Hajime Kuroda

Molecular pathogenesis of sporadic colorectal cancers

Colorectal cancer (CRC) results from the progressive accumulation of genetic and epigenetic alterations that lead to the transformation of normal colonic mucosa to adenocarcinoma. Approximately 75% of CRCs are sporadic and occur in people without genetic predisposition or family history of CRC. During the past two decades, sporadic CRCs were classified into three major groups according to frequently altered/mutated genes. These genes have been identified by linkage analyses of cancer-prone families and by individual mutation analyses of candidate genes selected on the basis of functional data. In the first half of this review, we describe the genetic pathways of sporadic CRCs and their clinicopathologic features. Recently, large-scale genome analyses have detected many infrequently mutated genes as well as a small number of frequently mutated genes. These infrequently mutated genes are likely described in a limited number of pathways. Gene-oriented models of CRC progression are being replaced by pathway-oriented models. In the second half of this review, we summarize the present knowledge of this research field and discuss its prospects.

Vascular invasion in triple-negative carcinoma of the breast identified by endothelial lymphatic and blood vessel markers.

The aim of this study was to determine lymph vessel invasion (LVI) and blood vessel invasion (BVI) using established biological markers and clinicopathological findings for triple-negative breast carcinoma. We reviewed all 202 cases of primary breast carcinoma that were surgically resected at Saitama Medical Center, Saitama Medical School, between 2006 and 2009. Tumor tissue was immunostained for estrogen receptor, progesterone receptor, Her2/neu, D2-40, and CD34. Among these, 26 cases of triple-negative carcinoma were reported retrospectively. The results were compared with those of 176 cases of non-triple-negative carcinomas that were included as controls. The frequency of LVI examined by hematoxylin and eosin and D2-40 (triple negative, 7 of 26; non—triple negative, 61 of 176) was not significantly different, and neither was BVI examined by HE, Elastica van Gieson, CD34 (triple negative, 2 of 26; non—triple negative, 16 of 176), and lymph node metastasis (triple negative 9 of 26, non—triple negative, 65 of 176). However, a specific pattern of distant metastasis with a high frequency of visceral metastases was detected in triple-negative carcinoma cases (triple negative, 6 of 26; non—triple negative, 8 of 176). Our findings show that triple-negative carcinoma of the breast may have a distinct biological behavior.

Differential expression of glu-tubulin in relation to mammary gland disease

Tubulin is one of the molecular components that regulate cytosketal structure relating to cell differentiation, invasion, and metastasis in cancer. Recently, glu-tubulin, in which the C-terminal tyrosine of α-tubulin is removed by tubulin carboxypeptidase, overexpression has been reported in malignant tumors of the mammary gland immunohistochemically. We identified 147 cases accessioned in the Department of Pathology, International University of Health and Welfare Hospital from 2003 to 2009. Of the 78 malignant tumor cases, staining for glu-tubulin was observed in 56 (71.8%), and only 22 cases showed no significant staining. However, in benign disease, glu-tubulin staining was detected in the cytoplasm of fibroblasts and endothelial cells, but was completely absent from epithelial cells in 64 of 69 cases. When the expression of glu-tubulin was compared between malignant tumor, benign tumor, and other benign disease, a significant differentiation was found among expressions of this protein. These results indicate that glu-tubulin represents a strong selective expression for cancer cells and may be useful to identify and quantify human breast cancer.

Intraoperative frozen section diagnosis of bile duct margin for extrahepatic cholangiocarcinoma

AIM To evaluate the usefulness of frozen section diagnosis (FSD) of bile duct margins during surgery for extrahepatic cholangiocarcinoma (CCA). METHODS We retrospectively analyzed 74 consecutive patients who underwent surgery for extrahepatic CCA from 2012 to 2017, during which FSD of bile duct margins was performed. They consisted of 40 distant and 34 perihilar CCAs (45 and 55 bile duct margins, respectively). The diagnosis was classified into three categories: negative, borderline (biliary intraepithelial neoplasia-1 and 2, and indefinite for neoplasia), or positive. FSD in the epithelial layer, subepithelial layer, and total layer was compared with corresponding permanent section diagnosis (PSD) postoperatively. Then, association between FSD and local recurrence was analyzed with special reference to borderline. RESULTS Analysis of 100 duct margins revealed that concordance rate between FSD and PSD was 68.0% in the total layer, 69.0% in the epithelial layer, and 98.0% in the subepithelial layer. The extent of remaining biliary epithelium was comparable between FSD and PSD, and more than half of the margins lost > 50% of the entire epithelium, suggesting low quality of the samples. In FSD, the rate of negative margins decreased and that of borderline and positive margins increased according to the extent of the remaining epithelium. Diagnostic discordance between FSD and PSD was observed in 31 epithelial layers and two subepithelial layers. Alteration from borderline to negative was the most frequent (20 of the 31 epithelial layers). Patients with positive margin in the total and epithelial layers by FSD demonstrated a significantly worse local recurrence-free survival (RFS) compared with patients with borderline and negative margins, which revealed comparable local RFS. Patients with borderline and negative margins in the epithelial layer by PSD also revealed comparable local RFS. These results suggested that epithelial borderline might be regarded substantially as negative. When classifying the status of the epithelial layer either as negative or positive, concordance rates between FSD and PSD in the total, epithelial, and subepithelial layers were 95.0%, 93.0%, and 98.0%, respectively. CONCLUSION During intraoperative assessment of bile duct margin, borderline in the epithelial layer can be substantially regarded as negative, under which condition FSD is comparable to PSD.

Characteristic Histological Findings of Asymptomatic EBV-associated Lymphoproliferative Disorders in Tonsils

Recently, an in situ hybridization (ISH) and immunohistochemical study demonstrated that Epstein-Barr virus (EBV) infection may be involved in tonsillar hypertrophy and recurrent tonsillitis in children and young adolescents. The present study was based on 630 consecutive specimens from tonsillectomies performed at the Dokkyo University School of Medicine between 2002 and May 2017. Clinical findings were obtained from hospital records. Histologically, a “pale clear zone” was characterized by hyperplastic germinal centers with ill-defined borders and interfollicular expansion. Immunohistologically, the majority of immunoblasts were CD20-positive, whereas medium to large lymphoid cells usually expressed CD3. Among 14 lesions, numerous EBV-encoded small RNA (EBER)-positive cells were detected in 10. In 7 of these 10 lesions, EBER-positive cells were detected in germinal centers as well as in the interfollicular area. Based on our results, the “pale clear zone” suggests asymptomatic EBV infection of the tonsil. The present study demonstrated that “pale clear zones” should be taken into consideration when diagnosing asymptomatic EBV-associated LPDs in the tonsils of children and young adolescents as well as in middle-aged patients.

Nuclear Morphometry of Lung Squamous Cell Carcinomas in Cytologic Study

Background: The nuclei of most cancer cells in histopathologic preparations differ from normal nuclei and vary individually in size, shape, and chromatin pattern. Although the cytologic characteristics of squamous cell carcinoma (SCC) of the lung have been described, quantification of the cytologic features has not been established. Methods: Cytologic investigations were performed on bronchial brushings or washings, or fine-needle aspirates. We analyzed the nuclear area (NA) of 50 tumor cells in 32 patients with SCC of the lung and 50 bronchial epithelial cells in 20 patients with no evidence of malignancy including inflammatory lesions. Results: The NA of tumor cells (102.4 ± 26.2 μm2) was significantly larger than that of bronchial epithelial cells (64.1 ± 16.9 μm2) (P = 0.001). The receiver operating characteristic (ROC) curve analysis showed that an NA cutoff level of 86 μm2 had a sensitivity of 75% and specificity of 88% to detect malignant components. Conclusion: We conducted quantitative analyses of NA in SCC using cytologic specimen, NA was a useful parameter for evaluation of differential diagnosis between SCC and non-malignancies even in cytologic specimens.

Laparoscopy-assisted total gastrectomy for advanced gastric cancer with carcinomatous ascites after S1 plus cisplatin chemotherapy: a case report.

A 29-year-old man with a type 4 tumor, in the lower third of the stomach, and carcinomatous ascites was diagnosed by aspiration cytology of the ascitic fluid. Curative resection was considered impossible, and S1 (120 mg/d) and cisplatin (90 mg/d) were given for 21 days in 1 course. The cancer lesion showed marked remission (partial response), and the ascites completely disappeared after the fourth course. Twenty-five days after completion of the S1 treatment, laparoscopy-assisted total gastrectomy was performed. Histopathological examination showed no remnant cancer cells in the resected specimen and no lymph node metastases. The tumor was replaced with fibrosis having a granulomatous change. The patients postoperative course was uneventful. The patient was continued with S1 monotherapy after surgery, and no signs of recurrence or metastases have been seen on any examination 12 months after the surgery.