Naoki Ishiwa

Aberrant Nuclear Localization and Gene Mutation of β-catenin in Low-Grade Adenocarcinoma of Fetal Lung Type: Up-Regulation of the Wnt Signaling Pathway May Be a Common Denominator for the Development of Tumors that Form Morules

The salient histopathologic features of low-grade adenocarcinoma of the fetal lung type (L-FLAC)/well-differentiated fetal adenocarcinoma (WDFA) include complex glandular structures and morules with biotin-rich optically clear nuclei. Interestingly, these characteristic features are shared by the cribriform-morular variant of papillary thyroid carcinoma, whose morphology is identical to that of familial adenomatous polyposis (FAP)-associated thyroid carcinoma. Furthermore, the single reported case of lung cancer associated with FAP was L-FLAC/WDFA. These observations lead us to hypothesize that up-regulation of the Wnt signaling pathway underlies the development of L-FLAC/WDFA. To verify this hypothesis, 11 cases of L-FLAC/WDFA, including the one FAP-associated case, eight cases of high-grade adenocarcinoma of the fetal lung type (H-FLAC), 24 cases of conventional pulmonary adenocarcinoma (CAC), and 13 fetal lungs were immunostained for β-catenin. All cases of L-FLAC/WDFA showed predominantly aberrant nuclear/cytoplasmic expression, especially in budding glands and morules, whereas six of eight cases (75%) of H-FLAC and all but one case (96%) of CAC showed predominantly membranous expression. Fetal lungs showed nuclear/cytoplasmic expression restricted to the distal branching airway epithelium. Mutational analysis of exon 3 of the β-catenin gene in five sporadic cases of L-FLAC/WDFA showed a point mutation at codon 34 and codon 37 in two cases, respectively. The present study indicates that up-regulating disturbances in the Wnt signaling pathway, including mutation of the β-catenin gene, underlie tumorigenesis of L-FLAC/WDFA. The expression pattern of β-catenin in L-FLAC/WDFA resembles that of the developing fetal lung airway. With the expression pattern of β-catenin as a marker, most cases of H-FLAC as well as CAC appear to have different oncogenic pathways from cases of L-FLAC/WDFA. The present study together with other available data also suggests that abnormal up-regulation of the Wnt signaling pathway may be a common denominator for the development of tumors with morular formation from a variety of anatomic sites.

High cyclin E and low p27/Kip1 expressions are potentially poor prognostic factors in lung adenocarcinoma patients

Cyclin E is an important regulator of entry into the S phase of the cell cycle. p27/Kip1 (p27) binds to cyclin E/Cdk2 complex and negatively regulates cell proliferation. We immunohistochemically examined the expression of cyclin E and p27 in 98 cases of resected lung adenocarcinoma to evaluate the prognostic significance of cyclin E and p27. Cyclin E was expressed in 16 cases (16%), and p27 was expressed in 41 cases (42%). Using Kaplan-Meier survival analysis, patients with cyclin E positive (P=0.0017) and p27 negative (P=0.011), both individually and in combination (P<0.0001), had a worse prognosis. We also analyzed the relationship of these findings to clinicopathological parameters, which revealed that cyclin E-positive, p27-negative cases had a higher Ki67 expression (P=0.012) and a higher rate of lymph node metastasis (P=0.0078) than other groups. Our results suggested that cyclin E over expression, in association with p27 reduction in particular, may potentially be a poor prognostic factor in lung adenocarcinoma patients. However, to verify the prognostic significance of these factors, a multivariate analysis of a larger number of patients should be undertaken.

Prognostic value of KRAS mutations and Ki-67 expression in stage I lung adenocarcinomas.

The purpose of the present study was to establish accurate prognostic markers to predict the post-operative recurrence of stage I lung adenocarcinomas (ADC). One-hundred and ninety cases of stage I ADC were examined for KRAS mutations and Ki-67 expression, and their associations with disease recurrence were analyzed. KRAS-mutated cases showed a significantly higher risk of recurrence than cases without mutations (5-year disease-free survival (DFS) 61.0% vs. 85.8%, P=0.017: adjusted Hazard ratio (HR) 4.55, 95% Confidence Interval (CI) 1.61-12.82, P=0.004). Ki-67 high-expressers (labeling index >10%) also showed a higher risk of recurrence than low-expressers (5-year DFS 68.7% vs. 93.2%, P<0.001: adjusted HR 3.84, 95% CI 1.18-12.45, P=0.025). Ki-67 high-expressers with KRAS mutations showed an additional higher risk of recurrence compared to low-expressers without mutations (5-year DFS 37.5% vs. 93.3%, P<0.001: adjusted HR 16.82, 95% CI 3.77-74.98, P<0.001) and their 5-year DFS was nearly equivalent to that of stage II non-small cell lung cancer (NSCLC) in our facility (37.5% vs. 37.2% for stage II NSCLC, p=0.577). The combined use of KRAS status and Ki-67 expression level could be an excellent prognostic marker to predict the post-operative recurrence of stage I ADC.

Prediction of postoperative pulmonary function using perfusion magnetic resonance imaging of the lung.

To assess semiquantitatively the regional distribution of lung perfusion using magnetic resonance (MR) perfusion imaging.

Osteoclast-like giant cell tumor of the pancreas.

Abstract. A rare case of osteoclast-like giant cell tumor of the pancreas is reported. A 45-year-old woman presented with upper abdominal pain and weight loss. Examination revealed a tumor in the tail of pancreas, and distal pancreatectomy with splenectomy was performed. Pathological findings showed the tumor was composed of two cell types: atypical mononuclear round cells and abundant osteoclast-like multinucleated giant cells with central nucleoli. Immunohistochemical study showed that the atypical cells were strongly reactive for vimentin and negative for CD68, while the giant cells were immunoreactive for CD68, but negative for vimentin. The tumor was diagnosed as osteoclast-like giant cell tumor of the pancreas. We report this case and review 31 cases previously described in the literature.

Long-Term Outcome After Hernia Repair with the Prolene Hernia System

PurposeWe evaluated the long-term outcome and symptoms after inguinal hernia repair using the Prolene Hernia System (PHS).MethodsWe reviewed the medical records of all patients who underwent PHS surgery at our hospital to assess the postoperative complications and recurrence rates. Late symptoms were evaluated by a standardized interview using a questionnaire.ResultsA total of 395 hernias in 367 patients were studied. Postoperative complications developed after 20 repairs (5.1%), including a severe mesh infection in one patient. Seven (1.8%) patients suffered recurrence. Of 395 cases, 363 (91.9%) responded to the interview. After a median follow-up interval of 19.3 months (range 1.0–55.8), moderate pain and moderate discomfort were reported by only 1.9% and 0.8% of patients, respectively.ConclusionsProlene Hernia System surgery is a safe and feasible procedure with low rates of complication, recurrence, and late symptoms.

Correlation between lymph node micrometastasis and histologic classification of small lung adenocarcinomas, in considering the indication of limited surgery

The validity of limited surgery for lung carcinomas have not been clearly established. Several reports suggest that not only tumor size but also the histological findings may be of importance in this role. By conducting immunohistochemical examinations of lymph node micrometastases from small lung adenocarcinomas, we considered the suitability of limited surgery for especially localized bronchioloalveolar carcinoma (LBAC) without active fibroblastic proliferation (Noguchis histologic classification types A and B). In this study, we enrolled 54 patients with lung adenocarcinoma smaller than 2 cm in diameter. Lymph node involvement was demonstrated in 11 (20.4%) patients. Lymph node micrometastasis was present in 11 (25.6%) of the 43 patients at pN0 disease. However, 13 patients with LBAC without active fibroblastic proliferation (types A and B) had neither lymph node involvement nor micrometastasis. Our results indicate that limited pulmonary resection may be acceptable procedure for LBAC without active fibroblastic proliferation.

Can surgical diagnosis of “early” gastric cancer and lymph node metastasis be accurate?

BackgroundThe objective of this study was to evaluate the accuracy of the intraoperative assessment of early gastric cancer (EGC) and lymph node status.MethodsA total of 280 patients underwent gastrectomy for primary gastric cancer at the Department of Surgery, Yokohama City Kowan Hospital, from 1994 to 2002. Of these 280 patients, 140 were diagnosed as having EGC during surgery (sT1), while the rest were diagnosed with advanced disease (sT2–T4). Of the former 140 patients, 136 patients, who underwent curative resection with D1 or D2 lymphadenectomy, were further investigated for the assessment of lymph node status.ResultsThe sensitivity, specificity, and accuracy of the surgical diagnosis of EGC were 96.4% (135 of 140), 90.0% (126 of 140), and 93.2% (261 of 280), respectively, while these values for the assessment of lymph node metastases were 55.6% (5 of 9), 94.5% (120 of 127), and 91.9% (125 of 136), respectively. In a further analysis in which patients with tumors of macroscopically depressed type and undifferentiated histology were excluded, all patients staged as sT1sN0 had no lymph node metastases pathologically.ConclusionAlthough the depth of tumor invasion can be correctly assessed intraoperatively, it is difficult to be precise regarding the presence of nodal metastases. One practical solution to this problem might be to employ limited surgery for those patients with macroscopically elevated and histologically differentiated tumors.