Yoko Tateishi

SALL4 represents fetal gut differentiation of gastric cancer, and is diagnostically useful in distinguishing hepatoid gastric carcinoma from hepatocellular carcinoma.

The novel stem cell marker SALL4 has been identified as a diagnostic marker of germ cell tumors, especially yolk sac tumors, in gonadal organs. To clarify the significance of SALL4 as an oncofetal protein, we investigated SALL4 expression by immunohistochemistry in non-neoplastic stomach and gastric carcinoma with particular emphasis on á-fetoprotein (AFP)-producing gastric carcinoma, as AFP-producing gastric carcinoma shares expression of AFP and glypican 3 (GPC3) with yolk sac tumors and hepatic neoplasms. A total of 338 gastric carcinomas, 60 hepatocellular carcinomas, and 48 cholangiocellular carcinomas were studied by immunohistochemistry on tissue microarrays. In addition, more detailed whole tissue section immunohistochemistry was performed on non-neoplastic gastric tissue from 5 adult and 8 fetal specimens, 6 hepatoblastomas, and 31 cases of AFP-producing gastric carcinomas. SALL4 expression was observed in the neofetal stomach in gestational week 9 and disappeared thereafter. It was also identified by tissue microarray study in a fraction of gastric carcinomas (51 of 338, 15%), associated with older age (P=0.0001), male sex (P=0.0033), intestinal-type histology (P=0.0001), and synchronous liver metastasis (P=0.0047). AFP and GPC3 were closely associated with SALL4 expression in gastric carcinoma (both, P<0.0001), and a full-section study indicated that SALL4 was positive in all 31 cases of AFP-producing gastric carcinoma with diffuse staining in 24 cases (78%). Diffuse SALL4 expression was observed in the histologic patterns of hepatoid (89%), glandular (57%), and clear cell (39%) AFP-producing gastric carcinoma. In addition, SALL4 expression was completely negative in hepatoblastoma (n=6) and hepatocellular carcinoma (n=60). SALL4 is an oncofetal protein similar to AFP and GPC3, but it represents fetal gut differentiation in gastric carcinoma. SALL4 is a sensitive marker for AFP-producing gastric carcinoma and is especially useful to distinguish hepatoid gastric carcinoma from hepatocellular carcinoma.

Gastric carcinoma with invasive micropapillary pattern and its association with lymph node metastasis.

Ushiku T, Matsusaka K, Iwasaki Y, Tateishi Y, Funata N, Seto Y & Fukayama M 
(2011) Histopathology 59, 1081–1089 
Gastric carcinoma with invasive micropapillary pattern and its association with lymph node metastasis

Palisade vessels as a new histologic marker of esophageal origin in ER specimens from columnar-lined esophagus.

It is difficult for surgical pathologists to determine the origin of tissues in samples taken from the columnar-lined esophagus (CLE) or stomach by biopsy or endoscopic resection (ER) on the basis of histologic examination alone. We examined histopathologically a single section (5 to 22 mm in size; mean, 12 mm) from each of 66 cases of CLE (36 short segments, 30 long segments) from German patients with reference to 3 histologic markers of esophageal origin: esophageal glands proper and/or ducts, squamous islands, and double muscularis mucosae, all of which had been reported previously, and palisade vessels as a new histologic parameter as well. Palisade vessels were defined histologically as veins >100 &mgr;m in size in and above the original muscularis mucosae. Esophageal glands proper and/or ducts, squamous islands, and double muscularis mucosae were seen in 33%, 18%, and 71% of the specimens, respectively. Palisade longitudinal vessels were observed in 78% and 63% of specimens of short-segment and long-segment CLE, respectively. Palisade vessels were never seen in ER specimens from the stomach or in the middle esophagus and stomach among control autopsy specimens. At least 1 of these 4 markers was seen in 88% of the sections. Therefore, ER specimens were confirmed to originate from CLE in 88% of single histologic sections of CLE on the basis of histologic examination alone.

Gastric carcinoma with osteoclast‐like giant cells. Lymphoepithelioma‐like carcinoma with Epstein–Barr virus infection is the predominant type

Osteoclast‐like giant cells (OGC) are rare in gastric carcinomas. Histopathological study of seven gastric carcinomas with OGC demonstrated three distinct types: lymphoepithelioma‐like carcinoma (LELC), non‐LELC, and giant cell tumor (GCT) types. LELC is a poorly differentiated adenocarcinoma with prominent lymphoid stroma. The LELC type (n= 4) showed similar histology to LELC of the stomach, except that they were accompanied by OGC and granulomatous reaction. Epstein‐Barr virus (EBV) infection was demonstrated by EBV‐encoded RNA (EBER) in situ hybridization (ISH) in all the neoplastic cells. The non‐LELC type (n= 2) consisted of EBV‐negative carcinoma cells with inflammatory infiltrates. OGC and granulomas were frequently observed in the glandular lumens with accumulated mucus. The GCT type (n= 1) was a neuroendocrine carcinoma, containing many OGC with metaplastic bone formation, which showed typical morphological features of OGC in GCT of the bone. In all three types, OGC expressed CD68, but not cytokeratin, indicating that OGC had a reactive histiocytic lineage. Both LELC and non‐LELC types are included in the differential diagnosis of isolated granulomatous gastritis, and EBER‐ISH was useful for the identification of LELC type. Both LELC and no‐LELC types were also suggested to have better prognoses, but the behavior of the GCT type needs to be further characterized.

Allelic Imbalance in the miR-31 Host Gene Locus in Lung Cancer - Its Potential Role in Carcinogenesis

Small non-protein coding RNA, microRNA (miR), which regulate messenger RNA levels, have recently been identified, and may play important roles in the pathogenesis of various diseases. The present study focused on miR-31 and investigated its potential involvement in lung carcinogenesis. The expression of miR-31 was altered in lung cancer cells through either the amplification or loss of the host gene locus. The strong expression of miR-31 in large cell carcinomas was attributed to the gene amplification. Meanwhile, the loss of miR-31 expression was more frequently observed in aggressive adenocarcinomas. Thus, miR-31 may play a pleiotropic role in the development of lung cancers among different histological types. To the best of our knowledge, this is the first study to show the potential causative mechanism of the altered expression of miR-31 and suggest its potentially diverse significance in the different histological types of lung cancers.

Proteome Analysis for Downstream Targets of Oncogenic KRAS - the Potential Participation of CLIC4 in Carcinogenesis in the Lung

This study investigated the proteome modulated by oncogenic KRAS in immortalized airway epithelial cells. Chloride intracellular channel protein 4 (CLIC4), S100 proteins (S100A2 and S100A11), tropomyosin 2, cathepsin L1, integrinsα3, eukaryotic elongation factor 1, vimentin, and others were discriminated. We here focused on CLIC4 to investigate its potential involvement in carcinogenesis in the lung because previous studies suggested that some chloride channels and chloride channel regulators could function as tumor suppressors. CILC4 protein levels were reduced in some lung cancer cell lines. The restoration of CLIC4 in lung cancer cell lines in which CLIC4 expression was reduced attenuated their growth activity. The immunohistochemical expression of the CLIC4 protein was weaker in primary lung cancer cells than in non-tumorous airway epithelial cells and was occasionally undetectable in some tumors. CLIC4 protein levels were significantly lower in a subtype of mucinous ADC than in others, and were also significantly lower in KRAS-mutated ADC than in EGFR-mutated ADC. These results suggest that the alteration in CLIC4 could be involved in restrictedly the development of a specific fraction of lung adenocarcinomas. The potential benefit of the proteome modulated by oncogenic KRAS to lung cancer research has been demonstrated.

Hepatocyte nuclear factor-1 α inactivated hepatocellular adenomas in patient with congenital absence of the portal vein: a case report.

Hepatocellular adenomas (HCAs) have been recognized recently as a heterogeneous group, and are subclassified according to genotype as well as morphological characteristics. We report a case of a 35‐year‐old Japanese woman who exhibited hepatocyte nuclear factor (HNF)‐1α‐inactivated HCA in the background of the congenital absence of the portal vein (CAPV). On a dynamic contrast computed tomography (CT) scan, the hypovascular tumor enlarged from 1 cm to 3 cm and another tumor emerged in the course of 7 years. Because the possibility of hepatocellular carcinoma (HCC) with multiple metastases was not excluded, partial hepatectomy was performed. On a cut section, two well‐demarcated tumors were observed and one tumor had a central fibrous scar. The histological features of these tumors were similar to those of focal nodular hyperplasia (FNH) with a central scar and HCA; however, these tumors were diagnosed as HNF‐1α‐inactivated HCA by immunohistochemistry according to the criteria of the current World Health Organization (WHO) classification. In non‐tumorous liver tissue, an abnormal architecture of the vessels and a vague nodular appearance of lobuli were observed, which were likely to be those of nodular regenerated hyperplasia (NRH). We discuss its pathogenesis and relationship with CAPV.

A comprehensive search for microRNAs with expression profiles modulated by oncogenic KRAS: potential involvement of miR-31 in lung carcinogenesis.

Small non-protein coding RNAs that regulate messenger RNA levels, namely microRNAs (miRNAs), have been implicated in the pathogenesis of various diseases. The purpose of the present study was to identify essential miRNAs involved in lung carcinogenesis. Previous studies demonstrated that an investigation into the downstream targets of oncogenic KRAS could be used as a strategy to elucidate the molecular mechanisms involved in lung cancer; therefore, we examined the expression profiles of mRNAs modulated by oncogenic KRAS in the present study. We focused on miR-31 from the miRNAs that were differentially expressed, and evaluated its potential role in the development of lung cancer. miR-31 was upregulated not only by oncogenic KRAS, but also by oncogenic EGFR. The expression of miR-31 was markedly attenuated in some lung cancer cell lines by deleting its host gene locus. The restoration of miR-31 in lung cancer cell lines that lost its expression attenuated their growth activities. The knockdown of miR-31 expression in lung cancer cell lines retaining its expression enhanced anchorage-independent growth activity. These results suggest that miR-31 may be a suppressor that regulates an essential oncogenic pathway, the loss of which may promote lung carcinogenesis.

The pathological features of idiopathic interstitial pneumonia-associated pulmonary adenocarcinomas.

To investigate the pathological features of idiopathic interstitial pneumonia (IIP)‐associated pulmonary adenocarcinoma.

A Histopathological Feature of EGFR-Mutated Lung Adenocarcinomas with Highly Malignant Potential – An Implication of Micropapillary Element -

The purpose of this study was to define histological features determining the malignant potential of EGFR-mutated lung adenocarcinoma (LADC). Surgically resected tumors (EGFR-mutated LADCs with (21) and without (79) lymph node metastasis and EGFR wild-type LADCs with (26) and without (108) lymph node metastasis) and biopsy samples from inoperably advanced tumors (EGFR-mutated LADCs (78) and EGFR wild-type LADCs (99)) were examined. In surgically resected tumors, the EGFR-mutated LADCs with lymph node metastasis had the micropapillary element in a significantly greater proportion than others (Mann-Whitney tests P ≤0.026). The proportion of micropapillary element was higher in the EGFR-mutated LADC at the advanced stage (stage II, III, or IV) than in the tumor at the early stage (stage I) (Mann-Whitney test, P<0.0001). In the biopsy samples from inoperably advanced LADCs (177), EGFR-mutated tumors also had micropapillary element at a higher frequency than EGFR-wild type tumors (53/78 (68%), versus 30/99 (30%), Pearson x2 test, P<0.0001). In stage I EGFR-mutated LADCs (84), the tumors with the micropapillary element (34) exhibited a significantly higher recurrence rate than tumors without micropapillary element (50) (5-year Recurrence-free survival 64.4% versus 93.3%, log-rank test P = 0.028). The micropapillary element may be an exclusive determinant of malignant potential in EGFR-mutated LADC. It is suggested that EGFR-mutated LADC may develop through a distinct histogenesis, in which the micropapillary element is important for promoting progression.