Search

Peritoneal carcinosarcoma is a highly aggressive and uncommon neoplasm that has carcinomatous and sarcomatous components; the malignancy rarely localizes to the omentum. We report a case of a bulky peritoneal carcinosarcoma with tiny high-grade serous carcinoma of the fallopian tube. A 60-year-old female with a huge pelvic mass (12 cm in diameter) underwent a total abdominal hysterectomy, bilateral salpingo-oophorectomy, and omentectomy for tumor debulking. Pathological findings showed minimally invasive high-grade serous carcinoma of the left fallopian tube and carcinosarcoma of the omentum. Similar p53 diffuse immunostaining in the omental carcinosarcoma and the tubal carcinoma provides evidence for a clonal relationship between the two neoplasias. This case suggests a small serous carcinoma, originating in the tubal mucosa, subsequently became implanted in the omentum and grew preferentially, converting to a carcinosarcoma at a remote site.

A woman in her seventies visited our hospital because of abdominal pain. Multiple hepatic tumors were detected and a liver biopsy revealed mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN), which was composed of cholangiocellular carcinoma and neuroendocrine tumor (NET). Diagnostic imaging ruled out primary malignancies other than the liver and identified that the tumor originated from the liver. Because a predominant and aggressive part of the tumor was considered to be cholangiocellular carcinoma, gemcitabine and S-1 were used as first-line treatment. After the treatment, octreotide acetate was administered for the NET component, followed by transcatheter arterial embolization. Subsequently, her gallbladder (GB) rapidly swelled with biliary tract obstruction, and cholecystectomy revealed carcinosarcoma of the GB. She is still undergoing treatment at 44 months after diagnosis. Herein we report this case of primary hepatic MiNEN consisting of cholangiocarcinoma and NET, followed by GB carcinosarcoma. This is the first case illustrating that a multidisciplinary treatment approach for MiNEN accompanied with carcinosarcoma, involving assessment and treatment targeting the most aggressive component, can result in a long survival time.

We herein report the case of a 76-year-old female patient who had undergone gastrectomy for advanced gastric cancer (histologically tubular adenocarcinoma)before 5 months, presenting with abdominal skin tumor. A skin biopsy revealed tubular adenocarcinoma. Positron emission tomography-computed tomographic scanning detected right breast tumor. A partial mastectomy of the right breast and local resection of abdominal skin tumor were performed and both tumors depicted similar histology of tubular adenocarcinoma in routine pathological examination. Immunohistochemically, positive for CDX2 and MUC5AC in previously resected gastric cancer and skin tumor tissues, whereas negative for both antigens in breast cancer. Thus, the final pathological diagnosis demonstrated skin metastasis originating from gastric cancer and primary breast cancer(invasive ductal carcinoma)histologically mimicking gastric cancer. We emphasize difficulties in diagnosis of this situation and that immunohistochemistry is helpful to distinguish primary breast cancer from gastric cancer metastasizing to the breast.

Objectives This study aimed to assess the pitfalls of the current International Association of Pancreatology guidelines (IAPCG2017) for pancreatic intraductal papillary mucinous neoplasm (IPMN) and identify the criteria for future guidelines. Methods Eighty surgically resected, consecutive IPMN cases were analyzed. Data including tumor site, IPMN duct type, and surgery type were collected. Based on radiological data, cases were retrospectively classified as high-risk stigmata (HRS) and non-HRS. Pathological grades and histological subtypes of IPMN cases were determined. Severe stromal sclerosis of the IPMN septa/marked parenchymal atrophy in the upstream pancreas was investigated pathologically. Positive/negative predictive values of the IAPCG2017 were calculated. Clinicopathological features of HRS-benign cases (pathologically benign IPMN cases meeting the HRS criteria) were extracted. Results The positive/negative predictive values were 72.7%/64.0%, 70.0%/34.6%, and 54.0%/63.3% for IAPCG2017, HRS-main pancreatic duct, and HRS-nodule criteria, respectively. The 15 HRS-benign cases (18.8%) included 13 pancreatoduodenectomies and 10 cases of gastric pyloric (GP) gland subtype. Severe upstream atrophy was significantly related to IPMN malignancy, unlike the severe sclerosis of IPMN septa. Conclusions Benign IPMNs of GP subtype are sometimes categorized as HRS with the IAPCG2017. Collecting data on the natural course of GP-IPMN is necessary. To evaluate upstream atrophy may be of value to predict IPMN malignancy.

Background: Hepatic inflammatory pseudotumor (IPT) is considered to be benign in biological behavior, and its malignant transformation is extremely rare. There has only been one published case of primary hepatic lymphoma complicated by hepatic IPT.Case presentation: A 73-year-old man presented with obstructive jaundice and a pancreatic head mass. Histology of the mass revealed chronic pancreatitis with lymphoid follicle formation, leading to a diagnosis of a suspicion of follicular pancreatitis. After a choledochojejunostomy, a hepatic tumor was detected, and a biopsy revealed lymphoplasmacytic infiltration. Immunohistochemistry confirmed the polyclonal nature of lymphoplasma cells, indicative of an IPT. The hepatic tumor disappeared during follow-up, but the patient exhibited a high fever related to tumor recurrence. A biopsy revealed the co-existence of a diffuse large B-cell lymphoma and an IPT. IgG4-related disease was excluded because storiform fibrosis, obliterative phlebitis, and a significant increase in IgG4-immunoreactive cells were absent in all investigated tissues. The tumor completely disappeared after chemotherapy.Conclusion: Careful observation is necessary in this kind of situation because the presence of a hepatic IPT may represent an increased risk of malignant transformation.Abbreviations: IPT: inflammatory pseudotumor; DLBCL: diffuse large B-cell lymphoma; CT: computed tomography; LDH: lactate dehydrogenase; sIL-2R: soluble interleukin-2 receptor; EBER: Epstein-Barr virus-encoded small RNA; R-CHOP: rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone

Gastric neoplasia of the fundic gland (chief cell-predominant) type (GNCCP) is a rare variant of gastric tumor. This tumor is associated with activation of the Wnt/β-catenin signaling pathway; however, the mechanisms underlying this activation remain unknown. To elucidate potential roles of Wnt/β-catenin signal-associated gene methylation in GNCCP, we performed β-catenin immunostaining and methylation-specific polymerase chain reaction (PCR) for their associated genes, including SFRPs, APC, AXIN2, and MCC, in 26 GNCCPs [i.e., 11 intramucosal (GNCCP-Ms) and 15 submucosal tumors (GNCCP-SMs)], and compared with 27 fundic gland polyps (FGPs), 12 FGPs with dysplasia (FGP-Ds), 27 conventional gastric adenocarcinomas (CGAs). Nuclear β-catenin labeling indices were higher in GNCCPs and CGAs than in FGPs and FGP-Ds. SFRPs, APC, and AXIN2 were more frequently methylated in GNCCPs and CGAs (SFRP1, 88%/96%; SFRP2, 85%/93%; SFRP4, 73%/81%; APC, 81%/81%; AXIN2, 81%/85%; respectively) than in FGPs and FGP-Ds (37%/50%; 41%/42%; 41%/58%; 37%/33%; 41%/50%; respectively). A significant correlation was seen between nuclear β-catenin expression and methylation of SFRP1 in GNCCPs. Furthermore, nuclear β-catenin expression was significantly frequent in high-methylated GNCCPs than in low-methylated tumors. In conclusion, our results suggest that activation of this pathway, mediated by gene methylation, may be associated with progression of some GNCCP cases, similar to CGAs.

Background/Aims: Gastric adenocarcinoma of fundic gland type (GAFG), which is a rare variant of gastric cancer, is reportedly associated with both Wnt/β-catenin signaling activation and guanine nucleotide binding protein, alpha stimulating complex (GNAS) mutations. This study aimed to elucidate potential roles of the Sonic hedgehog (Shh) signaling pathway in GAFG. Methods: We performed immunostaining for β-catenin and Shh signal-associated proteins, including Patched (Ptch), Smoothened (Smo), and Glioma-associated oncogene-1 (Gli1), and the direct sequencing of GNAS/BRAF/KRAS in 27 GAFGs, and compared them with 30 conventional gastric adenocarcinomas (CGAs). Results: GAFGs exhibited significantly lower immunoreactivity scores for Ptch, Smo, and Gli1 than CGAs. Moreover, while the Ptch score was significantly lower in the GAFG tumor areas than in the non-neoplastic areas adjacent to GAFG, the score was significantly higher in the CGA tumor areas than in the non-neoplastic areas. Similar trends were observed in the scores for Smo and Gli1. β-Catenin expression and GNAS mutations were found in 22 (81%) and 8 (30%) of the 27 GAFGs respectively. Gli1 expression was significantly associated with mutations in GNAS. Conclusion: GAFG and CGA exhibited distinct Ptch, Smo, and Gli1 expression patterns. Downregulation of the Shh signaling pathway, as well as activation of the Wnt/β-catenin signaling pathway, may therefore be associated with tumorigenesis in GAFG.

AIMS Recently, several morphological variants of traditional serrated adenoma (TSA) of the colorectum have been recognised, and mucin-rich TSA (MR-TSA) and serrated tubulovillous adenoma (S-TVA) were introduced as distinct morphological variants separate from conventional TSA (C-TSA). This aim of this study was to elucidate the immunohistochemical and genetic characteristics of MR-TSAs. METHODS AND RESULTS We performed immunostaining for cytokeratins (CKs) (e.g. CK7 and CK20), mucins (e.g. MUC2, MUC5AC, MUC6, and CD10), β-catenin, and MLH1, and direct sequencing of BRAF/KRAS, in 32 MR-TSAs, 35 C-TSAs, and 23 S-TVAs. Immunohistochemically, all studied cases were positive for CK20, whereas few cases were positive for CK7, with no significant differences between the three groups. Regarding mucin-phenotypic expression, all cases were positive for MUC2 but negative for MUC6 and CD10. MUC5AC positivity was found significantly more frequently in MR-TSAs (53%) than in C-TSAs (26%; P = 0.026). Nuclear β-catenin expression in MR-TSAs was significantly less frequent than in S-TVAs (P = 0.002). MLH1 nuclear staining was retained in all cases. Genetically, MR-TSAs (75%) more frequently harboured BRAF mutation than C-TSAs (49%; P = 0.044) or S-TVAs (4%; P < 0.001), whereas only two cases (6%) of MR-TSA harboured a KRAS mutation, a frequency that was significantly lower than that in C-TSAs (26%; P = 0.047) or S-TVAs (57%; P < 0.001). CONCLUSIONS MR-TSAs more frequently harboured BRAF mutations than C-TSAs, and had distinct immunohistochemical characteristics. Our findings indicated that MR-TSAs could be important precursors of BRAF-mutated, microsatellite-stable subtypes of colorectal carcinoma.

Gastric adenocarcinoma with enteroblastic differentiation (GAED) has been recognized as a variant of alpha-fetoprotein (AFP)-producing gastric carcinoma, although its clinicopathologic and immunohistochemical features have not been fully elucidated.To elucidate the clinicopathologic and immunohistochemical features of GAED, we analyzed 29 cases of GAED, including ten early and 19 advanced lesions, and compared these cases with 100 cases of conventional gastric adenocarcinoma (CGA). Immunohistochemistry for AFP, glypican 3, SALL4, and p53 was performed, and the phenotypic expression of the tumors was evaluated by immunostaining with antibodies against MUC5AC, MUC6, MUC2, CD10, and caudal-type homeobox 2 (CDX2).Lymphatic and venous invasion was more frequent in GAED (76 and 72 %) than in CGA (41 and 31 %; P ≤ 0.001). Lymph node metastasis was more frequently observed in GAED (69 %) than in CGA (38 %; P = 0.005), as were synchronous or metachronous liver metastases (GAED, 31 %; CGA, 6 %; P ≤ 0.001). Immunohistochemically, all GAED were positive for at least one of three enteroblastic linage markers (AFP, glypican 3, and SALL4). Glypican 3 was the most sensitive marker (83 %) for GAED, followed by SALL4 (72 %) and AFP (45 %), whereas no CGA was positive. Furthermore, the rate of positive p53 staining was 59 % in GAED. Regarding the mucin phenotype, CD10 and CDX2 were diffusely or focally expressed in all GAED cases. Invasive areas with hepatoid or enteroblastic differentiation were negative for CD10 and CDX2.Clinicopathologic features of GAED differ from those of CGA. GAED shows aggressive biological behavior, and is characteristically immunoreactive to AFP, glypican 3, or SALL4.

Frequent activation of the Wnt/β-catenin signaling pathway has recently been demonstrated in gastric adenocarcinoma/neoplasia of chief cell predominant type (GA-CCP/GN-CCP) with submucosal involvement. In this study, we examined the activation status of the Wnt/β-catenin signaling pathway in GN-CCP without submucosal involvement, which is referred to as gastric dysplasia-CCP (GD-CCP). We also examined β-catenin expression and the mutation spectrum of PPP2R1A and Wnt pathway genes in 11 cases of GD-CCP, 25 cases of gastric polyps of fundic gland type (GPs-FG), and 21 cases of GPs-FG with dysplasia (GP-FGD). β-catenin nuclear staining was observed in 3 cases of GD-CCP, none of GPs-FG, and 6 cases of GPs-FGD. Mutations in Wnt pathway genes, including PPP2R1A, were observed in 4 cases of GDs-CCP, 10 cases of GPs-FG, and 7 cases of GPs-FGD. Two of these seven GPs-FGD cases showed β-catenin nuclear staining. However, none of the 4 GD-CCP cases with mutations or the 10 GPs-FG cases with mutations showed β-catenin nuclear staining. PPP2R1A mutations were observed in 1 GD-CCP case and 1 GPs-FGD case. Although the mutation spectra of the Wnt pathway genes in GD-CCP and GP-FG differed, based on the absence of β-catenin nuclear staining despite the genetic alterations, GD-CCP is more similar to GP-FG than to GN-CCP, which shows β-catenin nuclear staining and submucosal involvement. Activation of the Wnt/β-catenin signaling by the β-catenin nuclear transition may be required during progression from GD-CCP to GN-CCP. Furthermore, this is the first report describing PPP2R1A mutations in gastric fundic gland-associated neoplasms.

The histopathological characteristics of colorectal submucosal invasive carcinoma arising in sessile serrated adenoma/polyp (SSA/P), a rare malignant tumour, have not yet been fully elucidated. To investigate the features of such, we retrospectively analysed 40 submucosal invasive carcinomas with SSA/P (CA-SSA/P) and compared them to 129 cases of submucosal invasive carcinoma with conventional tubular adenoma (CA-AD). We additionally performed hMLH1 immunostaining. CA-SSA/Ps were significantly smaller than CA-ADs (P

Gastric adenocarcinoma of the fundic gland type (GAFG) is a rare variant of gastric tumor. We have recently reported the frequent accumulation of β-catenin in GAFGs and showed that approximately half of the cases studied harbored at least 1 mutation in CTNNB1/AXINs/APC, leading to the constitutive activation of the Wnt/β-catenin pathway. However, the mechanisms of Wnt signaling activation in the remaining cases are unknown. Accumulating evidence showed that the activating mutation in GNAS promotes tumorigenesis via the activation of the Wnt/β-catenin pathway or the ERK1/2 MAPK pathway. Therefore, we analyzed the mutations in GNAS (exons 8 and 9) and in KRAS (exon 2) in 26 GAFGs. Immunohistochemistry revealed nuclear β-catenin expression in 22 of 26 GAFGs, and 10 (38.5%) of 26 cases harbored at least 1 mutation in CTNNB1/AXINs/APC. Activating mutations in GNAS were found in 5 (19.2%) of 26 GAFGs, all of which harbored R201C mutations. Activating mutations in KRAS were found in 2 (7.7%) of 26 GAFGs, and both of these also contained GNAS activating mutations. Four of 5 cases with GNAS mutation showed nuclear β-catenin expression, and presence of GNAS mutation was associated with β-catenin nuclear expression (P = .01). Furthermore, 3 of these 4 cases did not harbor mutations in CTNNB1, APC, or AXINs, suggesting that mutations in the Wnt component genes and those in GNAS occur almost exclusively. These results suggest that GNAS mutation might occur in a small subset of GAFG as an alternative mechanism of activating the Wnt/β-catenin signaling pathway.

Background and Aims The serrated colorectal carcinoma (CRC) as proposed to arise from serrated adenoma (SA) is characterized by upregulation of HIF1α, suppression of PTCH or EphB2, loss of DNA repair proteins, and BRAF mutation. The aim of this study was to evaluate alterations of these candidates involved in the serrated pathway in colorectal polyps. Methods We analyzed immunoreactivity of these proteins, methylation of PTCH and EphB2, and mutation of BRAF and Kras in sessile SAs (SSAs; n = 32), traditional SAs (n = 28), hyperplastic polyps (HPs; n = 24), and conventional adenomas (ADs; n = 21). Results Increase of nuclear HIF1α expression was more frequent in SA than HP, but less frequent in SA than AD (P

We reviewed the clinicopathological findings of eight cases of sessile serrated adenoma/polyps (SSA/Ps) with carcinoma, the largest diameter of which was 10 mm or less. All lesions were polyps located in the right side of the colon. Four lesions showed submucosal invasion and one lesion invaded the proper muscle layer. The depth of invasion, however, did not seem to be related to the carcinoma area size. Most carcinomas were well to moderately differentiated tubular adenocarcinomas focally showing some serrated appearances, and the predominant component of one carcinoma was a poorly differentiated medullary growth with inflammatory stroma. Rapid progression to invasive carcinoma from SSA/P was suggested for the carcinoma with proper muscle invasion whereas one submucosally invasive carcinoma was considered to progress over 7 years. Immunohistochemically, it was suggested that with or without hMLH1 protein loss, alterations of p53 and/or Wnt signaling pathway can be involved in the cancerization through SSA/Ps. The carcinomas irregularly imitated the mucin expression of the SSA/Ps (positive for MUC5AC and MUC2, and MUC6 expression in crypt bases), which was lost with progression of the carcinomas. Analyses of small SSA/P lesions with cancerization would facilitate the understanding of the mode of progression of SSA/Ps and their early detection.

The aim of this study was to investigate the expression pattern of manganese superoxide dismutase (MnSOD) in relation to inflammatory factors in ulcerative colitis (UC) and characterize this enzyme as a newly identified biomarker potentially linked to disease pathogenesis of UC. MnSOD expression was analyzed immunohistochemically in 48 formalin-fixed and paraffin-embedded specimens from patients with UC who had undergone endoscopical biopsy. MnSOD expression was observed in vascular endothelium, macrophages, and polymorphonuclear leukocytes within lamina propria of inflamed mucosa. The patients who did not express MnSOD tended to have stabilization of symptoms, but accompanied with status of inflammation. The MnSOD expression pattern was strongly correlated with disease type. MnSOD was expressed in polymorphonuclear leukocytes of all disease types, but cases of chronically counting and exacerbation type had particularly high frequency of immunopositive cells. MnSOD expression in macrophages was frequently observed in cases of symptom remaining type. The cases with MnSOD expression in the vascular endothelium showed a tendency to express in relapse-remission and exacerbation of symptoms. Immunohistochemical evaluation for MnSOD expression may be useful for predicting disease severity and activity in patients with UC.

Basaloid squamous cell carcinoma (BSCC) of the esophagus is a rare variant of typical squamous cell carcinoma (SCC) associated with poor survival. A characteristic feature is nuclear accumulation of β-catenin, without a mutation of the gene. We studied the methylation status of Wnt antagonist genes, such as secreted frizzled-related protein (sFRP) gene family members, Wnt inhibitory factor-1 (WIF-1), Dickkopf-1 (Dkk-1), and human Dapper protein-1 (HDPR-1), and alterations of the APC, Axin1, and Axin2 genes in 30 cases of esophageal BSCC. β-catenin and sFRP (sFRP-1, sFRP-2, sFRP-4, sFRP-5) protein expression was examined by immunohistochemistry. APC, Axin1, and Axin2 gene mutations were detected in 3, 2, and 2 cases, respectively, and 6 cases (20 %) harbored at least 1 alteration in these genes. Methylation of the sFRP-2 promoter region was observed in all cases, and methylation was frequent in sFRP-1 and sFRP-5, but infrequent in Dkk-1, WIF-1, sFRP-4, and HDPR-1. sFRP-2 expression was almost completely absent in 25 cases (83 %), consistent with the methylation status. Nuclear accumulation of β-catenin was observed in all cases. sFRP-5 expression was associated with a low nuclear β-catenin labeling index. These results show that sFRP-2 is a target gene of hypermethylation in esophageal BSCC and suggest that sFRP-2 might contribute to BSCC tumorigenesis through the Wnt/β-catenin signaling pathway.

Objective: Colorectal cancer patients bearing wild-type KRAS benefit from anti-epidermal growth factor receptor (EGFR) antibody treatment. Since clinical studies showed the efficacy of anti-EGFR antibody treatment for metastatic colorectal cancer (mCRC), we analyzed KRAS mutations in mCRC to gain insight into the association between these mutations and clinicopathological characteristics. Methods:KRAS mutations were analyzed in 109 tissue samples of mCRC using amplification refractory mutation system-Scorpion (ARMS/S) assay (68 samples) and direct sequencing (41 samples). Results: In the ARMS/S assay, 36.5 and 7.4% of mCRCs harbored mutations at codons 12 and 13, respectively. In direct sequencing, corresponding values were 24.4 and 19.5%. Overall, 37.6% (codon 12/13, 25.7/11.9%) of mCRCs harbored KRAS mutations. No significant differences were found between KRAS mutations and clinicopathological variables. Among mCRC patients KRAS mutations at codon 13 was significantly higher in female than male patients (p = 0.035). Conclusion: The incidence of KRAS mutations in mCRC was similar to that of non-mCRC as previously reported. KRAS codon 13 mutations might be associated with younger female patients with mCRC, but further investigation is necessary to clarify the association between this type of mutation and metastatic potential in female CRC patients.

We previously reported a relationship between depth of submucosal invasion of early colorectal carcinomas and desmoplastic reaction (DR). However, poor inter-observer agreement on the histopathological diagnosis of DR in biopsy specimens with hematoxylin and eosin (H&E) staining has been the major critique of this tool. In this study, reproducibility of the histopathological diagnosis of DR was evaluated. Furthermore, we investigated the possible improvement of the reproducibility after education about histological characteristics and tried to identify histological characteristics that are most important in the recognition of DR. A total of 34 H&E stained slides were included in this study and analyzed by three pathologists. Slides were reviewed before and after education about histological characteristics of DR. Kappa statistics were used to compare the inter-observer variability. We investigated the relationship between DR and histopathological factor. The inter-observer agreement during the first session varied between 0.30 and 0.63, which improved during the second session toward an agreement between 0.58 and 0.71. Myofibroblast proliferation associated with cancer invasion was found to be the most useful in the diagnosis of DR. In conclusion, the correct detection of myofibroblasts may facilitate the standardization of diagnosis of DR.

The aim of our study was to evaluate the diagnosis of desmoplastic reaction (DR) by immunostaining for α-smooth muscle actin (αSMA) and desmin, for predicting the depth of submucosal invasion in biopsy specimens of early colorectal carcinomas (CRCs). Thirty-eight cases of non-pedunculated early CRCs were included in this study. Positive for DR was defined as αSMA-positive and desmin-negative stroma in the CRC. The depth of submucosal invasion was measured in endoscopically or surgically resected specimens and the lesions were subsequently divided into two groups: Group A (carcinoma in situ/intramucosal carcinoma and submucosal invasive carcinoma with a depth

INTRODUCTION Low-grade myofibroblastic sarcoma (myofibrosarcoma) is described to be a distinct atypical myofibroblastic tumor often with fibromatosis-like features and predilection for head and neck. Low-grade myofibroblastic sarcoma of bone is extremely rare. PRESENTATION OF CASE A 50-year-old woman was admitted to our hospital because she had experienced right knee pain for 2 years. Plain radiography showed a honeycombed lesion on the right distal femur, and computed tomography showed a bone tumor with cortex destruction invading the soft tissue. A biopsy specimen from the intraosseous lesion showed a hypocellular area of spindle cell proliferation with dense collagen deposition, which is reminiscent of a histological feature of desmoplastic fibroma. However, histological examination of the extraosseous lesion indicated a slightly hypercellular area containing scattered spindle-shaped atypical cells with enlarged nuclei, suggestive of low-grade sarcoma. Spindle-shaped atypical cells were immunohistochemically positive for SMA. A final diagnosis of low-grade myofibroiblastic sarcoma of the bone was made from a surgically resected specimen. DISCUSSION The patient was alive and well with no evidence of disease at 15 months after the surgery without any additional therapy. CONCLUSION Extensive sampling of a tumor may be necessary to determine the true nature of the tumor and to make an accurate diagnosis.

Gastric neoplasia of the fundic gland (chief cell-predominant) type (GNCCP) is a rare variant of gastric tumor. This tumor is associated with activation of the Wnt/β-catenin signaling pathway; however, the mechanisms underlying this activation remain unknown. To elucidate potential roles of Wnt/β-catenin signal-associated gene methylation in GNCCP, we performed β-catenin immunostaining and methylation-specific polymerase chain reaction (PCR) for their associated genes, including SFRPs, APC, AXIN2, and MCC, in 26 GNCCPs [i.e., 11 intramucosal (GNCCP-Ms) and 15 submucosal tumors (GNCCP-SMs)], and compared with 27 fundic gland polyps (FGPs), 12 FGPs with dysplasia (FGP-Ds), 27 conventional gastric adenocarcinomas (CGAs). Nuclear β-catenin labeling indices were higher in GNCCPs and CGAs than in FGPs and FGP-Ds. SFRPs, APC, and AXIN2 were more frequently methylated in GNCCPs and CGAs (SFRP1, 88%/96%; SFRP2, 85%/93%; SFRP4, 73%/81%; APC, 81%/81%; AXIN2, 81%/85%; respectively) than in FGPs and FGP-Ds (37%/50%; 41%/42%; 41%/58%; 37%/33%; 41%/50%; respectively). A significant correlation was seen between nuclear β-catenin expression and methylation of SFRP1 in GNCCPs. Furthermore, nuclear β-catenin expression was significantly frequent in high-methylated GNCCPs than in low-methylated tumors. In conclusion, our results suggest that activation of this pathway, mediated by gene methylation, may be associated with progression of some GNCCP cases, similar to CGAs.

Background and Aims Sessile serrated adenoma/polyp (SSA/P) is a colorectal polyp that has malignant potential. However, the dysplastic components within an SSA/P can be difficult to detect. This study aimed to clarify the endoscopic characteristics of SSA/P with advanced histology. Methods We examined 462 endoscopically or surgically resected lesions that were pathologically diagnosed as SSA/P, including 414 without and 41 with cytologic dysplasia, and 7 with invasive carcinoma. We retrospectively studied the clinicopathologic and endoscopic characteristics and performed pit pattern analysis. Results A stepwise increase in the size of the SSA/P series was identified along with their dysplastic progression, although 19 of 48 (39.6%) SSA/Ps with dysplasia/carcinoma were ≤10 mm in size. Most lesions were covered with a mucus cap. Macroscopically, (semi)pedunculated morphology, double elevation, central depression, and reddishness were found more frequently in SSA/P with cytologic dysplasia and invasive carcinoma ([semi]pedunculated morphology, 17.1%/28.6%; double elevation, 63.4%/57.1%; central depression, 9.8%/28.6%; reddishness, 39.0%/85.7%) than in those without dysplasia (4.6%, 4.6%, 3.9%, and 3.4%, respectively). Furthermore, the presence of at least 1 of these 4 markers had high sensitivity (91.7%) for identifying the dysplasia/carcinoma within a SSA/P, with a specificity of 85.3%. In the pit pattern analysis, all SSA/Ps without dysplasia exhibited type II pit pattern only, whereas 94.4% of SSA/Ps with dysplasia/carcinoma showed type II in addition to type III L , IV, V I , or V N pit patterns. Conclusions In an SSA/P series, endoscopic characteristics, including (semi)pedunculated morphology, double elevation, central depression, and reddishness, in addition to the use of magnifying endoscopy, may be useful to accurately diagnose advanced histology within an SSA/P.

We herein report five cases of ulcerative colitis-associated cancer/dysplasia. Although clinical remission had been achieved in all patients, mucosal inflammation had been resolved in only one patient. Thus, in order to prevent cancer from developing, appropriate medical therapy aiming not only to relieve the clinical symptoms, but also to suppress chronic inflammation appears to be necessary. Moreover, cancer occurred as early as 4 years after the diagnosis in one patient. In patients without complete resolution of mucosal inflammation, careful surveillance colonoscopy should be initiated in the early phase.

Basaloid squamous cell carcinoma of the esophagus is a rare variant of squamous cell carcinoma. We reviewed 878 cases of esophageal squamous cell carcinoma and detected 22 cases (3%) of basaloid squamous cell carcinoma. These tumors and stage-matched paired conventional squamous cell carcinomas were investigated for clinicopathologic features and immunoreactivity of cytokeratin subtypes, p53, B-cell lymphoma 2 (bcl-2), β-catenin, and epidermal growth factor receptor. Molecular aberrations in p53, CTNNB1 (the gene encoding β-catenin), and epidermal growth factor receptor (EGFR) were also determined. Patients with basaloid squamous cell carcinomas demonstrated a 5-year survival rate of 42%, significantly worse than those with well-differentiated squamous cell carcinoma (P

Purpose This study compared the results of laparoscopic surgery for colon cancer in obese patients with a body-mass index (BMI) of 25 kg/m2 or higher with those in nonobese patients (BMI

Puppa G, Senore C, Sheahan K, Vieth M, Lugli A, Zlobec I, Pecori S, Wang L M, Langner C, Mitomi H, Nakamura T, Watanabe M, Ueno H, Chasle J, Conley S A, Herlin P, Lauwers G Y & Risio M (2012) Histopathology Diagnostic reproducibility of tumour budding in colorectal cancer: a multicentre, multinational study using virtual microscopy Aims: Despite the established prognostic relevance of tumour budding in colorectal cancer, the reproducibility of the methods reported for its assessment has not yet been determined, limiting its use and reporting in routine pathology practice. Methods and results: A morphometric system within telepathology was devised to evaluate the reproducibility of the various methods published for the assessment of tumour budding in colorectal cancer. Five methods were selected to evaluate the diagnostic reproducibility among 10 investigators, using haematoxylin and eosin (H&E) and AE1-3 cytokeratin-immunostained, whole-slide digital scans from 50 pT1-pT4 colorectal cancers. The overall interobserver agreement was fair for all methods, and increased to moderate for pT1 cancers. The intraobserver agreement was also fair for all methods and moderate for pT1 cancers. Agreement was dependent on the participants' experience with tumour budding reporting and performance time. Cytokeratin immunohistochemistry detected a higher percentage of tumour budding-positive cases with all methods compared to H&E-stained slides, but did not influence agreement levels. Conclusions: An overall fair level of diagnostic agreement for tumour budding in colorectal cancer was demonstrated, which was significantly higher in early cancer and among experienced gastrointestinal pathologists. Cytokeratin immunostaining facilitated detection of budding cancer cells, but did not result in improved interobserver agreement.

This report describes the laparoscopic resection of a rectal GIST after treatment with imatinib mesylate. A 56-year-old male presented with a submucosal tumor (longest diameter, 8 cm) arising in the lower rectum. A core needle biopsy revealed that the tumor contained bundles of spindle-like cells. Immunostaining revealed that the tumor was positive for c-kit and CD34. Analysis of the c-kit gene revealed a substitution of ACA (threonine) by GCA (alanine) at codon 574 of exon 11. Imatinib mesylate (400 mg/day) was given as preoperative adjuvant therapy for 3 months, and the tumor shrank to 5 cm in diameter. Proctectomy with transanal anastomosis could be performed laparoscopically, while preserving the anus. There was no evidence of recurrence 2 years 6 months after surgery. Preoperative adjuvant chemotherapy with imatinib mesylate may permit the use of less invasive treatment procedures, allowing anal preservation.

INTRODUCTIONIntraneural lipoma and fibrolipomatous hamartoma of the nerve are rare soft tissue tumors that most commonly occur in the forearm and the wrist, and particularly within the median nerve. When the lesions are large enough, they may cause progressive compression neuropathy. They are distinct entities each other with different clinical and radiological findings and thereby need different surgical treatments.PRESENTATION OF CASEWe report here 3 cases of intraneural lipomatous tumors of the median nerve (1 case of intraneural lipoma and 2 cases of fibrolipomatous hamartoma).DISCUSSIONAll patients were surgically treated successfully with complete excision for intraneural lipoma and with carpal tunnel releases for the both fibrolipomatous hamartomas.CONCLUSIONA careful preoperative planning is necessary for the optimal treatment by distinguishing whether it is a resectable or non-resectable tumor based on the clinical and radiological findings, because they have characteristic findings each other.

The cutaneous clear cell squamous cell carcinoma (SCC) is a rare tumor thought to be associated with hair follicle or skin appendage differentiation. We report herein a rare variant case of a clear cell SCC originating in the esophagus. A 70-year-old Japanese man was found to have a tumor in the esophagus. The excised neoplasm showed dominance of clear cell over conventional SCC components; the two components in an apparent continuum. The clear cells, regular in size with a moderate nuclear/cytoplasmic ratio and relatively hyperchromatic and centrally located nuclei, were compactly arranged in sheets. Glycogen deposition was apparent on PAS staining with or without diastase digestion and under the electron microscope. The clear cell SCC components were positive for cytokeratin (CK)7, CK8, CK18 and CK19, but were negative for CK5/6 or CK14. Reciprocal staining patterns of CKs were apparent in conventional SCC components. The present case and cutaneous clear cell SCC counterparts share some histopathologic characteristics whereas CKs expression differs between the two. Overexpression of p53 protein, without evidence of any mutation, and reduced p16(INK4a) were noted in both clear cell and conventional SCC components. No mutations of Kras, BRAF or β-catenin genes were found in both tumor components.

Gastrointestinal stromal tumors feature a wide spectrum of biologic behavior, ranging from benign to extremely malignant. To determine the role of p16(INK4a) alteration in progression of gastrointestinal stromal tumors of the stomach, we have investigated protein expression and gene methylation in correlation with clinicopathologic factors and survival. In addition to immunohistochemical analysis of p16(INK4a) in a series of 95 cases, real-time quantitative methylation specific polymerase chain reaction for p16(INK4a) and immunostaining for cyclin D1, cyclin E, pRb, DP-1, E2F-1, and Ki-67 were also evaluated in randomly selected samples. The p16(INK4a) labeling indices ranged from 0% to 74% (median, 21%), demonstrating a significant inverse correlation with size (P = .046). On univariate (P = .003) and multivariate (P = .067) analyses, loss of p16(INK4a) expression increased the likelihood of a poor tumor-related survival. In addition, size (P = .036) and the mitotic index (P = .005) had independent prognostic influence. The p16(INK4a) methylation index, which ranged from 0% to 100% (median, 17%), was significantly higher in larger tumors (P < .001) and in high-risk category lesions (P = .001) and inversely correlated with protein expression. Hierarchical cluster analysis based on expression of p16(INK4a) network members identified 2 clusters in 27 randomly selected tumor samples, containing 11 and 16 tumors each. Former cluster samples demonstrated higher risk category (P = .022), higher p16(INK4a) methylation (P < .001), and more reduced pRb expression (P < .018). In addition, p16(INK4a) network members clustered into 2 groups: (1) showing down-regulated p16(INK4a) protein and up-regulating of both cyclin D1 and DP-1 and (2) down-regulated pRb and up-regulated E2F-1. We conclude that p16(INK4a) alteration has an important role in progression of gastrointestinal stromal tumors of the stomach. Furthermore, the study provides a possible link between regulation of p16(INK4a) network members and gastrointestinal stromal tumors.

A 19-year-old woman was admitted to the hospital with a complaint of right wrist pain. A plain radiograph showed an osteolytic lesion in the right distal radius. Surgical treatment with curettage and bone grafting was performed under the clinical diagnosis of a giant-cell tumor. However, local recurrence was noticed 6 months after the treatment, and the curettage and bone graft were performed again. The histology of the recurrent lesion revealed a malignant giant-cell tumor that was entirely composed of highly atypical stromal cells and tumor giant cells. After a retrospective review of the primary lesion, it was found to also contain a small focus of pleomorphic cells within the conventional giant-cell tumor. Immunohistochemical and genetic analysis revealed p53 overexpression in the tumor giant cells and loss of heterozygosity of p53 gene only in the recurrent tumor; thus, a diagnosis of secondary malignant giant-cell tumor was finally made. The patient underwent systemic chemotherapy along with curettage and cryosurgery using liquid nitrogen. It is now 1 year and 4 months after the last treatment, and the patient is well and alive with no evidence of the disease. Identification of p53 genetic alteration may help in diagnosing malignant giant-cell tumor.

Objective When cultured in monolayers, articular chondrocytes undergo an obvious phenotypic change. Although the involvement of integrins has been suggested, the exact mechanisms of the change have not been determined. This study was undertaken to clarify the mechanisms underlying the loss of chondrocyte phenotype early after plating. Methods Primary cultured human articular chondrocytes were used for the experiments. Involvement of respective integrins in the phenotypic change was investigated in RNA interference (RNAi) experiments. A signaling pathway involved in the change was identified in experiments using specific inhibitors and adenoviruses encoding mutated genes involved in the pathway. Adenoviruses carrying mutated GTPases were used to determine the involvement of small GTPases in the process. Results In monolayer-cultured chondrocytes, suppression of αv or β5 integrin expression by RNAi inhibited morphologic changes in the cells and increased (or prevented a reduction in) the expression of various cartilage matrix genes. Consistent results were obtained in experiments using a blocking antibody and a synthetic inhibitor of αvβ5 integrin. The decrease in cartilage matrix gene expression in chondrocytes after plating was mediated by ERK signaling, which was promoted primarily by αvβ5 integrin. In articular chondrocytes, the affinity of αvβ5 integrin for ligands was regulated by the small GTPase R-Ras. R-Ras was gradually activated in monolayer-cultured chondrocytes after plating, which caused a gradual decline in cartilage matrix gene expression through enhanced αvβ5 integrin activation and the subsequent increase in ERK signaling. Conclusion Our findings indicate that αvβ5 integrin may be involved in the change that occurs in monolayer-cultured chondrocytes after plating.

Sacrococcygeal teratoma is a relatively rare congenital retroperitoneal tumor in adults. The standard treatment is a complete tumor resection. This report describes the successful laparoscopic resection of a sacrococcygeal teratoma. The patient was a 27-year-old woman with a well-demarcated cystic mass, 6 cm in diameter, in the retroperitoneum overlying the anterior surface of the sacrum. The mass was resected laparoscopically. A histopathological examination showed a mature teratoma. The magnifying function of the laparoscope allowed an en bloc resection in the narrow pelvic cavity, without damaging the tumor. The aesthetic outcome was excellent. The patient remains relapse-free at 1 year 6 months after surgery.

Background and Objectives Intercellular adhesion mediated by the claudin and cadherin/catenin complex is a prerequisite for epithelial integrity and differentiation, and has been suggested to be frequently disturbed in cancers. The aim of this study was to assess the relationship between such abnormality and clinicopathological features of colorectal carcinomas. Methods Immunohistochemical analysis of claudin-1 and -4, E-cadherin, and β-catenin was performed on a series of 156 cases. Results Significant positive associations (P

Chronic eosinophilic inflammation may promote airway remodeling, including thickening of the reticular basement membrane (RBM), hypertrophy and hyperplasia of the airway smooth muscles (ASM), and an increase in the production of tenascin. The authors examined the correlation between airway remodeling and bronchial reactivity to histamine (Hist) and acetylcholine (ACh) in patients with moderate to severe asthma.In 30 adult patients with asthma, the authors assessed bronchial hyperresponsiveness (BHR) to various concentrations of ACh and Hist by measuring decreases in forced expiratory volume in one second (FEV₁) of20% from the preprovocation state, and % recoveries of FEV₁ after inhalation of β-stimulant. After corticosteroid therapy, the authors evaluated the thickening of RBM and ASM and the production of tenascin in bronchial specimens.The % decrease in FEV₁ was correlated with the % recovery in FEV₁ after provocation by ACh or Hist. Hypertrophy of ASM was correlated with the % decrease in FEV₁ after provocation by Hist, but not by ACh. Thickening of ASM, up-regulation of tenascin in RBM, and duration of asthma were inversely correlated with the % recovery of FEV₁ after provocation by Hist, but not by ACh.In adult patients with moderate to severe asthma, a strong bronchial contraction provoked by Hist and a subsequent small recovery indicate airway remodeling.

Summary Objective To investigate the changes of knee menisci in osteoarthritis (OA) in human. Methods OA and control menisci were obtained from 42 end-stage OA knees with medial involvement and 28 non-arthritic knees of age-matched donors, respectively. The change of menisci in OA was evaluated by histology, and gene expression of major matrix components and anabolic factors was analyzed in the anterior horn segments by quantitative PCR (qPCR). In those regions of menisci, the rate of collagen neo-synthesis was evaluated by [ 3 H]proline incorporation, and the change of matrix was investigated by ultrastructural observation and biomechanical measurement. Results In OA menisci, the change in histology was rather moderate in the anterior horn segments. However, despite the modest change in histology, the expression of type I, II, III procollagens was dramatically increased in those regions. The expression of insulin-like growth factor 1 (IGF-1) was markedly enhanced in OA menisci, which was considered to be responsible, at least partly, for the increase in procollagen gene expression. Interestingly, in spite of marked increase in procollagen gene expression, incorporation of [ 3 H]proline increased only modestly in OA menisci, and impaired collagen synthesis was suggested. This finding was consistent with the results of ultrastructural observation and biomechanical measurement, which indicated that the change of meniscal matrix was modest in the macroscopically preserved areas of OA menisci. Conclusion Although the expression of major matrix components was markedly enhanced, matrix synthesis was enhanced only modestly, and the changes of matrix in human OA menisci were rather modest in the non-degenerated areas.

The short- and long-term outcomes of laparoscopic surgery for right-sided colon cancer remain largely uninvestigated. This study was undertaken to compare the morbidity and mortality after either a laparoscopic right hemicolectomy (LRHC) or an open right hemicolectomy (ORHC) for this type of tumor.The study group included 100 patients who underwent an LRHC and 100 patients who underwent an ORHC for right-sided colon cancer from 1990 through 2004. The two groups were retrospectively well matched with respect to sex, age (+/-5 years), and pathological tumor-node-metastasis (TNM) stage.The median follow-up period was 83 months in the LRHC group and 105 months in the ORHC group. The LRHC group had a lower volume of intraoperative bleeding (P0.001), a lower rate of wound infection (P = 0.019) or postoperative intestinal obstruction (P = 0.013), and a shorter hospital stay (P0.001) than the ORHC group. The rate of recurrence did not differ significantly between the LRHC group (19%) and the ORHC group (22%). In patients with TNM stage I or II, the disease-free survival (DFS) rate (94.9% vs 95.1%) and overall survival (OS) rate (95.8% vs 95.0%) did not differ significantly between the two groups. A similar tendency was observed in patients with stage III with the rates for DFS (71.3% vs 60.4%) and OS (73.6% vs 64.1%), respectively.An LRHC for right-sided colon cancer has the advantage over an ORHC of better short-term outcomes, and both groups have similar long-term oncologic outcomes. An LRHC is thus an acceptable alternative to an ORHC for the treatment of this type cancer.

Background and Objectives The p16INK4a (p16), cyclin D1, cyclin-dependent kinase (CDK) 4 and retinoblastoma (Rb) genes are components of the Rb pathway that controls the G1-S checkpoint of the cell cycle. The aim of this study was to assess the relationship between their abnormalities and clinicopathological features in gastric carcinomas. Mehtods Immunohistochemical analysis of the encoded proteins was performed on a series of 158 cases. Results Loss of p16/Rb protein (pRb) expression and overexpression of cyclin D1/CDK4 were observed in 49%/40% and 37%/37% of gastric carcinomas, respectively. At least 1 of these abnormalities was found in 86% of the cases and a positive correlation was noted between p16 and pRb (P = 0.009). Cyclin D1 (P = 0.042) and CDK4 (P = 0.008) overexpession was inversely associated with lymph node metastasis and depth of invasion, respectively. Loss of pRb expression was more frequently in diffuse type lesions than in the intestinal type (P = 0.022). The patients with p16+/pRb−/cyclin D1−/CDK4− or p16−/pRb+/cyclin D1−/CDK4− tumors demonstrated particularly poor survival. With multivariate survival analysis, only depth of invasion and TNM stage could be proven as independent predictors. Conclusions The Rb pathway is disrupted in the vast majority of gastric carcinomas. This study also identified specific immunohistochemical marker profiles for prognosis. J. Surg. Oncol. 2008;98:60–66. © 2008 Wiley-Liss, Inc.

Among complications after surgery for colorectal cancer, wound infections may prolong hospitalization and increase healthcare costs. This study was designed to clarify the incidence, risk factors, and pathogens responsible for wound infections after surgery for colorectal cancer.The study group comprised 144 patients (94 men and 50 women) with colorectal cancer in whom the same surgeon at Kitasato University Hospital performed resection from January 2004 through December 2005. Their mean age was 67.1 years (range = 38-90). To identify risk factors for surgical wound infections, we examined the following 11 variables: gender, age (65 vs.or=65 years), body-mass index (25 vs.or=25 kg/m(2)), the presence or absence of diabetes mellitus, physical status according to the American Society of Anesthesiologists classification (ASA score), stage of cancer according to the TNM staging system, surgical procedure (laparoscopic colectomy vs. open colectomy), procedure type (right colectomy vs. left colectomy vs. anterior resection), operation time (180 vs.or=180 min), intraoperative bleeding volume (120 vs.or=120 ml), and the presence or absence of intraoperative transfusion. Tissue specimens of infected wounds were cultured to identify pathogens.Postoperative wound infections occurred in 12% (17/144) of the patients. In univariate analyses, the incidence of wound infection was 26% (11/43) in patients who underwent open colectomy compared with 6% (6/101) in those who underwent laparoscopic colectomy. This difference was significant (P = 0.001). In multivariate analyses, only surgical procedure was identified as an independent risk factor for wound infection. The odds ratio for open colectomy compared with laparoscopic colectomy was 3.322 (P = 0.021). Pus from infected wounds was cultured in 7 of the 17 patients and cultures were positive for pathogens in 5 patients: 1 laparoscopic colectomy and 4 open colectomy. Bacteroides species were the most common pathogen.To prevent wound infections after surgery for colorectal cancer, laparoscopic surgery should be performed when indicated.

In spite of the clinicopathological differences between Crohn's disease (CD) and ulcerative colitis (UC), they share the fundamental feature of destructive inflammatory processes involving the intestinal wall. The aim of the present study was to investigate the contribution of cell-mediated cytotoxicity to mucosal damage in CD and UC. Colonic mucosal biopsy specimens from patients with active CD (n=25) and UC (n=26) and normal controls (n=12) were immunohistochemically analyzed for the expression of CD3, CD4, CD8, and T cell-restricted intracellular antigen (TIA)-1, which promotes apoptosis by alternative splicing of pre-messenger RNA of the Fas receptor, and granzyme B (GrB), which leads to apoptosis through induction of perforin. Histological scores for cryptal apoptosis and ulceration were assessed in hematoxylin- and eosin-stained sections. In patients with CD and UC, CD3+(P

P21WAF1/CIP1 is a cyclin-dependent kinase inhibitor activated by p53 to produce cell cycle arrest. A consensus has not been reached concerning the prognostic value of p21WAF1/CIP1 expression in colorectal cancers. P21WAF1/CIP1 expression was determined immunohistochemically in a series of 211 cases of colorectal carcinomas, together with its relation to p53, bcl-2, cell turnover (as assessed by Ki67 expression and apoptotic counts) and the Kras gene status. The expression of p21WAF1/CIP1 was also compared with reference to clinicopathological parameters and patient survival. The median value for nuclear p21WAF1/CIP1 expression was 31% (interquartile range, 13–47%) and the fraction of cases considered to be high expressers (>20%) was 66%. Expression of p21WAF1/CIP1 was not associated with immunoreactivity for p53 or bcl-2, or cell turnover. P21WAF1/CIP1 high-expressing tumors were more often well differentiated (P

Objective To determine the change in metabolic activity of chondrocytes in osteoarthritic (OA) cartilage, considering regional difference and degree of cartilage degeneration. Methods OA cartilage was obtained from knee joints with end-stage OA, at both macroscopically intact areas and areas with various degrees of cartilage degeneration. Control cartilage was obtained from age-matched donors. Using laser capture microdissection, cartilage samples were separated into superficial, middle, and deep zones, and gene expression was compared quantitatively in the respective zones between OA and control cartilage. Results In OA cartilage, gene expression changed markedly with the site. The expression of cartilage matrix genes was highly enhanced in macroscopically intact areas, but the enhancement was less obvious in the degenerated areas, especially in the upper regions. In contrast, in those regions, the expression of type III collagen and fibronectin was most enhanced, suggesting that chondrocytes underwent a phenotypic change there. Within OA cartilage, the expression of cartilage matrix genes was significantly correlated with SOX9 expression, but not with SOX5 or SOX6 expression. In OA cartilage, the strongest correlation was observed between the expression of type III collagen and fibronectin, suggesting the presence of a certain link(s) between their expression. Conclusion The results of this study revealed a comprehensive view of the metabolic change of the chondrocytes in OA cartilage. The change of gene expression profile was most obvious in the upper region of the degenerated cartilage. The altered gene expression at that region may be responsible for the loss of cartilage matrix associated with OA.