Margin status and excision of cervical intraepithelial neoplasia: a review.

UNLABELLED: Excisional biopsy of the cervix for diagnosis and treatment of cervical neoplasia is common. Management of patients with involved margins of resection is unresolved. Data concerning use of thermal techniques show that this technique yields equivalent results in most cases. Important exceptions are microinvasive squamous disease and adenocarcinoma. Conservative management of involved squamous margins is possible. Techniques for follow-up include cytology, colposcopy, and endocervical curettage. Adenocarcinoma in situ (AIS) should be treated with cold-knife conization. The standard of care for AIS is hysterectomy except in certain specific indications. Data concerning technique, follow-up, use of endocervical curettage, and the need for reexcision will be presented. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this article, the reader will be able to compare the efficacy of the various excisional procedures in the treatment of cervical dysplasia, list the indications for additional surgery after positive margins on cervical excisions, and describe the proper management of a patient with adenocarcinoma in situ.

Overexpression of p21WAF1/CIP1 and MDM2 characterizes serous borderline ovarian tumors.

Ovarian epithelial tumors are classically divided into benign, malignant, and borderline or of low malignant potential. It is controversial whether this last group of tumors should be considered benign or malignant. Expression of cell cycle markers has recently been linked to tumor behavior and response to treatment. It has been shown that one of the pathways through which the p53 gene controls the cell cycle is by transactivating p21WAF1/CIP1, a cyclin-dependent kinase (cdk) inhibitor. By inhibiting cdks, p21WAF1/CIP1 blocks the G-1 to S-phase transition in the cell cycle. p53 can be regulated by MDM2 (murine double minute-2) through direct inactivation or promotion of its cytoplasmic degradation. In an attempt to investigate the cell cycle checkpoint mechanisms of these tumors, we studied the expression of p53, Ki-67, MDM2, and p21WAF1/CIP1 by immunohistochemistry. We analyzed the expression of these proteins in 19 cystadenomas (8 serous and 11 mucinous), 40 borderline tumors (31 serous and 9 mucinous), and 18 serous carcinomas of the ovary. p21WAF1/CIP1 was expressed in 7 of 19 (37%) benign cystadenomas, 32 of 40 (80%) borderline tumors (93.5% of serous and 33% of mucinous), and in 9 of 18 (50%) serous carcinomas. Ki-67 was only weakly expressed in 8 of 19 (42%) benign cystadenomas, all borderline tumors showed Ki-67 staining in less than 50% of the cells, and 55% of serous carcinomas stained in more than 50% of tumor cells. p53 was absent in all but 1 of the cystadenomas, was expressed in 9 of 40 (22.5%) borderline tumors (25.8% of serous and 11% of mucinous), and in 10 of 18 (55%) carcinomas. All 11 implants of serous borderline tumors expressed p21WAF1/CIP1. Most serous borderline tumors expressed higher levels of MDM2 compared with the benign cystadenomas and carcinomas. Four of the serous borderline implants (40%) expressed MDM2. Coexpression of p21WAF1/CIP1 and MDM2 characterizes serous borderline tumors of the ovary and their implants, which suggests that these cell cycle control proteins are important in these tumors and may be related to tumor progression. Low expression of p53 protein in serous borderline tumors might be in part mediated by MDM2. This suggests that the p53 pathway is intact in most of these tumors, in contrast with carcinomas, in which high expression of p53 has been related to mutations of this gene.

Topotecan has substantial antitumor activity as first-line salvage therapy in platinum-sensitive epithelial ovarian carcinoma: A Gynecologic Oncology Group Study.

PURPOSE: Topotecan is known to be active in recurrent ovarian cancer, but most prior studies have focused on platinum-resistant or refractory populations. This study was undertaken to define the response rate and progression-free interval in platinum-sensitive patients. PATIENTS AND METHODS: Patients with recurrent ovarian cancer after one or two prior chemotherapy regimens and in whom the interval between prior platinum therapy and the initiation of protocol therapy was greater than 6 months were treated with topotecan 1.5 mg/m(2) intravenously over 30 minutes daily for 5 days, with this cycle repeated every 21 days. RESULTS: Forty-eight patients were entered onto the study; 47 were assessable for toxicity and 46 for response. The response rate was 33% (two complete responses and 13 partial responses), with a median response duration of 11.2 months. Hematologic toxicity predominated but was manageable in most patients with frequent incorporation of cytokines and RBC and platelet transfusions. Fatigue was reported in 15 patients and resulted in the discontinuation of therapy in five responding patients. CONCLUSION: Topotecan is an active drug in platinum-sensitive ovarian cancer, with significant but manageable hematologic toxicity. Fatigue is also a common problem that may be dose-limiting in some patients.

Complete response to topotecan of recurrent fallopian tube carcinoma.

OBJECTIVE: To describe the first complete response of recurrent Fallopian tube carcinoma to topotecan. METHODS: A patient with recurrent Fallopian tube carcinoma previously treated with paclitaxel (Taxol) and carboplatin is described. RESULTS: This patient demonstrated a complete clinical response to topotecan. Radiographic and CA-125 measurements were used to determine response. Response was noted after four cycles and a complete response demonstrated after six treatments. CONCLUSION: Topotecan appears active in recurrent Fallopian tube carcinoma.

Hysteroscopic resection of uterine lipoleiomyoma: case study and literature review.

▪ ABSTRACT: : A case of a uterine lipoleiomyoma within an endometrial polyp is presented. Lipoleiomyomas represent a rare, benign gynecological entity that can present as post-menopausal bleeding or pelvic mass. Hysteroscopic appearance, MRI images, and histological images of the polyp are included. The English literature pertaining to the radiological appearance and cytological origins of lipoleiomyoma is reviewed.

Dactinomycin in the treatment of recurrent or persistent endometrial carcinoma: A Phase II study of the Gynecologic Oncology Group.

OBJECTIVES: The search for effective systemic chemotherapy for endometrial cancer is ongoing. Complete responses to current drugs or regimens are infrequent, and overall survival for patients with disease not amenable to surgery or radiation therapy is poor. Dactinomycin has proven activity against a wide variety of solid tumors but has not been tested against endometrial cancer. Using pharmacokinetic data supporting an intermittent, single-dose schedule, this Phase II Gynecologic Oncology Group study was conducted to determine the antitumor activity and toxicity of dactinomycin in patients with persistent or recurrent endometrial adenocarcinoma. METHODS: Eligibility was limited to patients with measurable disease, adequate renal, hepatic, and bone marrow function, and no more than one prior chemotherapy regimen. Treatment consisted of 2 mg/m(2) slow intravenous push of dactinomycin over 15 min with courses repeated every 4 weeks. RESULTS: A total of 27 patients were entered in this study between April 1996 and September 1996; all were evaluable for toxicity and 25 were evaluable for response. Overall, 12/25 (48%) patients had received prior radiation therapy and all had received prior chemotherapy. Sites of measurable disease were pelvis (9 patients) and distant (16 patients). There was 1 complete response and 2 partial responses for an overall objective response rate of 12%. Aside from emesis (grade 3, 2 patients; grade 4, 2 patients) significant nonhematologic toxicity was rare. The most common toxicity was neutropenia (grade 3, 2 patients; grade 4, 10 patients). CONCLUSION: Toxicity was deemed acceptable but the limited effectiveness of dactinomycin precludes further clinical development in this patient population.

Onycholysis associated with weekly administration of paclitaxel.

OBJECTIVE: To report an unusual reaction associated with weekly administration of paclitaxel. CASE SUMMARIES: Onycholysis was seen in four women with recurrent ovarian cancer being treated with low-dose, weekly paclitaxel. Two of the patients had previously received higher doses of paclitaxel on an every-three-week schedule without similar reactions. Onycholysis developed between weeks 10-13 of treatment in three of the patients. In the fourth patient, it developed shortly after initiation of weekly paclitaxel. None of the reactions required dose adjustments or discontinuation of therapy. Direct toxicity to the nail bed or inhibition of angiogenesis are possible mechanisms for this reaction. DISCUSSION: Onycholysis, separation of the nail from the nail bed, is an infrequent adverse effect of drug therapy. Antineoplastic drugs have previously been reported to cause onycholysis, pigmentation, bands, thickening or thinning of the nail bed, and nail shedding. Nail changes with the taxanes, primarily docetaxel, are reported in up to 30-40% of patients. Paclitaxel is not commonly associated with dermatologic reactions, although localized skin reactions and tissue necrosis have been reported. Nail changes, pigmentation or discoloration of the nail bed, occur in 2% of patients receiving paclitaxel. CONCLUSIONS: Onycholysis is an uncommon reaction that may occur in some patients receiving weekly, low-dose paclitaxel therapy. The reaction is not life-threatening and does not warrant discontinuation of therapy. However, clinicians should be aware of the possibility of this effect and be prepared to advise patients who develop signs of nail changes.

Stereotactic Irradiation: potential new treatment method for brain metastases resulting from ovarian cancer.

Stereotactic irradiation (radiosurgery) is a method of precisely focusing well-defined beams of radiation at small intracranial targets. The technique has been applied to the treatment of brain lesions that are benign (e.g., arteriovenous malformations, meningiomas, pituitary adenomas) and malignant (e.g., gliomas, metastases). This paper introduces preliminary data suggesting the possible value of radiosurgery in the management of ovarian cancer metastatic to the brain. Among 32 women with ovarian cancer metastatic to the brain treated with whole brain irradiation, nine (29%) experienced a complete radiographic response, compared with two of the five patients (40%) treated with radiosurgery. The 2-year survival rate was 60% among those treated with radiosurgery and 15% among those who received whole brain irradiation without radiosurgical boost. Stereotactic irradiation may be of clinical benefit to select patients with brain metastases resulting from ovarian cancer. A prospective randomized trial has been implemented by the Radiation Therapy Oncology Group (RTOG 95-08) to determine whether such observations are reproducible on a national scale.

Endometrial cancer in polyps associated with tamoxifen use.

We report 5 cases of carcinoma arising within tamoxifen-associated endometrial polyps. In 4 of 5 cases there were no other changes within the endometrium. Given these findings, the sonohysterographic differentiation between a polypoid structure and thickened endometrium does not eliminate the need for histologic sampling of the uterine cavity.

Bipolar electrosurgical loop excision procedure for cervical intraepithelial neoplasia.

OBJECTIVES: We sought to determine the safety and efficacy of a bipolar electrosurgical loop excision instrument in the diagnosis and treatment of cervical intraepithelial neoplasia (CIN). MATERIALS AND METHODS: Twenty-eight patients underwent treatment for CIN using a 20 x 10-mm bipolar electrosurgical loop device (Valley Forge Scientific, Oaks, PA). A Malis (Valley Forge Scientific) electrosurgical generator unit (60 watts cutting) was used to remove the cervical lesion and transformation zone under colposcopic guidance. Specimens were evaluated for histopathological diagnosis, tissue depth, fragmentation of specimens, mean maximal thermal artifact, and mean maximal endocervical and ectocervical thermal artifact. RESULTS: Final pathology from bipolar electrosurgical loop excision revealed CIN3 (8), CIN2 (4), CIN1 (11), human papillomavirus changes (3), and normal findings (2). Mean operating time was less than 15 minutes, and mean estimated blood loss was less than 10 ml. Average number of tissue pieces was 1.6 (range, 1-4). No complications occurred. Mean maximal thermal artifact was 0.318 mm. Mean endocervical mucosal and ectocervical mucosal thermal artifacts were 0.177 mm and 0.176 mm, respectively. Mean tissue depth of the excised specimen was 0.40 cm. Histopathological diagnosis was possible on all specimens. In five specimens (17.9%), evaluation of the cauterized endocervical margin for CIN was not possible, owing to thermal artifact. No correlation was observed between tissue depth and thermal artifact. CONCLUSION: Bipolar electrosurgical loop excision for the treatment of CIN is a safe and effective alternative to the traditional unipolar electrosurgical loop excision. Thermal artifact did not interfere with histopathological diagnosis, and the presence of artifact at cauterized margins was similar to that reported for historically unipolar specimens. A randomized control trial comparing therapeutic effectiveness of bipolar electrosurgical loop excision and unipolar electrosurgical loop excision is planned.

Clinical significance of histiocytes found on cervical cytology.

OBJECTIVE: Our aim was to determine the incidence of cervical and endometrial pathology associated with the diagnosis of histiocytes on cervical cytology. MATERIALS AND METHODS: A retrospective review was conducted from 1993 to 1995 of cervical cytology reports in which histiocytes were named in the descriptive diagnosis. Charts were reviewed and follow-up was performed on all patients for an additional 2 years. RESULTS: Histiocytes were diagnosed in 226 of 82,018 (0.27%) cytology reports. Histiocytes alone (110), histiocytes and endometrial cells (40), and histiocytes and inflammation (45) were reported in the patients with complete follow-up. Final pathological findings after 2 years of follow-up were normal in 169 cases; other findings included polyps (6), simple hyperplasia (10), complex hyperplasia (1), previously treated cervical cancer (4), and endometrial cancer (5). All patients with endometrial cancer had clinical signs and symptoms of disease. CONCLUSION: The diagnosis of histiocytes on cervical cytology is associated with neoplasia (7.8%) or cancer (2.6%) in some cases. However, significant neoplasia (i.e., carcinoma or atypical hyperplasia) was associated with clinical signs and symptoms. On cytological workup, the finding of histiocytes in the absence of symptoms appears not to be associated with significant pathology.

Autologous, hapten-modified vaccine as a treatment for human cancers.

We have devised a novel approach to active immunotherapy based on modification of autologous cancer cells with the hapten, dinitrophenyl (DNP). The treatment program consists of multiple intradermal injections of DNP-modified autologous tumor cells mixed with BCG. Administration of DNP-vaccine to patients with metastatic melanoma induces a unique reaction- the development of inflammation in metastatic masses. Histologically, this consists of infiltration of T lymphocytes, most of which are CD8+. These T cells usually produce interferon-gamma in situ. Moreover, they represent expansion of T-cell clones with novel T-cell receptor (TCR) structures. Occasionally, administration of DNP-vaccine results in regression of measurable metastases. The most common site of regression has been small lung metastases. Administration of DNP-vaccine to patients in the postsurgical adjuvant setting produces a more striking clinical effect. Of 62 patients with clinically evident stage III melanoma who had undergone lymphadenectomy, the 5-year relapse-free survival rate was 45% and the overall survival rate was 58%. These results appear to be better than those obtained with high-dose interferon, although a randomized phase III trial is required to prove that point. A recent phase I study suggests that this therapeutic approach is also applicable to stage III ovarian cancer. There appear to be no insurmountable impediments to applying this approach to much larger numbers of patients or to developing it as a standard cancer treatment.

Dilated fallopian tubes: MR imaging characteristics.

PURPOSE: To determine the magnetic resonance (MR) imaging characteristics of hydrosalpinx and the accuracy of MR imaging for distinguishing hydrosalpinx from other adnexal masses. MATERIALS AND METHODS: Cross-referencing of pathologic records and MR studies from two institutions disclosed 41 study patients with surgically proved dilated fallopian tubes. A set of 38 patients with surgically evaluated adnexal masses, but no hydrosalpinx, were randomly chosen as control subjects. All MR examinations included T1-weighted spin-echo and T2-weighted fast spin-echo imaging in multiple planes with a phased-array multicoil. Two blinded readers scored each adnexa for the presence of a dilated fallopian tube or thickened tubal wall and mucosal folds and the signal intensity of the intratubal fluid. Blinded readings were compared with surgical findings of dilated fallopian tube, endometriosis, and salpingitis. Radiologic-pathologic correlation was performed with adnexal specimens imaged in vitro in three study patients. RESULTS: On a per patient basis, the blinded readers correctly identified dilated fallopian tubes in 31 of 41 study patients and correctly excluded dilated tubes in a mean 34 of 38 control subjects. On T1-weighted images, hyperintense tubal fluid was significantly correlated with the presence of endometriosis in the pelvis at surgery (P < .002, chi 2). CONCLUSION: MR imaging can depict most dilated fallopian tubes and differentiate them from other adnexal masses on the basis of morphologic features. On T1-weighted images, high signal intensity is correlated with the presence of endometriosis affecting the tube.

Secondary response of ovarian tumors to topotecan treatment.

Three patients presented with ovarian cancer that was initially treated with paclitaxel and platinum-based compounds. Although responses to these agents occurred, tumor progression was evident by elevated CA 125 levels after a period of 11 to 35 months. These patients were then treated with topotecan and exhibited a response and stopped therapy. All patients subsequently had progression of disease. The patients were again treated with topotecan and have experienced favorable responses. All three patients are currently receiving treatment with topotecan and have stable disease. The results presented here suggest that re-treatment with anti-tumor agents, such as topotecan, may be able to elicit a response in tumors previously sensitive to these agents.

Concomitant irradiation and dose-escalating carboplatin for locally advanced carcinoma of the uterine cervix: an updated report.

The combination of radiotherapy and carboplatin is associated with high response rates among women who have cervical cancer. To improve control rates for patients who have locally advanced carcinoma of the uterine cervix, oncologists have explored combinations of radiotherapy and chemotherapy. Carboplatin is an analogue of cisplatin, with similar efficacy against cervix cancer and a toxicity profile that is theoretically appealing for this group of patients because it is not nephrotoxic. Fifteen women with International Federation of Gynecology and Obstetrics (FIGO) stages IB2 through IIIB or recurrent carcinoma of the cervix were treated with megavoltage irradiation and weekly intravenous carboplatin (7 women, 60 mg/m2; 8 women, 90 mg/m2). Response was documented among all patients treated at 60 mg/m2 (three complete responses, four partial responses) and in 6 women treated with 90 mg/m2 (four complete responses, two partial responses). The two nonresponders in the series presented with recurrent glassy cell carcinoma of the cervix. All patients completed the planned course of therapy without the need for treatment interruption. At 60 mg/m2, one dose of carboplatin was withheld because of grade 2 thrombocytopenia. At 90 mg/m2, one case of grade 2 leukopenia was documented. The leukocyte counts remained within normal limits for all 3 patients who were irradiated through extended portals that encompassed the paraaortic nodes (2 women, 60 mg/m2; 1 woman, 90 mg/m2). To date, 2 of 7 patients treated at the lower dose level have died of disease (one local progression and distant failure at 11 months, one distant failure alone at 6 months). The remaining patients treated at 60 mg/m2 are alive at a median of 24 months (range, 21-37 months). Among those treated at the higher dose level, 1 patient is alive with local and distant failure at 14 months, and 1 woman succumbed to local and distant disease at 4 months. The remainder are alive at a median follow-up of 6 months (range, 2-10 months). The regimen was unsuccessful in salvaging women with recurrent glassy cell carcinoma. We conclude that the combination of radiotherapy and carboplatin can be safely delivered at both of the chemotherapy schedules studied. The regimen should not be offered to women who have recurrent glassy cell tumors. To prove the efficacy of this approach, phase III testing should be considered that compares the combination of agents to irradiation alone.