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.     

Vascular pseudoinvasion in a solitary Peutz‐Jeghers polyp in the ileum

A Peutz‐Jeghers polyp (PJP) is a hamartomatous lesion characterized by arborescent smooth muscle bundles covered with mucosa native to the site of involvement. PJPs in the small intestine may represent misplacement of non‐neoplastic epithelium into the submucosa, muscularis propria and subserosa. Although epithelial misplacement in PJPs is a well‐documented phenomenon, pseudoinvasion even into the vascular space in PJPs has not previously been reported. We report a case of a 22‐year‐old Japanese woman with a solitary PJP in the ileum. The ileal PJP in this patient showed epithelial herniation even into the vascular space. All the herniated epithelium, including the epithelial components invaginated into the vascular space, demonstrated features of pseudoinvasion, that is, presence of normal small intestinal type mucosa accompanied by the lamina propria, absence of any stromal desmoplastic reaction, and retention of the basal‐luminal gradient. Pathologists must be aware of the possibility of vascular pseudoinvasion in small intestinal PJPs to avoid overdiagnosis of carcinoma and resulting unnecessary major surgery.     

Gastric polyps and polyposis syndromes

Gastric polyps show significant morphologic overlap, and some polyps defy classification altogether. Nevertheless, gastric polyps, particularly when profuse, should prompt further clinical and endoscopic investigation, as it may lead to the diagnosis of a polyposis syndrome. This review summarizes the common gastric polyps that are found in familial and non-inherited polyposis syndromes of the gastrointestinal tract. Examples of the gastric polyps are illustrated, and a discussion of polyp morphology and distribution is paired with a discussion of relevant clinical features and diagnostic criteria of polyposis syndromes. This information provides pathologists guidance for further patient workup, genetic testing, and cancer surveillance.     

Activating PDGFRA mutations in inflammatory fibroid polyps occur in exons 12, 14 and 18 and are associated with tumour localization

Huss S, Wardelmann E, Goltz D, Binot E, Hartmann W, Merkelbach‐Bruse S, Büttner R & Schildhaus H‐U (2012) Histopathology  61, 59–68 Activating PDGFRA mutations in inflammatory fibroid polyps occur in exons 12, 14 and 18 and are associated with tumour localization Aims: Inflammatory fibroid polyps (IFP) are mesenchymal tumours of the gastrointestinal tract. This study was performed to broaden the base of evidence of the pathogenic role of PDGFR mutations in IFP with particular regard to clinicopathological data and mutational patterns among IFP subtypes. Methods and results: Molecular analysis of 38 tumours revealed activating mutations in three different exons of PDGFRA in 25 IFP. For the first time we report two cases with PDGFRA‐exon 14 mutations (p.N659K; p.[N659K(+)T665A]). The results of our study and cases reported earlier indicate clearly that there is a localization‐specific pattern: exon 12 mutations predominate in the small intestine, while exon 18 mutations occur frequently in the stomach (P < 0.001). Codons 567–571 of PDGFRA represent an IFP specific mutational hot spot and are affected most frequently by deletions. Furthermore, in our series IFP of the stomach share common features. In contrast to intestinal IFP, gastric tumours occur at higher age, show heavy inflammation and tend to be smaller. IFP located in the small intestine are frequently associated with intussusception. Conclusion: We conclude that there is a ‘small bowel’ and a ‘gastric’ phenotype of IFPs which are associated with exon 12 and exon 18 PDGFRA mutations, respectively.     

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.     

Nine novel APC mutations in Italian FAP patients

Familial adenomatous polyposis (FAP) is a common hereditary syndrome characterized by early development of colorectal cancer consequent to extensive adenomatous polyps of the colon. In addition to the colonic manifestations the syndrome presents several extracolonic features including polyps of the upper gastrointestinal tract, congenital hypertrophy of the retinal pigment, jaw cysts, osteomata and desmoid tumors. In this study the entire APC coding region has been analysed for mutation in a panel of one Turcot and 33 unrelated Italian FAP patients using SSCP analysis, PTT and DNA sequencing. We detected APC mutations in 23 of them and identified nine which, to our knowledge were not previously reported. All of these novel mutations are in exon 15, including two nonsense mutations, 6 deletions or insertions leading to premature termination of the protein and one missense mutation (7697G>A). This last mutation occurs in the EB1-binding domain of the APC protein and segregates in four relatives of the patient with three of them presenting 2-3 adenomatous polyps.     

Conditional deletion of the Lkb1 gene in the mouse mammary gland induces tumour formation

Heterozygous germline mutations in the LKB1 (STK11) gene cause Peutz‐Jeghers syndrome (PJS), an autosomal dominant disorder characterized by hamartomatous polyposis of the gastrointestinal tract and an increased risk of colorectal, breast, and other cancers. To model the role of LKB1 mutation in mammary tumourigenesis, we have used a conditional gene targeting strategy to generate a mouse in which exons encoding the kinase domain of Lkb1 were deleted specifically in the mammary gland. Mammary gland tumours developed in these mice with a latency of 46–85 weeks and occurred in the thoracic or inguinal glands. These tumours were grade 2 invasive ductal carcinomas or solid papillary carcinomas with histological features similar to those described in breast cancers arising in patients with PJS. This mouse model of Lkb1 deficiency provides a potentially useful tool to investigate the role of Lkb1 in tumourigenesis and to guide the development of therapeutic approaches. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

High proportion of large genomic STK11 deletions in Peutz-Jeghers syndrome

Germline mutations in the STK11 gene have been identified in 10-70% of patients with Peutz-Jeghers syndrome (PJS), an autosomal-dominant hamartomatous polyposis syndrome. A second locus was assumed in a large proportion of PJS patients. To date, STK11 alterations comprise mainly point mutations; only a small number of large deletions have been reported. We performed a mutation analysis for the STK11 gene in 71 patients. Of these, 56 met the clinical criteria for PJS and 12 were presumed to have PJS because of mucocutaneous pigmentation only or bowel problems due to isolated PJS polyps. No clinical information was available for the remaining three patients. By direct sequencing of the coding region of the STK11 gene, we identified point mutations in 37 of 71 patients (52%). We examined the remaining 34 patients by means of the multiplex ligation-dependent probe amplification (MLPA) method, and detected deletions in 17 patients. In four patients the deletion extended over all 10 exons, and in eight patients only the promoter region and exon 1 were deleted. The remaining deletions encompassed exons 2-10 (in two patients), exons 2-3, exons 4-5, or exon 8. When only patients who met the clinical criteria for PJS are considered, the overall mutation detection rate increases to 94% (64% point mutations and 30% large deletions). No mutation was identified in any of the 12 presumed cases. In conclusion, we found that approximately one-third of the patients who met the clinical PJS criteria exhibited large genomic deletions that were readily detectable by MLPA. Screening for point mutations and large deletions by direct sequencing or MLPA, respectively, increased the mutation detection rate in the STK11 gene up to 94%. There may be still other mutations in the STK11 gene that are not detectable by the methods applied here. Therefore, it is questionable whether a second PJS locus exists at all.     

APC mutations in synovial sarcoma

It has previously been demonstrated that accumulated beta-catenin serves as an oncoprotein in synovial sarcoma and results in a poor overall survival rate, but the frequency of beta-catenin mutation was quite low (8.2%). The present study, using essentially the same study group of cases, screened for genetic alterations in the mutation cluster region (MCR) of the APC gene in 49 cases of synovial sarcoma. SSCP analysis followed by DNA direct sequencing revealed five missense APC mutations in four cases of synovial sarcoma (8.2%). The mutational sites comprised one case each at codons 1299 (GCT to ACT, Ala to Thr), 1412 (GGA to AGA, Gly to Arg), and 1414 (GTA to ATA, Val to Ile), in addition to one case with double point mutations at codon 1398 (AGT to AAT, Ser to Asn) and at codon 1413 (ATG to ATA, Met to Ile), together with beta-catenin mutation at codon 32 (GAC to TAC, Asp to Tyr). All four cases with APC mutations were histologically of the monophasic fibrous type and showed beta-catenin accumulation. All three cases with APC mutations available for follow-up data were long survivors. This study provides the first evidence that APC mutations also occur in the field of sarcoma, especially in synovial sarcoma.     

Novel mutations in the LKB1/STK11 gene in Dutch Peutz‐Jeghers families

The Peutz‐Jeghers syndrome (PJS) is a rare hereditary disorder in which gastrointestinal hamartomatous polyposis, mucocutaneous pigmentation, and a predisposition for developing cancer are transmitted in an autosomal dominant fashion. The recently identified LKB1/STK11 gene located at chromosome 19p13.3 is mutated in a number of PJS pedigrees. We performed mutation analysis in 19, predominantly Dutch, PJS families. In 12 of these families, we identified LKB1/STK11 mutations, none of which has been described before. These 12 novel LKB1/STK11 mutations consist of one nonsense mutation, three frameshift deletions, three frameshift insertions, two acceptor splice site mutations, and three missense mutations. In addition, we detected four polymorphisms in LKB1/STK11. In the remaining seven PJS families, we found no apparent abnormalities of the LKB1/STK11 gene, which could reflect the existence of locus heterogeneity in PJS. None of the mutations occurred in more than one family, and a number were demonstrated to have arisen de novo. The diverse array of mutations found, the apparent high mutation rate, as well as the existence of a possible second PJS locus, renders diagnostic or predictive genetic testing in individual patients difficult, although future identification of additional mutations or even gene(s) will help in increasing the yield of direct mutation analysis. Hum Mutat 13:476–481, 1999. © 1999 Wiley‐Liss, Inc.     

Mutations in the human LKB1/STK11 gene

The human LKB gene (official HUGO symbol, STK11) encodes a serine/threonine protein kinase that is defective in patients with Peutz-Jeghers syndrome (PJS). PJS is an autosomal dominantly inherited syndrome characterized by hamartomatous polyposis of the gastrointestinal tract and mucocutaneous pigmentation. To date, 145 different germline LKB1 mutations have been reported. The majority of the mutations lead to a truncated protein product. One mutational hotspot has been observed. A 1-bp deletion and a 1-bp insertion at the mononucleotide repeat (C6 repeat, c.837-c.842) between the codons 279-281 have been found in six and seven unrelated PJS families, respectively. However, these mutations account only for approximately 7% of all mutations identified in the PJS families (13/193). A review of the literature provides a total of 40 different somatic LKB1 mutations in 41 sporadic tumors and seven cancer cell lines. Mutations occur particularly in lung and colorectal cancer. Most of the somatic LKB1 mutations result in truncation of the protein. A mutational hotspot seems to be a C6 repeat accounting for 12.5% of all somatic mutations (6/48). These results are concordant with the germline mutation spectrum. However, the proportion of the missense mutations seems to be higher among the somatic mutations (45%) than among the germline mutations (21%), and only seven of the mutations are exactly the same in both of the mutation types.     

First genotype characterization of Argentinean FAP patients: identification of 14 novel APC mutations

We examined the adenomatous polyposis coli (APC) gene for disease-causing mutations in 51 unrelated Argentinean probands affected by familial adenomatous polyposis (FAP). Using a combination of the protein truncation test, the single strand conformation polymorphism technique, DNA sequencing and quantitative PCR analysis, we identified the specific mutation in 39 (average age: 28.4 years) of the 51 probands (detection rate: 76.47%); 13 are novel germline mutations and one is a novel sequence variant. There were 27 small deletions, four small duplications, five nonsense mutations in exon 15, three nonsense mutations in exons 6, 11, and 12, and one sequence variant in exon 3 identified in a patient bearing a truncating mutation in exon 15. The most common mutation (found in 10 cases) was at codon 1309. All patients negative for APC mutations were also negative for the MutY homolog (MYH) gene mutation, as expected because of fully penetrant FAP cases. This study enlarges the spectrum of APC gene mutations, and reinforces the concept of mutation heterogeneity. It also sheds light on correlations between the site of APC germline mutations and the clinical manifestations of FAP. Our data indicate that the genotype/phenotype correlations in Argentinean patients are similar to those observed in other populations.     

Large deletions and splicing‐site mutations in the STK11 gene in Peutz‐Jeghers Chilean families

Peutz‐Jeghers syndrome (PJS) is an autosomal dominant disorder characterized by mucocutaneous melanocytic macules, gastrointestinal hamartomatous polyposis and an increased risk of various neoplasms. Germline mutations in the serine/threonine kinase 11 (STK11) gene have been identified as a cause for PJS. The aim of this study was to characterize the genotype of Chilean PJS patients. Mutation screening of 13 patients from eight PJS families was performed using a single strand conformation polymorphism analysis, DNA sequencing and multiplex ligation‐dependent probe amplification assay. The breakpoints of the genomic rearrangements were assessed by a long‐range polymerase chain reaction and sequencing. The results revealed the existence of seven different pathogenic mutations in STK11 gene in seven unrelated families, including three point mutations and four large genomic deletions. Three of these point mutations (43%, 3/7) may be considered as novel. Our results showed that a germline mutation is present in STK11 in 88% of probands fulfilling the diagnostic criteria of PJS. In this study, the combination of two different experimental approaches in the screening of the STK11 in PJS, led to a higher percentage of mutation detection.     

Gastric‐type endocervical glandular neoplasms associated with aberrant p16 expression and K‐RAS gene mutation in Peutz‐Jeghers syndrome

In this report, unique endocervical glandular lesions exhibiting gastric differentiation were examined in a patient with Peutz‐Jeghers syndrome. The result of the human papillomavirus (HPV) in situ hybridization (ISH) for the hysterectomy specimens was negative, but they demonstrated a papillary mucinous adenocarcinoma at the proximal endocervix continuous to atypical lobular endocervical glandular hyperplasia. Both contained MUC6‐positive neutral mucin in cytoplasm, and showed different immunoreactivity to p16, Ki‐67, and p53. Moreover, they harbored the identical K‐RAS gene mutation suggesting that there was a common origin. Somatic K‐RAS mutation and defective function of p16 may have been involved in the tumorigenesis of these unusual mucinous neoplasms.     

Quality of life and psychological distress in patients with Peutz–Jeghers syndrome

van Lier MGF, Mathus‐Vliegen EMH, van Leerdam ME, Kuipers EJ, Looman CWN, Wagner A, Vanheusden K. Quality of life and psychological distress in patients with Peutz–Jeghers syndrome. Little is known about psychological distress and quality of life (QoL) in patients with Peutz–Jeghers syndrome (PJS), a rare hereditary disorder. We aimed to assess QoL and psychological distress in PJS patients compared to the general population, and to evaluate determinants of QoL and psychological distress in a cross‐sectional study. PJS patients completed a questionnaire on QoL, psychological distress, and illness perceptions. The questionnaire was returned by 52 patients (85% response rate, 56% females, median age 44.5 years). PJS patients reported similar anxiety (p = 0.57) and depression (p = 0.61) scores as the general population. They reported a lower general health perception (p = 0.003), more limitations due to emotional problems (p = 0.045) and a lower mental well‐being (p = 0.036). Strong beliefs in negative consequences of PJS on daily life, a relapsing course of the disease, strong emotional reactions to PJS, and female gender were major determinants for a lower QoL. PJS patients experience a similar level of psychological distress as the general population, but a poorer general health perception, more limitations due to emotional problems, and a poorer mental QoL. Illness perceptions and female gender were major predictors for this lower QoL. These results may help to recognize PJS patients who might benefit from psychological support.     

Somatic mutations in familial adenomatous polyps. Nuclear translocation of beta-catenin requires more than biallelic APC inactivation

Germline mutations of the APC gene cause familial adenomatous polyposis coli (FAP). APC inactivation results in dysregulation of wnt/wingless signaling and contributes to chromosomal instability in vitro. To investigate somatic alterations that follow a known germline mutation and contribute to the transition from normal to neoplastic mucosa, we studied 10 adenomatous polyps from a 27-year-old patient with an APC germline mutation at codon 554. Chromosomal imbalances were analyzed by comparative genomic hybridization; APC and K-ras were screened for somatic mutations. Before DNA analysis, the polyps were bisected to compare the genetic alterations with the corresponding immunohistologic phenotype of beta-catenin, a proto-oncogene product degraded by the APC tumor suppressor. Gains at chromosome 20 were the most frequent chromosomal alterations (6 polyps). Losses were found predominantly at chromosome 4q (3 polyps). A K-ras mutation was seen in 1 polyp, while all polyps displayed somatic intragenic APC mutations. Comparative immunohistologic analysis revealed strong membranous staining for beta-catenin in all adenomatous polyps, but only 1 adenoma showed nuclear accumulation. Our results suggest chromosomal aberrations contribute early to the progression of adenomatous polyps after biallelic APC inactivation. APC inactivation itself is insufficient for immunohistochemically detectable nuclear translocation of beta-catenin.     

Molecular genetic analysis of exons 1 to 6 of the APC gene in non-polyposis familial colorectal cancer

Familial adenomatous polyposis coli is caused by constitutional mutations in the APC gene. The hallmark of familial adenomatous polyposis coli is the presence of numerous (>100) colorectal polyps, but mutations in the 5' end of the APC gene have been associated with familial colorectal cancer without florid polyposis. Although familial adenomatous polyposis coli accounts for only a minority of familial colorectal cancer cases, we hypothesised that APC mutations which were not associated with florid polyposis might make a significant contribution to nonpolyposis familial colorectal cancer. To investigate this possibility, we analysed 40 unrelated patients with familial colorectal cancer without classical familial adenomatous polyposis coli for mutations in exons 1 to 6 (codons 1 to 243) of the APC gene. No mutations were detected, but a C→T polymorphism at nucleotide 333 (Arg→Trp at codon 99) was identified. No 5' APC mutations were detected in two patients with desmoid tumours and a family history of colorectal cancer and polyps. We conclude that mutations in exons 1 to 6 of the APC gene are infrequent in patients with familial colorectal cancer who do not have many colorectal polyps.     

Somatic mutations of the APC gene in primary breast cancers

APC gene mutations play an important role in the initiation step of colorectal carcinogenesis in both familial adenomatous polyposis (FAP) patients and non-FAP patients. Although the APC gene is expressed in most tissues, including the lung, liver, kidney, and mammary gland, its somatic mutations have rarely been found in primary tumors affecting these organs. We have developed a sensitive yeast-based assay for screening almost the entire coding region of the APC gene. By this method, we have been able to detect somatic mutations of the APC gene in 57% of colorectal cancers and none in non-small cell lung cancers. Interestingly, the assay detected somatic APC gene mutations in 18% of breast cancers, in which APC gene mutation was previously considered rare. In the breast cancers, most of the APC mutations were distributed outside the mutation cluster region that has been advocated for colorectal cancers. We also noted a difference in the mutation pattern of the APC between colorectal and breast cancers. In colorectal cancers, all base substitutions were observed at C residues (5 of 5), whereas in breast cancers the majority of them were found at G residues (4 of 5). Furthermore, APC mutations were observed at a significantly high frequency in advanced stages of primary breast cancers (TNM classification, P < 0.05; T category, P < 0.01). Our data suggest that the etiology of the APC mutations and their biological role in carcinogenesis may differ between colorectal and breast cancers.     

Juvenile and inflammatory polyps of the colon—a histological and histochemical study

A light microscopy and histochemical study of 24 juvenile and 27 inflammatory polyps showed that both may derive from inflammatory processes. Granulation tissue, secondary to spontaneous local inflammation or due to surgical procedures may subsequently be covered by regenerating epithelium which lines haemorrhagic cavities and mucus lakes to form irregular, elongated and cystic glands, which are characteristic of juvenile polyps. Both juvenile and inflammatory polyps showed cystic, metaplastic and 'transitional-type' glands. The mucin distribution was identical in both types of polyps. All these findings suggest a common origin of the polyps. The presence of 'transitional-type' glands seems to confirm these as a secondary regenerative phenomenon rather than pre-neoplastic, although dysplastic changes in juvenile polyps have been described. It is suggested that both the juvenile and inflammatory polyps may undergo dysplasia only in genetically predisposed subjects. However, this event seems to be very rare.