First report of ovarian dysgerminoma in Cowden syndrome with germline PTEN mutation and PTEN-related 10q loss of tumor heterozygosity

We present the first report of ovarian dysgerminoma in Cowden syndrome, presenting in a 7-year-old girl. In her second decade, a hamartomatous soft tissue extremity mass and diffuse gastrointestinal hamartomatous polyposis with pathologic features suggestive of either juvenile, Peutz-Jeghers, or Cowden polyps were identified, along with diffuse esophageal glycogenic acanthosis and skin manifestations. During regular thyroid cancer surveillance under the provisional diagnosis of Cowden syndrome, papillary thyroid carcinoma and benign follicular nodules were diagnosed at age 23. PTEN mutational analysis revealed a novel germline nonsense point mutation of Q219X. Loss of PTEN heterozygosity was also present in the ovarian dysgerminoma. Parental mutation testing and phenotype screening were negative. The correct classification of Cowden syndrome is difficult because of its protean manifestations and overlapping phenotypes with other genetic and noninherited pathologies, particularly regarding various gastrointestinal polyposis syndromes. Despite the challenges, correct classification is critical to patient care because of the associated cancer predispositions and necessary surveillance programs. This is the first report of Cowden syndrome presenting with ovarian dysgerminoma, which implicates PTEN in the molecular pathogenesis of dysgerminoma and adds it to the phenotypic manifestations of Cowden syndrome.     

Hereditary colorectal cancer associated with polyposis syndromes

This study reviews different aspects of hereditary colorectal cancer associated with three polyposis syndromes: familial adenomatous polyposis, juvenile polyposis coli and Peutz-Jeghers syndrome. All these syndromes share some similarities: low incidence, autosomal dominant inheritance, genetic predisposition to colorectal cancer and/or other extracolonic cancers. Classical familial adenomatous polyposis is clinically defined by the presence of hundreds of adenomatous polyps in the colon and rectum, whereas less than 100 polyps are found in attenuated familial adenomatous polyposis. Without prophylactic colectomy, colorectal cancer develops inevitably by the age of 40. Restorative proctocolectomy with ileal anal-pouch anastomosis is the operation of choice in familial adenomatous polyposis. In juvenile polyposis coli, 50-200 hamartomatous polyps are found in the colon, rectum, stomach and small bowel. Life-time cumulative risk for colorectal cancer is estimated to be 50%. Prophylactic colectomy is required only in cases in which endoscopic surveillance is not able to control polyp development. Hereditary mixed polyposis syndrome is a variant form of juvenile polyposis coli, consisting of multiple mixed adenomatous, hyperplastic and hamartomatous polyps. Peutz-Jeghers syndrome is characterized by multiple hamartomatous polyps located in the small bowel, colon and stomach. Small bowel follow through and colonoscopy is advised for surveillance. Surgery is warranted only in cases of polyps larger than 1 cm. The causative genes of these syndromes have been cloned. Molecular genetic testing of affected and at-risk individuals is proposed in order to advise surveillance and management.     

Hereditary gastrointestinal polyposis syndromes

Hereditary gastrointestinal polyposis syndromes can be divided into adenomatous and hamartomatous types. Familial adenomatous polyposis coli (FAPC) is the prototype adenomatous polyposis syndrome and is defined by the autosomal dominant transmission of multiple (more than 100) colorectal adenomas. Virtually all affected patients develop colorectal carcinoma if untreated. Adenomas may develop also in the stomach and small bowel in FAPC patients, but the incidence of carcinoma in these sites is low. A variety of extracolonic manifestations has been reported in FAPC, with the name Gardner's syndrome applied to kindreds with osteomas of the skull and mandible, multiple epidermal cysts, and other skin and soft-tissue lesions. In Turcot's syndrome, brain tumors are present. The distinction between Gardner's and Turcot's syndromes and classical FAPC has become blurred because of marked overlap between them; some authorities consider them to be varying manifestations of a single genetic defect. The hamartomatous polyposes include Peutz-Jeghers syndrome, familial juvenile polyposis, Cowden's disease, intestinal ganglioneuromatosis, and the Ruvalcaba-Myrhe-Smith syndrome. The incidence of gastrointestinal cancer in patients with Peutz-Jeghers syndrome and familial juvenile polyposis exceeds that in the normal population, but is relatively low. In Cowden's disease, the gastrointestinal tract may be the site of multiple hamartomas, but there is no associated increase in the incidence of gastrointestinal cancers; instead, there is an increased incidence of carcinoma of the breast and thyroid. Intestinal ganglioneuromatosis occurs in von Recklinghausen's disease, in association with multiple endocrine neoplasia, type 2b, or as an isolated abnormality. Patients with ganglioneuromatosis do not appear to have an increased risk of developing gastrointestinal cancer. Ruvalcaba-Myrhe-Smith syndrome comprises macrocephaly, mental deficiency, an unusual craniofacial appearance, hamartomatous intestinal polyposis, and pigmented macules on the penis. No increased risk of developing cancer has been identified in the few reported cases.     

Comment prendre en charge un patient porteur de polype hamartomateux ?

Digestive hamartomatous polyps are a rare entity. They may be sporadic (solitary Peutz-Jeghers polyp or solitary juvenile polyp) or reveal a real genetic predisposition like Peutz-Jeghers syndrome, juvenile polyposis, Cowden disease or Cronkhite-Canada syndrome. The diagnosis is based on personal and family history and on the clinical data including the number of polyps and their histological features. The risk of intestinal and extra-intestinal cancers related to these genetic predispositions is high and requires multidisciplinary management (oncogenetic counseling, gastroenterologist, pathologist, dermatologist, gynecologist, and endocrinologist) for such patients. Endoscopic evaluation is very helpful to establish a current situation, to perform polypectomy, and to allow a good histological examination of these polyps whose degeneration has been exceptionally described.     

遗传性结直肠癌突变基因序列的研究进展

目的总结遗传性结直肠癌不同病种相关基因测序的研究进展。方法查阅近年来国内外关于遗传性结直肠癌基因测序的相关文献并加以综述。结果依据是否与已知致癌基因的种系突变相关可将遗传性结直肠癌分为两大类。已知种系突变基因中,腺瘤样结肠息肉易感基因(adenomatous polyposis coli,APC)、MUTYH基因、胸腺嘧啶乙二醇DNA糖基化酶1(NTHL1)基因、编码DNA聚合酶ε基因[polymerase(DNA)epsilon,catalytic subunit,POLE]和编码DNA聚合酶δ基因[polymerase(DNA)delta 1,catalytic subunit,POLD1]与腺瘤性息肉病综合征相关;错配修复(mismatch repair,MMR)相关基因与林奇综合征相关;丝氨酸/苏氨酸激酶11(serine/threonine kinase 11,STK-11)基因与Peutz-Jeghers综合征相关;幼年性息肉病综合征个体中发现SMAD4基因和骨形态发生蛋白1A型受体(bone morphogenetic protein receptor type 1A,BMPR1A)基因突变;考登综合征由磷酸酶张力蛋白同源物基因(phosphatase and tensin homology deleted on chromosome ten,PTEN)突变引起。种系突变未知但遗传特性明显的结直肠癌病种中(如增生性息肉病),也逐渐搜寻出可能相关的基因,有待进一步取证。结论结直肠癌是一种具有遗传特性的恶性肿瘤,相比散发性结直肠癌,遗传性结直肠癌从腺瘤演变为癌的时间缩短更明显,并且发生异时性肿瘤的概率也明显增高,但积极干预后的生存率却高于散发者。研究遗传性结直肠癌相关病种的突变基因序列,是当代医学在疾病掌控方面的提升和发展。     

Hereditary polypoid diseases of the gastrointestinal tract: A working classification

Almost all published cases of hereditary intestinal polypoid diseases can be meaningfully classified into a relatively few distinct syndromes including familial polyposis of the colon, Peutz-Jeghers syndrome, and juvenile polyposis.Familial polyposis is characterized by the development of numerous adenomatous polyps of the colon and subsequent development of colorectal carcinoma in nearly all patients. Extracolonic manifestations are common but do not influence the premalignant nature of this syndrome.Peutz-Jeghers syndrome is identifiable by a combination of circumoral melanin pigmentation and hamartomatous polyps. These polypoid lesions have an unusually wide distribution and may occur in the respiratory, gastrointestinal, or genitourinary tract. There is a small but definite increased incidence of gastrointestinal cancer in these patients.Juvenile polyposis presents a more variable spectrum. In one form there is extensive intestinal involvement leading to diarrhea, inanition, and increased susceptibility to infection. Another form is limited to the colon and easily confused with familial polyposis. With the third form, there is involvement of the stomach, intestines, and colon, which makes it easily mistaken for the Peutz-Jeghers syndrome.     

Inherited tumors of the gastrointestinal tract. Diagnosis and therapeutic aspects]

Familial tumors of the gastrointestinal tract, which often appear as autosomal-dominantly inherited tumor syndromes, account for only a small proportion of all gastrointestinal tumors. With the opportunities of modern molecular diagnostics, identifying the pathogenic mutation in families is often possible, with the option of predictive molecular testing and differentiation between mutation carriers and noncarriers. Thus a good chance exists for detection of early tumor stages by individually tailored surveillance programs and for improving prognosis by early intervention and prophylactic resection. Clinical manifestation, molecular basis at the root, individual surveillance programs, and their consequences for the treatment of familial gastric cancer, familial adenomatous polyposis coli, hereditary nonpolyposis colorectal cancer, Peutz-Jeghers syndrome, juvenile polyposis, hyperplastic polyposis, and familial pancreatic cancer are presented.     

Erbliche Tumoren im Gastrointestinaltrakt

Familial tumors of the gastrointestinal tract, which often appear as autosomal-dominantly inherited tumor syndromes, account for only a small proportion of all gastrointestinal tumors. With the opportunities of modern molecular diagnostics, identifying the pathogenic mutation in families is often possible, with the option of predictive molecular testing and differentiation between mutation carriers and noncarriers. Thus a good chance exists for detection of early tumor stages by individually tailored surveillance programs and for improving prognosis by early intervention and prophylactic resection. Clinical manifestation, molecular basis at the root, individual surveillance programs, and their consequences for the treatment of familial gastric cancer, familial adenomatous polyposis coli, hereditary nonpolyposis colorectal cancer, Peutz-Jeghers syndrome, juvenile polyposis, hyperplastic polyposis, and familial pancreatic cancer are presented.     

Phenotypic characteristics of hereditary non-polyposis colorectal cancer by the Amsterdam criteria: an Asian perspective

Background: Hereditary non‐polyposis colorectal cancer (HNPCC) is an autosomal disease with a 68–82% lifetime risk of colorectal cancer (CRC). This study examined the phenotypic characteristics of CRC in Amsterdam criteria‐positive Asian patients from the Singapore Polyposis Registry. Methods: Hereditary non‐polyposis CRC patients, defined by the Amsterdam I and II criteria, prospectively monitored in the Singapore Polyposis Registry over a 16‐year period were reviewed. Clinical data were obtained from a computerized database and parameters, such as age of diagnosis, type and location of CRC, other associated cancers in the pedigree, cancer recurrence and survival were analysed. Results: Fifty‐two patients (31 men and 21 women) from 42 unrelated families, with a median age of 44.5 years (range 27–73 years), fulfilled either Amsterdam I or II criteria and were included in our analysis. The racial distribution was 91% (n = 47) Chinese and 9% (n = 5) Malays, with a median follow up of 44.9 months (range 2–183 months). Significantly, 69% of tumours in this Amsterdam‐defined cohort were left sided, with most being sigmoid cancers. Sixty per cent of all the tumours presented at a late stage (Dukes’ C or D). Left‐sided tumours presented with more advanced Dukes’ stage (P = 0.096) and a higher rate of metastatic disease (P = 0.08) compared with right‐sided lesions. There were, however, no significant differences in either disease‐free or overall survival between right‐sided and left‐sided tumours. Conclusion: This study emphasized the significant left‐sided predominance of CRC in Amsterdam I and II‐defined patients from our predominantly Chinese population, in contrast to those classically described in Lynch syndrome. Amsterdam criteria thus may not be suitable for diagnosing HNPCC in Asian populations and a greater emphasis should be made towards routine molecular diagnosis of mismatch repair gene defects in suspected HNPCC patients of Asian decent.     

Colorectal carcinogenesis. 1. Hereditary predisposition and colorectal cancer

Tumors arising sporadically represent 70-80% of colorectal cancer (CRC). The two best defined forms of inherited CRC-familial multiple polyposis (FMP) and Hereditary Non-Polyposis Colon Cancer (HNPCC) account respectively for<1% and 2-3% of CRC. These rare genetic syndromes (FMP, HNPCC, Peutz-Jeghers Syndrome) are caused by major predisposing gene mutations (APC gene, MMR gene, BMPR1A. SMAD4,...) and local environmental factors play only a minor role. In the sporadic forms of CRC, 25% have significant genetic predisposition probably related to alleles with weak penetration (APC*I1307K, TGFbR1*6Ala...) and are more strongly affected by environmental factors.     

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.     

Puetz-Jeghers syndrome involving appendix

Puetz-Jegher's syndrome is an autosomal dominant hereditary disease, which is characterized by hamartomatous polyposis and mucocutaneous pigmentation mainly over the circum-oral region. Patients with Peutz-Jeghers syndrome seek medical attention whenever there are complications such as intussusception, bleeding from the polyps, etc. Occasionally, gastrointestinal tract malignancies have been reported in Peutz-Jeghers syndrome. In this paper, we report a patient with Peutz-Jeghers syndrome who had multiple complications and polyposis involving the appendix, because involvement of the appendix is extremely rare in Peutz-Jeghers syndrome.     

Evaluating Causes of Death in Familial Adenomatous Polyposis

Background  

Familial adenomatous polyposis is a genetic syndrome associated with an increased risk of colorectal cancer (CRC) and different extracolonic manifestations.     

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.     

Clinical management and surgical treatment of distal fibular tumours: a case series and review of the literature

Purpose

Study reports clinical and functional outcomes of surgical treatment in a case series of nine patients with distal fibular tumours.

Methods

Nine patients with distal fibular tumours were observed between 2005 and 2010. A PubMed search was performed using the terms “fibula”, “lower limb tumour [cancer]”, “sarcoma”, “Ewing”, “peroneal”, “fibular metastasis”, and “limb-salvage surgery”.

Results

In all our patients, lesions were unilateral. All patients complained of pain; limping was present in 5 of 9 tumours. Patients were managed surgically, except one who underwent local radiotherapy. In six patients, a benign or tumor-like lesion was detected. Malignancies consisted of metastatic lung adenocarcinoma (two cases) or multifocal mesenchymal cancer (one case). Non-malignant lesions were treated by curettage and filling, followed by internal fixation when needed. In malignant or locally aggressive lesions, metadiaphyseal fibular resection was performed. The literature search retrieved either case reports or small case series, reflecting the rarity of distal fibular tumours. Surgical treatment was successful in all patients with benign lesions, whereas the rate of success was 40–100 % in case of malignancies.

Conclusions

Given the low incidence of distal fibular tumours, controversies exist about the optimal surgical management. Clinical observation and imaging should be reserved to asymptomatic benign lesions. In non-malignant tumours causing pain, limping, and pathological fractures; in malignancies, surgery is recommended. Finally, in patients with asymptomatic lesions of uncertain nature, biopsy and histological examination should be performed to plan appropriate management.     

Is omentectomy necessary in the treatment of benign or malignant abdominal pathologies? A systematic review

BACKGROUNDThe omentum is an organ that is easily sacrificed during abdominal surgery. The scope of omentectomy and whether a routine omentectomy should be performed are still unknown. AIMTo review the literature in order to determine the physiological functions of the omentum and the roles it plays in pathological events in order to reveal the necessity for removal and preservation of the omentum. METHODSA clinical review of the English language literature based on the MEDLINE (PubMed) database was conducted using the keywords: “abdomen”, “gastrointestinal”, “tumor”, “inflammation”, “omental flap”, “metastasis”, “omentum”, and “omentectomy”. In addition, reports were also identified by systematically reviewing all references in retrieved papers.RESULTSThe omentum functions as a natural barrier in areas where pathological processes occur in the abdominal cavity. The omentum limits and controls inflammatory and infectious pathologies that occur in the abdomen. It also aids in treatment due to its cellular functions including lymphatic drainage and phagocytosis. It shows similar behavior in tumors, but it cannot cope with increasing tumor burden. The stage of the disease changes due to the tumor mass it tries to control. Therefore, it is considered an indicator of poor prognosis. Due to this feature, the omentum is one of the first organs to be sacrificed during surgical procedures. However, there are many unknowns regarding the role and efficacy of the omentum in cancer.CONCLUSIONThe omentum is a unique organ that limits and controls inflammatory processes, foreign masses, and lesions that develop in the abdominal cavity. Omental flaps can be used in all anatomical areas, including the thorax, abdomen, pelvis, and extremities. The omentum is an organ that deserves the title of the abdominal policeman. It is generally accepted that the omentum should be removed in cases where there is tumor invasion. However, the positive or negative contribution of omental resection in the treatment of abdominal pathologies should be questioned.     

Cowden syndrome: report of a case with immunohistochemical analysis and review of the literature.

Cowden syndrome is a rare condition defined by multiple hamartomatous growths and a guarded prognosis owing to the high risk of cancer development. The syndrome is inherited as an autosomal dominant trait with incomplete penetrance and variable expressivity. The PTEN/MMAC1/TEP1 tumor suppressor gene on chromosome 10q23.3, has proven to contain a germline mutation predisposing for uncontrolled cell growth and survival via the PI3K/AKT pathway. Presented here is a case of Cowden syndrome in a patient with multiple hamartomas of the nose, midfacial skin and oral mucosa, and fissured tongue; plus a history of bipolar disease, iron deficiency anemia, basal cell carcinoma, fibroids of the uterus, and arthritis. The family history was significant for a daughter diagnosed with lung cancer. A final diagnosis of Cowden syndrome was made on the basis of established criteria and confirmed using immunohistochemistry directed against PTEN and phosphorylated-AKT.     

Watch and wait approach to rectal cancer: A review

In 2014, there were an estimated 136800 new cases of colorectal cancer, making it the most common gastrointestinal malignancy. It is the second leadingcause of cancer death in both men and women in the United States and over one-third of newly diagnosed patients have stage Ⅲ(node-positive) disease. For stage Ⅱ and Ⅲ colorectal cancer patients, the mainstay of curative therapy is neoadjuvant therapy, followed by radical surgical resection of the rectum. However, the consequences of a proctectomy, either by low anterior resection or abdominoperineal resection, can lead to very extensive comorbidities, such as the need for a permanent colostomy, fecal incontinence, sexual and urinary dysfunction, and even mortality. Recently, trends of complete regression of the rectal cancer after neoadjuvant chemoradiation therapy have been confirmed by clinical and radiographic evaluationthis is known as complete clinical response(cC R). The "watch and wait" approach was first proposed by Dr. Angelita Habr-Gama in Brazil in 2009. Those patients with c CR are followed with close surveillance physical examinations, endoscopy, and imaging. Here, we review management of rectal cancer, the development of the "watch and wait" approach and its outcomes.