RAS/RAF mutation and defective DNA mismatch repair in endometrial cancers

OBJECTIVE: Defective DNA mismatch repair is a common genetic abnormality in both colon cancers and endometrial cancers. Cancers with defective DNA mismatch repair have the so-called mutator phenotype and accumulate genetic errors at an increased rate. An early mutational target in cells with defect DNA mismatch repair may be the RAS/RAF pathway. Colon cancers often have KRAS2 mutations and, if not KRAS2 mutations, may have BRAF mutations. This study investigated the spectrum and frequency of mutations in BRAF and KRAS2 in endometrial carcinomas on the basis of mismatch repair status. STUDY DESIGN: Four hundred forty-one patients with endometrial cancer were staged properly and graded and evaluated for mismatch repair status. These patients were then stratified to groups by the degree of microsatellite instability that was observed in their tumors. One hundred forty-six of the selected tumors were then evaluated for KRAS2 and BRAF mutations on the basis of their microsatellite instability. RESULTS: One hundred forty-six endometrioid endometrial cancers were evaluated for KRAS2 and BRAF mutations. Thirty-five cancers (24%) had activating KRAS2 mutations, but only a single BRAF mutation was identified in an microsatellite instability-positive cancer. Twenty-four of 81 microsatellite instability high cancers (29.6%) in which the MLH1 repair gene was methylated had KRAS2 mutations. When compared with the other groups, this finding approached statistical significance (P=.06). KRAS2 mutation status was associated with increasing age at diagnosis (P=.02). CONCLUSION: Despite many similarities between colon and endometrial cancers, the mechanism of the development of endometrial cancers appears to be different from colon cancers in that BRAF is not affected by a mismatch repair problem, because only KRAS2 mutations were seen. In addition, increasing age appears to lead to an increased likelihood that such a mutation will occur.     

Association of elevated C-reactive protein levels with an impaired prognosis in patients with surgically treated endometrial cancer

OBJECTIVE: To evaluate whether C-reactive protein (CRP) serum levels are associated with prognosis in surgically treated endometrial cancer. METHODS: In the present multicenter study, CRP serum levels were measured preoperatively in 403 surgically staged patients with endometrioid endometrial cancer. Results were correlated to clinical data. RESULTS: The mean (standard deviation) serum CRP level in patients with endometrial cancer was 1.0 (1.8) mg/dL. Serum CRP levels were associated with tumor stage (P=.01), but not with tumor grade (P=.8), lymph node involvement (P=.8), and age at diagnosis (P=.9). In a univariable survival analysis, serum CRP levels, tumor stage, tumor grade, and age at diagnosis were associated with disease-free and overall survival (all P <.001). In a multivariable Cox regression model, serum CRP levels (P=.001, P=.004), tumor stage (P <.001, P <.001), tumor grade (P=.02, P=.009), and age at diagnosis (P=.002, P=.001) were independent prognostic factors for disease-free and overall survival. CONCLUSION: Our results suggest that elevated serum CRP levels are associated with a less favorable prognosis in patients with surgically treated endometrial cancer. LEVEL OF EVIDENCE: II.     

Molecular genetic characterization of tamoxifen-associated endometrial cancer

OBJECTIVES: The non-steroidal, selective estrogen receptor modulator tamoxifen is currently the most extensively used hormonal agent for the prevention and treatment of estrogen receptor-positive breast cancer. Epidemiologic studies and clinical trials have shown an increased risk of endometrial cancer with tamoxifen exposure; however, few studies have examined these tumors on a molecular level. We sought to elucidate the molecular genetic alterations found in tamoxifen-associated endometrial cancer. METHODS: Twenty-nine breast cancer patients with a history of tamoxifen use who subsequently developed endometrial cancer were retrospectively identified and matched for endometrial histologic subtype and grade to 29 endometrial cancers from breast cancer patients never exposed to tamoxifen. Endometrial tumor tissue was microdissected and genomic DNA extracted for each case. Direct DNA sequencing of the most commonly mutated genes in sporadic endometrial cancer, PTEN, K-RAS, TP53, and CTNNB1, was performed in addition to microsatellite instability (MI) studies. Fisher's Exact Test was utilized for statistical analyses. RESULTS: Of 29 tamoxifen-associated cancers, 10 (34.5%) contained PTEN mutations compared to 13 (44.8%) of the non-tamoxifen-associated cancers (P = 0.59). All PTEN mutations were found in tumors with endometrioid histology, reflecting what is seen in sporadic endometrial cancers. Mutations of K-RAS, TP53, and microsatellite instability were present in similar frequencies between the two breast cancer groups, and moreover, these were similar to mutational frequencies found in sporadic endometrial cancer. CONCLUSION: Tamoxifen and non-tamoxifen-associated endometrial carcinomas arising in women with breast cancer contain similar genetic alterations to those of sporadic endometrial carcinomas.     

p53 Mutations and microsatellite instability in ovarian cancer: Yin and yang

OBJECTIVE: We tested the hypothesis that p53 frameshift mutations in ovarian cancer occur as a result of genomic instability rather than as a proximal cause of this process. STUDY DESIGN: Sequencing of the p53 tumor suppressor gene has been carried out on 305 ovarian, fallopian tube, and peritoneal cancers. Two groups of p53 null mutations were identified: (1) those caused by frameshift insertion or deletion mutations (n = 31) and (2) those caused by nonsense mutations (n = 28). As a control group 59 tumors with p53 missense mutations were selected by matching with the p53 null tumors on the basis of patient age at diagnosis, stage and grade of cancer, cancer site, and year of diagnosis. Microsatellite instability was determined from paired normal and tumor tissue deoxyribonucleic acid by means of the following different markers: D2S123, D5S346, D17S250, BAT25, and BAT26. Amplimers from polymerase chain reactions were evaluated on 7% polyacrylamide gels. RESULTS: The p53 null tumors were more likely to be of higher stage and grade. Fallopian tube cancers were more common (P =.02) in the p53 frameshift group. The overall incidence of microsatellite instability was 39%, 36%, and 25% for tumors with p53 frameshift nonsense and missense mutations (P =.30). Microsatellite instability was seen almost exclusively with ovarian cancer (P =.04). CONCLUSIONS: Microsatellite instability is a relatively common event in ovarian cancer and is dependent on marker selection. The p53 frameshift mutations do not appear to occur as a consequence of genomic instability.     

Body mass index: relationship to clinical, pathologic and features of microsatellite instability in endometrial cancer

OBJECTIVES: There is a well known association between obesity and endometrial cancer. We sought to examine the relationships between body mass index (BMI), as a measure of obesity, and known demographic, clinical, and molecular characteristics of microsatellite instability and MLH1 promoter methylation in a cohort of patients with endometrial cancer. METHODS: Corpus cancer specimens were prospectively obtained from 473 consecutively enrolled patients between 1992 and 2004. Clinical and pathologic data were extracted from review of the medical record. Microsatellite instability (MSI) was evaluated in all tumors, and methylation of the MLH1 promoter was determined for MSI positive tumors. RESULTS: The median (SD) age and BMI were 64.8 years (11.9) and 33.5 (9.4), respectively. Histology included 376 endometrioid (79%), 69 serous/clear cell or mixed (15%), and 28 sarcomas (6%). Median BMI was 32.4 for endometrioid, 31.0 for serous/clear cell or mixed, and 27.8 for sarcomas (p=0.14). BMI was negatively associated with age at surgery (p<0.01). The remainder of analyses excluded sarcoma histology. BMI was associated with stage of disease; patients with stage I/II disease had significantly higher BMI than those with stage III/IV disease (32.6 vs. 30.6; p=0.02). In relation to molecular features of endometrial cancer, BMI was significantly different between MSI positive tumors compared to MSI negative tumors (30.3 vs. 32.7; p=0.02). MSI was also significantly different between tumor histology, occurring with a higher frequency in Type I than Type II tumors (p<0.01). CONCLUSIONS: The majority of endometrial cancer patients are obese. Those with higher BMI are more likely to be younger, present with early stage disease, and have MSI negative tumors.     

Molecular carcinogenesis of endometrial cancer

In 1983, Bokhman proposed a dualistic model of endometrial tumorigenesis based on the clinical observations and clinicopathologic correlations. The majority of endometrial cancers (approximately 70-80%), designated as type I carcinomas, follow the estrogen-related pathway. Histologically, most of the type I tumors seem to arise in the background of hyperplastic endometrium, show an endometrioid differentiation, and are of low grade. Clinically, they are overall characterized by a favorable behavior. Another 10-20% of endometrial cancers, designated as type II carcinomas, follow the estrogen-unrelated pathway and arise in the background of atrophic endometrium. Type II tumors usually occur at an older age, approximately 5-10 years later than type I tumors. They are typically high-grade carcinomas of nonendometrioid differentiation, most frequently serous, less frequently clear cell. Type II carcinomas behave as an aggressive clinical course and poor prognosis. This dualistic model was subsequently supported by the molecular studies, approximately a decade later. At present, endometrioid and serous carcinoma, which represent the major phenotypes of types I and II endometrial carcinomas, respectively, are characterized by distinctive types of genetic instability and molecular alterations. In endometrioid (type I) carcinoma, four major genetic changes are responsible for the tumorigenesis, i.e. silencing of PTEN tumor suppressor gene, presence of microsatellite instability due to alterations of the mismatch repair genes, mutation of K-ras protooncogene, and alteration of beta-catenin gene. On the other hand, p53 mutation and overexpression of Her2/neu oncogene are two major genetic alterations in serous and clear cell (type II) carcinomas. However, like in any model, there is evidence for exceptions. Many endometrial carcinomas are in the gray zone with overlapping clinical, morphologic, immunohistochemical, and molecular features of types I and II endometrial cancers. Finally, a small group of endometrial carcinoma is noted to be hereditary. It is known as the most common extracolonic malignancy in hereditary nonpolyposis colorectal cancer (Lynch syndrome), an autosomal dominantly inherited disorder of cancer susceptibility. Inactivation of the mismatch repair genes MSH2 and MSH6 seems to play a central role in the tumorigenesis.     

Molecular analysis of endometrial hyperplasia in HNPCC-suspicious patients may predict progression to endometrial carcinoma.

Women predisposed to hereditary nonpolyposis colorectal cancer are at high risk of developing endometrial carcinoma at a young age. Hereditary nonpolyposis colorectal cancer-associated endometrial carcinomas are of the endometrioid type, usually arise from complex atypical hyperplasia, and often show microsatellite instability. To identify occult hereditary nonpolyposis colorectal cancer individuals among endometrial carcinoma patients, we examined complex atypical hyperplasias and endometrial carcinomas of 60 women < or =50 years of age (mean age: 35.7 years) using microsatellite instability, immunohistochemistry, and DNA sequence analysis. Three patient groups were recruited: group 1, patients with complex atypical hyperplasia exclusively (n = 27); group 2, patients with complex atypical hyperplasia and synchronous or metachronous endometrial carcinoma (n = 15); group 3, patients with endometrial carcinoma only (n = 18). Overall, 13 of 33 endometrial carcinomas (39%) displayed high-level microsatellite instability. None of the complex atypical hyperplasias in group 1 had high-level microsatellite instability or loss of hMLH1/hMSH2 protein expression. In group 2 patients, 33% of complex atypical hyperplasias and 53% of endometrial carcinomas had high-level microsatellite instability. Loss of hMSH2 protein expression was found in six endometrial carcinoma patients, five of them with verified hMSH2 germline mutations, including four patients with high-level microsatellite instability in complex atypical hyperplasia. Among group 3 patients, 28% of endometrial carcinomas displayed high-level microsatellite instability; three of those five endometrial carcinomas were from patients with multiple extrauterine hereditary nonpolyposis colorectal cancer-associated tumors. We conclude that young women (< or =50 years of age) with concurrent complex atypical hyperplasia and multiple hereditary nonpolyposis colorectal cancer-associated carcinomas are at risk of developing high-level microsatellite instability endometrial carcinoma. Combined microsatellite instability and immunohistochemistry analysis allows the identification of a high proportion of hereditary nonpolyposis colorectal cancer patients among young women with endometrial carcinoma and complex atypical hyperplasia. All complex atypical hyperplasias with high-level microsatellite instability progressed to endometrial carcinoma. Only one third of the complex atypical hyperplasias with microsatellite stability progressed to high-level microsatellite instability endometrial carcinoma, while seven complex atypical hyperplasias progressed to microsatellite stability endometrial carcinoma. Microsatellite analysis of complex atypical hyperplasia in young patients may therefore be a useful prognostic marker for predicting possible progression to high-level microsatellite instability endometrial carcinomas.     

Microsatellite instability in mitochondrial genome of common female cancers

Abstract.   Wang Y, Liu VWS, Tsang PCK, Chiu PM, Cheung ANY, Khoo US, Nagley P, Ngan HYS. Microsatellite instability in mitochondrial genome of common female cancers. Int J Gynecol Cancer 2006; 16(Suppl. 1): 259–266.
To investigate the occurrence of mitochondrial genome instability in primary cervical, endometrial, ovarian, and breast carcinomas, we analyzed 12 microsatellite regions in mitochondrial DNA (mtDNA) of tumor tissues and their matched normal controls. Four of the 12 microsatellite markers starting at nucleotide position (np) 303, 514, 956, and 16184, respectively, exhibited instability as indicated by the change in length of short base-repetitive sequences of mtDNA in cancer tissue relative to that in control normal tissue from the same patient. About 25.4% of cervical cancers, 48.4% of endometrial cancers, 21.9% of ovarian cancers, and 29.4% of breast cancers carried one or more mitochondrial microsatellite instability (mtMSI). mtMSI was frequently detected in the D-loop region but rarely occurred in the coding region. A relatively long C tract interrupted by a T residue is the mtMSI hot spot in all four types of cancer studied. Different tumors have different mtMSI profiles. In particular, the frequency of mtMSI in endometrial cancer was significantly higher than in the other three types of cancer. Furthermore, carriers of a germ-line T to C polymorphism at np 16189 could be more susceptible to breast cancer development in light of the higher frequency detected in cancer patients than in normal individuals.     

Synchronous primary cancers of the endometrium and ovary: a single institution review of 84 cases

OBJECTIVES: Synchronous primary cancers of the endometrium and ovary are found in 10% of women with ovarian cancer and 5% of women with endometrial cancer. The purpose of this study was to characterize patients diagnosed with synchronous primary cancers of the endometrium and ovary with an emphasis on risk factors. METHODS: Between 1989 and 2002, 84 patients with synchronous primary cancers of the endometrium and ovary were identified. Patients with uterine papillary serous carcinoma were excluded. Clinical and pathologic information was obtained from medical records. Parametric methods were used to compare clinical and pathologic features. Kaplan-Meier survival analyses were performed and compared using the log rank test. RESULTS: Median age at diagnosis was 50 years. Median body mass index (BMI) was 28 kg/m(2). Fifty-one percent (43/84) of the women were premenopausal and 33% (28/84) were nulliparous. The most common presenting symptom was abnormal vaginal bleeding; in those women with abnormal vaginal bleeding, 69% had stage I ovarian cancer. Ovarian cancer was an incidental finding in 48% of these patients. Sixty-eight percent of patients (57/84) had endometrioid histology of both their endometrial and ovarian cancers. Patients with early stage ovarian cancer tended to have a more favorable prognosis than those with advanced stage disease (median survival not reached in stage I and II versus 66 months in stage III and IV, P = 0.06). Patients with concordant endometrioid histology had a favorable prognosis (median survival 119 versus 48 months in all other groups, P = 0.02). CONCLUSIONS: In this large series of patients, women with synchronous primary cancers of the endometrium and ovary were young, obese, nulliparous, and premenopausal. Patients with concordant endometrioid tumors of the endometrium and ovary had a favorable prognosis, with median survival approaching 10 years.     

子宫内膜癌的微卫星不稳定性与临床病理和雌、孕激素受体水平的关系

目的 探讨子宫内膜癌『微卫星不稳定性（ｍｉｃｒｏｓａｔｅｌｌｉｔｅ ｉｎｓｔａｂｉｌｉｔｙ,ＭＩ）的发生及其与各临床病理参数和雌激受体（ＥＲ）、孕激素受体（ＰＲ）水平的关系。方法 采用聚合酶链反应（ＰＣＲ）、变性聚丙烯酰胺凝胶电泳等技术,在８个位点上对４０例散发性子宫内膜癌病人进行ＭＩ测定。以免疫组织化学法检测了２７例病人的ＥＲ、ＰＲ水平,并比较ＭＩ与临床病理参数和ＥＲ、ＰＲ水平的关系。结果 ９例     

Lynch syndrome in women less than 50 years of age with endometrial cancer

OBJECTIVE: To estimate the frequency of mismatch repair deficiencies associated with hereditary nonpolyposis colorectal cancer, or Lynch syndrome, in women less than age 50 with endometrial cancer. METHODS: Consecutive patients less than age 50 diagnosed with endometrial adenocarcinoma were identified. Available pathologic specimens were freshly sliced, and protein expression for MLH1, MSH2, MSH6, and PMS2 was evaluated by immunohistochemistry. Slides were scored on a semiquantitative method with complete absence of any of the four proteins suggesting a deficiency. All results were confirmed by microsatellite instability testing. RESULTS: Sixty-one pathology specimens were analyzed. Twenty-one (34%) of the tumors had absence of staining of at least one of the four mismatch repair proteins determined by immunohistochemistry and confirmed by microsatellite instability testing. Obese patients were less likely than nonobese patients to have a mismatch repair deficiency (21% versus 59%, respectively). Non-obese patients had a relative risk for a mismatch repair deficiency of 5.5 (95% confidence interval 1.6-19.1; P=.01). CONCLUSION: Many women diagnosed with endometrial cancer before age 50 will have a mismatch repair deficiency discovered by immunohistochemistry and microsatellite instability testing. A number of young women diagnosed with endometrial cancer will require further genetic testing for mismatch repair mutations. LEVEL OF EVIDENCE: III.     

Adjuvant radiotherapy in incompletely staged IC and II endometrioid uterine cancer

OBJECTIVES: To estimate if adjuvant radiotherapy improves the disease-specific survival of patients with clinical stage IC and II endometrioid corpus cancer who did not undergo lymphadenectomy. METHODS: Information was obtained on patients with endometrioid corpus cancer from the National Cancer Institute database between 1988 and 2001. Data were analyzed using Kaplan-Meier and Cox proportional hazards regression methods. RESULTS: A total of 3,664 patients (median age 70 years) with clinical stage IC to II endometrioid carcinoma did not undergo lymphadenectomy, of which 2,170 had stage IC and 1,494 stage II disease. Of these, 1,175 had grade 1, 1,637 had grade 2, 693 had grade 3, and in 159, grade was unknown. The 5-year disease-specific survival rates of clinical stage IC compared with stage II patients were 91.3% and 86.7% (P<.001). Of the 1,964 who received adjuvant radiotherapy, the 5-year disease-specific survival rate was 89.9% compared with 87.8% in those who did not undergo further treatment (P=.04). Adjuvant radiation improved the disease-specific survival rate of those with stage II disease, (86.5% compared with 81.9%; P=.02), but not in those with stage IC disease (91.7% compared with 92.6%; P=.68). The benefit of radiotherapy was significant in patients with grade 3 disease and patients 70 years or older (88.2% compared with 83.3%; P<.001). On multivariable analysis, age, stage, and grade were significant independent prognostic factors for disease-specific survival. CONCLUSION: Adjuvant radiotherapy marginally improved the survival of clinically staged IC-II endometrioid uterine cancer patients without lymphadenectomy. After excluding those without hysterectomy, radiotherapy did not significantly affect disease-specific survival. LEVEL OF EVIDENCE: II.     

Prognostic factors relating to survival in uterine endometrioid carcinoma.

OBJECTIVE: Epidemiologic and clinicohistopathologic prognostic factors of uterine endometrioid carcinomas were analyzed. The association of estrogen related factors, focused on adenomyosis in the prognosis of endometrioid carcinomas was also examined. METHODS: Risk factors of surgically treated 286 patients with endometrioid carcinoma (Stage I-III) were statistically analyzed. RESULTS: Overall a recurrence-free 5-year survival rate was 81% (Stage I, 94%, Stage II, 71% and Stage III, 40%). Significant prognostic factors were lymph node metastases (P = 0.0035) and serosal/parametrial invasion (P = 0.014) by multivariate analysis. Endometrioid carcinomas with co-existing adenomyosis tend to be associated with endometrial hyperplasia (P = 0.04, Fisher's exact test), diagnosed in less invasive status (myometrial invasion, P = 0.004 and serosal/parametrial invasion, P = 0.006) and therefore have a favorable prognosis (P = 0.01, log rank test). CONCLUSIONS: A favorable prognosis of endometrioid carcinomas with co-existing estrogen related factors (adenomyosis and endometrial hyperplasia) was suggested.     

p53 Expression as a Prognostic Indicator of 5-Year Survival in Endometrial Cancer

BACKGROUND: One of the most common genetic alterations to occur in human cancers is an alteration of the p53 tumor suppressor gene. The purpose of this article was to build upon the authors' previous work with p53 and determine whether p53 was a prognostic indicator of 5-year survival. METHODS: One hundred thirty-seven consecutively surgically treated patients with endometrial cancer had their p53 expression studied by immunoperoxidase staining and quantified by image analysis. All patients were evaluable for 5-year survival. RESULTS: One hundred three patients had endometrioid adenocarcinoma; 6, adenosquamous carcinoma; 14, papillary serous carcinoma; 10, clear cell carcinoma; and 4, undifferentiated carcinoma. p53 expression ranged from 0.0 to 58.2% positive nuclear area with a mean of 11.5% (median 2.6%) for the cohort. For the patients with endometrioid carcinoma, the mean p53 expression was 7.1% while for the nonendometrioid tumors it was 24.6% (P<0.001). Fifty-nine of the 103 endometrioid tumors (57.3%) stained positive for p53 while 32 of the 34 nonendometrioid (94.1%) tumors stained positive (P<0.001). Increasing histologic grade correlated with an increasing p53 expression (P = 0.003). The percentage of tumors expressing p53 was found to be higher in FIGO stage II, III, and IV than in FIGO stage I cancer (P = 0.003). However, mean p53 expression did not differ between early (stage I) and advanced (stage II, III, and IV) cancers (P = 0.088). Utilizing 5-year survival as the endpoint for multivariate analysis, FIGO stage (P = 0.0028) and p53 expression (P<0.001) were the only independent prognostic indicators found. CONCLUSION: p53 expression is more commonly found in nonendometrioid than in endometrioid adenocarcinoma of the endometrium. It, along with FIGO stage, is an independent prognostic indicator of 5-year survival.     

Microsatellite instability in uterine sarcomas

Abstract. Amant F, Dorfling CM, Dreyer L, Vergote I, Lindeque BG, Van Rensburg EJ. Microsatellite instability in uterine sarcomas.
Studies have shown a 15–30% frequency of microsatellite instability in endometrial cancer. In addition, we found a 21% frequency of microsatellite instability in endometrial cancer. Our aim was to investigate the presence of microsatellite instability and loss of heterozygosity in uterine sarcomas. The records of 69 women referred to Kalafong Academic and Pretoria Academic Hospital with a primary diagnosis of uterine sarcoma were reviewed. At histological review of 43 cases with a primary diagnosis of leiomyosarcoma, diagnosis of mitotically active leiomyoma was made in 21. Diagnosis of carcinosarcoma was made in 21 cases and endometrial stromal sarcoma in five. In all cases, genomic DNA was extracted from normal myometrium and tumor and analyzed for microsatellite instability and loss of heterozygosity. High-frequency microsatellite instability was absent in leiomyosarcoma, endometrial stromal sarcoma, and mitotically active leiomyomas and was observed in 1 (5%) carcinosarcoma. Loss of heterozygosity for chromosome 11 was present in 8/48 (17%) of uterine sarcomas, equally distributed between leiomyosarcomas (4/22 = 18%) and carcinosarcomas (4/21 = 19%). There was no loss of alleles in endometrial stromal sarcoma nor mitotically active leiomyomas. In conclusion, it is suggested that tumor suppressor genes may play a role in the tumorigenesis of uterine mesenchymal cells, whereas mismatch repair genes contribute to the carcinogenesis of endometrial cancer.     

Microsatellite instability in endometrial cancer: relation to histological subtypes.

Fifty-one endometrial cancers were analyzed with regard to whether or how microsatellite instability (MI) was associated with the development of different types of endometrial malignant neoplasms. We investigated 6 loci previously reported as informative for colorectal cancer and a group of 8 loci located on 6q. Replication error (RER+) phenotype was detected in 10 of 51 (19.6%) endometrial cancers (ECs), all but one of which showed endometrioid differentiation. On the contrary, the RER+ phenotype was not detected in serous carcinomas and malignant mixed Müllerian tumors. MI was present in both early and advanced stage ECs. No correlation was found between age, grade, stage, familial pattern, mitotic index, and the RER+ phenotype of ECs. Only 1 of 8 endometrial carcinomas showing MI was associated with mutant p53 expression, while the majority of RER+ tumors were positive for estrogen and progesterone receptors. Our findings suggest that MI plays an early role in endometrial tumorigenesis and is significantly correlated with adenocarcinomas showing endometrioid features (EAs). The frequent involvement of the telomeric region of chromosome 6 in the MI of EA is an indication that this region may be crucial in the process of EA tumorigenesis.     

Pathological findings in early-stage endometrial cancer

OBJECTIVE: The aim of this study was to assess the pathological characteristics of early-stage endometrial cancer, with regard to endometrioid versus serous papillary adenocarcinoma. METHODS: Sixty-six cases of early-stage endometrial carcinoma were classified into two groups: group I--36 cases of endometrioid endometrial cancer, staged IA-IB and graded G1-G2; group II--30 cases of Stage I serous papillary endometrial cancer. The pathological characteristics compared between the two groups included features such as tumor location in the uterine cavity, tumor focality, lymphovascular invasion, as well as the status of the uninvolved endometrium, adjacent to the tumor. Patient clinical characteristics were obtained from the medical records. RESULTS: Significantly more patients with endometrioid endometrial cancer were premenopausal (p < 0.0001), obese (p < 0.02), had hypertension (p < 0.00001) and familial cancer (p < 0.0001). On the other hand, significantly more patients with serous papillary cancer had another primary malignancy (p < 0.001). Considering the pathological characteristics, 75% of endometrioid as compared with 6.7% of serous papillary cancer cases were found in the upper uterine segment only (p < 0.0001). Multifocality was observed in 16.7% of endometrioid as compared with 100% of serous papillary cancer cases (p < 0.0001). Lymphovascular space invasion was absent in all cases of endometrioid cancer, while present in 90% of serous papillary cancer cases (p < 0.0001). Seventy-five percent of endometrioid and 100% of serous papillary cancer cases were associated with an atrophic endometrium. CONCLUSION: The clinical and pathological features of early-stage endometrial cancer differ according to the histological type of the cancer. The majority of endometrioid cancers are probably associated with an atrophic or normally cycling endometrium, and not with endometrial hyperplasia.     

Papillary Serous Carcinoma of the Uterus: Increased Risk of Subsequent or Concurrent Development of Breast Carcinoma

OBJECTIVE: Some women with endometrial cancer may be at increased risk for developing breast cancer. The histologic type of endometrial cancer associated with synchronous or subsequent breast cancer has not been clearly established. Our purpose was to determine if a certain histologic type of endometrial cancer was associated with an increased risk of synchronous or subsequent breast cancer. METHODS: The University of Iowa Hospitals and Clinics tumor registry was queried to ascertain all patients with the diagnosis of uterine cancer from January 1, 1983, to December 31, 1994. Statistics were performed utilizing SPSS for Windows version 9.0 (SPSS Inc., Chicago, IL), including Student's t tests and chi(2) tests. RESULTS: Five hundred ninety-two patients had endometrial adenocarcinoma during the study period. Five hundred thirty-six women had endometrioid adenocarcinoma, 23 women had papillary serous carcinoma (UPSC), 21 women had adenosquamous carcinoma, 10 women had clear-cell carcinoma, and 1 woman each had mucinous or squamous carcinoma. Twelve patients had previously been diagnosed with breast carcinomas. Twenty-five patients were diagnosed with breast cancer either concurrently or subsequent to their diagnosis of endometrial cancer. Synchronous or subsequent breast cancers developed in 3.2% of patients with endometrioid carcinoma and in 25% of patients with UPSC (P < 0.001). CONCLUSION: Patients with UPSC have an increased risk of development of breast cancer as compared to patients with endometrioid adenocarcinoma of the uterus.     

Bokhman Redux: Endometrial cancer “types” in the 21st century

In 1983 Jan V. Bokhman, M.D. published a landmark paper entitled “Two Pathogenetic Types of Endometrial Carcinoma” in which an enduring dualistic view of endometrial cancer was first proposed. “Type I” cancers are thought to represent estrogen driven mostly low grade endometrioid tumors strongly associated with obesity and other components of the metabolic syndrome. “Type II” cancers represent higher grade non-endometrioid tumors for which the latter associations are less significant. Basic tenets of this dichotomy including significant prognostic differences have been abundantly confirmed by later literature. The construct has in turn contributed a useful framework for decades of teaching and scientific advancement across disciplines. However, recent large epidemiologic studies indicate a more complex web of risk factors with obesity and hormones likely playing an important role across the entire endometrial cancer histologic and clinical spectrum. Moreover, high quality molecular data and refinements in pathologic classification challenge any simplistic classification of endometrial cancer. For example, the Cancer Genome Atlas (TCGA) recently defined four clinically distinct endometrial cancer types based on their overall mutational burden, specific p53, POLE and PTEN mutations, microsatellite instability and histology. Additionally, new histologic categories with clear prognostic implications have been accepted and it is becoming evident from an epidemiologic point of view that metabolic factors may play an important role in endometrial cancer overall. While Bokhman's intuitive dualistic model remains relevant when working with large registries and databases lacking granular information; most other efforts should integrate clinical, pathological and molecular specifics into more nuanced classifications.     

E-cadherin expression in endometrioid,papillary serous,and clear cell carcinoma of the endometrium

OBJECTIVE: To compare the frequency and pattern of E-cadherin expression in endometrioid, papillary serous, and clear cell carcinomas of the endometrium. METHODS: E-cadherin expression was examined in 76 endometrial carcinomas by immunohistochemistry using a monoclonal antibody to E-cadherin and was correlated with poor prognostic indicators such as depth of myometrial invasion, lymph node status, and intraperitoneal spread. The frequency of expression was compared between endometrioid, papillary serous, and clear cell carcinomas by the Fisher exact test. Logistic regression was used to examine the simultaneous effect of histological type and tumor grade on E-cadherin expression. RESULTS: Sixty-three endometrioid, nine papillary serous, two clear cell, and two carcinomas of mixed histology were examined. E-cadherin negative tumors were more likely to be poorly differentiated (P <.01), have cervical extension (P =.02), have positive peritoneal cytology (P <.01), and have adnexal spread (P =.01) when compared with E-cadherin positive tumors. Papillary serous and clear cell carcinomas were significantly less likely to express E-cadherin than endometrioid carcinoma (38% versus 95%, P <.001). Tumor grade and histological type were identified as significant predictors of E-cadherin expression in univariable analysis; however, only histological type remained significant in multivariable analysis (P =.01). When grade was controlled, endometrioid carcinoma remained 23 times more likely to express E-cadherin than papillary serous and clear cell carcinomas. CONCLUSION: Papillary serous and clear cell carcinomas are significantly less likely to express E-cadherin than endometrioid tumors. This difference may account for the more aggressive behavior of papillary serous and clear cell carcinomas.