Focus: A Multifaceted Battle Against Cancer: The Benefit and Burden of Cancer Screening in Li-Fraumeni Syndrome: A Case Report

Li-Fraumeni syndrome is a rare cancer predisposition syndrome classically associated with remarkably early onset of cancer in families with a typical spectrum of malignancies, including sarcoma, breast cancer, brain tumors, and adrenocortical carcinoma. Because the risks of cancer development are strikingly high for Li-Fraumeni syndrome, aggressive cancer surveillance is often pursued in these individuals. However, optimal screening methods and intervals for Li-Fraumeni syndrome have yet to be determined. In addition, there may be a significant psychosocial burden to intensive cancer surveillance and some prevention modalities. Here, we describe a case of a young woman with a de novo mutation in TP53 and multiple malignancies, with her most recent cancers found at early, curable stages due to aggressive cancer screening. The potential benefits and risks of intensive cancer surveillance in hereditary cancer syndromes is discussed.     

Endometrial Cancer as a Familial Tumor: Pathology and Molecular Carcinogenesis (Review)

Some cases of endometrial cancer are associated with a familial tumor and are referred to as hereditary nonpolyposis colorectal cancer (HNPCC or Lynch syndrome). Such tumors are thought to be induced by germline mutation of the DNA mismatch repair (MMR) gene, but many aspects of the pathology of familial endometrial cancer are unclear and no effective screening method has been established. However, the pathology of endometrial cancer with familial tumor has been progressively clarified in recent studies. At present, about 0.5% of all cases of endometrial cancers meet the clinical diagnostic criteria for HNPCC. A recent analysis of the three MMR genes (hMLH1, hMSH2 and hMSH6) revealed germline mutations in 18 of 120 cases (15.0%) of endometrial cancer with familial accumulation of cancer or double cancer, with a frameshift mutation of the hMSH6 gene being the most common. Many cases with mutation did not meet the current clinical diagnostic criteria for HNPCC, indicating that familial endometrial cancer is often not diagnosed as HNPCC. The results suggest that the hMSH6 gene mutation may be important in carcinogenesis in endometrial cancer and germline mutations of the MMR gene may be more prevalent in cases associated with familial accumulation of cancer. An international large-scale muticenter study is required to obtain further information about the pathology of endometrial cancer as a familial tumor.Key Words: HNPCC, Endometrial cancer, DNA mismatch repair gene, hMLH1, hMSH6.     

Reduced frequency of extracolonic cancers in hereditary nonpolyposis colorectal cancer families with monoallelic hMLH1 expression.

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disease caused by mutations in one of at least four different DNA mismatch repair genes, hMLH1, hMSH2, hPMS1, and hPMS2. Phenotypically, HNPCC is characterized by the early onset of colorectal cancers and various extracolonic cancers. Depending on the presence or absence of extracolonic tumors, HNPCG-has been divided into two syndromes (Lynch syndrome I and Lynch syndrome II), but, so far, no correlation to distinct genotypes has been demonstrated. In this study, we present a frequent hMLH1 intron 14 founder mutation that is associated with a highly reduced frequency of extracolonic tumors. The mutation disrupts the splice donor site and silences the mutated allele. Tumors exhibited microsatellite instability, and loss of the wild-type hMLH1 allele was prevalent. We propose that the mutation results in a milder phenotype, because the mutated hMLH1 protein is prevented from exerting a dominant negative effect on the concerted action of the mismatch repair system.     

Nationwide Surveillance in Uterine Cancer: Survival Analysis and the Importance of Birth Cohort: 30-Year Population-Based Registry in Taiwan

Introduction

Uterine cancer was the most rapidly increasing malignancy and the second most common gynecologic malignancy in Taiwan.

Methods

We analyzed the secular trend of uterine cancer incidence and compare the survival of women with uterine carcinomas and uterine sarcomas in Taiwan. Data on women diagnosed with uterine cancer between 1979 and 2008 were obtained from the Taiwan cancer registry. Survival data were analyzed by using Kaplan-Meier and Cox proportional hazards regression methods.

Results

Records of 11,558 women with uterine carcinomas and 1,226 women with uterine sarcomas were analyzed. The age-adjusted incidence rate of endometrioid adenocarcinoma increased from 0.83 per 100,000 women per year between 1979 and 1983 to 7.50 per 100,000 women per year between 2004 and 2008. The 5-year survival rate of women with endometrioid adenocarcinoma (83.2%) was higher than that for women with clear cell carcinoma (58.3%), serous carcinoma (54.4%), and carcinosarcoma (35.2%) (p<0.0001, log-rank test). The 5-year survival rates of women with low grade endometrial stromal sarcoma, endometrial stromal sarcoma, leiomyosarcoma (LMS), and adenosarcoma were 97.5%, 73.5%, 60.1%, and 77.2%, respectively (p<0.0001, log rank test). The histologic type of endometrioid adenocarcinoma, young age, and treatment period after 2000 were independent, favorable prognostic factors in women with uterine carcinomas by multivariate analysis. The histologic type of LMS, old age, and treatment period after 2000 were independent, poor prognostic factors in women with uterine sarcomas by multivariate analysis.

Conclusions

An increase over time in the number of patients with endometrioid adenocarcinomas was noted in this 30-year, nationwide, population-based study. Histologic type, age and treatment period were survival factors for uterine cancers. A more comprehensive assessment of uterine cancers and patient care should be undertaken on this increasingly common type of cancer.     

Genomic rearrangements in BRCA1 and BRCA2: A literature review

Women with mutations in the breast cancer genes BRCA1 or BRCA2 have an increased lifetime risk of developing breast, ovarian and other BRCA-associated cancers. However, the number of detected germline mutations in families with hereditary breast and ovarian cancer (HBOC) syndrome is lower than expected based upon genetic linkage data. Undetected deleterious mutations in the BRCA genes in some high-risk families are due to the presence of intragenic rearrangements such as deletions, duplications or insertions that span whole exons. This article reviews the molecular aspects of BRCA1 and BRCA2 rearrangements and their frequency among different populations. An overview of the techniques used to screen for large rearrangements in BRCA1 and BRCA2 is also presented. The detection of rearrangements in BRCA genes, especially BRCA1, offers a promising outlook for mutation screening in clinical practice, particularly in HBOC families that test negative for a germline mutation assessed by traditional methods.     

Biomarkers as prognostic factors in endometrial cancer

Endometrial cancer is the most common gynecologic malignancy in more developed countries. Approximately 75% of cases are diagnosed at an early stage with a tumor confined to the uterine corpus. Although most patients are cured by surgery alone, about 15-20% with no signs of locally advanced or metastatic disease at primary treatment recurs, with limited responsiveness to systemic therapy. The most common basis for determining the risk of recurrent disease has been classification of endometrial cancers into two subtypes. Type I, associated with a good prognosis and endometrioid histology and type II, associated with a poor prognosis and non-endometrioid histology. This review will focus primarily on the molecular biomarkers that have supported the dualistic model of endometrial carcinoma and help determine which patients would benefit from either adjuvant therapy or more aggressive primary treatment.     

Systematic profiling of ACE2 expression in diverse physiological and pathological conditions for COVID‐19/SARS‐CoV‐2

Recent retrospective studies of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) disease (COVID‐19) revealed that the patients with common comorbidities of cancers and chronic diseases face significantly poorer clinical outcomes than those without. Since the expression profile of ACE2, a crucial cell entry receptor for SARS‐CoV‐2, could indicate the susceptibility to SARS‐CoV‐2 infection, here we systematically dissected ACE2 expression using large‐scale multi‐omics data from 30 organs/tissues, 33 cancer types and some common chronic diseases involving >28 000 samples. It was found that sex and age could be correlated with the susceptibility of SARS‐CoV‐2 infection for certain tissues. Strikingly, ACE2 was up‐regulated in cervical squamous cell carcinoma and endocervical adenocarcinoma, colon adenocarcinoma, oesophageal carcinoma, kidney renal papillary cell carcinoma, lung adenocarcinoma and uterine corpus endometrial carcinoma compared to controls. Furthermore, the patients with common chronic diseases regarding angiocardiopathy, type 2 diabetes, liver, pneumonia and hypertension were also with higher ACE2 expression compared to related controls, which were validated using independent data sets. Collectively, our study may reveal a novel important mechanism that the patients with certain cancers and chronic diseases may express higher ACE2 expression compared to the individuals without diseases, which could lead to their higher susceptibility to multi‐organ injury of SARS‐CoV‐2 infection.     

Endometrial carcinoma detected with SurePath liquid-based cervical cytology: comparison with conventional cytology

Introduction: Conventional Pap smears (CPS) have little impact on the detection of endometrial carcinoma. Although liquid‐based cytology (LBC) is replacing CPS in the UK, experience with identification of endometrial cancers with this technique is limited. Aim: To compare the accuracy of the SurePath LBC with that of CPS for detection of endometrial cancers. Methods: Our study group comprised SurePath LBC samples reported as atypical endometrial cells and endometrial adenocarcinoma (classified respectively as borderline, code 8 and ?glandular neoplasia, code 6 for the NHS Cervical Screening Programme statistics) in 2004–2005. CPS reported as atypical endometrial cells or adenocarcinoma in 1993–1998 comprised the control group. Histological follow‐up was obtained. Results: Endometrial abnormalities were reported in 95 (0.073%) of 130 352 LBC samples, comprising 75 (0.058%) atypical endometrial cells and 20 (0.015%) endometrial adenocarcinoma reports. Of 409 495 CPS, 117 (0.029%) were diagnosed as endometrial abnormalities, comprising 59 (0.014%) atypical endometrial cells and 58 (0.014%) endometrial adenocarcinoma reports. Thus, the endometrial adenocarcinoma reporting rate was similar in both groups, but that for atypical endometrial cells was higher with LBC (P < 0.001). The positive predictive value for endometrial cancer of endometrial adenocarcinoma and atypical endometrial cell reports in the LBC group was 73.3 and 18.8%, respectively, compared with 42.3 and 6.7% in the CPS group. The endometrial adenocarcinoma patients in CPS group were older (mean age 62.5 years versus 56.5 years) and most (22/25) were symptomatic, whereas most (13/17) patients in the LBC group were asymptomatic at the time of sampling (P < 0.001). Conclusion: SurePath LBC is at least as accurate a method for detecting endometrial cancer as CPS. SurePath LBC demonstrates enhanced identification of endometrial pathology in asymptomatic women in the cervical screening programme.     

PTEN基因和P53基因在子宫内膜癌中的表达及意义

目的:探讨PTEN基因和P53基因在子宫内膜癌中的表达及临床意义,为子宫内膜癌的治疗提供参考依据。方法:用免疫组化法检测50例子宫内膜癌患者PTEN基因缺失和P53基因突变情况,并分析两者与子宫内膜癌不同病理变化的相关性。结果:PTEN缺失24例,缺失率48.00%,进一步研究显示PTEN缺失与细胞分化程度和肌层浸润情况密切相关(P0.05),P53突变32例,缺失率64.00%,并进一步研究显示P53突变与FIGO分期,细胞分化程度和肌层浸润情况密切相关(P0.05)。结论:PTEN基因缺失和P53基因突变与子宫内膜癌发生和发展密切相关,以PTEN基因和P53基因为靶点的生物治疗在进展期内膜癌中的治疗价值值得进一步深入研究。     

PTEN基因和P53基因在子宫内膜癌中的表达及意义

目的：探讨PTEN基因和P53基因在子宫内膜癌中的表达及临床意义,为子宫内膜癌的治疗提供参考依据。方法：用免疫组化法检测50例子宫内膜癌患者PTEN基因缺失和P53基因突变情况,并分析两者与子宫内膜癌不同病理变化的相关性。结果：PTEN缺失24例,缺失率48.00%,进一步研究显示PTEN缺失与细胞分化程度和肌层浸润情况密切相关（P〈0.05）,P53突变32例,缺失率64.00%,并进一步研究显示P53突变与FIGO分期,细胞分化程度和肌层浸润情况密切相关（P〈0.05）。结论：PTEN基因缺失和P53基因突变与子宫内膜癌发生和发展密切相关,以PTEN基因和P53基因为靶点的生物治疗在进展期内膜癌中的治疗价值值得进一步深入研究。     

子宫内膜癌中PTEN与PI3K-Akt通路的表达及意义

目的：研究PTEN与P1K3-Akt通路在子宫内膜癌中的表达及临床意义。方法：采用免疫组化技术检测正常子宫内膜组织（24例）、子宫内膜样腺癌组织（55例）及子宫内膜浆液性癌组织（26例）中PTEN、P13Kp110α及P—AKTSer473的表达情况,分析其表达与组织病理参数的关系。结果：免疫组化结果显示：子宫内膜癌的PTEN表达缺失率,P13Kp110α及p-AKTser473表达阳性率均高于正常子宫内膜组织,且正常子宫内膜组织与子宫内膜样腺癌组织比较有统计学意义（P〈0．05）;随着肌层浸润深度增加,PTEN表达缺失率增加（P〈0．05）。结论：PTEN的表达缺失及P13Kp110α与P-AKTSer473的表达可能与子宫内膜癌的发生发展有关,尤其是在子宫内膜样腺癌的发生发展机制中占重要地位。     

Endometrial scraping cytology in women with extragenital malignancies

OBJECTIVE: To clarify the usefulness of endometrial scraping smears in women with extragenital malignancies. STUDY DESIGN: A total of 4,335 endometrial scraping smears were obtained during the 5-year period 1995-1999 at the National Kyushu Cancer Center and were retrospectively analyzed regarding extragenital malignancies. RESULTS: There were 88 cases of extragenital malignancies. Extragenital malignant cells were detected in endometrial smears in 13 cases. The cases consisted of 4 gastric cancers, 4 breast cancers, 2 lung cancers, 1 rectal cancer, 1 gastrointestinal stromal tumor of the small intestine and 1 case of adenocarcinoma of unknown origin. The patients' average age was 52.5 years. The symptoms and signs included abnormal vaginal bleeding, abdominal and lumbar pain, lower limb edema, abdominal mass and neck lymph node swelling. Both ascites and peritoneal dissemination were found in 8 cases. Ten of the 13 cases were diagnosed as of extrauterine origin based on the characteristic cancer cell appearance, the absence of cellular detritus among the poorly differentiated adenocarcinomas and, above all, the morphologic difference between normal endometrial cells and cancer cells. CONCLUSION: Endometrial scraping smears are useful for detecting extragenital malignant cells that enter the uterine cavity.     

Irrelevance of Microsatellite Instability in the Epidemiology of Sporadic Pancreatic Ductal Adenocarcinoma

Background and Aims

Pancreatic cancer risk is increased in Lynch syndrome (LS) patients with mismatch repair gene defects predisposing to colonic and extracolonic cancers with microsatellite instability (MSI). However, the frequency of MSI pancreatic cancers has never been ascertained in consecutive, unselected clinical series, and their contribution to the sporadic and inherited burden of pancreatic cancer remains to be established. Aims of the study were to determine the prevalence of MSI in surgically resected pancreatic cancers in a multicentric, retrospective study, and to assess the occurrence of pancreatic cancer in LS.

Methods

MS-status was screened by a panel of 5 mononucleotide repeats (Bat26, Bat25, NR-21, NR-24 and NR-27) in 338 consecutive pancreatic ductal adenocarcinoma (PDAC), resected at two Italian and one German referral centres. The personal history of pancreatic cancer was assessed in an independent set of 58 probands with LS and in 138 first degree relatives who had cancers.

Results

Only one PDAC (0.3%) showed MSI. This was a medullary type cancer, with hMLH1-deficiency, and no identified germ-line mutation but methylation of hMLH1. Pancreatic cancer occurred in 5 (2.5%) LS patients. Histological sampling was available for 2 cases, revealing PDAC in one case and an ampullary cancer in the other one.

Conclusions

MSI prevalence is negligible in sporadic, resected PDAC. Differently, the prevalence of pancreatic cancer is 2.5% in LS patients, and cancers other than PDAC may be encountered in this setting. Surveillance for pancreatic cancer should be advised in LS mutation carriers at referral centers.     

子宫内膜癌中PTEN与PI3K-Akt通路的表达及意义

目的:研究PTEN与PIK3-Akt通路在子宫内膜癌中的表达及临床意义。方法:采用免疫组化技术检测正常子宫内膜组织(24例)、子宫内膜样腺癌组织(55例)及子宫内膜浆液性癌组织(26例)中PTEN、P13Kp110α及p-AKTSer473的表达情况,分析其表达与组织病理参数的关系。结果:免疫组化结果显示:子宫内膜癌的PTEN表达缺失率,P13Kp110α及p-AKTSer473表达阳性率均高于正常子宫内膜组织,且正常子宫内膜组织与子宫内膜样腺癌组织比较有统计学意义(P0.05);随着肌层浸润深度增加,PTEN表达缺失率增加(P0.05)。结论:PTEN的表达缺失及P13Kp110α与p-AKTSer473的表达可能与子宫内膜癌的发生发展有关,尤其是在子宫内膜样腺癌的发生发展机制中占重要地位。     

Three novel germline mutations in MLH1 and MSH2 in families with Lynch syndrome living on Jeju island, Korea

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant syndrome characterized by predisposition to early-onset cancers. HNPCC is caused by heterozygous loss-of-function mutations within the mismatch repair genes MLH1, MSH2, MSH6, PMS1, and PMS2. We genotyped the MLH1 and MSH2 genes in patients suffering from Lynch syndrome and in 11 unrelated patients who were diagnosed with colorectal cancer and had subsequently undergone surgery. Five Lynch syndrome patients carried germline mutations in MLH1 or MSH2. Two of these were identified as known mutations in MLH1: deletion of exon 10 and a point mutation (V384D). The remaining three patients exhibited novel mutations: a duplication (937_942dupGAAGTT) in MLH1; deletion of exons 8, 9, and 10; and a point mutation in MLH1 (F396I) combined with multiple missense mutations in MSH2 (D295G, K808E, Q855P, and I884T). The findings underline the importance of efficient pre-screening of conspicuous cases.     

Constitutional mismatch repair-deficiency syndrome: have we so far seen only the tip of an iceberg?

Heterozygous mutations in one of the mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 cause the dominant adult cancer syndrome termed Lynch syndrome or hereditary non-polyposis colorectal cancer. During the past 10 years, some 35 reports have delineated the phenotype of patients with biallelic inheritance of mutations in one of these MMR genes. The patients suffer from a condition that is characterised by the development of childhood cancers, mainly haematological malignancies and/or brain tumours, as well as early-onset colorectal cancers. Almost all patients also show signs reminiscent of neurofibromatosis type 1, mainly café au lait spots. Alluding to the underlying mechanism, this condition may be termed as “constitutional mismatch repair-deficiency (CMMR-D) syndrome”. To give an overview of the current knowledge and its implications of this recessively inherited cancer syndrome we summarise here the genetic, clinical and pathological findings of the so far 78 reported patients of 46 families suffering from this syndrome.     

Isocitrate dehydrogenase 1 R132C mutation occurs exclusively in microsatellite stable colorectal cancers with the CpG island methylator phenotype

The CpG Island Methylator Phenotype (CIMP) is fundamental to an important subset of colorectal cancer; however, its cause is unknown. CIMP is associated with microsatellite instability but is also found in BRAF mutant microsatellite stable cancers that are associated with poor prognosis. The isocitrate dehydrogenase 1 (IDH1) gene causes CIMP in glioma due to an activating mutation that produces the 2-hydroxyglutarate oncometabolite. We therefore examined IDH1 alteration as a potential cause of CIMP in colorectal cancer. The IDH1 mutational hotspot was screened in 86 CIMP-positive and 80 CIMP-negative cancers. The entire coding sequence was examined in 81 CIMP-positive colorectal cancers. Forty-seven cancers varying by CIMP-status and IDH1 mutation status were examined using Illumina 450K DNA methylation microarrays. The R132C IDH1 mutation was detected in 4/166 cancers. All IDH1 mutations were in CIMP cancers that were BRAF mutant and microsatellite stable (4/45, 8.9%). Unsupervised hierarchical cluster analysis identified an IDH1 mutation-like methylation signature in approximately half of the CIMP-positive cancers. IDH1 mutation appears to cause CIMP in a small proportion of BRAF mutant, microsatellite stable colorectal cancers. This study provides a precedent that a single gene mutation may cause CIMP in colorectal cancer, and that this will be associated with a specific epigenetic signature and clinicopathological features.     

Impact of middle and lower jugular neck dissection on supraclavicular lymph node metastasis from endometrial carcinoma

ABSTRACT: Supraclavicular lymph node metastasis from endometrial carcinoma is considerably rarer than metastasis from uterine cervical cancer. To date, there have been no reported cases regarding systematic neck dissection as a salvage treatment. In this report, we describe the neck dissection procedure carried out on a 74-year-old woman with supraclavicular lymph node metastasis. Our objective was to histologically determine the origin of the metastasis while simultaneously providing appropriate treatment. The patient's past medical history included two prior cases of cancer: rectal cancer 7?years earlier and endometrial adenocarcinoma 4?years earlier. We determined that middle and lower jugular neck dissection was appropriate in treating this case based on the results of our preoperative FDG-PET and tumor markers. This surgery provided histological evidence that metastasis occurred from endometrial carcinoma. Middle and lower jugular neck dissection was expected to improve the patient's prognosis without impacting the patient's active daily life. We have continued to monitor the patient closely over an extended period.     

Usefulness of endometrial aspiration cytology for the preoperative diagnosis of ovarian carcinoma

OBJECTIVE: To evaluate the usefulness of endometrial aspiration cytology for the preoperative diagnosis of ovarian carcinoma. STUDY DESIGN: A total of 210 patients with ovarian carcinoma were investigated by endometrial aspiration cytology. RESULTS: Fifty-five of 210 patients (26.2%) had positive endometrial aspiration cytology. The positive rates of endometrial cytology were 3.9% in stage I, 23.8% in stage II, 36.5% in stage III and 53.3% in stage IV. When classified by histologic type, the positive rates of endometrial cytology in patients with serous adenocarcinoma, mucinous adenocarcinoma, clear cell adenocarcinoma, undifferentiated carcinoma and yolk sac tumor were 38.9%, 11.8%, 21.1%, 16.7% and 16.7%, respectively. One hundred twenty-eight of 210 patients (61.0%) were positive on peritoneal cytology, and 54 of these 128 cases (42.2%) were also positive on endometrial cytology. The positive rates of endometrial cytology were especially high in patients with serous adenocarcinoma (51.2%) and those with clear cell adenocarcinoma (40.0%) among those who were positive on peritoneal cytology. Of 74 patients who were negative on peritoneal cytology, only one (1.4%) with mucinous adenocarcinoma had positive endometrial cytology. Hysterectomy was performed on 130 patients, and the positive rate of endometrial cytology was 100% in 4 patients with endometrial invasion and 15.9% in 126 cases without invasion. CONCLUSION: Endometrial aspiration cytology can detect ovarian carcinoma cells not only in patients with endometrial involvement but also in patients with positive peritoneal cytology. Endometrial aspiration cytology appears to be useful for the preoperative diagnosis of ovarian carcinoma.