Murray Joseph Casey

Peritoneal carcinoma in women with genetic susceptibility: implications for Jewish populations

Women from families with multiple cases of breast and ovarian cancer, specifically those who carry cancer-associated mutations of BRCA1or BRCA2are at increased life-time risk for peritoneal carcinoma, even after previous surgery to remove the ovaries, fallopian tubes and uterus. Hereditary breast–ovarian cancer (HBOC) syndrome and the associated BRCA1and BRCA2mutations are particularly prevalent in women of Jewish lineage, and specific BRCA1and BRCA2germline mutations have been linked with peritoneal carcinoma and HBOC syndrome in Jewish populations, especially those of Ashkenazi descent. This review presents the currently available data and looks forward toward further and better understanding of peritoneal carcinoma in women with inherited susceptibility. Over 90% of peritoneal cancer in patients from HBOC syndrome kindreds and associated with BRCA1and BRCA2mutations are serous carcinomas, which is equivalent with the proportion of ovarian cancers that are serous carcinomas in similar patients. The best indications are that while many peritoneal carcinomas in genetically susceptible women may arise directly from malignant transformation of the peritoneum, others might represent metastases from primary ovarian or fallopian tube carcinomas. Although the incidence of borderline ovarian tumors may not be increased in HBOC syndrome kindreds and those who carry cancer-associated BRCA1and BRCA2mutations, these individuals could be susceptible to malignant transformation of borderline lesions of the ovaries and peritoneum. Moreover, recent reports raise the question of possibly increased risk in Jewish carriers of germline BRCA1mutations for uterine papillary serous carcinoma, which could be the source of metastasis to the peritoneum in some cases. The penetrance of cancer-associated BRCA1mutations for ovarian cancer is estimated to be 11%–54%, and for BRCA2mutations the penetrance for ovarian cancer is 11%–23%. So far, available screening methods appear to be insufficient for early detection of many ovarian cancers. Prophylactic oophorectomy has been found to reduce the risk for ovarian cancer in women from HBOC kindreds and those who carry cancer-associated BRCA1and BRCA2mutations, leaving a residual risk for peritoneal carcinomatosis of well less than 5%. Therefore, surgical removal of the ovaries, fallopian tubes and uterus, after child-bearing has been completed and by early in the fifth decade of life, are appropriate prophylactic procedures in women whose genetic susceptibility puts them at increased risk for cancers of mullerian tract origin, including ovarian and fallopian tube carcinomas and possibly serous carcinoma of the uterus. Hysterectomy, as well as salpingo-oophorectomy, removes the gynecologic organs targeted for malignant transformation in genetically susceptible women and simplifies decisions regarding hormone replacement therapy and chemical prophylaxis and treatment of breast cancer. Unless a transabdominal operative approach is otherwise indicated, laparoscopic-assisted transvaginal techniques are well suited for intra-abdominal exploration, cytology, biopsies and prophylactic salpingo-oophorectomy and hysterectomy in women with hereditary susceptibility to gynecologic cancer.

Gynecologic cancer clues to Lynch syndrome II diagnosis: A family report

Lynch syndrome II was diagnosed when two sisters manifested early-onset synchronous carcinomas of the ovary and endometrium and a third sister was found to have Dukes A carcinoma of the cecum. A detailed cancer family history indicated paternal transmission of the deleterious genotype. The pattern of carcinoma of the colorectum and extracolonic sites throughout the extended family was then found to be consonant with this hereditary cancer-prone disorder. Lynch syndrome II may be exceedingly difficult to diagnose due to an absence of premonitory clinical signs or biomarkers of genotypic susceptibility. Its recognition is therefore dependent on a detailed cancer family history (all anatomic sites), coupled with knowledge of the pattern of the cancer spectrum, distribution, and natural history, as manifested in this hereditary disorder. We describe the decision logic that was involved in the diagnosis of Lynch syndrome II in this family and indicate the important role of the gynecologists in this process.

Endodermal sinus tumor of the ovary with virilization. Light- and electron-microscopic study

A case of endodermal sinus tumor of the ovary associated with hirsutism and increased testosterone production is described. Electron-microscopic examination revealed accumulation of basement membrane-like material and other ultrastructural features consistent with endodermal sinus tumor. Groups of polyhedral cells associated with the tumor were found to contain abundant lipid material. These luteinized stromal cells were evidently responsible for the endocrine manifestations.

Current status of prophylactic surgery for hereditary breast and gynecologic cancers

Given the limitations regarding the impact of screening and the uncertainties concerning chemoprevention for women with significant genetic susceptibilities to breast, endometrial and ovarian cancers, recent research and publications on prophylactic surgery for cancer prevention and improved long-term survival for women at hereditary risk have increasing importance.

Ethical dilemma of mandated contraception in pharmaceutical research at catholic medical institutions.

The Catholic Church proscribes methods of birth control other than sexual abstinence. Although the U.S. Food and Drug Administration (FDA) recognizes abstinence as an acceptable method of birth control in research studies, some pharmaceutical companies mandate the use of artificial contraceptive techniques to avoid pregnancy as a condition for participation in their studies. These requirements are unacceptable at Catholic health care institutions, leading to conflicts among institutional review boards, clinical investigators, and sponsors. Subjects may feel coerced by such mandates to adopt contraceptive techniques inconsistent with their personal situation and beliefs; women committed to celibacy or who engage exclusively in non-heterosexual activities are negatively impacted. We propose principles to insure informed consent to safeguard the rights of research subjects at Catholic institutions while mitigating this ethical conflict. At the same time, our proposal respects the interests of pharmaceutical research agencies and Catholic moral precepts, and fully abides by regulatory guidance.

Endometrial cancers in mutation carriers from hereditary breast ovarian cancer syndrome kindreds: report from the Creighton University Hereditary Cancer Registry with review of the implications.

Objective The aim of this study was to categorize and report endometrial cancers in mutation carriers from hereditary breast ovarian cancer families. Methods Our Hereditary Cancer Registry was searched for gynecologic and peritoneal cancers linked to mutations in BRCA1 or BRCA2. Invasive cancers were registered in 101 mutation carriers with complete pathology reports. Efforts were made to secure diagnostic surgical pathology tissues for review. All records and available diagnostic slides were meticulously studied, and primary cancers were classified. Findings Eight malignancies were classified as primary endometrial cancers. Five of these were low- or intermediate-grade endometrioid carcinomas, and 3 were pure serous carcinomas or contained serous carcinoma elements mixed with high-grade endometrioid carcinoma. Breast cancers were diagnosed in 5 patients before and in 1 patient after endometrial carcinoma. Three endometrioid carcinomas were preceded by estrogen treatment, 2 for many years and the other for only 2 months, and 2 of the patients with serous carcinoma had been treated with tamoxifen. Conclusions The finding that 8 of gynecologic and peritoneal cancers in 101 mutation carriers were endometrial cancers with a smaller proportion of endometrioid carcinomas than reported in general populations is added to the current controversial literature on endometrial cancer, particularly regarding serous carcinomas, in hereditary breast ovarian cancer syndrome. Well-designed prospective programs for standardized surgical and pathologic handling, processing, and reporting are essential for working out the pathogenesis, true risks, and best management of this disease in carriers of deleterious BRCA1 and BRCA2 germline mutations.

Therapeutic, Prophylactic, Untoward, and Contraceptive Effects of Combined Oral Contraceptives: Catholic Teaching, Natural Law, and the Principle of Double Effect When Deciding to Prescribe and Use

Combined oral contraceptives (COC) have been demonstrated to have significant benefits for the treatment and prevention of disease. These medications also are associated with untoward health effects, and they may be directly contraceptive. Prescribers and users must compare and weigh the intended beneficial health effects against foreseeable but unintended possible adverse effects in their decisions to prescribe and use. Additionally, those who intend to abide by Catholic teachings must consider prohibitions against contraception. Ethical judgments concerning both health benefits and contraception are approached in this essay through an overview of the therapeutic, prophylactic, untoward, and contraceptive effects of COC and discussion of magisterial and traditional Catholic teachings from natural law. Discerning through the principle of double effect, proportionate reason, and evidence gathered from the sciences, medical and moral conclusions are drawn that we believe to be fully compliant with good medicine and Catholic teaching.

Hereditary gynecologic cancer

It is estimated that approximately 1.3 million new cases of cancer will occur in the United States in 1997 (785,800 males, 596,600 females) [1]. Given a conservative estimate that 5% of these cases are hereditary, at least 65,000 patients will merit DNA testing annually. Using this same 5% estimate, then of the 181,600 cases of carcinoma of the breast and the 26,800 cases of carcinoma of the ovary that will occur in the United States during this same year, approximately 9080 patients with breast cancer and 1340 patients with ovarian carcinoma will fit a hereditary etiology. Barring new germline mutations, this means that each individual will be a member of a cancer-prone family. When viewed as annual incidence rates of hereditary cancer, it is clear that the prevalence of hereditary breast and ovarian carcinoma in the United States will truly be enormous. Similar calculations can be made for virtually all forms of cancer that will strike women.

Endometrial Screening of Asymptomatic Women by Irrigation Technique in the Private Gynecology Office

A study was made of 201 asymptomatic women over age 40 (range, 40–74 years) who underwent uterine sounding and endometrial screening by the negative‐pressure jet irrigation technique, without anesthesia, in private gynecologists’ offices. Introduction of the irrigator was accomplished in 88 percent of these patients. In 97 percent of the successful irrigations, the specimens obtained were satisfactory for cytologic and histologic diagnosis of neoplasia. No occult endometrial carcinomas were discovered. The factors which interfered with endometrial screening by these methods are analyzed. Cervical stenosis prevented endometrial irrigation in 13 of the 24 unsuccessful attempts. Acceptance by the patients was high, in that 74.2 percent reported slight or no discomfort and only 4.7 percent complained of severe discomfort. Although 12.5 percent experienced pelvic cramping after irrigation, no other significant side effects were observed. The results of this investigation indicate the feasibility of using the endometrial irrigation technique for massive screening studies of asymptomatic women who are at risk for the development of endometrial carcinoma.

Phenotypic and genotypic heterogeneity of Lynch syndrome: a complex diagnostic challenge

Lynch syndrome is the hereditary disorder that most frequently predisposes to colorectal cancer as well as predisposing to a number of extracolonic cancers, most prominently endometrial cancer. It is caused by germline mutations in the mismatch repair genes. Both its phenotype and genotype show marked heterogeneity. This review gives a historical overview of the syndrome, its heterogeneity, its genomic landscape, and its implications for complex diagnosis, genetic counseling and putative implications for immunotherapy.