Frequent activating HRAS mutations in trichilemmoma.

BACKGROUND: Trichilemmoma is a benign follicular epithelial tumour exhibiting outer root sheath differentiation. It is associated with Cowden syndrome and naevus sebaceus (NS), but the pathogenesis of sporadic tumours is poorly understood. Recently, NS was found to be caused by postzygotic HRAS or KRAS mutations. OBJECTIVES: We sought to determine whether NS-related and NS-unrelated trichilemmomas harbour RAS mutations. METHODS: Formalin-fixed and paraffin-embedded blocks of 12 NS-related and 15 NS-unrelated trichilemmomas from 26 individuals were retrieved and analysed to determine the presence of mutations in exons 1 and 2 of the HRAS, KRAS and NRAS genes by polymerase chain reaction and direct sequencing. Mutational hotspots of the FGFR3 and PIK3CA genes were also analysed for NS-unrelated cases. RESULTS: Among the 27 cases, mutually exclusive HRAS c.37G>C and c.182A>G mutations were observed in 17 and three tumours, respectively. Of the 12 NS-related tumours, 11 (92%) harboured the HRAS c.37G>C substitution. Of the 15 sporadic tumours, nine (60%) harboured HRAS mutations, including six c.37G>C and three c.182A>G. An HRAS c.182A>G mutation was observed only in sporadic tumours. No mutations were observed in the other genes that were tested. CONCLUSIONS: The high frequency of HRAS activating mutations, including the c.182A>G substitution, which was rather rare in NS, suggests that most trichilemmomas are authentic neoplasms.

Low viraemia at enrollment in children with chronic hepatitis C favours spontaneous viral clearance.

The significance of hepatitis C viral (HCV)-RNA levels in long-term clinical outcomes of children with chronic HCV infection is not well understood. We conducted a long-term follow-up study of 42 children with chronic HCV infection that included clinical evaluation, biochemical tests, HCV genotyping and repeated quantitative HCV-RNA detection. Patients were divided into low and high viraemia groups according to RNA levels at enrollment (below/above 4.5 x 10(4) IU/mL), and clinical, biochemical and virological factors were evaluated. Overall, 14.3% (6/42) of patients developed spontaneous viral clearance during a median 10.1 years of follow-up. HCV-RNA levels at enrollment and mean RNA levels during follow-up for each patient were significantly correlated (R = 0.9018, 95% CI: 0.6637-0.9038, P < or = 0.001). HCV-RNA level fluctuation was within two log units in 76% of patients. Cumulative viraemia probability during follow-up could be predicted by viraemia levels at enrollment (P = 0.0092). Chronic HCV-infected children, with an RNA level below 4.5 x 10(4) IU/mL at enrollment, have a higher spontaneous viral clearance rate.

Prognostic significance of insulin-like growth factor II mRNA-binding protein 3 expression in gastric adenocarcinoma.

BACKGROUND: Insulin-like growth factor II mRNA-binding protein (IMP) 3 is expressed in embryonic tissues and multiple cancers. The aim was to establish the prognostic value of IMP-3 expression in gastric adenocarcinoma. METHODS: IMP-3 expression in resected gastric adenocarcinomas was analysed by immunohistochemistry. RESULTS: IMP-3 was expressed in 183 (58.1 per cent) of 315 tumours. Expression was associated with older age (P < 0.001), larger tumour size (P = 0.009), deep tumour invasion (P < 0.001) and lymph node metastasis (P < 0.001). IMP-3-positive tumours were associated with poorer 5-year survival than negative tumours at all stages (stage I, 82 versus 97 per cent; stage II, 55 versus 78 per cent; stage III and IV, 11 versus 25 per cent; P = 0.005, P = 0.033 and P = 0.036 respectively). Multivariable analysis identified IMP-3 (hazard ratio (HR) 1.93), depth of tumour invasion (HR 3.69, 9.77 and 10.69 for pathological tumour stage (pT) 2, pT3 and pT4 respectively versus pT1), and lymph node metastasis (HR 1.57, 3.29 and 3.40 for pathological node stage (pN) 1, pN2 and pN3 respectively versus pN0) as independent prognostic factors. CONCLUSION: IMP-3 expression correlates with the metastatic potential of gastric adenocarcinoma and is an independent prognostic factor.

Correction to: CCN2 inhibits lung cancer metastasis through promoting DAPK-dependent anoikis and inducing EGFR degradation.

Following publication of their article "CCN2 inhibits lung cancer metastasis through promoting DAPK-dependent anoikis and inducing EGFR degradation", the authors reported an error in Fig.6b. α-Tubulin image of rCCN2 treatment  (upper panel in CL1-5) only showed eight lanes, when there should be nine.

Brca1 heterozygous mice have shortened life span and are prone to ovarian tumorigenesis with haploinsufficiency upon ionizing irradiation.

BRCA1 mutation carriers have an 85% lifetime risk of breast cancer and 60% for ovarian cancer. BRCA1 facilitates DNA double-strand break repair, and dysfunction of BRCA1 leads to hypersensitivity to DNA damaging agents and consequently genomic instability of cells. In this communication, we have examined the tumor incidence and survival of Brca1 heterozygous female mice. Brca1 heterozygotes appear to have a shortened life span with 70% tumor incidence. Lymphoma, but not ovarian and mammary gland tumors, occurs commonly in these mice. After a whole-body exposure to ionizing radiation, Brca1 heterozygous mice have a 3-5-fold higher incidence specific to ovarian tumors, but not lymphoma, when compared with the Brca1+/+ mice. All the tumors from heterozygous mice examined retain the wild-type allele and the cancer cells express Brca1 protein, precluding the chromosomal mechanism for loss of heterozygosity of Brca1 locus. Although the manifestation of BRCA1 haploinsufficiency may be different between human and mouse, this study suggests that women carrying Brca1 mutations may be more prone to ovarian tumor formation after IR exposure than nonmutation carriers.

Tumor angiogenesis and its possible role in intravasation of colorectal epithelial cells.

PURPOSE: To determine whether an increase in tumor angiogenesis facilitates intravasation of colorectal epithelial cells, we compared intratumoral microvessel counts with the presence of circulating colorectal epithelial cells in the portal venous blood from patients with colorectal carcinomas. EXPERIMENTAL DESIGN: Circulating colorectal epithelial cells were detected by a reverse transcription-PCR assay to amplify guanylyl cyclase C (GCC) transcripts. The extent of tumor vascularization was quantitatively assessed by immunohistochemical staining with anti-CD31 antibody. RESULTS: Colorectal epithelial cells (as measured by GCC mRNA expression) were detected in the portal venous blood in 30 of 58 patients (52%). The mean (+/- SD) microvessel count in the tumors from patients with expression of GCC mRNA in their portal venous blood was 82.74 +/- 24.97. The corresponding values in the tumors from patients without expression of GCC mRNA in portal venous blood was 65.96 +/- 19. For each 10-microvessel increase per x200 field, the risk of colorectal epithelial cell presence in the portal venous blood increased 1.52-fold (95% confidence interval, 1.19-2.12; P = 0.005). CONCLUSION: High intratumoral vessel count was noted to be a valuable factor for predicting the presence of colorectal epithelial cells in the portal venous blood.

Lymphoepithelioma-like cholangiocarcinoma: an Epstein-Barr virus-associated tumor.

Epstein-Barr virus (EBV) has been linked to carcinomas of several body sites, especially of the nasopharynx, salivary gland, lung, and stomach. We present five cases of lymphoepithelioma-like cholangiocarcinoma, including one that had been previously reported. Two patients were men and three were women. Their ages ranged from 42 to 66 years. Histologically, all five tumors were composed of variable proportions of undifferentiated epithelial cells and glandular components in a lymphocyte-rich stroma. EBV was detected in all five tumors by in situ hybridization for EBER-1 in both lymphoepithelioma-like carcinoma (LELC) and glandular parts, but not in 36 cases of cholangiocarcinoma without the LELC component. Taken together, these observations indicate that lymphoepithelioma-like cholangiocarcinoma is strongly linked to EBV. The LELC type of cholangiocarcinoma, like LELC of other body sites, may be more common in areas with endemic EBV infection.

Congenital interstitial cell of cajal hyperplasia with neuronal intestinal dysplasia.

Interstitial cells of Cajal (ICCs) are intestinal pacemaker cells that initiate peristalsis in the stomach and intestine, and are considered to be precursors of gastrointestinal stromal tumors (GISTs). We report a 2-year-old girl who suffered from scanty stool passage since birth. On barium enema, the distal colon was rigid with narrow lumen, whereas the proximal colon was dilated and atonic. She received right hemicolectomy and ileostomy. Histopathologically, there was continuous proliferation of spindle cells located between the layers of the muscularis propria throughout the right colon. These spindle cells were positive for c-kit and CD34 but negative for myogenic or neurogenic markers, indicating they are ICCs. No germline or somatic mutation of the juxtamembrane domain of c-kit gene was detected. In addition, the changes of the submucosal plexus fulfilled the histologic criteria of neuronal intestinal dysplasia type B. To our knowledge, this is the first reported case of congenital ICC hyperplasia. Further studies of ICC development may contribute to better understanding of the pathogenesis of this congenital malformation and the tumorigenesis of GIST.

Expression of the c-kit protein is associated with certain subtypes of salivary gland carcinoma.

The c-Kit protein, a receptor type tyrosine kinase that plays an important role in the development of hematopoietic cells, melanocytes, and germ cells, is expressed in mastocytosis, gastrointestinal stromal cell tumors (GISTs), germ cell tumors, and several other tumors. Gain-of-function mutations in exon 11 and exon 17 have been shown as a mechanism of c-kit activation in some tumors. To study the role of c-kit in salivary gland carcinomas, we analyzed the c-kit protein expression in 79 carcinomas of major and minor salivary glands by immunohistochemistry. Although varying in intensity of staining, c-kit expression was identified very often in adenoid cystic carcinomas (20/25), lymphoepithelioma-like carcinomas (6/6) and myoepithelial carcinomas (2/2), but not in other types of salivary gland carcinoma (0/46), P<0.00001. By DNA sequencing, genetic alteration of c-kit juxtamembrane domain (exon 11) and tyrosine kinase domain (exon 17) was not found in all the three types of salivary carcinoma that had c-kit protein expression. In conclusion, c-kit protein overexpression is involved in the pathogenesis of certain types of salivary gland carcinoma, but mutation of the gene is not the mechanism of c-kit activation.

Somatic mutations of beta-catenin play a crucial role in the tumorigenesis of sporadic hepatoblastoma.

Hepatoblastoma (HB) is the most common malignant hepatic tumor during early childhood. Its molecular pathogenesis is still poorly understood. Mutations of adenomatous polyposis coli (APC) gene have been identified in sporadic cases and in individuals associated with familial adenomatous polyposis syndrome. beta-catenin is a key element in the cadherin-mediated cell adhesion system and Wnt/wingless pathway, and is controlled by APC. APC affects the degradation of beta-catenin by its NH(2)-terminal phosphorylation on the serine/threonine residues of exon 3. Mutations of these phosphorylation sites are primary targets for activating mutations in several types of human cancer and lead to nuclear accumulation of beta-catenin protein. In this study, we examined nine patients with HB using immunohistochemistry and direct DNA sequencing. All nine cases showed predominant nuclear expression of beta-catenin. Eight cases (89%) showed mutations involving exon 3 of the beta-catenin gene, including five with deletions and three with missense mutations. All five deletions were in-frame deletions without frameshift. The very high frequency of mutations in the beta-catenin gene suggests that beta-catenin mutations are crucial in the tumorigenesis of HB.

Interferon-alpha reduces insulin resistance and beta-cell secretion in responders among patients with chronic hepatitis B and C.

This study aimed at elucidating the effects of interferon (IFN)-alpha on glucose metabolism in patients with chronic hepatitis B and C infections. Twenty-eight biopsy-proven patients with chronic hepatitis B (ten cases) and hepatitis C (18 cases) were given IFN-alpha for a total of 24 weeks. The patients received a 75 g oral glucose tolerance test (OGTT), glucagon stimulation test, tests for type 1 diabetes-related autoantibodies and an insulin suppression test before and after IFN-alpha therapy. Ten of the 28 patients responded to IFN-alpha therapy. Steady-state plasma glucose of the insulin suppression test decreased significantly in responders (13.32+/-1.48 (S.E.M.) vs 11.33+/-1.19 mmol/l, P=0.0501) but not in non-responders (12.29+/-1.24 vs 11.11+/-0.99 mmol/l, P=0.2110) immediately after completion of IFN-alpha treatment. In the oral glucose tolerance test, no significant difference was observed in plasma glucose in either responders (10.17+/-0.23 vs 10.03+/-0.22 mmol/l) or non-responders (10.11+/-0.22 vs 9.97+/-0.21 mmol/l) 3 Months after completion of IFN-alpha treatment. However, significant differences were noted in C-peptide in both responders (2.90+/-0.13 vs 2.20+/-0.09 nmol/l, P=0.0040) and non-responders (2.45+/-0.11 vs 2.22+/-0.08 nmol/l, P=0.0287) before vs after treatment. The changes of C-peptide in an OGTT between responders and non-responders were also significantly different (P=0.0028), with responders reporting a greater reduction in C-peptide. No case developed autoantibodies during the treatment. In patients who were successfully treated with IFN-alpha, insulin sensitivity improved and their plasma glucose stayed at the same level without secreting as much insulin from islet beta-cells.

Prevalence and rapid identification of clarithromycin-resistant Helicobacter pylori isolates in children.

BACKGROUND: Little is known about the prevalence of antibiotic-resistant Helicobacter pylori infection in children. Culture and antimicrobial susceptibility testing are generally time-consuming and not a routine in many hospitals. OBJECTIVE: To investigate the prevalence of clarithromycin-resistant H. pylori strains in children, to identify those isolates via rapid methodology and to examine the severity of gastritis caused by the antibiotic-resistant H. pylori isolates. METHODS: Enrolled were 245 children investigated for H. pylori infection by endoscopic examination. The gastric antral specimens were subjected to DNA extraction and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) with primers specific to the H. pylori 23S rRNA gene. Conventional bacterial cultures were performed simultaneously as the diagnostic standard. Minimal inhibitory concentrations of clarithromycin and metronidazole were determined by E test. This was used as a standard to determine the sensitivity and specificity of the above PCR-RFLP assay. The specimens were processed for histologic examination and evaluated by the updated Sydney system. RESULTS: H. pylori was isolated in 67 of the 245 children; 12 (18%) of them were clarithromycin-resistant and 6 (9%) were metronidazole-resistant. No difference in histologic examinations was noted between the antibiotic-resistant and -susceptible strains. We performed PCR-RFLP with all 12 clarithromycin-resistant isolates: 10 had a 23S ribosomal RNA A2144G point mutation; 1 had a mixture of an A2143G point mutant and susceptible strains; and 1 had neither of the 2 mutations. CONCLUSIONS: The prevalence of clarithromycin-resistant H. pylori isolates in Taiwanese children is 18%. PCR-RFLP had a high sensitivity (92%) and specificity (100%) for the clarithromycin resistance gene mutation determination. The dominant mutation is A2144G. PCR-RFLP provides a rapid and accurate approach to detect clarithromycin-resistant strains within 24 h.

Congenital generalized lipodystrophy in a 4-month-old infant.

Congenital generalized lipodystrophy (CGL, Berardinelli-Seip syndrome) is a rare autosomal recessive disorder with a clinical presentation of paucity of adipose tissue, muscular hypertrophy, organomegaly, and insulin-resistant diabetes. A 4-month-old Taiwanese female infant had hepatosplenomegaly and low body weight gain despite a voracious appetite. Hypermetabolism, hyperhidrosis, loss of subcutaneous fat, muscular hypertrophy, acanthosis nigricans, hypertrichosis, and marked hypertriglyceridemia were also noted. Liver histology revealed fatty change and portal-to-portal bridging fibrosis. Clinical features, serum biochemistry, and liver histology were compatible with the diagnosis of CGL. She was given a special diet characterized by calorie restriction and partial substitution of long-chain triglycerides with medium-chain triglycerides. The serum triglyceride concentration subsequently decreased. This present case suggests that extensive fatty infiltration and subsequent cirrhosis of the liver may be the earliest complication of CGL.

Hepatoblastoma in an infant with Beckwith-Wiedemann Syndrome.

A 3-month-old Chinese male infant with typical manifestations of Beckwith-Wiedemann Syndrome (BWS), such as macroglossia, hepatomegaly, umbilical hernia and hypoglycemia, presented with a large hepatic tumor. The tumor measured 7.6 x 8.0 x 7.5 cm. An open biopsy of the tumor revealed hepatoblastoma. The family refused chemotherapy, so only supportive care was given. The tumor grew very rapidly and the infant died 17 days after admission due to respiratory failure. To our knowledge, this is the first report of BWS associated with hepatoblastoma in a Chinese infant. This patient was a typical example of the association of BWS and hepatoblastoma, and the possible effect of growth factors on the rapid proliferation of the neoplasm in BWS.

Autocrine/paracrine mechanism of interleukin-17B receptor promotes breast tumorigenesis through NF-κB-mediated antiapoptotic pathway.

Gain of function of membrane receptor was a good strategy exploited by cancer cells to benefit own growth and survival. Overexpression of HER2 has been found to serve as a target for developing trastuzumab to treat 20-25% of breast cancer. However, little or none of the other membrane receptor was found to be useful as a potential target for breast cancer treatment since then. Here, we showed that amplified signaling of interleukin-17 receptor B (IL-17RB) and its ligand IL-17B promoted tumorigenicity in breast cancer cells and impeded acinus formation in immortalized normal mammary epithelial cells. External signal transmitted through IL-17RB activated nuclear factor-κB to upregulate antiapoptotic factor Bcl-2 and induced etoposide resistance. Elevated expression of IL-17RB had a stronger correlation with poor prognosis than HER2 in breast cancer patients. Interestingly, breast cancer patients with high expression of IL-17RB and HER2 had the shortest survival rate. Depletion of IL-17RB in trastuzumab-resistant breast cancer cells significantly reduced their tumorigenic activity, suggesting that IL-17RB and HER2 have an independent role in breast carcinogenesis. Furthermore, treatment with antibodies specifically against IL-17RB or IL-17B effectively attenuated tumorigenicity of breast cancer cells. These results suggest that the amplified IL-17RB/IL-17B signaling pathways may serve as a therapeutic target for developing treatment to manage IL-17RB-associated breast cancer.

CCN2 inhibits lung cancer metastasis through promoting DAPK-dependent anoikis and inducing EGFR degradation.

CCN family protein 2 (CCN2), also known as connective tissue growth factor, is a secreting protein that modulates multiple cellular events. We previously demonstrated the metastasis-suppressive effect of CCN2 in lung cancer cells. In this study, we investigate the role of CCN2 in anoikis, a form of programmed cell death that is critical in suppressing cancer metastasis. CCN2 binds to the epidermal growth factor receptor (EGFR) and triggers ubiquitination by inhibiting the formation of the ß-pix/Cbl complex, resulting in the degradation of EGFR. Binding of CCN2 to EGFR suppresses the phosphorylation of c-Src and extracellular signal-regulated kinase but increases the expression of death-associated protein kinase, which leads to anoikis. Overall, our findings provide evidence validating the use of CCN2 as an anti-metastatic therapy in lung cancer patients, and prospect a potential therapeutic synergy between CCN2 and the anti-EGFR antibody for the treatment of lung cancer.

MiR-520h-mediated FOXC2 regulation is critical for inhibition of lung cancer progression by resveratrol.

Resveratrol, a phytochemical found in various plants and Chinese herbs, is associated with multiple tumor-suppressing activities, has been tested in clinical trials. However, the molecular mechanisms involved in resveratrol-mediated tumor suppressing activities are not yet completely defined. Here, we showed that treatment with resveratrol inhibited cell mobility through induction of the mesenchymal-epithelial transition (MET) in lung cancer cells. We also found that downregulation of FOXC2 (forkhead box C2) is critical for resveratrol-mediated suppression of tumor metastasis in an in vitro and in vivo models. We also identified a signal cascade, namely, resveratrol-∣miRNA-520h-∣PP2A/C-∣Akt → NF-κB → FOXC2, in which resveratrol inhibited the expression of FOXC2 through regulation of miRNA-520h-mediated signal cascade. This study identified a new miRNA-520h-related signal cascade involved in resveratrol-mediated tumor suppression activity and provide the clinical significances of miR-520h, PP2A/C and FOXC2 in lung cancer patients. Our results indicated a functional link between resveratrol-mediated miRNA-520h regulation and tumor suppressing ability, and provide a new insight into the role of resveratrol-induced molecular and epigenetic regulations in tumor suppression.

Immunostaining of glutamine synthetase is a sensitive and specific marker for diagnosing focal nodular hyperplasia in needle biopsy.

AIMS: Focal nodular hyperplasia (FNH) has characteristic histological features which may not be seen in needle biopsy specimens. We investigate the diagnostic role of glutamine synthetase (GS) in needle biopsy specimens. METHODS: Sixty-one hepatic tumours were categorised into 20 'definite' FNHs, 13 'probable' FNHs, and 28 cases without specific diagnosis. Needle biopsy specimens of 92 non-tumourous lesions, 25 well-differentiated hepatocellular carcinomas (WDHCCs), and 4 high-grade dysplastic nodules (HGDNs) and resection specimens of 10 macroregenerative nodules were also selected for immunohistochemical stain of GS for comparison. RESULTS: All 20 'definite' FNHs, nine 'probable' FNHs, and five cases without specific diagnosis expressed typical map-like staining pattern of GS. The demographic data of these five cases were similar to those of FNH. All cases of chronic hepatitis B and C, cirrhosis, macroregenerative nodule and peritumourous liver tissue showed normal pericentral/periseptal pattern. Fifteen of 25 WDHCCs and one HGDN showed diffuse pattern. Ten WDHCCs and two HGDNs showed negative staining. One HGDN showed mosaic pattern. CONCLUSIONS: Immunohistochemical staining of GS increases the diagnostic sensitivity of FNH in needle biopsy, especially in those without typical morphology. It also helps in differentiating FNH from other tumourous and non-tumourous lesions.

Connective tissue growth factor modulates oral squamous cell carcinoma invasion by activating a miR-504/FOXP1 signalling.

Connective tissue growth factor (CTGF) is a multi-functional secreted protein, and it has been shown either to promote or suppress tumor progression among different kinds of cancers. Here, we investigated the role of CTGF in oral squamous cell carcinoma (OSCC) invasion and metastasis. In five OSCC cell lines, endogenous CTGF negatively correlated with invasiveness. Exogenous CTGF protein or forced expression of CTGF gene in the oral cancer cell line SAS significantly decreased their invasive and migratory abilities. MicroRNA (miRNA) microarray analysis was performed in CTGF-overexpressed SAS cells (SAS/CTGF-M3) versus control cells to investigate the mechanism of CTGF-mediated inhibition of OSCC invasion. Among the miRNAs regulated by CTGF, miR-504 and miR-346 were the top two miRNAs downregulated in CTGF transfectants, and the result was confirmed by quantitative reverse transcriptase-PCR. Ectopic miR-504 increased migration and invasion in SAS/CTGF-M3, however, miR-346 did not have such impact on migration/invasion. Furthermore, we identified FOXP1, a member of forkhead transcription factors, as a target gene that takes part in the miR-504-induced cellular invasion. Knockdown of FOXP1 increased invasiveness in SAS/CTGF-M3, confirming the signal axis of CTGF/miR-504/FOXP1 in OSCC. Animal experiments showed that SAS/CTGF-M3-formed orthotopic tumors were associated with a lesser invasive phenotype than control cells. Expression of miR-504 in SAS/CTGF-M3 increased lymph node metastasis, and co-expression of FOXP1 in miR-504-transfected SAS/CTGF-M3 alleviated miR-504-induced metastasis. In OSCC samples, high CTGF was associated with a lower clinical stage and a better outcome. A reverse correlation between CTGF and miR-504, miR-504 and FOXP1, and a positive correlation between CTGF and FOXP1 were shown. Our study discovers a novel signal pathway involving the regulation of miRNA machinery by a secreted cytokine, which will be beneficial for developing therapeutic strategy against advanced OSCC.

Frequent nuclear expression of beta-catenin protein but rare beta-catenin mutation in pulmonary sclerosing haemangioma.

BACKGROUND: Pulmonary sclerosing haemangioma (PSH) is an uncommon tumour that is composed of glandular/papillary lining cells and polygonal cells. The biological behaviour of this tumour has been investigated; however, the molecular pathogenesis of PSH remains unknown. AIMS: To characterise the role of the Wnt/beta-catenin pathway in the genesis of PSH. METHODS: 37 PSH samples were investigated immunohistochemically for detection of the beta-catenin protein and direct sequencing of exon 3 of the beta-catenin gene. RESULTS: Nuclear expression of beta-catenin was found in the lining component of 23 tumours (62%) and in the polygonal component of 11 tumours (30%). The expression of beta-catenin was stronger in the lining component, but weaker in the polygonal component. Interestingly, all the tumours with expression of beta-catenin in the polygonal component also expressed beta-catenin in the lining component. However, mutation of exon 3 of the beta-catenin gene was detected in only one tumour that expressed nuclear beta-catenin in lining and polygonal components. CONCLUSIONS: The Wnt/beta-catenin pathway is involved in the genesis of PSH, but mutation of exon 3 of the beta-catenin gene rarely contributes to the activation of the Wnt/beta-catenin pathway in PSH.