The Papanicolaou smear histories of 237 patients with cervical cancer.
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Biomedical subjects
Publications and source records attributed to N F Hacker.
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A phase II trial of concurrent cisplatin and 5-fluorouracil (5-FU) chemotherapy and radiation therapy (CT + RT) was conducted for the primary treatment of 12 patients with retrospective surgical FIGO stages III-IV squamous carcinoma of the vulva. Eight patients were stage III and four were stage IV. Chemotherapy was used as a radiation sensitizer and it was administered in two 5-day cycles 28 days apart. Cisplatin, 50 mg/m2/day iv on Days 1 and 2 or 100 mg/m2 on Day 1 or 2, plus continuous-infusion 5-FU, 1000 mg/m2/day for 4-5 days commencing on Days 1 and 28 of external-beam radiation therapy, are given. The pelvic radiation to a dose of 4400-5400 cGy is administered AP and PA to treat the primary tumor, the groin nodes, and the iliac vessels to the level below the common iliac nodes. Complete tumor responses were seen in 8 of 12 (67%) patients. Responses were observed in 6 of 8 (75%) stage III patients and 2 of 4 (50%) stage IV patients. Partial response were observed in 3 patients, and 1 patient had persistent disease. At the completion of concurrent chemoradiation therapy, radical vulvectomy or excision was used in 3 patients and posterior exenteration in 1. With a median follow-up of 37 months (range, 7-60 months), 10 patients are alive and free of disease, and 2 patients died at 12 and 15 months. There were no treatment-related deaths and no grade 4 toxicity. The morbidity included moist desquamation of the vulva in all patients, with grade 2 toxicity in 10 and grade 3 in 2. One patient had a deep venous thrombosis that responded to anticoagulation therapy. These data support the use of concurrent cisplatin and 5-FU chemotherapy and radiation therapy as an alternative to primary radical surgery to treat advanced-stage squamous carcinoma of the vulva.
One hundred and thirty-five patients with squamous carcinoma of the vulva were treated at UCLA and City of Hope Medical Centers between 1957 and 1985. Sixty-two cases were stage I, 48 stage II, 18 stage III, and 7 stage IV. Twenty-one patients developed a local vulvar recurrence after primary radical resection. Ninety-one patients had a surgical tumor-free margin greater than or equal to 8 mm on tissue section and none had a local vulvar recurrence. Forty-four patients had a margin less than 8 mm; 21 had a local recurrence and 23 did not (P less than 0.0001). Of the 23 patients with a margin less than 8 mm who did not recur locally, 14 remained free of disease, and 9 had either advanced disease, declining health, or short follow-up. Depth of invasion is associated with local recurrence, with a 9.1-mm reference value correctly predicting outcome in 81.5% of cases. Increasing tumor thickness is associated with local recurrence, with a 10-mm reference value predictive of 90% non-recurrence and 33% recurrences. A pushing border pattern is less likely to recur than an infiltrative growth pattern. Lymph-vascular space invasion has a combined predictive accuracy of 81.5%. Increasing keratin and greater than 10 mitoses per 10 high-power fields correlate with local recurrence. Neither clinical tumor size nor coexisting benign vulvar pathology correlates with local recurrence. Fourteen of twenty-one patients with vulvar recurrence died of metastatic disease, four died of intercurrent disease, and three were alive at 32, 68, and 157 months, with 16 recurring in less than 1 year. Surgical margin is the most powerful predictor of local vulvar recurrence. Combining factors in a stepwise logistical regression does not significantly improve this predictive value. Accounting for specimen preparation and fixation, a 1-cm tumor-free surgical margin on the vulva results in a high rate of local control, whereas a margin less than 8 mm is associated with a 50% chance of recurrence.
One hundred and ten women who underwent vulvectomy and inguinal-femoral lymphadenectomy for stages I-IV vulvar squamous cell carcinoma were studied. The most important factors that affected the inguinal lymph node status in the order of importance were vascular invasion, clinical stage, tumor thickness, depth of stromal invasion, and amount of keratin. Fourteen (88%) of 16 tumors with vascular invasion in the primary tumor metastasized. In the absence of vascular invasion, 18 (19%) of 94 tumors metastasized. Overall, 82% of tumors were correctly classified into lymph node negative and positive groups on the basis of vascular invasion. Tumor thickness and depth of stromal invasion had a similar accuracy in predicting lymph node status. The risk of lymph node metastasis increased from 0% when tumor thickness or depth of stromal invasion was less than 2 mm, to over 20% when depth of stromal invasion was greater than 2 mm, and to over 40% when tumor thickness exceeded 4 mm. A combination of vascular invasion, tumor thickness (or depth of stromal invasion), and the amount of keratin correctly classified 97% (76/78) of the lymph node negative group and 63% (20/32) of the positive group with an overall accuracy of 87%. The probability of having lymph node metastasis was computed for individual patients on the basis of one or more pathologic parameters using a logistic regression model. This feasibility is an important step toward individualized therapy for vulvar carcinoma.
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About half of patients with squamous cell carcinoma of the vulva have tumors 2 cm or less in diameter at the time of diagnosis. These Stage I tumors have an excellent prognosis. There is no standard operation applicable to every patient, but the trend is toward a more conservative resection of the primary lesion, with treatment individualized with respect to both the primary tumor and the groin nodes. Risk factors for local recurrence and groin metastasis should be analyzed, in order to determine the most conservative operation compatible with cure.
Radical, curative surgery may not be considered in elderly patients with gynecologic cancer, yet the morbidity for this population from radiotherapy and cytotoxics may be high. This study compared the feasibility and outcome of such surgery in 226 consecutive patients, 72 women over 70 years old and 154 younger patients, in our institution over a 26-month period. Older patients presented with more advanced-stage cancers and, as a group, had significantly poorer presurgical performance status and more intercurrent medical problems. Nevertheless, the planned radical surgical procedure could be carried out in 90% of elderly patients, with a postoperative mortality of 1.5%. Minor postoperative complication rates were similar for the two groups and, except for vulvectomy patients, the mean inpatient stay was the same for both groups. Chronological age alone is a poor determinant of surgical risk, and elderly patients withstand radical surgery almost as well as their younger counterparts.
The pharmacokinetics of intraperitoneal (ip) cisplatin were investigated in a murine model. Groups of six animals were studied at initial cisplatin concentrations (Ci) of 50, 100, 200, and 400 micrograms/ml, and at injection volumes (V) of 0.5, 1, 2, and 4 ml. For each Ci and V, four dwell times (Dt) between 1.5 and 120 min were studied. At 180 min mice were killed and five tissues (heart, kidney, liver, bowel, and peritoneum) were obtained for platinum measurement. Platinum recovered from the peritoneal cavity at the end of the dwell time and platinum tissue levels were determined by a radioactive tracer assay using Pt 195m-labeled cisplatin. A total of 384 mice were studied. The permeability times the effective surface area product (pS) was found to be independent of Ci, V, and Dt. Platinum tissue levels were proportional to absorbed dose. As the ratio of platinum tissue level to absorbed dose is constant, it is not possible to change Ci, V, nor Dt to minimize toxicity from a given absorbed dose. This study suggests that the therapeutic index of an individual intraperitoneal cisplatin treatment will not be changed by modifying Ci, V, nor Dt.
No prospective study has been done to elucidate definitely the value of cytoreductive surgery. However, all retrospective studies demonstrate that the size of residual disease prior to initiation of chemotherapy is the single most important determinant of prognosis. In experienced hands, optimal cytoreduction (residual nodules less than or equal to 1.5 cm) is feasible in about 85% of patients, and serious morbidity is acceptably low. Although patients with large metastatic disease usually have phenotypically resistant cells present, even in the small residual nodules, optimal cytoreduction followed by combination chemotherapy which includes cis-platinum can prolong survival by about 12 months and can improve the quality of life. Interval cytoreduction (following chemotherapy) is significantly less beneficial than primary cytoreduction.
Clinical staging is inaccurate in about 50% of patients with cervical cancer. Most patients will be upstaged on the basis of surgical exploration, usually because of occult nodal metastases. Data from surgical staging indicate that the incidence of positive para-aortic nodes is about 7% for patients with Stage I disease, about 17% for Stage II, and 28% for Stage III. Extended field radiation, to the level of T12, can salvage about 25% of patients with positive para-aortic nodes. About 40% of patients having extended field radiation develop distant metastases, and about 25% develop a pelvic recurrence. These data suggest the need for prospective clinical trials to evaluate the role of chemoradiation for improved local control, prophylactic extended field radiation for improved regional control, and prophylactic chemotherapy for improved systemic control.
Although the microscopic grade of epithelial ovarian carcinoma is recognized as an important prognostic factor, the grading systems are still controversial. A cytohistological grading system is described using the sum of the scores (from 1 to 4) of eight histological and cytological features. This grading is applied to the initial surgical specimens of 37 patients seen at UCLA Center for the Health Sciences; it is also used for evaluation of pathologic specimens obtained at subsequent laparotomies. The evolution of the score at subsequent laparotomies (stable, increasing, or decreasing) is correlated with the type of therapy, response to treatment, and prognosis. An increasing score at the second-look laparotomy is a poor prognostic factor with a significantly shorter patient survival (p less than 0.05). The tumor score at second-look laparotomy is significantly increased in cases of macroscopically positive operation (p less than 0.05) and tumor progression (p less than 0.001). The type of therapy has no significant effect on the tumor score. A multivariate analysis shows that a decreasing score is related to a lower mitotic activity. Conversely, an increasing score is related to a change in tumor pattern. This study demonstrates the prognostic value of our grading system, which needs to be further validated by prospective studies.
An analysis was performed of malignant and host cells found in peritoneal fluids obtained during intraperitoneal chemotherapy and immunotherapy in patients with ovarian cancer. The concentration of malignant cells and the surgically documented response to the intraperitoneal treatment were correlated. Twenty-three patients were treated with intraperitoneal cisplatin or alpha-2 interferon (rIFN-alpha 2) after persistent carcinoma was documented at second-look laparotomy. Six patients (26%) had a complete response to therapy, and all of these patients had a malignant cell concentration of less than 10(2)cells/cm2/dL. No responses were seen in patients whose initial malignant cell concentration was greater than 10(3)cells/cm2/dL. Among patients treated with intraperitoneal alpha-interferon, five of 11 whose initial concentration of malignant cells was less than 10(2) cells/cm2/dL responded to therapy, whereas none of the patients whose malignant cell concentration was 10(2) cells/cm2/dL or greater responded. In patients treated with intraperitoneal cisplatin, the initial concentration of malignant cells associated with any surgically documented response was less than 10(3)cells/cm2/dL. A host mesothelial reaction was prominent after intraperitoneal alpha-interferon, but not observed in women treated with intraperitoneal cis-platin. The fluctuating pattern of peritoneal white blood cells documented during therapy did not correlate with response. THe evaluation of peritoneal cytology specimens during intraperitoneal chemotherapy should include a quantitative assessment of malignant cells and reactive mesothelial cells in order to reflect more accurately the histologically documented findings. Initial quantitative cytology appears to correlate with the likelihood of a surgically documented response to intraperitoneal therapy.
Adenocarcinoma of the uterine cervix appears to be more prevalent now than a decade ago, and currently constitutes 10-20% of invasive cervical cancers. Because precursor lesions arise within the endocervical canal, identification and diagnosis of invasive disease is often more difficult than for squamous carcinoma. There is disagreement regarding the optimal treatment of adenocarcinoma. Adenocarcinoma may have a poorer prognosis than squamous carcinoma because it may be more difficult to detect and because it tends to metastasize earlier in its course. The controversies in the diagnosis and management of adenocarcinoma and adenosquamous carcinoma of the uterine cervix are reviewed.
Malignant transformation of endometriosis is a well documented phenomenon. Although it occurs most commonly in the ovaries, there have been approximately 50 reported cases of extraovarian malignant transformation of endometriosis. This paper presents two cases of malignancy arising from a dormant focus of endometriosis after total abdominal hysterectomy, bilateral salpingo-oophorectomy, and exogenous estrogen replacement therapy. These malignancies are often well differentiated and may behave similarly to estrogen-induced endometrial carcinomas. After surgical castration of a premenopausal woman with endometriosis, the use of progestins in replacement therapy may reduce the risk of malignancy arising in endometriosis.
Five new cases of central nervous system (CNS) metastases from epithelial ovarian cancer are described. They are discovered among 255 patients treated at University of California, Los Angeles (UCLA) Medical Center, giving an incidence of CNS metastases of 1.96%. All five patients had intraparenchymal brain metastases. It seems likely that the incidence of CNS involvement is increasing in this disease, consonant with improvement of local tumor control and prolonged overall survival. The median duration from the diagnosis of ovarian cancer to the diagnosis of CNS metastases was 25 months (range, 10-126 months). Median survival after diagnosis was 1.3 months (range, 1-10 months). Therapeutic options are discussed, as are possible mechanisms for the occurrence of these metastases.
Twenty-one cases of sarcoma botryoides of the uterine cervix, including four previously unreported cases, are reviewed. The age of the patients ranged from 5 months to 48 years, with a peak incidence in the group aged 14 to 18 years. Eighty percent of the patients are alive, with a mean follow-up period of 68 months. Seventy-five percent of the patients had Group I disease, of whom 88% are alive. Eleven of 14 patients (79%) receiving vincristine and dactinomycin based chemotherapy are alive. There were five patients with recurrent disease (24%) of whom two (40%) are alive. The prognosis for cervical sarcoma botryoides is similar to that of other female genital tract embryonal rhabdomyosarcomas. Primary therapy should consist of vincristine and dactinomycin based chemotherapy. Surgery should be guided by the response to initial chemotherapy and should attempt to conserve the function of the bladder, rectum, vagina, and ovaries.