Thomas J. Herzog

Prevalence of defective DNA mismatch repair and MSH6 mutation in an unselected series of endometrial cancers

Endometrial cancer is the most common gynecologic malignancy in the United States and the most frequent extracolonic tumor in hereditary nonpolyposis colorectal cancer (HNPCC). HNPCC patients have inherited defects in DNA mismatch repair and the microsatellite instability (MSI) tumor phenotype. Sporadic endometrial cancers also exhibit MSI, usually associated with methylation of the MLH1 promoter. Germ-line MSH6 mutations, which are rare in HNPCC, have been reported in several families with multiple members affected with endometrial carcinoma. We reasoned that MSH6 mutation might account for loss of mismatch repair in MSI-positive endometrial cancers in which the cause of MSI is unknown. We therefore investigated MSI and MLH1 promoter methylation in 441 endometrial cancer patients unselected for age or personal and family history of cancers. MSI and MLH1 promoter methylation status were associated with age of onset and tumor histology. One hundred cases (23% of the entire series) were evaluated for MSH6 defects. Inactivating germ-line MSH6 mutations were identified in seven women with MSI-positive, MLH1 promoter unmethylated cancers. Most of the MSI in these cases was seen with mononucleotide repeat markers. The MSH6 mutation carriers were significantly younger than the rest of the population (mean age 54.8 versus 64.6, P = 0.04). Somatic mutations were seen in 17 tumors, all of which had MSI. Our data suggest that inherited defects in MSH6 in women with endometrial cancer are relatively common. The minimum estimate of the prevalence of inherited MSH6 mutation in endometrial cancer is 1.6% (7 of 441), comparable with the predicted prevalence for patients with colorectal cancer.

Mutational analysis of MLH1 and MSH2 in 25 prospectively-acquired RER+ endometrial cancers.

Mutations in the DNA mismatch repair (MMR) genes MLH1 and MSH2 have been linked to several human cancers which display the replication error (RER) phenotype. Germline mutations in these two genes have been implicated in about 90% of families with hereditary nonpolyposis colorectal cancer (HNPCC). A significant proportion of endometrial cancers, the second most common malignancy of the HNPCC syndrome, also exhibit RER. We screened 125 primary endometrial adenocarcinomas with seven microsatellite markers and identified 25 specimens with RER (20%). We used single‐strand conformation variant analysis to search for mutations in MLH1 and MSH2. Direct sequencing of variants revealed only one germline mutation in MLH1 and a single somatic mutation in MSH2. However, six previously unreported sequence polymorphisms in MLH1 were identified. Four of these polymorphisms show clear population‐based differences in allele frequency. In addition, a highly informative marker for MLH1 was characterized. The low frequency of mutations in MLH1 and MSH2 in this large series of cancers suggests that other MMR genes are responsible for the RER phenotype in endometrial cancers. Genes Chromosom. Cancer 18:219–227, 1997.

Occult supraclavicular lymph node metastasis identified by FDG-PET in patients with carcinoma of the uterine cervix

PURPOSEnThe objective was to evaluate the frequency and prognostic significance of occult supraclavicular lymph node metastases identified by 2-[(18)F]fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) in patients with cervical carcinoma.nnnPATIENTS AND METHODSnBetween March 1998 and January 2002, 186 patients with a new diagnosis of cervical cancer underwent whole-body FDG-PET before therapy. Fourteen patients had abnormal FDG uptake in left supraclavicular lymph nodes without palpable disease. All 14 patients underwent sonographically guided fine-needle aspiration of the left supraclavicular lymph nodes. One patient refused therapy, 6 were treated with palliative intent, and 7 received definitive irradiation and concurrent chemotherapy. Survival was calculated by the Kaplan-Meier method.nnnRESULTSnThe overall frequency of FDG-positive left supraclavicular lymph nodes was 8% (14/186). Metastasis was pathologically confirmed in all 14 patients. Therefore, the positive predictive value of abnormal FDG uptake in left supraclavicular lymph nodes was 100%. Nineteen percent of all patients (35/186) had abnormal FDG uptake in para-aortic lymph nodes. The frequency of positive FDG uptake in the left supraclavicular lymph nodes was 40% (14/35) in those with para-aortic lymph node uptake and 15% in those with stage IIIb disease. The median overall survival was 7.5 months. At last follow-up, 11 patients were dead and 3 were alive with disease. All patients developed metastatic disease, most commonly to bone and lung.nnnCONCLUSIONnThe positive predictive value of abnormal FDG uptake in left supraclavicular lymph nodes was 100%. Prognosis for these patients was dismal despite aggressive therapy.

FDG-PET lymph node staging and survival of patients with FIGO stage IIIB cervical carcinoma

PURPOSEnTo evaluate the outcome of patients with International Federation of Gynecology and Obstetrics (FIGO) clinical Stage IIIb cervical carcinoma as a function of site of initial regional lymph node metastasis as detected by 2[18F]fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography (PET).nnnMETHODS AND MATERIALSnForty-seven patients with FIGO Stage IIIb cervical cancer were evaluated before therapy with whole-body FDG-PET. Most patients were treated with external beam irradiation, intracavitary brachytherapy, and weekly cisplatin for six cycles. Overall and cause-specific survival rates were calculated by the Kaplan-Meier method.nnnRESULTSnThe pretreatment whole-body FDG-PET demonstrated that all patients had FDG uptake in the cervix. Of 47 patients, 13 (28%) had no evidence of lymph node metastasis, 20 (43%) had metastasis to pelvic lymph nodes only, 7 (15%) had pelvic and para-aortic lymph node metastases, and 7 (15%) had metastases to pelvic, para-aortic, and supraclavicular lymph nodes. The 3-year estimate of cause-specific survival was 73% for those with no lymph node metastasis, 58% for those with only pelvic lymph node metastasis, 29% for those with pelvic and para-aortic lymph node metastases, and 0% for those with pelvic, para-aortic, and supraclavicular lymph node metastasis (p = 0.0005).nnnCONCLUSIONnThe cause-specific survival for patients with FIGO Stage IIIb carcinoma is highly dependent on the extent of lymph node metastasis as demonstrated by whole-body FDG-PET.

Penetrance and Expressivity of MSH6 Germline Mutations in Seven Kindreds Not Ascertained by Family History

Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by inherited mutations in DNA mismatch-repair genes, most commonly MLH1 or MSH2. The role MSH6 plays in inherited cancer susceptibility is less well defined. The aim of this study was to investigate the penetrance and expressivity of MSH6 mutations in kindreds ascertained through endometrial cancer probands unselected for family history. Detailed pedigrees were constructed for six MSH6 mutation carriers. All reported cancers and precancers were confirmed, and tissues were obtained when available. Tumors were analyzed for microsatellite instability (MSI) and for expression of MSH2, MLH1, and MSH6. MSH6 mutation status was determined for 59 family members. Of these 59 individuals, 19 (32%) had confirmed cancers and precancers. There was an excess of mutation carriers among the 19 affected family members (11 [58%] of 19) compared with those among the 40 unaffecteds (8 [20%] of 40, P=.0065, odds ratio = 5.5, 95% CI = 1.66-18.19). In four of the seven tumors analyzed from mutation carriers other than the probands, MSI and/or MMR protein expression was consistent with the involvement of MSH6. Overall estimated penetrance of the MHS6 mutations was 57.7%. Of the tumors in mutation carriers, 78% were part of the extended HNPCC spectrum. This study demonstrates that MSH6 germline mutations are, indeed, associated with increased cancer risk and that the penetrance of mutations may be higher than appreciated elsewhere. A combination of MSI and immunohistochemistry analyses may be helpful in screening for MSH6 mutation carriers.

Morbidity and mortality of peripartum hysterectomy.

OBJECTIVE: To perform a population-based analysis to examine the morbidity and mortality of peripartum hysterectomy in comparison with nonobstetric hysterectomy. METHODS: Data from the Nationwide Inpatient Sample were used to compare peripartum and nonobstetric hysterectomy in women younger than 50 years of age. Intraoperative, perioperative, and postoperative medical complications were examined. The outcomes of peripartum and nonobstetric hysterectomy were compared using chi square. Odds ratios were calculated using multivariable logistic regression models for each individual complication. RESULTS: A total of 4,967 women who underwent peripartum hysterectomy and 578,179 patients who had a nonobstetric hysterectomy were identified. Bladder (9% compared with 1%) and ureteral (0.7% compared with 0.1%) injuries were more common for peripartum hysterectomy (P<.001). There were no differences in the rates of intestinal or vascular injuries between peripartum and nonobstetric hysterectomy. Rates of reoperation (4% compared with 0.5%), postoperative hemorrhage (5% compared with 2%), wound complications (10% compared with 3%), and venous thromboembolism (1% compared with 0.7%) were all higher in women who underwent peripartum hysterectomy. In multivariable analysis, the odds ratio for death for peripartum compared to nonobstetric hysterectomy was 14.4 (95% confidence interval 9.84–20.98). CONCLUSION: Peripartum hysterectomy is accompanied by substantial morbidity and mortality. Compared with nonobstetric hysterectomy, the procedure is associated with increased rates of both intraoperative and postoperative complications. The mortality of peripartum hysterectomy is more than 25 times that of hysterectomy performed outside of pregnancy. LEVEL OF EVIDENCE: II

Epithelial ovarian tumors of low malignant potential: The role of microinvasion

OBJECTIVE To identify prognostic factors that may be used to predict an aggressive disease course and poor outcome in patients with epithelial ovarian tumors of low malignant potential (borderline tumors). METHODS Data on 126 patients with ovarian borderline tumors were analyzed with regard to demographic characteristics, staging, presence of microinvasion, duration of follow‐up, recurrence rate, rate of recurrence as invasive disease, mortality rate, preoperative and postoperative CA‐125, and treatment. Chi‐square and Fisher exact tests were used to evaluate proportions for statistical significance. Disease‐free and overall survival was calculated by using the Kaplan–Meier method and log‐rank test. RESULTS Patients were followed for a median of 39.0 months (mean 47.8 months). Seven patients (5.6%) had recurrent disease. Advanced stage disease and microinvasion were associated with significantly higher recurrence and mortality rates than were stage I/II disease and borderline tumors without microinvasion, respectively. Two of 13 (15%, 95% CI 8.7, 21.3) patients with microinvasion died of recurrent invasive cancer, whereas only 1 out of 113 patients without microinvasion died of recurrent borderline tumor (OR 20.4, 95% CI 1.2, 239). All 3 patients with an aggressive disease course and poor outcome had increasing CA 125 levels at the time of recurrence. CONCLUSION Certain patients with microinvasion may be at higher risk for recurrence as invasive disease and may require different treatment strategies. CA 125 monitoring may have a role in early detection of recurrence in patients with aggressive disease.

Regionalization of care for obstetric hemorrhage and its effect on maternal mortality.

OBJECTIVE: To examine factors that influence the morbidity and mortality of peripartum hysterectomy and analyze the effect of hospital volume on maternal mortality. METHODS: We examined women who underwent peripartum hysterectomy at the time of cesarean delivery in a quality and resource utilization database. Procedure-associated intraoperative, perioperative, and postoperative medical complications, length of stay, intensive care unit use, and maternal mortality were analyzed. Hospitals were stratified into tertiles based on procedure volume and complications and compared using adjusted generalized estimating equations. Results are reported as odds ratios. RESULTS: Maternal mortality among the 2,209 women who underwent peripartum hysterectomy was 1.2%. After adjusting for other clinical and demographic factors, perioperative mortality was 71% (odds ratio 0.29, 95% confidence interval 0.10–0.88) lower in women who underwent operation at high-volume hospitals compared with those treated at low-volume facilities. Hospital volume had no effect on the rates of intraoperative injuries, medical complications, length of stay, or transfusion. In contrast, compared with women treated at low-volume centers, patients who underwent operation at high-volume hospitals had a lower incidence of perioperative surgical complications (odds ratio 0.66, 95% confidence interval 0.47–0.93) and a lower rate of intensive care unit usage (odds ratio 0.53, 95% confidence interval 0.34–0.83). CONCLUSION: Peripartum hysterectomy is associated with substantial morbidity and mortality. Maternal mortality is lower when the procedure is performed in high-volume hospital settings. LEVEL OF EVIDENCE: II

Successful in vitro fertilization pregnancy after conservative management of endometrial cancer

OBJECTIVEnTo report a successful IVF pregnancy in an infertile couple after conservative treatment of endometrial cancer.nnnDESIGNnCase report and literature review.nnnSETTINGnUniversity teaching hospital.nnnPATIENT(S)nA 29-year-old infertile white woman.nnnMAIN OUTCOME MEASURE(S)nSuccessful pregnancy after conservative management of endometrial cancer.nnnINTERVENTION(S)nGrade 1 endometrial adenocarcinoma diagnosed at hysteroscopy, followed by dilatation and curettage (D&C). On follow-up D&C, pathologic examination was normal after high-dose progesterone therapy. The patient subsequently underwent an IVF cycle with transfer of three blastocysts.nnnRESULT(S)nThe patient delivered triplets by cesarean section. Laparoscopic-assisted vaginal hysterectomy and bilateral salpingo-oophorectomy was then done. No residual endometrial cancer was evident in the hysterectomy specimen, but a 1.1-cm cystic mixed endometrioid and clear cell-type adenocarcinoma was discovered in the left ovary. The patient is doing well after 3 cycles of chemotherapy; her CA-125 level is normal. The triplets are also doing well.nnnCONCLUSION(S)nIn carefully chosen situations, deferring surgery in infertile patients with endometrial cancer may be a viable option permitting subsequent successful pregnancy.

Radiation therapy for carcinoma of the cervix with biopsy-proven positive para-aortic lymph nodes

PURPOSEnTo evaluate local tumor control, cause-specific survival, patterns of relapse, and toxicity in patients with cervical cancer and positive para-aortic lymph nodes treated with radiation therapy alone.nnnMETHODSnThis is a retrospective chart review of 43 patients with cervical cancer and biopsy-proven positive para-aortic lymph nodes treated with radiation therapy treated from 1965 to 1993. There were 15 patients with clinical Stage I disease, 12 with Stage II, and 16 with Stage III. Patients were treated with external irradiation to the pelvis and para-aortic regions combined with brachytherapy. None received chemotherapy.nnnRESULTSnThe 5-year overall survival rate was 32% and the median overall survival was 2.2 years. The 5-year cause-specific survival rate was 49% and the median cause-specific survival was 2.7 years. The cause-specific survivals at 5 years were 47% for Stage I, 64% for Stage II, and 46% for Stage III. Tumor recurrence occurred in 20 patients. The sites of recurrence were in the pelvis only in 3, the pelvis and distant metastasis in 9, and distant metastasis only in 8 patients. Severe, grade 3 complications occurred in 2 patients. One patient developed an enterovaginal fistulas and 1 developed radiation myelitis.nnnCONCLUSIONnPelvic and para-aortic irradiation and brachytherapy resulted in a 49%, 5-year, cause-specific survival. Clinical tumor stage did not effect outcome. The majority of relapses occurred at distant sites. Toxicity was acceptable. Systemic chemotherapy should be considered as adjunctive therapy for these patients.