Ryo Wada

Optimal Colorectal Cancer Staging Criteria in TNM Classification

PURPOSE Histologic components of the TNM classification system have been repeatedly revised since the fifth edition (TNM5). TNM classification revisions provide different criteria for categorizing tumor nodules without residual lymph node structure (ND). However, there are few systematic evaluations regarding the effectiveness of these revisions. PATIENTS AND METHODS A multicenter pathologic review for ND in colorectal cancer (CRC) was performed. Tumor staging defined by TNM5, sixth edition (TNM6), and seventh edition (TNM7) were compared on the basis of Akaike information criterion (AIC) and Harrells concordance index (c-index). Moreover, TNM7s prognostic value was compared between the original ND and modified criteria, which considered all regional NDs as lymph node metastasis (LNM) irrespective of the original structure. RESULTS In 1,716 treated patients with CRC (1994 to 1998), tumor stages (I/II/III) exhibited better prognoses in TNM7 (AIC, 3055.1; c-index, 0.7215) than in TNM6 (AIC, 3063.7; c-index, 0.7149), but not better than in TNM5 (AIC, 3051.6; c-index, 0.7240). Comparing the original TNM7 and modified criteria, 4.2% of patients were classified in different N stages (N0/N1/N2a/N2b); both AIC and the c-index were superior in the modified criteria (AIC, 3029.40; c-index, 0.7271) compared with the original criteria (AIC, 3040.58; c-index, 0.7230). Modified criteria were also associated with improved prognostic power of tumor stages (I/IIA/IIB/IIC/IIIA/IIIB/IIIC). These results were similar in another cohort of 2,242 treated patients with CRC (1999 to 2003). CONCLUSION The prognostic value of TNM7 is better than that of TNM6; however, improvement over TNM5 is insignificant. By considering all regional NDs as LNM irrespective of their morphology, TNM classification can be simplified and its prognostic value improved.

Gastric stump carcinosarcoma with rhabdomyosarcomatous differentiation

Gastric carclnosarcoma is an unusual tumor and its occurrence in the gastric stump Is extremely rare. A report is presented here of a unique case of gastric stump carcinosarcoma with rhabdomyosarcomatous differentiation In a 74‐year‐old man. The patient had undergone partial gastrectomy with gastrojejunostomy (Billroth II method) 30 years previously. The tumor had both adenocarcinoma and sarcoma components, and an immunohistochemlcal study suggested a focal transition between these components. The main sarcomatous components showed fibrosarcomatous features with a scattered distribution of rounded tumor cells, whose rhabdomyosarcomatous differentiation was lmmuno‐histochemlcaily determined. Ultrastructural examination supported the rhabdomyosarcomatous natures. Experience with the present tumor indicates that carclnosarcoma with rhabdomyosarcomatous differentiation can occur in the gastric stump and that this disease Is capable of aggressive behavior.

Pseudolymphoma of the liver associated with Sjögren's syndrome

Sjo¨grens syndrome (SS) is known to be associated with pseudolymphoma in several organs. We describe a patient with SS complicated by a hepatic pseudolymphoma. Although the development of a hepatic pseudolymphoma is extremely rare, this disorder should be taken into consideration in the differential diagnosis of space occupying lesions related to autoimmune diseases such as SS.Sjögrens syndrome (SS) is known to be associated with pseudolymphoma in several organs. We describe a patient with SS complicated by a hepatic pseudolymphoma. Although the development of a hepatic pseudolymphoma is extremely rare, this disorder should be taken into consideration in the differential diagnosis of space occupying lesions related to autoimmune diseases such as SS.

Multicenter study for optimal categorization of extramural tumor deposits for colorectal cancer staging.

Objective:This study aimed to determine the optimal categorization of extramural tumor deposits lacking residual lymph node (LN) structure (EX) in colorectal cancer staging. Background:The TNM classification system categorizes EX on the basis of their contour characteristics (the contour rule). Methods:We conducted a multicenter, retrospective, pathological review of 1716 patients with stage I to III curatively resected colorectal cancer who were treated at 11 institutions (1994–1998). In addition, 2242 patients from 9 institutions (1999–2003) were enrolled as a second cohort for validating results. EX were classified as isolated foci confined to vascular or perineural spaces (ie, lymphatic, venous, or perineural invasion) or as tumor nodules (ND). N- and T-staging systems employing different categories for staging were compared in terms of their prognostic power. In addition, the diagnoses of extramural, discontinuously spreading lesions made by 11 observers from different institutions were assessed for interobserver agreement. Results:EX were observed in 18.2% of patients in the first cohort. The method of categorization of EX in tumor staging has a stronger impact on N than T staging. The N-staging system in which all ND types were classified as N factor (the ND rule) could more effectively stratify the survival outcome than the contour rule (Akaike information criterion, 3040.8 vs 3059.5; the Harrell C-index, 0.7255 vs 0.7103). EX were observed in 16.9% of patients in the second cohort. Statistically, the ND rule was more informative than the contour rule for N staging. The Fleiss kappa coefficient for distinguishing LN metastases from EX (0.74) was lower than expected for complete agreement, and it decreased further to 0.51 when calculated for the judgment of ND with smooth contours. Conclusions:Classifying all ND types as N factors irrespective of contours can simplify the tumor staging system by enhancing diagnostic objectivity, resulting in improved prognostic accuracy.

Actual status of distribution and prognostic impact of extramural discontinuous cancer spread in colorectal cancer.

PURPOSE To clarify the prognostic impact of tumor nodules without residual lymph node (LN) structure (ND) in colorectal cancer and to determine optimal categorization of ND in tumor staging. PATIENTS AND METHODS A multicenter, retrospective pathologic review was performed for 1716 patients with stages I to III curatively resected colorectal cancer treated at 11 institutions between 1994 and 1998. An additional 2242 patients from nine institutions were enrolled between 1999 and 2003 as a second cohort to validate the results. RESULTS LN metastasis (LNM) and ND were observed in 33.7% and 16.0% (smooth-contour nodule [S-ND], 8.2%; irregular-contour nodule [I-ND], 10.7%) of patients in the first cohort. S-ND and I-ND were similarly distributed in the regional area. There was no considerable difference in the impact on survival between S-ND (hazard ratio [HR], 2.7; 95% CI, 1.9 to 3.8) and I-ND (HR, 4.3; 95% CI, 3.3 to 5.8) or between LNM (HR, 4.5; 95% CI, 3.4 to 6.0) and ND (HR, 4.0; 95% CI, 3.1 to 5.3). LNM and ND were similarly associated with the mode of recurrence. Tumor nodules ≥ 5 mm growing with venous/perineural invasion (ND [v/pni+]), judged with 0.61 κ value among 11 observers, had an independent prognostic value for 5-year survival of 42%; similar results were observed in the second cohort. CONCLUSION These results do not support the TNM system in which S-ND is treated differently from I-ND in tumor staging; LNM and ND should be considered together in the same category. The presence of ND (v/pni+) has a considerable adverse prognostic effect.

Multiple esophagogastric granular cell tumors.

Multiple granular cell tumors of the esophagus and the stomach found in a 53-year-old man are reported. One lesion was detected within the lower thoracic esophagus and seven lesions were detected in the stomach. The esophageal tumor was resected endoscopically, and gastrectomy was performed for the multiple gastric lesions. Histologically, the tumors consisted of spindle or polyhedral cells and the cytoplasm contained punctated eosinophilic granules with positive immunohistochemical staining for S-100 protein. The tumors were mainly located in the submucosal layer. Some tumor cells were seen in the mucosae propria and the muscularis propria. The tumor cells were only slightly positive for p53- and Ki-67-immunohistochemical stainings. Based on these findings, we diagnosed the granular cell tumors as benign. Granular cell tumor is comparatively rare in clinical practice, but a few such tumors have been seen in the digestive tract. A few cases of multiple esophagogastric granular cell tumors have also been reported in the literature.

Incidence of Paneth Cells in Minute Tubular Adenomas and Adenocarcinomas of the Large Bowel

This study attempted to demonstrate the incidence of Paneth cells within large bowel tubular adenoma and adenocarcinoma according to location and macroscopic appearance using minute tumors (up to 5 mm in size). We have shown that Paneth cells were sometimes seen in the early stage of the development of large bowel epithelial neoplasia. According to the macroscopic appearance (elevated or depressed type), in large bowel epithelial neoplasia, there was a statistical difference between the depressed type (32.5%, 14 of 40 cases) and the elevated type (16.6%, 24 of 145 cases) (Chi square analysis, p < 0.05) in the incidence of Paneth cells. Paneth cells were seen more frequently in adenocarcinoma (45.8%, 11 of 24 cases) than in tubular adenoma (16.8%, 27 of 161 cases), with a significant statistical difference (Chi square analysis, p < 0.01). According to location, in both tubular adenoma and adenocarcinoma, Paneth cells were more frequently observed in the proximal colon (tubular adenoma: p < 0.01, adenocarcinoma: p < 0.05, Chi square analysis). Acta Pathol Jpn 42: 579 584, 1992.

Colonic Paneth cell metaplasia is pre-neoplastic condition of colonic cancer or not?

Background The carcinogenesis of colorectal cancer has been accepted by a model for a cascade of genetic alterations, named the adenoma-carcinoma sequence. In order to elucidate the carcinogenesis of the colorectal cancer more clearly, the genetic abnormalies of the non-neoplastic mucosal epithelium of the colon and rectum should be investigated. It has been speculated that colonic Paneth cell metaplasia (PaM) is one of the pre-neoplastic mucosa of colonic cancer. Therefore, we studied the propria mucosa of the right colon with PaM from the standpoints of the frequency of the K-ras codon 12 mutations (K-ras), which is initial genetic abnormality in colorectal cancer, and the loss of heterozygosity of microsatellite markers (LOH-MS), which has a relationship to development of colorectal cancer. Methods Fifty-two regions with PaM histopathologically from 12 surgically resected right colon specimens were studied. DNA extraction of the colonic mucosa with PaM was obtained using a microdissection method, and the frequency of the K-ras of PaM was investigated by enriched polymerase chain reaction-enzyme linked mini-sequence assay, and the frequency of the LOH-MS (D2S123, D17S250 and D5S346) of PaM was examined by high resolution fluorescenced labeled PCR primers. Results K-ras mutation was detected in fifteen regions among 52 PaM (28.9%). All mutations were a single mutation and GGT changed to AGT in eleven and GAT in four. LOH-MS were detected in twenty-one regions among 52 PaM (40.4%) (D2S123: 35.4%, 17/48 regions, D17S250: 13.7%, 7/51 regions, and D5S346: 0%, 0/52 regions). No K-ras mutations and LOH-MS were detected in the controls (Colorectal mucosa with no PaM). Conclusions Colonic mucosa with Paneth cell metaplasia may be one of the pre-neoplastic mucosa in the development of the colonic epithelial neoplasia.

Expression of Aldo-Keto Reductase Family 1 Member B10 in the Early Stages of Human Hepatocarcinogenesis

Aldo-keto reductase family 1, member B10 (AKR1B10), a cancer-related oxidoreductase, is expressed in well-differentiated hepatocellular carcinomas (HCCs). However, AKR1B10 levels are minimal in normal liver tissues (NLs), similar to the 70-kilodalton heat shock protein (HSP70) and glypican-3. Moreover, the role of AKR1B10 in chronic hepatitis or cirrhosis, which are considered preneoplastic conditions for HCC, has not been fully elucidated. The aim of this study was to evaluate the expression of AKR1B10, HSP70, and glypican-3 in 61 HCC tissue samples compared to corresponding non-tumorous liver tissues (NTs), comprising 42 chronic hepatitis and 19 cirrhosis cases to clarify the significance of molecular changes at the preneoplastic stages of HCC. Immunohistochemical analysis demonstrated that the median expression levels of AKR1B10 were higher in HCCs than in NTs (p < 0.001) and higher in NTs than NLs (p < 0.001) with 54.8%, 2.1%, and 0.3% expression in HCCs, NTs, and NLs, respectively. HSP70 and glypican-3 were expressed in HCCs, but minimally in NTs and NLs with no significant difference between expression in NTs and NLs. Furthermore, a multivariate analysis identified an association between hepatic steatosis and AKR1B10 expression in NTs (p = 0.020). Of the three protein expressed in well-differentiated HCCs, only AKR1B10 was upregulated in preneoplastic conditions, and a steatosis-related factor might influence its expression.

Successful treatment of relapsing neuro-Sweet's disease with corticosteroid and dapsone combination therapy.

Sweets disease with central nervous system involvement, tentatively named neuro-Sweets disease, has rarely been reported. Although systemic corticosteroid therapy is highly effective for neurologic symptoms in neuro-Sweets disease, relapse is common. Here, we describe the case of a 38-year-old Japanese man who presented with relapsing neuro-Sweets disease that was successfully treated with a combination of corticosteroid and dapsone. Dapsone should be considered as a therapeutic option for neuro-Sweets disease patients showing relapse.