Neville F. Hacker

Three biomarkers identified from serum proteomic analysis for the detection of early stage ovarian cancer

Early detection remains the most promising approach to improve long-term survival of patients with ovarian cancer. In a five-center case-control study, serum proteomic expressions were analyzed on 153 patients with invasive epithelial ovarian cancer, 42 with other ovarian cancers, 166 with benign pelvic masses, and 142 healthy women. Data from patients with early stage ovarian cancer and healthy women at two centers were analyzed independently and the results cross-validated to discover potential biomarkers. The results were validated using the samples from two of the remaining centers. After protein identification, biomarkers for which an immunoassay was available were tested on samples from the fifth center, which included 41 healthy women, 41 patients with ovarian cancer, and 20 each with breast, colon, and prostate cancers. Three biomarkers were identified as follows: (a) apolipoprotein A1 (down-regulated in cancer); (b) a truncated form of transthyretin (down-regulated); and (c) a cleavage fragment of inter-α-trypsin inhibitor heavy chain H4 (up-regulated). In independent validation to detect early stage invasive epithelial ovarian cancer from healthy controls, the sensitivity of a multivariate model combining the three biomarkers and CA125 [74% (95% CI, 52–90%)] was higher than that of CA125 alone [65% (95% CI, 43–84%)] at a matched specificity of 97% (95% CI, 89–100%). When compared at a fixed sensitivity of 83% (95% CI, 61–95%), the specificity of the model [94% (95% CI, 85–98%)] was significantly better than that of CA125 alone [52% (95% CI, 39–65%)]. These biomarkers demonstrated the potential to improve the detection of early stage ovarian cancer.

Surgical-pathologic variables predictive of local recurrence in squamous cell 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.

Distant metastases in epithelial ovarian carcinoma.

A review of 255 patients with epithelial ovarian carcinoma revealed that metastases consistent with Stage IV disease developed in 97 patients (38.0%) at some time during the natural history of their disease. Malignant pleural effusions developed in 63 patients (24.7%), and their median survival (from the time of diagnosis of the effusion) was 6 months. Parenchymal liver metastases developed in 24 patients (9.4%; median survival, 5 months); parenchymal lung metastases in 18 patients (7.1%; median survival, 8 months); distant lymph node metastases in 18 patients (7.1%; median survival, 9 months); subcutaneous nodules in nine patients (3.5%; median survival, 12 months); a malignant pericardial effusion in six patients (2.4%; median survival, 2.3 months); central nervous system metastases in five patients (2%; median survival, 1.3 months); and bone metastases in four patients (1.6%; median survival, 4 months). Patients with Stage IV disease at the time of diagnosis had a median survival of 9.1 months, while patients with a delayed occurrence of distant metastases had a median survival of only 4 months from the time of diagnosis of the distant metastases. Significant risk factors for distant metastases were malignant ascites, peritoneal carcinomatosis, large metastatic disease within the abdomen, and retroperitoneal lymph node involvement at the time of the initial surgery. The significance of positive retroperitoneal nodes and bulky upper abdominal disease has important therapeutic implications.

Endometrial cancer in premenopausal women 45 years and younger

Objective To evaluate the experience with endometrial carcinoma in women 45 years or younger at the Royal Hospital for Women, Sydney, Australia. Methods We evaluated the clinical history, morphology, treatment, and follow-up of 17 premenopausal women 45 years or younger who had been diagnosed with endometrial cancer. All histopathology was reviewed. Results Sixteen patients received their primary treatment at the Royal Hospital for Women, and one was referred with recurrent disease. Synchronous ovarian malignancies were found in five of 17 cases (29.4%), compared with 11 of 237 (4.6%) women older than 45 (P < .001). Three other patients had secondary ovarian involvement. Five (29%) patients had stage III or IV disease. Thirteen (76.5%) women were alive with no evidence of disease 12–78 months after primary surgery; two were lost to follow-up, but had no evidence of disease at 21 and 29 months, respectively. Two women died of recurrent disease. All but two patients with stage IV disease receiving primary treatment at the Royal Hospital for Women were offered hormone replacement therapy on discharge from the hospital. Conclusion Ovarian and lymph node involvement were common in women 45 years and younger with endometrial cancer. Hormone replacement therapy did not appear to compromise survival.

Management of Regional Lymph Nodes and their Prognostic Influence on Vulvar Cancer

One hundred thirteen patients with invasive carcinoma of the vulva underwent radical vulvectomy and bilateral inguinal-femoral lymphadenectomy between 1957 and 1978. Eighteen had unilateral pelvic lymphadenectomy. Thirty-one patients (27.4%) had positive lymph nodes. The corrected actuarial five-year survival for patients with negative nodes was 96%, whereas it was 94% for patients with one positive node, 80% for those with two positive nodes, and 12% for those with three or more positive nodes. All patients with positive pelvic nodes or pelvic recurrence had three or more positive unilateral groin nodes, and all had palpably suspicious groin nodes preoperatively. Groin and systemic recurrences occurred in 2.9 and 3.8%, respectively, of patients with fewer than three positive unilateral inguinalfemoral nodes, as compared to 33 and 66%, respectively, of patients with three or more positive nodes. These data do not support routine pelvic lymphadenectomy in patients who have no clinically suspicious groin nodes and fewer than three positive nodes on histologic examination.

Cytoreductive surgery in ovarian carcinoma: feasibility and morbidity.

Between 1974 and 1984, 70 patients underwent primary cytoreductive surgery for ovarian carcinoma at the University of California at Los Angeles. During the period of January 1974 to December 1978, optimal cytoreduction was achieved in 56.4% of the patients. With increased experience, this figure improved to 87.1% in the period of January 1979 to December 1983. The most common morbidity associated with the procedure was fever and prolonged ileus. Bowel resection was required in 20% of the patients and was not associated with increased morbidity. More liberal use of the end-to-end anastomosis stapling device facilitated low colon reanastomosis without colostomy, which contributed to the improved patient acceptance.(Obstet Gynecol 67:783, 1986)

DNA methylation changes in ovarian cancer: Implications for early diagnosis, prognosis and treatment

OBJECTIVE To review epigenetic changes identified in ovarian cancer, focusing on their potential as clinical markers for detection, monitoring of disease progression and as markers of therapeutic response. METHODS A comprehensive review of English language scientific literature on the topics of methylation and ovarian cancer was conducted. RESULTS Genome-wide demethylation of normally methylated and silenced chromosomal regions, and hypermethylation and silencing of genes including tumor suppressors are common features of cancer cells. Epigenetic alterations, including CpG island DNA methylation, occur in ovarian cancer and the identification of specific genes that are altered by epigenetic events is an area of intense research. Aberrant DNA methylation in ovarian cancer is observed in early cancer development, can be detected in DNA circulating in the blood and hence provides the promise of a non-invasive cancer detection test. In addition, identification of ovarian cancer-specific epigenetic changes has promise in molecular classification and disease stratification. CONCLUSIONS The detection of cancer-specific DNA methylation changes heralds an exciting new era in cancer diagnosis as well as evaluation of prognosis and therapeutic responsiveness and warrants further investigation.

Resection of bulky positive lymph nodes in patients with cervical carcinoma.

From January 1987 to April 1992, 34 patients had resection of bulky positive lymph nodes, detected either at the time of radical hysterectomy (n = 23) or by computed tomographic (CT) scan of the pelvis and abdomen prior to radiation therapy for more advanced cervical cancer (n = 11). Following nodal resection, 33 patients received pelvic external beam radiation, 28 received pelvic and para-aortic radiation, and 23 received four cycles of cisplatin chemotherapy. The median number of resected positive nodes was 4, with a range of 1–44. All macroscopic nodal metastases could be resected in each patient and morbidity was acceptably low. Positive nodes were confined to the pelvis in 17 patients, involved the common iliac group in nine patients, and involved the para-aortic area in eight patients. With a mean follow-up of 36 months, 23 patients (67.6%) were alive, of whom 20 were free of disease. For patients having a radical hysterectomy, actuarial 5-year survival was 80% for patients with disease involving pelvic and common iliac lymph nodes, and 48% for those with positive para-aortic nodes. Survival for patients with completely resected bulky pelvic and common iliac nodes was comparable to that for patients with micrometastases. This study suggests that every effort should be made to identify patients with cervical cancer who have bulky positive lymph node metastases, and to remove these nodes surgically prior to radiation therapy.

Secondary cytoreductive surgery for recurrent epithelial ovarian cancer.

OBJECTIVE To review our experience with secondary cytoreductive surgery for recurrent epithelial ovarian cancer with regard to its feasibility, morbidity, mortality, patient selection, and survival. METHODS Forty‐six patients who underwent secondary cytoreductive surgery at the Royal Hospital for Women, Sydney, between July 1988 and October 1996 were retrospectively reviewed. The mean age at surgery was 50.3 years, and the median disease‐free interval was 26 months. Eighty‐nine percent of patients had a disease‐free interval of at least 12 months. Twenty‐five patients (54%) had localized disease at the time of surgery. Univariate survival outcomes were analyzed using the log rank test, and survival curves were calculated using the method of Kaplan‐Meier. RESULTS Two patients (4%) were inoperable and 19 patients (41%) were cytoreduced to no macroscopic disease. There was one postoperative death (2%), and four patients (8.7%) had significant postoperative morbidity. With a median follow‐up of 88 months, the overall median survival was 22.5 months. Patients with a disease‐free interval of less than 12 months after their initial treatment had a median survival of 6 months, compared with 11 months if the disease‐free interval was 12–24 months and 39 months for those with a disease‐free interval of 24 months or more (P = .001, log rank). Patients who had any residual disease had a median survival of 11 months, whereas those with no residual disease had a median survival of 38 months (P = .002, log rank). CONCLUSION For carefully selected patients with recurrent epithelial ovarian cancer: 1) complete surgical resection is feasible more commonly than with primary cytoreduction, 2) serious morbidity and mortality are acceptable, and 3) significant survival benefit accrues when a) all macroscopic disease can be resected, or b) the disease‐free interval is 24 months or more.

Positive groin lymph nodes in superficial squamous cell vulvar cancer: A gynecologic oncology group study

The term microinvasive carcinoma is inappropriate when applied to all vulvar cancers less than or equal to 5 mm thick because approximately 50% of vulvar carcinomas are no thicker than 5 mm and 20% of those superficial tumors metastasize to the lymph nodes. The significant predictors of groin node metastases in patients with superficial vulvar cancer are tumor thickness, histologic grade (proportion of undifferentiated tumor pattern), capillary-like space involvement with the tumor, clitoral or perineal location, and clinically suspicious nodes, according to the linear logistic model analysis of clinicopathologic data in 272 women. No lymph node metastases occurred in approximately one fourth of patients with a combination of low-risk factors: no clinically suspicious nodes, negative capillary-like space, and nonmidline vulvar cancers that were either grade 1 and 1 to 5 mm thick or grade 2 and 1 to 2 mm thick. In contrast, all 10 patients with clinically suspicious nodes and grade 4 tumors had positive groin nodes. The risk of lymph node metastases is best determined by simultaneous evaluation of all risk factors rather than a single factor such as tumor thickness.