Mario E. Beiner

Surgery Insight: radical vaginal trachelectomy as a method of fertility preservation for cervical cancer

Over the past decade, the treatment of cervical cancer has evolved with an increased emphasis on preservation of fertility. There has been a gradual abandonment of radical surgical procedures in favor of more conservative techniques in an effort to decrease morbidity and preserve fertility without compromising overall survival. Radical vaginal trachelectomy (RVT) with laparoscopic pelvic lymphadenectomy is a fertility-preserving procedure that has recently gained worldwide acceptance as a method of surgically treating small invasive cancers of the cervix. Since the original description of RVT by Daniel Dargent in 1994, over 500 cases of utilization of this technique have been reported in the literature, with over 100 live births reported following this procedure. The morbidity associated with RVT is low, with a tumor recurrence rate of 5% and a mortality rate of 3%. The current literature indicates no difference in the rate of recurrence with this technique compared with radical hysterectomy when proper selection criteria are used. Combining RVT with laparoscopic sentinel lymph-node biopsy can further reduce the duration, extent, and complications of surgery.

Radical vaginal trachelectomy vs. radical hysterectomy for small early stage cervical cancer: A matched case-control study

OBJECTIVEnTo determine the efficacy and outcome from radical vaginal trachelectomy (RVT) compared to a matched group of patients undergoing radical hysterectomy for small early stage cervical cancer.nnnMETHODSnAll patient data were entered prospectively. Patients wishing preservation of fertility with cervical cancer, tumor <2 cm, and not meeting the definition of microinvasive cancer were offered RVT. The outcomes were compared to a matched group of patients who underwent radical hysterectomy for stage IA/IB cervical cancer. Groups were matched 1:1 for age (+/-5 years), tumor size (+/-1 mm), histology, grade, depth of invasion (+/-1 mm), presence of capillary lymphatic space invasion, pelvic lymph node metastasis, and adjuvant radiotherapy.nnnRESULTSnA total of 137 patients underwent RVT between 1994 and 2007. Of them, 90 patients were successfully matched. Median tumor size was microscopic. Moreover, 43% and 49% were squamous and had adeno/adenosquamous histology. Median depth of invasion was 3.1 mm. Capillary lymphatic space invasion was present in 68% of cases. Of the tumors, 60% were grade 1, 29% were grade 2, and 11% were grade 3. After a median follow-up of 51 and 58 months, 5 and 1 recurrences were diagnosed in the RVT and radical hysterectomy groups, respectively. Five-year recurrence-free survival rates were present in 95% and 100% of the groups, respectively (p=0.17). In addition, 3 and 1 deaths occurred in the RVT and radical hysterectomy groups, resulting in 5-year survival rates of 99% and 100%, respectively (p=0.55).nnnCONCLUSIONSnRVT seems to be the procedure of choice for women with small early stage cervical cancers wishing to preserve fertility.

Endometrial Cancer Risk Is Associated with Variants of the Mismatch Repair Genes MLH1 and MSH2

Women with germ-line mutations in the mismatch repair genes (responsible for hereditary nonpolyposis colorectal cancer) face an increased risk of colonic and endometrial cancer. However, these germ-line mutations are rare and are responsible for fewer than 1% of endometrial cancers. Therefore, we examined whether or not common variants of the hereditary nonpolyposis colorectal cancer–associated genes might also be associated with an increased risk of endometrial cancer. Three single-nucleotide polymorphisms were selected in the MLH1 and MSH2 mismatch repair genes. All the various 672 women with endometrial cancer and 880 controls were genotyped. Each of these three single-nucleotide polymorphisms was associated with an increased risk of endometrial cancer. Carriers of the MLH1 nt-93 A allele were at a 1.5-fold increased risk of developing endometrial cancer compared with controls [95% confidence interval (95% CI), 1.2-2.0; P = 0.001]. The risk was higher for homozygote carriers [odds ratio (OR), 1.9; 95% CI, 1.2-3.2; P = 0.009]. For carriers of the MSH2 rs2303428 C allele, the OR was 1.4 (95% CI, 1.0-1.9; P = 0.05), and for carriers of the MSH2 rs2059520 G allele, the OR was 1.3 (95% CI, 1.0-1.7; P = 0.03). More than 9% of endometrial cancer cases carried a variant allele in both MLH1 and MSH2. For these women, the risk of endometrial cancer was particularly high (OR, 2.1; 95% CI, 1.2-3.6; P = 0.005). For patients younger than 50 years at diagnosis who carried both variants, the risk was even higher (OR, 3.4; 95% CI, 1.7-6.6; P = 0.0005). In summary, two common variant alleles of the MLH1 and MSH2 genes make a substantial contribution to endometrial cancer incidence in Ontario. (Cancer Epidemiol Biomarkers Prev 2006;15(9):1636–40)

Pure dysgerminoma of the ovary 35 years on: A single institutional experience

OBJECTIVEnThe aim of this study was to evaluate clinicopathologic characteristics, long-term outcome and reproductive function in women diagnosed with pure dysgerminoma of the ovary.nnnMETHODSnSixty-five women with stage IA to IIIC pure ovarian dysgerminoma were identified and included in this retrospective study. Patients were treated at one institution between 1970 and 2005.nnnRESULTSnMedian age at diagnosis was 22.2 years (range 8.2-64.1 years). 72.3% of patients presented with stage I, 4.6% stage II and 21.5% stage III disease (1.5% stage unknown). Initial management was surgical for all patients: unilateral oophorectomy in 47 patients (72.2%), bilateral oophorectomy +/- hysterectomy in 14 (21.5%) and cystectomy alone in 3 (4.6%). Seventeen patients received chemotherapy (15 adjuvant, 2 for residual disease), 20 received adjuvant radiotherapy and one patient received both. Recurrence occurred in 6 (9.2%) patients (5 stage IA, 1 stage IIA). All recurrences occurred within 19 months of primary diagnosis. All patients were successfully salvaged with radiotherapy (2 patients), chemotherapy (1 patient) or a combination of surgery and chemotherapy (3 patients). Overall, median follow up from time of recurrence was 22.5 years (range 9.3-31.4 years). Median follow-up of all patients was 10.5 years (range 1.1-31.9 years). Fifteen patients reported an attempt to conceive posttreatment resulting in 12 pregnancies and 12 live births in 8 women.nnnCONCLUSIONnThe long-term outcome of patients with pure ovarian dysgerminoma is excellent. Recurrences occur within 2 years of diagnosis and are treatable. Patients can be treated with fertility-sparing surgery and can expect good reproductive outcomes.

Mutations of the MYH gene do not substantially contribute to the risk of breast cancer

Purpose To explore whether or not there is an association between the presence of either of the germline mutations in the MutY human homologue (MYH) gene (Y165C and G382D) and the risk of breast cancer. Methods 691 breast cancer patients and 812 healthy controls were genotyped for the MYH Y165C and G382D mutations. The frequencies of heterozygotes, homozygotes and compound heterozygotes were compared for the two groups. Results Four (0.6%) of 691 breast cancer cases carried a MYH Y165C mutant allele, compared to five (0.6%) of the controls (OR 1.1, 95%CI 0.29–4.0, Pxa0=xa00.9). Eight (1.2%) cases carried a MYH G382D mutant allele, compared to eight (1.0%) of the controls (OR 1.2, 95%CI 0.44–3.3, Pxa0=xa00.7). No case or control was homozygous for the variant and none were compound heterozygotes. Conclusion Carriers of the MYH Y165C or G382D mutant alleles do not appear to be at increased risk for breast cancer.

Ovarian immature teratoma: Treatment and outcome in a single institutional cohort

OBJECTIVEnThe aim of this study was to evaluate clinicopathologic characteristics, treatment outcome and reproductive function in women diagnosed with ovarian immature teratoma.nnnMETHODSnThirty-four women with ovarian immature teratoma stages IA to IIIA were identified and included in this study. Patients were treated at one institution; Princess Margaret Hospital, Toronto, Canada between 1970 and 2005.nnnRESULTSnThe median age at diagnosis was 25.0 years (range: 9.8-60.2 years). Twenty seven (79%) presented with stage IA disease, 5 (15%) with stage IC, 1 (3%) with stage 2B, and 1 (3%) with stage IIIA disease. Thirteen (38%) of the tumors were found to be grade 1, 12 (35%) grade 2, and 9 (27%) grade 3. Initial management was surgical for all patients: 22 (65%) unilateral oophorectomy, 7 (20%) cystectomy only, and 5 (15%) bilateral oophorectomy (4 with hysterectomy). Fourteen (41.8%) patients received adjuvant therapy. The median follow up was 4.8 years (range 0.2-24.3 years). Four patients recurred (histological grade 2 or 3) within 22 months (87.1% 2-year progression free survival). Only one clinical stage I patient who received adjuvant chemotherapy developed a recurrence. Three of the patients who recurred died from their disease. Eleven patients reported an attempt to conceive resulting in 11 pregnancies in 6 women (3 post chemotherapy).nnnCONCLUSIONnThe majority of patients diagnosed with an immature teratoma are cured of their disease. However, grade 2 or 3 tumors are associated with a greater chance of recurrence that can be fatal, predominantly within 2 years of diagnosis.

Ovarian cancer risk is associated with a common variant in the promoter sequence of the mismatch repair gene MLH1

OBJECTIVESnInherited mutations in the MLH1 gene are associated with a proportion of families with the hereditary non-polyposis colon cancer syndrome (HNPCC). The cardinal features of the syndrome are a predisposition to colon, endometrial and ovarian cancers. Recently, it has been shown that a non-coding polymorphic variant in MLH1 (G>A nt-93) predisposes to colon and endometrial cancer, but with much reduced penetrance. We sought to establish whether or not this polymorphic variant also predisposes to ovarian cancer.nnnMETHODSnWe genotyped 899 women with invasive ovarian cancer and 931 controls for the G>A nt-93 variant.nnnRESULTSnThe presence of the variant was associated with a modest, but highly significant risk of ovarian cancer (OR=1.5; 95% CI 1.3-1.9; p=0.00005). The association was present in cancers of all histologies except clear cell, and in all ethnic groups.nnnCONCLUSIONSnThe G>A nt-93 variant of the MLH1 gene is associated with an increased risk of invasive ovarian cancer.

Salpingo -oophorectomy and the risk of ovarian, fallopian tube, and peritoneal cancers in women with a BRCA1 or BRCA2 mutation

CONTEXTnWomen with BRCA1 or BRCA2 mutation are often advised to undergo preventive oophorectomy. The effectiveness of this intervention has not been prospectively evaluated in a large cohort.nnnOBJECTIVESnTo estimate the incidence of ovarian, fallopian tube, and primary peritoneal cancer in women who carry a deleterious mutation in BRCA1 or BRCA2. To estimate the reduction in risk of these cancers associated with a bilateral prophylactic salpingo-oophorectomy.nnnDESIGN, SETTING, AND PARTICIPANTSnWomen known to carry a BRCA1 or BRCA2 mutation were identified from an international registry between 1992 and 2003. A total of 1828 carriers at 1 of 32 centers in Canada, the United States, Europe, and Israel completed questionnaires at baseline and follow-up. Participants were observed from the date of study entry until: diagnosis of ovarian, fallopian tube, or peritoneal cancer; death; or the date of the most recent follow-up.nnnINTERVENTIONnParticipants were divided into women who had undergone bilateral prophylactic oophorectomy and those who had not.nnnMAIN OUTCOME MEASUREnThe incidence of ovarian, peritoneal, and fallopian tube cancer was determined by survival analysis. The risk reduction associated with prophylactic salpingo-oophorectomy was evaluated by a time-dependent survival analysis, adjusting for covariates.nnnRESULTSnAfter a mean follow-up of 3.5 years, 50 incident ovarian, fallopian tube, and peritoneal cancer cases were reported in the cohort. Of the 1828 women, 555 (30%) underwent a bilateral prophylactic salpingo-oophorectomy prior to study entry, 490 (27%) underwent the procedure after entering the study, and 783 (43%) did not undergo the procedure. There were 32 incident cancers diagnosed in women with intact ovaries (1015/100,000 per year). Eleven cancer cases were identified at the time of prophylactic oophorectomy and 7 were diagnosed following prophylactic oophorectomy (217/100,000 per year). The estimated cumulative incidence of peritoneal cancer is 4.3% at 20 years after oophorectomy. The overall (adjusted) reduction in cancer risk associated with bilateral oophorectomy is 80% (multivariate hazard ratio = 0.20; 95% confidence interval, 0.07-0.58; P = .003).nnnCONCLUSIONnOophorectomy is associated with reduced risk of ovarian and fallopian tube cancer in high-risk women, although there is a substantial residual risk for peritoneal cancer in BRCA1 and BRCA2 mutation carriers following prophylactic salpingo-oophorectomy.