of the positive Papanicolaou smears were obtained from clinically disease-free areas. Although the cytologic evaluation of the parietal peritoneal surfaces was more frequently positive than were biopsy specimens, each method identified disease in 16 patients when paired with standard techniques of examination and washing. We conclude that the peritoneal cytologic smear offers an alternative method of further evaluating the extent of disease, particularly when no gross evidence of extraovarian disease is detected.

Treatment of stage II endometrial carcinoma.

The optimal management of stage II carcinoma of the endometrium remains to be established. We reviewed our experience in treating 42 patients with stage II endometrial cancer by surgery, radiation, or combined radiation and surgery at the Hospital of the University of Pennsylvania. The overall 5-year survival was 47.6%. The 5-year survivals of patients treated by surgery only, radiation only, or combination radiation and surgery were 68.5, 36.5, and 46.1%, respectively, which were not significantly different. Histologic grade was found a significant prognostic factor but type of cervical involvement was not. Major complication rates were similar in each treatment group. We conclude that the majority of patients with stage II endometrial carcinoma are best treated by combination radiation and surgery, but in a select subset of patients, radical hysterectomy and lymphadenectomy constitute a reasonable treatment option.

Malignant struma ovarii.

Malignant struma ovarii is a very rare tumor, with considerable disagreement concerning the necessary histologic features for malignancy. The prognosis with patients with a malignant struma ovarii is difficult to make because of inadequate follow-up of the reported cases and long clinical courses. In most cases the patients responded well to surgical treatment but sometimes patients have died from malignant struma ovarii, in particular, if there is metastasis. There is evidence that radioactive iodine is effective in treating metastatic struma. The present case reports the use of intraperitoneal chronic phosphate for metastatic intraperitoneal disease, with thyroid suppression. Long-term follow-up will be necessary to properly evaluate this therapy. Prophylactic administration of thyroid hormone should be considered in cases of malignant struma ovarii.