Lynch syndrome and sextuple primary malignancies

Lynch syndrome or hereditary nonpolyposis colorectal cancer is the most common of hereditary colorectal cancer and accounts for 1–3%. Lynch and Chapelle estimated that it accounts 5–8% for all colorectal cancers. It is an autosomal dominant syndrome characterized by predisposition of various cancers (colorectal, stomach, endometrial, ovarian, renal, small bowel, and hepatobiliary tract) at earlier age than in general population and occurs as a result of mutation in DNA mismatch repair genes. This article presents a rare clinical of a 61-year-old female diagnosed with extracolonic Lynch syndrome with six metachronous tumours acquiring in digestive tract during the period from 1993 to 2014 (over 21 years). No other cases of six primary malignancies in patient with Lynch syndrome have been reported in literature. Upon diagnosis of Lynch syndrome, it is important to screen patient for malignancies of different localization as this syndrome predisposes appearance of various cancers at earlier age than in general population.     

Ovarian Cancer in Hereditary Cancer Susceptibility Syndromes

Hereditary breast and ovarian cancer (HBOC) syndrome and Lynch syndrome (LS) are associated with increased risk of developing ovarian carcinoma. Patients with HBOC have a lifetime risk of up to 50% of developing high-grade serous carcinoma of tube or ovary; patients with LS have a 10% lifetime risk of developing endometrioid or clear cell carcinoma of the ovary. Testing all patients with tubo-ovarian high-grade serous carcinoma for mutations associated with HBOC syndrome, and all patients presenting with endometrioid or clear cell carcinoma of the ovary for mutations associated with LS can identify patients with undiagnosed underlying hereditary cancer susceptibility syndromes.     

Lynch Syndrome: Female Genital Tract Cancer Diagnosis and Screening

Lynch syndrome is responsible for approximately 5% of endometrial cancers and 1% of ovarian cancers. The molecular basis for Lynch syndrome is a heritable functional deficiency in the DNA mismatch repair system, typically due to a germline mutation. This review discusses the rationales and relative merits of current Lynch syndrome screening tests for endometrial and ovarian cancers and provides pathologists with an informed algorithmic approach to Lynch syndrome testing in gynecologic cancers. Pitfalls in test interpretation and strategies to resolve discordant test results are presented. The potential role for next-generation sequencing panels in future screening efforts is discussed.     

Carcinomas associated with Lynch syndrome: a family history

Lynch syndrome is a rare and inherited defect disorder. People who have Lynch syndrome are strongly predisposed to develop colorectal cancer as well as several other types of cancer. The aim of this study was to explore features of ovarian cancers arising in families with Lynch syndrome. This study was a case report based on family history examining three patients with a new diagnosis of colorectal adenocarcinoma with ovarian cancer. Family members of carriers of the mutations were counseled, and those found to be at risk were offered mutation testing. The clinical criteria of the Amsterdam II guidelines for Lynch syndrome were used in this study. This is a maternal history of a 27-year-old woman sharing the destiny of her 48-year-old mother and 45-year-old aunt, both of which were suffering from Lynch syndrome associated with ovarian cancer. The maternal grandmother and maternal uncle of this young woman also suffered from colon cancer in their forties. The medical implications for the carrier relatives were considered as the maternal branch of the family.     

Emerging Concepts in Gastric Neoplasia: Heritable Gastric Cancers and Polyposis Disorders

Hereditary gastric cancer is a relatively rare disease with specific clinical and histopathologic characteristics. Hereditary gastric cancer of the diffuse type is predominantly caused by germline mutations in CDH1. The inherited cause of familial intestinal gastric cancer is unknown. Gastric adenocarcinoma and proximal polyposis of the stomach is a hereditary cancer syndrome caused by germline mutations in promoter 1B of APC. Other well-defined cancer syndromes, such as Lynch, Li-Fraumeni, and hereditary breast or ovarian cancer syndromes, are associated with increased risk of gastric cancer. This article reviews important histopathologic features and emerging concepts regarding gastric carcinogenesis in these syndromes.     

Ovarian endometrioid adenocarcinoma: incidence and clinical significance of the morphologic and immunohistochemical markers of mismatch repair protein defects and tumor microsatellite instability

A subset of women with uterine cancer exhibiting defective mismatch repair (MMR) proteins and microsatellite instability (MSI) may have Lynch syndrome, which also confers a risk for colorectal cancer and other cancers in the patient and in her family. Screening algorithms based on clinical and pathologic criteria are effective in determining which patients with uterine cancer are most likely to benefit from definitive genetic testing for Lynch syndrome. Ovarian cancer, particularly endometrioid adenocarcinoma, is also associated with Lynch syndrome, although the risk is much smaller than for uterine cancer. This study evaluated whether the morphologic criteria [tumor-infiltrating lymphocytes (TILs), peritumoral lymphocytes (PTLs), dedifferentiated morphology)] currently used to screen uterine cancer for further Lynch syndrome testing can be applied to ovarian cancer. Among 71 patients with pure ovarian endometrioid adenocarcinoma treated at a single institution, 13% had a tumor with TILs, 3% had PTLs, and none had dedifferentiated morphology. Overall, 10% of tumors had abnormal MMR protein status, defined as complete immunohistochemical loss of expression of MLH1, MSH2, MSH6, and/or PMS2. Each of these tumors with abnormal MMR status demonstrated MSI using a polymerase chain reaction-based assay evaluating 5 mononucleotide repeat markers. No relationship was found between patient age, TILs, PTLs, or a spectrum of other morphologic variables and MMR protein status/MSI. Only 1/7 tumors with abnormal MMR/MSI had TILs/PTLs. Among 14 patients who died, 12 (86%) had normal MMR status. Among 7 patients with tumors with abnormal MMR/MSI, 5 (71%) were alive without disease. Concurrent uterine tumor was present in 5/7 patients whose ovarian tumor had abnormal MMR/MSI. This study suggests that the morphologic criteria used to screen patients with uterine cancer for further Lynch syndrome testing are not applicable in patients with ovarian cancer. Although abnormal MMR/MSI did not carry prognostic value in this study, it did predict the involvement of the uterus by the tumor. Thus, in patients with ovarian endometrioid adenocarcinoma who undergo uterus-sparing surgery, abnormal MMR/MSI should prompt further diagnostic evaluation of the endometrium for tumor.     

Hereditäres kolorektales Karzinom

One of the main challenges in the clinical management of familial colorectal cancer (CRC) remains the overlap of syndromes with different underlying genetic causes and the differentiated risk management of colorectal and associated malignancies. The Lynch syndrome (hereditary non-polyposis colorectal cancer, HNPCC) is characterized by the development of colorectal, endometrial, gastric and other cancers and is caused by a mutation in one of the mismatch repair (MMR) genes. Microsatellite instability (MSI) and/or immunohistochemistry (IHC) are important prognostic factors and may predict the response to chemotherapy. Familial adenomatous polyposis (FAP) may be seen as a counterpart to Lynch syndrome, responsible for <1% of all CRC cases. Recently the MUTYH gene has been identified as a further polyposis gene. The associated disorder has been termed MYH-associated polyposis (MAP) and displays an autosomal recessive pattern of inheritance. For clinical management, distinguishing between Lynch syndrome, attenuated FAP and MAP is important for risk assessment, surveillance recommendations and indication for prophylactic surgery.     

Formes familiales des cancers colorectaux : techniques diagnostiques

Hereditary colorectal cancers encompass polyposis and non-polyposis syndromes. Diagnostic methods are mainly available for Lynch syndrome. These have to be well recognised so that this type of cancer can be better identified and to avoid delays in diagnosis which may be very damaging. The diagnostic strategy for Lynch syndrome is based on molecular biological techniques to identify microsatellite instability (MSI) and immunohistochemical study of the expression of proteins of the mismatch repair (MMR) system. These 2 techniques are complementary. MSI is nearly always present in Lynch syndrome and thus constitutes a good screening marker. However, it is not specific. Immunohistochemistry is strongly correlated to MSI status and may point towards the gene mutation by identifying the loss of a protein of the MMR system. For hereditary polyposis syndromes other than Lynch syndrome, there is no molecular or immunohistochemical somatic marker.     

家族性胰腺癌

家族性胰腺癌（familial pancreatic cancer,FPC）是已经确定的遗传肿瘤综合征,占全部胰腺癌的3％左右。因此,对FPC的研究将有利于发现胰腺癌的高危人群,包括家族中出现胰腺癌的其他成员和其他遗传肿瘤综合征：如皮肤黏膜黑色素斑一胃肠道多发性息肉综合征（Peutz—Jeghers综合征）,家族性非典型恶性黑色素瘤,家族性乳腺卵巢癌综合征,遗传性非腺瘤性结直肠癌等。胰腺癌易患基因和环境因素的确定将能够更加准确预测发病的危险,加强对高危人群的随访和及时的根治性手术是改善预后的重要方法。     

Clinical significance of microsatellite instability in colorectal cancer

Introduction

Colorectal cancer is a heterogeneous tumor type with regard to molecular pathogenesis and genetic instability. The majority of colorectal cancers display chromosomal instability and follow the classical adenoma-carcinoma sequence of tumor progression. A subset of about 15 % of colorectal cancers, however, displays DNA mismatch repair (MMR) deficiency and the high-level microsatellite instability (MSI-H) phenotype. MSI-H colorectal cancers can occur as sporadic tumors or in the context of hereditary non-polyposis colorectal cancer (HNPCC) or Lynch syndrome.

Clinical relevance

The MSI-H phenotype is a hallmark of Lynch syndrome-associated cancers, which is of diagnostic relevance for the identification of Lynch syndrome mutation carriers. MSI-H colorectal cancers are characterized by a distinct clinical behavior, which results from their particular molecular pathogenesis and gives microsatellite instability testing its clinical significance. The MSI-H phenotype shows association with proximal tumor localization, a dense local lymphocyte infiltration, and a low frequency of distant organ metastasis. Moreover, MSI-H colorectal cancers have a better prognosis than their microsatellite-stable counterparts. A distinct responsiveness of MSI-H colorectal cancer patients towards chemotherapy has been shown in several studies.

Conclusions

The clinical characteristics of MSI-H cancers are closely linked to their molecular pathogenesis, and research on the molecular alteration characteristic of MSI-H cancers may provide the basis for novel diagnostic or therapeutic approaches.     

Hereditary colorectal cancer syndromes: familial adenomatous polyposis and lynch syndrome

Familial colorectal cancer (CRC) accounts for 10% to 20% of all cases of CRC. Two major autosomal dominant forms of heritable CRC are familial adenomatous polyposis (FAP) and Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer). Along with the risk for CRC, both syndromes are associated with elevated risk for other tumors. Improved understanding of the genetic basis of these diseases has not only facilitated the identification and screening of at-risk individuals and the development of prophylactic or early-stage intervention strategies but also provided better insight into sporadic CRC. This article reviews the clinical and genetic characteristics of FAP and Lynch syndrome, recommended screening and surveillance practices, and appropriate surgical and nonsurgical interventions.     

Prophylaktische Chirurgie des Mamma- und Ovarialkarzinoms

New insights into the genetic basis of carcinogenesis have been obtained by modern molecular biological techniques. Several susceptibility genes are known. The hereditary breast and ovarian cancer syndrome (germline mutations in BRCA1 and BRCA2) and endometrial cancer in the context of the hereditary non-polyposis colorectal cancer syndrome (HNPCC), germline mutations in mismatch-repair genes, are the most frequent hereditary cancer syndromes in gynaecology. Mutations in TP53 (Li-Fraumeni syndrome) and PTEN (Cowden's disease), associated with increased risk of breast cancer, are responsible for a smaller portion of familial breast cancer.The risk of inheritance and disease can be identified and defined by investigating family history, risk calculation programs, and genetic testing. Afterwards, options of primary, secondary, and tertiary prevention can be formulated. Presently, prophylactic surgery is the only option proven by clinical trials that can reduce the mortality of hereditary breast and ovarian cancer.     

Hereditary breast cancer: part II. Management of hereditary breast cancer: implications of molecular genetics and pathology

Abstract:  Management of patients at high risk for hereditary breast cancer (HBC) must critically assess its phenotypic and genotypic heterogeneity, particularly evidenced by the varying spectra of cancer sites that are integral to the respective HBC syndromes. Targeted management must consider their biology, pathology, and molecular genetics, all in concert with their respective carcinogenic pathways, as they may differ significantly from one breast cancer syndrome to the next. A striking example of management differences pertains to BRCA1 and BRCA2 mutation-positive breast cancers wherein those with BRCA1 mutations are frequently estrogen receptor (ER)-negative in contrast to BRCA2 mutations which are more frequently ER-positive; therein, significant differences exist with respect to anti-estrogen therapy which will be more amenable to BRCA2 versus BRCA1 mutation carriers manifesting breast cancer. In turn, tumors that are negative for ER, PR, and Her2-neu, often referred to as "triple negative" tumors, may also harbor a unique basal-like gene expression profile and are characterized by poor prognosis wherein endocrine and/or Her2-neu-targeted therapies are not effective treatment options. A further confounder pertains to the lifetime risk for ovarian cancer, which differs strikingly between BRCA1 mutation carriers, who show a 40–60% lifetime risk, and their BRCA2 counterparts, who carry a lifetime risk of approximately 12–15% for ovarian cancer. It is clear that as we learn more about the biology and the molecular aspects of hereditary forms of breast cancer, it will be compelling for the clinician to integrate this knowledge with pharmacologic, radiologic, and surgical treatment options for these high-risk patients.     

The Lynch syndrome II and urological malignancies

The role of host factors in the etiology of carcinoma of the ureter has received only limited attention. We describe 4 Lynch syndrome II kindreds in which carcinoma of the ureter, as well as other forms of urological cancer, have occurred either in obligate gene carriers and/or in association with multiple primary cancers that are integral to this autosomal dominantly inherited disorder. These new findings are in accord with increasing recognition of tumor heterogeneity in the Lynch syndrome II, which currently, in addition to an excess of proximal colonic cancer as well as carcinoma of the endometrium, ovary and small bowel, also may include carcinoma of the ureter as well as other urological forms of cancer as integral lesions in subsets of these families. These observations have important ramifications for better understanding of the etiology, pathogenesis and control of urological cancer in this disorder.     

Clinicopathological characteristics of patients with upper urinary tract urothelial cancer with loss of immunohistochemical expression of the DNA mismatch repair proteins in universal screening

Objectives

To assess the detection rate of putative Lynch syndrome‐associated upper urinary tract urothelial cancer among all upper urinary tract urothelial cancers and to examine its clinicopathological characteristics.

Methods

A total of 143 patients with upper urinary tract urothelial cancer who had received total nephroureterectomy were immunohistochemically stained for the expression of mismatch repair proteins MLH1, PMS2, MSH2 and MSH6. For all suspected mismatch repair‐deficient cases, MMR genetic testing was recommended and clinicopathological features were examined.

Results

Loss of mismatch repair proteins was found in seven patients (5%) who were thus categorized as putative Lynch syndrome‐associated upper urinary tract urothelial cancer. Five of these patients showed dual loss of MSH2/MSH6. Two patients were confirmed to be MSH2 germline mutation carriers. Histologically, all seven tumors were low‐grade atypical urothelial carcinoma and showed its unique histological features, such as an inverted papilloma‐like growth pattern and a villous to papillary structure with mild stratification of tumor cells. Six tumors had no invasion of the muscularis propria. No recurrence or cancer‐related deaths were reported in these seven patients. Just three patients met the revised Amsterdam criteria.

Conclusions

This is the first report that universally examined mismatch repair immunohistochemical screening for upper urinary tract urothelial cancers. The prevalence (5%) of putative Lynch syndrome‐associated upper urinary tract urothelial cancers is much higher than we had expected. We ascertained that putative Lynch syndrome‐associated upper urinary tract urothelial cancers were clinically in the early stage and histologically classified into low‐grade malignancy with its characteristic pathological features. The clinicopathological characteristics that we found in the present study could become additional possible markers in the diagnosis of Lynch syndrome‐associated upper urinary tract urothelial cancers.     

Hereditary Breast Cancer: Risk Assessment Is the Easy Part

Individuals who seek genetic testing to determine hereditary risk of breast cancer may not be aware that genetic testing is uninformative in many high-risk families or that they may be at increased risk of other cancers as well. Many mistakenly believe that current genetic testing provides definitive information about the magnitude of cancer risk to carriers. This article describes the assessment of hereditary risk by pedigree analysis, epidemiology, and genetic testing within the cancer risk assessment and counseling setting, and discusses other information that helps patients to make informed health care decisions. Because the risk of ovarian cancer is increased in many families at high risk of breast cancer, information about prophylactic oophorectomy and hormone replacement therapy is essential. A case history is presented to show the efficacy of cancer risk assessment and counseling when genetic testing is uninformative. ▪     

Testing for Hereditary Predisposition in Patients with Gynecologic Cancers,Quo Vadis?

Genetic testing for a hereditary predisposition to gynecologic cancers has been available clinically since the 1990s. Since then, knowledge of the hereditary contribution to gynecologic cancers has dramatically increased, especially with respect to ovarian cancer. Although knowledge of the number of gynecologic cancer–predisposing genes has increased, the integration of genetic predisposition testing into routine clinical practice has been much slower. This article summarizes the technical and practical aspects of genetic testing in gynecologic cancers, the potential barriers to more widespread access and practice of genetic testing for hereditary predisposition to gynecologic cancers, and the potential solutions to these barriers.     

Breast Cancer Genes

Abstract: The identification of familial breast cancer genes heralds an era of directed breast cancer treatment. Currently, two hereditary breast cancer genes have been identified, BRCA-1 and BRCA-2 . Although accounting for only approximately 5% of all breast cancers, they are being used to identify women with germ-line alterations that are at high risk of developing breast or ovarian cancer. With the identification of such genes comes a need for consideration of the ethical issues associated with testing. These genes are also being examined from a biochemical standpoint encompassing both their biological roles and biochemical pathways in which they reside. Such studies are likely to lead to novel breast cancer therapies.