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.

Phenotypic heterogeneity of hereditary gynecologic cancers: a report from the Creighton hereditary cancer registry.

To determine the validity of observations suggesting a significant dichotomy of gynecologic cancers determined by linkage to specific genetic defects associated with two major autosomal dominant hereditary cancer syndromes; the Creighton University Hereditary Cancer Registry was searched for female carriers of germ line mutations in BRCA1 and BRCA2, associated with the Hereditary Breast Ovarian Cancer syndrome, and in the mismatch repair (MMR) genes MLH1, MSH2 and MSH6, associated with Lynch syndrome, who were registered with invasive uterine, ovarian, fallopian tube or peritoneal cancers between January 1, 1959 and December 31, 2010. From 217 such cases, a total of 174 subjects, consisting of 95 BRCA1 and BRCA2 mutation carriers and 79 carriers of mutations in MMR genes, were identified who had current signed Health Insurance Portability and Accountability Act forms and complete primary diagnostic pathology reports and clinical records. Data meticulously extracted from these cases were categorized and statistically analyzed. There were highly significant differences between carriers of BRCA1 and BRCA2 mutations and carriers of MMR gene mutations in the proportion of serous carcinomas compared with endometrioid carcinomas of the uterus, including cervix and endometium (p < 0.002), ovaries (p < 0.001) and overall, including fallopian tube and peritoneum cancers (p < 0.001). Endometrioid carcinoma was found in one and transitional carcinoma in another of the 14 BRCA1 mutation carriers with fallopian tube cancer, and endometrioid carcinoma was found in two of four MMR gene mutation carriers with fallopian tube cancers. All other fallopian tube cancers were serous carcinomas. Seven BRCA1 and one BRCA2 mutation carriers were diagnosed with primary peritoneal serous carcinoma; no peritoneal carcinomas were registered in MMR gene mutation carriers. Nine of 14 gynecologic cancers with associated endometriosis in mutation carriers were endometrioid or endometrioid mixed carcinomas compared with just three of other histologic types. Primary breast cancers, that characterize the HBOC syndrome, were much more frequent in BRCA1 and BRCA2 mutation carriers; while multiple gynecologic cancers and associated colorectal and urinary tract cancers, which are features of Lynch syndrome, were more common in MMR gene mutation carriers. Both serous and endometrioid carcinomas were diagnosed in MMR gene mutation carriers at significantly younger ages than in BRCA1 and BRCA2 mutation carriers (p < 0.0006). These findings confirm a clear dichotomy of uterine, ovarian and fallopian tube cancers associated with inheritance of mutations in BRCA1 and BRCA2 contrasted with inheritance of MMR gene mutations. This opens possibilities for new approaches to molecular genetic research into carcinogenic pathways and raises important new considerations regarding counseling, screening, prophylaxis and treatment of mutation carriers.

Tumors metastatic to thyroid neoplasms: a case report and review of the literature.

Metastasis into a thyroid neoplasm-tumor-to-tumor metastasis-is exceedingly rare. We describe the 28th documented case of a tumor metastatic to a thyroid neoplasm and review the literature on tumor-to-tumor metastasis involving a thyroid neoplasm as recipient. All cases showed a recipient thyroid neoplasm with an abrupt transition to a morphologically distinct neoplasm. Metastasis into primary thyroid neoplasm was synchronous in 33% of cases and metachronous in 67%. Follicular adenoma was the most common recipient thyroid neoplasm overall (16/28), and papillary thyroid carcinoma was the most common malignant recipient neoplasm (9/28). Of the 9 recipient papillary carcinomas, 6 were follicular variants. Renal cell carcinoma was the most common neoplasm to metastasize to a primary thyroid neoplasm (9/28), followed by lung (6/28), breast (5/28), and colon (3/28) carcinoma. Tumor-to-tumor metastasis should be considered whenever a dimorphic pattern is encountered in a thyroid tumor.

The cost of doing business.

In diagnostic pathology, the use of immunohistochemical stains and other ancillary procedures is of immense help. However, indiscriminate use of these tests often adds to unnecessary expense. We need to define ways to use these tests in a logical, focused manner, in moderation, and only when needed for providing clinically significant diagnostic or prognostic information.

Cervical and endometrial metastases of appendiceal goblet cell carcinoid.

Appendiceal goblet cell carcinoid (GCC) is a rare tumor with histologic features of both adenocarcinoma and neuroendocrine tumor (carcinoid). Clinically, it behaves more aggressively than classic appendiceal carcinoid and commonly presents with peritoneal carcinomatosis. We report 2 cases of appendiceal GCC, one with uterine cervical involvement and the other with endometrial involvement as the initial presentations. The first patient's invasive cervical signet ring cell carcinoma was diagnosed on routine screening. The second patient presented with abnormal uterine bleeding, and endometrial curettage showed an adenocarcinoma with signet ring cell features. Primary appendiceal GCC was demonstrated in both cases after systematic clinical investigations. Metastatic appendiceal GCC to uterine cervix and endometrium can potentially be misinterpreted as primary cervical or endometrial signet ring cell carcinoma. Therefore, for any uterine cervical/endometrial signet ring cell carcinoma, a metastatic appendiceal GCC should be considered in the differential diagnosis, especially after excluding other primary sites.

Rare potential pitfall in endoscopic ultrasound-guided fine needle aspiration biopsy in gastric duplication cyst: a case report.

BACKGROUND: Foregut duplication cyst (FDC) is rare in the adult population. It is usually an incidental finding in clinical settings. As endoscopic ultrasound-guided fine needle aspiration biopsy (EUS-FNAB) becomes a preferred and popular procedure, it is imperative for cytopathologists recognize this rare lesion and avoid the diagnostic pitfall. CASE: A 48-year-old man presented with a 3-cm mass on the lesser curvature of the stomach with regional lymphoadenopathy. EUS-FNAB revealed abundant tenacious, viscous, mucinous material with scattered histiocytes and gastric and esophageal mucosal cells. A mucinous neoplasm was suspected, and partial sleeve gastrectomy was subsequently performed for removal of the gastric mass. The histopathologic finding was characteristic of gastric duplication cyst. CONCLUSION: The cytologic features of FDCs may closely resemble those of mucinous neoplasms, especially with clinically elevated carcinogenic embryonic antigen and CA19-9. The abundant mutinous material with scattered mucophages can create a diagnostic challenge and pitfall. Clinical information with endoscopic findings and knowledge of FDC are important for appropriate diagnosis of mucinous lesions.

Hereditary ovarian carcinoma: heterogeneity, molecular genetics, pathology, and management.

Hereditary ovarian cancer accounts for at least 5% of the estimated 22,000 new cases of this disease during 2009. During this same time, over 15,000 will die from malignancy ascribed to ovarian origin. The bulk of these hereditary cases fits the hereditary breast-ovarian cancer syndrome, while virtually all of the remainder will be consonant with the Lynch syndrome, disorders which are autosomal dominantly inherited. Advances in molecular genetics have led to the identification of BRCA1 and BRCA2 gene mutations which predispose to the hereditary breast-ovarian cancer syndrome, and mutations in mismatch repair genes, the most common of which are MSH2 and MLH1, which predispose to Lynch syndrome. These discoveries enable relatively certain diagnosis, limited only by their variable penetrance, so that identification of mutation carriers through a comprehensive cancer family history might be possible. This paper reviews the subject of hereditary ovarian cancer, with particular attention to its molecular genetic basis, its pathology, and its phenotypic/genotypic heterogeneity.

Fibroadenoma in women in Ghana.

BACKGROUND: Fibroadenoma is the commonest benign tumor of female breast. It is particularly common in young women in Africa. METHOD: This paper describes the clinicopathologic features of fibroadenoma of breast in African women from central Ghana and compares them to the data from African-American women. RESULTS: Fibroadenomas constituted 47.7% of all palpable breast masses. The median age of women was 22 years (range 14-49). Almost a third of the cases occurred in teenager. The mean size of masses was 3.8 cm (range 1-9 cm), with 22.5% showing larger sizes. A total of 16.1% had multiple and/or bilateral lesions. CONCLUSION: Women from Central Ghana tend to have proportionately more fibroadenomas and larger (>5 cm) variants compared to published data from African-American women, however, the average age, size, multifocality and bilaterality do not differ significantly between these two groups of women.

Increase in normal placental weights related to increase in maternal body mass index.

OBJECTIVE: Reference values of normal placental weights are many decades old. Recently, a trend of increasing weights of normal placentas has been noted. We aimed to confirm this observation and to find any associated fetal and maternal factors. METHODS: Information on all live singleton deliveries that met our inclusion criteria was collected for the years 1995 and 2004 at Creighton University Medical Center in Omaha, Nebraska. This information was compared to the standards set forth in the older references. The Student's t-test and correlation-regression statistics were applied. RESULTS: The mean weight of the mature, term (37-42 weeks of gestation) placenta has increased significantly from 1995 to 2004 (499 g to 537 g, p = 0.02), as well as from the older standards (27% increase at 40 weeks of gestation). There has also been a significant increase in the maternal body mass index (BMI) from 1995 to 2004 (25.2 to 26.5, p = 0.02), which correlates with maternal weight gain during pregnancy, and fetal and placental weights. CONCLUSIONS: Normal placental weights have increased over the last decades and this may correlate with increasing maternal obesity. Further studies with larger populations are needed to confirm these findings.

Intra-abdominal carcinomatosis after prophylactic oophorectomy in women of hereditary breast ovarian cancer syndrome kindreds associated with BRCA1 and BRCA2 mutations.

OBJECTIVE: Prophylactic surgical removal of the ovaries has been offered for many years as a potential preventative of ovarian cancer in women deemed to be at increased hereditary risk for this disease. Now, it is possible to test for specific mutations of the BRCA1 and BRCA2 genes that render members of hereditary breast ovarian cancer (HBOC) syndrome families susceptible to cancer. Widespread intra-abdominal carcinomatosis, which mimics metastatic ovarian serous carcinoma, has been reported following oophorectomy in individuals at increased hereditary risk. This study was undertaken to examine and report particularly the occurrence of intra-abdominal carcinomatosis, as well as other cancers, following prophylactic oophorectomy in patients who carry cancer susceptibility mutations of BRCA1 and BRCA2 and to assess the cumulative risks for this disease in order to assist in developing appropriate surgical interventions, based on currently available information, and to counsel patients who choose prophylactic surgery, concerning the potential prognosis, thereafter. METHODS: The Creighton University Hereditary Cancer Institute registry was searched for members of HBOC syndrome families who had undergone prophylactic oophorectomy. The histories and results of DNA testing for the BRCA1 and BRCA2 mutations carried in their families were recorded, tabulated and examined, and the aggregate data are reported along with pertinent details of those individuals who developed neoplastic diseases after prophylactic oophorectomy. All available histologic and cytologic materials of patients who were diagnosed with intra-abdominal carcinomatosis were reviewed, and life-table calculations were performed to assess cumulative risks for this disease following prophylactic oophorectomy. RESULTS: From 72 HBOC syndrome families that carried either BRCA1 or BRCA2 cancer-associated mutations, 238 individuals who had undergone prophylactic oophorectomy were recorded in our registry between January 1985 and December 2002. During a mean follow-up of 9.3 years, cancers were diagnosed in 27 subjects, including 16 individuals with breast cancer and five patients with intra-abdominal carcinomatosis. Breast cancers were stage I in 10 of 12 proven carriers of cancer-associated mutations. All five cases of intra-abdominal carcinomatosis were serous carcinomas, and all occurred in BRCA1 mutation carriers. Histologic review of the prophylactically removed ovaries found borderline lesions in two cases, one with possible early stromal invasion. Two of the five patients who developed intra-abdominal carcinomatosis were among 78 patients in this series who were diagnosed and treated for breast cancer before prophylactic oophorectomy. A 3.5% cumulative risk for all mutation carriers and a 3.9% cumulative risk for BRCA1 mutation carriers were calculated through 20 years of follow-up after prophylactic oophorectomy. CONCLUSIONS: Intra-abdominal carcinomatosis in our series was diagnosed only in BRCA1 mutation carriers. The calculated cumulative risks of developing intra-abdominal carcinomatosis after prophylactic oophorectomy in members of HBOC syndrome families, specifically those who carry deleterious mutations, are well below the estimated risks of ovarian cancer published in the literature for similar patients. Breast cancers, which tended to be small and localized, were the most common malignancy in BRCA1 and BRCA2 mutation carriers after prophylactic oophorectomy.

Ichthyosis uteri: a case report and review of the literature.

Squamous metaplasia of endometrium is mostly manifested by morules or nodules of benign nonkeratinizing squamous cells intimately mixed with benign or malignant endometrial glands. It has been described with low-grade adenocarcinoma of the endometrium, as well as with various benign conditions, including hyperplasia, chronic endometritis, and endometrial polyps. However, extensive plaquelike, keratinizing squamous change is distinctly uncommon. To our knowledge, we describe the first case of extensive benign squamous keratinization with underlying endometrial adenocarcinoma.

Monosomy 22 as a diagnostic aid in a case of late recurrence of adult granulosa cell tumor of the ovary.

Cytogenetic analysis of a case of metastatic granulosa cell tumor recurring 21 years after oophorectomy revealed monosomy 22. This anomaly, typical of granulosa cell tumor, coupled with the pathologic and immunophenotypic findings assisted in establishing the proper diagnosis of this lesion in the absence of the original histopathologic slides.

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 BRCA1 or BRCA2 are 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 BRCA1 and BRCA2 mutations are particularly prevalent in women of Jewish lineage, and specific BRCA1 and BRCA2 germline 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 BRCA1 and BRCA2 mutations 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 BRCA1 and BRCA2 mutations, 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 BRCA1 mutations for uterine papillary serous carcinoma, which could be the source of metastasis to the peritoneum in some cases. The penetrance of cancer-associated BRCA1 mutations for ovarian cancer is estimated to be 11%-54%, and for BRCA2 mutations 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 BRCA1 and BRCA2 mutations, 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.

Abnormal Pap smears with negative follow-up biopsies: improving cytohistologic correlations.

A review of the literature noted 11-16% discrepancy rates in cytology and histology diagnoses. We collected 358 cases with abnormal cytology and matching cervical biopsies. There were 123 (30%) discrepant pairs, of which 34 (27%) had negative biopsies following Papanicolaou (Pap) smears with squamous intraepithelial lesions (SIL). These constituted our study group. All biopsies were obtained within an average of 5 wk after Pap smears (range, 0-18 wk). After confirming original diagnoses, all biopsies were evaluated for the presence of squamocolumnar junction, proper orientation, gross size of specimen, denudation of superficial mucosa, and inadequate sectioning through blocks. Each block was recut at three levels and reviewed microscopically. Five biopsies (14%) needed reorientation. Nine biopsies (26%) showed more than a 2-mm difference from gross size. Eleven (32%) new SILs were found. Adequate deep sectioning and proper orientation of tissues can significantly improve cytohistologic correlations.