Molecular genetic alterations in hamartomatous polyps and carcinomas of patients with Peutz-Jeghers syndrome

AIM: To investigate whether mutations in the STK11/LKB1 gene and genes implicated in the colorectal adenoma-carcinoma sequence are involved in Peutz-Jeghers syndrome (PJS) related tumorigenesis. METHODS: Thirty nine polyps and five carcinomas from 17 patients (from 13 families) with PJS were analysed for loss of heterozygosity (LOH) at 19p13.3 (STK11/LKB1 gene locus), 5q21 (APC gene locus), 18q21-22 (Smad4 and Smad2 gene locus), and 17p13 (p53 gene locus), and evaluated for immunohistochemical staining of p53. In addition, mutational analysis of K-ras codon 12, APC, and p53 and immunohistochemistry for Smad4 expression were performed on all carcinomas. RESULTS: LOH at 19p was seen in 15 of the 39 polyps and in all carcinomas (n = 5). Interestingly, six of the seven polyps from patients with cancer had LOH, compared with nine of the 31 polyps from the remaining patients (p = 0.01). In one polyp from a patient without a germline STK11/LKB1 mutation, no LOH at 19p or at three alternative PJS candidate loci (19q, 6p, and 6q) was found. No LOH at 5q was observed. However, mutational analysis revealed an APC mutation in four of the five carcinomas. LOH at 17p was not seen in polyps or carcinomas; immunohistochemistry showed expression of p53 in one carcinoma and focal expression in three polyps. At subsequent sequence analysis, no p53 mutation was found. One carcinoma had an activating K-ras codon 12 mutation and another carcinoma showed 18q LOH; however, no loss of Smad4 expression was seen. CONCLUSIONS: These results provide further evidence that STK11/LKB1 acts as a tumour suppressor gene, and may be involved in the early stages of PJS tumorigenesis. Further research is needed to see whether LOH in PJS polyps could be used as a biomarker to predict cancer. Differences in molecular genetic alterations noted between the adenoma-carcinoma sequence and PJS related tumours suggest the presence of a distinct pathway of carcinogenesis.     

A case of Peutz-Jeghers syndrome associated with high-grade intramucosal neoplasia

Peutz-Jeghers syndrome (PJS) is a rare, inherited autosomal dominant disease characterized by mucocutaneous pigmentation and polyps in the gastrointestinal tract. Here, we report the rare case of a 64-year-old female patient with pigmentation on her lips and extremities for over 63 years and intermittent abdominal pain and, diarrhea for 3 years. The presence of intestinal and colorectal hamartomatous polyps was confirmed. The removal and characterization of her rectal polyp showed it to be a typical hamartomatous polyp with a portion of it being an adenoma with high-grade intramucosal neoplasia. A survey of the patient’s family identified 9 people in the family with Peutz-Jeghers syndrome and three of them have already died from colorectal cancer. This case study serves as an example of how imperative it is to survey the patient about their family history in order to detect early cancerous lesions.     

Intra-abdominal desmoplastic small cell tumour in a patient with Peutz-Jeghers syndrome

A surgical case of intra-abdominal desmoplastic small cell tumour with divergent differentiation (IDS-CT) in a patient with Peutz-Jeghers syndrome (PJS) is reported. The patient was a 23-year-old woman who underwent surgery for a tumour in the left paraovarian region. Widespread peritoneal metastases were noted. Histopathological examination revealed solid cell nests composed of medium-sized cells demarcated by desmoplastic stroma. Gland-like spaces were found within many cell nests. Tumour cells were positive for cytokeratin and smooth muscle actin, but negative for desmin. Both ovaries contained minute foci of a sex cord tumour with annular tubules. This is the first documentation of the association of IDSCT with PJS. Since patients with PJS have an increased risk of cancer in various organs, the occurrence of IDSCT in the present patient might not be fortuitous.     

Peutz-Jeghers syndrome with osseous metaplasia of the intestinal polyps

A cam of Peutz-Jeghers syndrome (PJS) with osseous metaplasia In three of 15 hamartomatous polyps of the small Intestine Is reported. At 35 years of age, the patient was diagnosed as having PJS by cutaneous pigmentation around the mouth and polyposis of the stomach, duodenum and Intestine. Fifty-two polyps of the large intestine were resected, which were Characteristic of those of PJS. Three of them showed adenomatous and carcinomatous changes, but there was no osseous metaplasia in any of the resected polyps. At age 40, he had surgery under the diagnosis of Intestinal obstruction. There were 15 polyps in the resected jejunum. These polyps were also characteristic of those of PJS. Additionally, three of these polyps were accompanied by osseous metaplasia. Histologically, mature bone formation and Calcification were found close to the hyperplastic glands In the submucosa or in the propriate muscle. Malignant transformation was not observed. Osseous metaplasia is extremely rare in benign potyps, and it has not been reported in hamartomatous polyps of PJS to date. The knowledge of this association may be helpful in the clinical diagnosis of this benign lesion in PJS.     

家族性Peutz-Jeghers综合征患者LKB1基因胚系突变的分析

目的 研究家族性Peutz-Jeghers综合征患者中LKB1基因胚系突变特征.方法 收集11个Peutz-Jeghers综合征家系,各家系先证者均有典型的黏膜黑斑以及肠道错构瘤性息肉.提取先证者外周血DNA,PCR扩增LKB1基因的9个外显子及其侧翼的部分内含子序列,测序并分析其变异情况和突变性质.收集250名正常人外周血并提取DNA,聚合酶链反应-变性高效液相色谱筛查验证.结果 11个家系先证者中有8例患者LKB1基因外显子及侧翼碱基序列存在杂合性变异,变异类型共9种,包括7种点突变,1种外显子区域小片段碱基缺失以及1种侧翼内含子小片段碱基插入.其中4种考虑为病理性突变,还有4种仅为基因多态性表现,另外有1种变异性质未定.结论 LKB1基因病理性突变是中国人家族性Peutz-Jeghers综合征患者的常见病因,且以点突变为主.     

When to suspect and how to diagnose syndromic polyps and carcinomas of the gastrointestinal tract: focus on Lynch syndrome and colonic hamartomatous polyposis

An estimated 130,000 individuals are diagnosed with colorectal carcinoma each year, and approximately 50,000 will die from this disease, making colorectal carcinoma the third leading cause of cancer deaths in the United States.¹ Heritable forms of colorectal carcinoma are common. These heritable conditions may manifest as a polyposis or as colorectal carcinoma. In this review, the pathology of hamartomatous polyps will be discussed with particular emphasis on clues that should alert pathologists to the possibility of a polyposis syndrome. This review will also provide tools for pathologists to identify patients at risk for Lynch syndrome.     

应用多重连接依赖性探针扩增和变性高效液相色谱技术筛查Peutz-Jeghers综合征家系致病基因突变

目的 联合应用多重连接依赖性探针扩增(MLPA)和变性高效液相色谱(DHPLC)技术快速筛查Peutz-Jeghers综合征家系致病基因的突变.方法 收集家系成员的外周血,采用MLPA、PCR-DNA测序等方法分别检测了LKB基因大片段缺失、碱基突变、碱基插入和缺失.同时收集250名正常人外周血,PCR-DHPLC筛查验证突变位点在正常人群中的分布.生物信息学分析突变位点对编码蛋白质结构和功能的影响.结果 2名家系受累成员均携带LKB基因924G＞C点的突变,这一突变位点在家系正常人和正常人群中都不存在.突变导致位于功能结构域的第308位编码氨基酸由色氨酸变为半胱氨酸,变异蛋白质结构和功能发生改变.结论 c.924G＞C位点的突变是一种病理性胚系突变,编码氨基酸的改变(Trp308Cys)是此家系的致病性因素.     

Metaplastic polyps and polyposis of the colorectum

Five hundred and fifty-four colorectal metaplastic polyps have been studied histologically. Whilst most lesions were small and sessile, 16.1% measured greater than 0.5 cm in diameter and 0.9% were greater than 1 cm. The larger polyps were frequently pedunculated and occasionally showed a tubulo-villous or villous pattern. A structural similarity between the larger metaplastic polyps and colorectal adenomas is illustrated and the importance of the distinction of metaplastic from dysplastic epithelium in the differentiation of these lesions is stressed. Other unusual features of metaplastic polyps are described. Evidence is given to suggest that males have a greater propensity to develop metaplastic polyps than females. A search for metaplastic-like areas in other colorectal polyps revealed that they are rare (0.6%) in adenomas, but relatively frequent (20.8%) in juvenile polyps. Finally, seven patients with multiple metaplastic polyps of the colorectum are described, in whom a diagnosis of adenomatous polyposis had been made at some stage in their management. Six of the seven patients were males and the mean age at presentation was 37.4 years. Larger metaplastic polyps were frequent in these cases. The necessity for histological confirmation in all cases of intestinal polyposis is stressed, and the possibility that 'metaplastic polyposis' is a pathological entity is discussed.     

结直肠非浸润性上皮性病变:炎性病变相关性息肉和错构瘤性息肉的病理诊断

结直肠炎性病变相关性息肉比较常见,由于形态多样容易误诊,从而造成临床过度治疗或不必要的干预;也有些少见病变如内翻性憩室则易漏诊而延误治疗。错构瘤性息肉如多发者或出现少数特殊形态常提示患者可能有相关综合征,具较高的癌症发生危险,需要及时治疗和规范随访。     

An unusual bandlike web in an infant with lethal multiple pterygium syndrome

We report on a patient with a lethal multiple pterygium syndrome who also had an unusual, bandlike web across one axilla and partial intestinal atresia. Umbilical cord wrapping with subsequent vascular compromise appears to be the most likely pathogenetic mechanism for the additional anomalies.     

P16-positive continuous minimal deviation adenocarcinoma and gastric type adenocarcinoma in a patient with Peutz-Jeghers syndrome

We report a case of Peutz-Jeghers syndrome (PJS) in a 33-year-old female patient with synchronous uterine cervical minimal deviation adenocarcinoma (MDA) and gastric type adenocarcinoma (GTA). The patient was diagnosed with PJS at the age of 10. At the time of consultation, she complained of watery discharge. Magnetic resonance imaging of the pelvis showed a poorly circumscribed mass in the uterine cervix. Histologically, both MDA and GTA components, as well as their transitional area, were observed. Both components were diffusely positive for MUC6, CK7 and, robustly, for p16. Moreover, the components were negative for ER, PgR and CEA, while HIK1083 and CK20 positive cells were found focally. Ki-67 labeling index in the MDA component was 5% while that in the GTA component was 50%. This case of GTA accompanied by MDA in a patient with PJS is distinct from the single previously-reported comparable case of which we are aware, with respect to the overexpression of p16 protein, an event considered rare in these tumors, and the continuity between the MDA and GTA components. This continuity favors the hypothesis that GTA arises from the dedifferentiation of MDA.     

Germline mutations of the LKB1 (STK11) gene in Peutz-Jeghers patients

Germline mutations of the LKB1 (STK11) serine/threonine kinase gene (chromosome 19p13.3) cause Peutz-Jeghers syndrome, which is characterised by hamartomas of the gastrointestinal tract and typical pigmentation. Peutz-Jeghers syndrome carries an overall risk of cancer that may be up to 20 times that of the general population. Here, we report the results of a screen for germline LKB1 mutations by DNA sequencing in 12 Peutz-Jeghers patients (three sporadic and nine familial cases). Mutations were found in seven (58%) cases, in exons 1, 2, 4, 6, and 9. Five of these mutations, two of which are identical, are predicted to lead to a truncated protein (three frameshifts, two nonsense changes). A further mutation is an in frame deletion of 6 bp, resulting in a deletion of lysine and asparagine; the second of these amino acids is conserved between species. The seventh mutation is a missense change in exon 2, converting lysine to arginine, affecting non-conserved amino acids and of uncertain functional significance. Despite the fact that Peutz-Jeghers syndrome is usually an early onset disease with characteristic clinical features, predictive and diagnostic testing for LKB1 mutations will be useful for selected patients in both familial and non-familial contexts.     

Fascin与上皮组织肿瘤

Fasc in基因属于fasc ins家族,其蛋白质编码产物是一种结构独特、进化保守的肌动蛋白(actin)交联蛋白,位于细胞膜皱褶、微棘及应力纤维,在各种转化细胞中促使细胞膜突起并增加细胞运动性。近年来的研究发现,fasc in在许多上皮来源的肿瘤组织细胞中表达上调,在肿瘤的进展中起重要作用。本文综述了fasc in的研究现状及其在上皮组织肿瘤中的研究进展。     

Sotos syndrome with intestinal polyposis and pigmentary changes of the genitalia

We report two adult males with the Sotos syndrome, who also presented intestinal polyposis and pigmentary spotting of the shaft and glans penis. We propose that patients with the Sotos syndrome may develop hamartoneoplastic disease and we urge clinicians to consider this possibility in those patients.     

骨髓增殖性肿瘤患者并发急性冠脉综合征相关因素分析

目的通过病例总结,分析骨髓增殖性肿瘤(MPN)患者中急性冠脉综合征(ACS)病例的特征,探讨其相关因素。方法选择2004年至2014年于北京协和医院住院并确诊MPN的125例患者,收集其人口学资料(年龄,性别)、心血管病危险因素(吸烟、高血压病、高脂血症和糖尿病)等信息,分析ACS病例的基本特征,通过Spearman相关性分析寻找ACS的可能相关因素。结果共7例ACS病例(发病率为5.6%);ACS组与非ACS组相比,既往冠心病史、血红蛋白(HGB)(P0.001)和白细胞(WBC)(P0.05)3个项目存在显著性差异;分析发现ACS与既往冠心病史、WBC计数呈显著正相关(P0.01)。结论 ACS是MPN人群主要血栓并发症之一;既往冠心病史,外周血白细胞增多可能与MPN人群的ACS相关。     

Identification of a novel STK11 gene mutation in a family affected with hereditary Peutz-Jeghers syndromeCSCD

Objective: To explore the genetic basis for a family affected with Peutz-Jeghers syndrome (PJS). Methods: Genomic DNA was extracted from peripheral blood and oral swab samples from the patient and her relatives. Next-generation sequencing (NGS) was used to analyze 106 target genes by capturing the exons and adjacent intronic regions. Suspected pathogenic mutation was verified by NGS. Results: A missense STK11 mutation was detected in the proband, which was not reported previously. The mutation has caused substitution of Leucine by Proline. NGS has detected the same mutation in the mother but not among other relatives. Conclusion: This hereditary case of PJS may be attributed to the missense mutation of the STK11 gene. © 2018 West China University of Medical Sciences. All rights reserved.     

Peutz-Jeghers Syndrome with multiple genital tract tumors and breast cancer: a case report with a review of literatures

We report here on the multiple genital tract neoplasms in a 41-yr-old Korean woman with Peutz-Jeghers Syndrome (PJS). The patient presented with lower abdominal pain. Her previous medical history was PJS and breast cancer. Pelvic ultrasound showed a multilocular cyst at the right adnexal region, diagnosed as bilateral ovarian mucinous borderline tumors. An ovarian sex cord tumor with annular tubules was incidentally diagnosed together with a minimal deviation adenocarcinoma of the uterine cervix and mucinous metaplasia of both the Fallopian tubal mucosa and the endometrium. Although the cases of multiple genital tract tumors with PJS has rarely been reported, the present case appears to be the first in Korea in which the PJS syndrome was complicated by multiple genital tract tumors and infiltrating carcinoma of the breast. The clinical significance of the multiple genital tract tumors and breast cancer associated with PJS is reviewed.     

Human intestinal spirochetosis is significantly associated with sessile serrated adenomas/polyps

It remains unclear whether or not human intestinal spirochetosis (HIS) has any associated symptoms or lesions. In this study, we assessed the prevalence of HIS in sessile serrated adenomas/polyps (SSA/Ps) and their possible association.     

A giant colonic hamartoma and multiple colonic hamartomatous polyps in a middle-aged man

Colonic hamartomas are rare polypoid lesions. We report an unusual case of multiple colonic hamartomatous polyps, including a giant hamartoma, unrelated to hereditary or familial polyposis syndromes, in a 48-year-old man. The diameter of the largest polyp was 9.5 cm, and endoscopy revealed that the lesion caused colonic obstruction. The clinical, endoscopic and histological aspects of this case are discussed.