Junichi Fukushima

Solid pseudopapillary tumor of the pancreas with metastases to the lung and liver

Presented herein is the case of a 41‐year‐old woman who was admitted to Teikyo University Hospital with abdominal and back pain. Clinical examination revealed a large mass of the pancreas and multiple nodules in the liver. After surgical resection of the pancreatic and liver tumors, liver nodules recurred repeatedly, and a solitary mass lesion occurred in the right lung. Grossly, the pancreatic tumor was large and partially cystic. Histologically, small and uniform tumor cells proliferated, having solid and pseudopapillary patterns. These pathological findings enabled a pathological diagnosis of solid pseudopapillary tumor (SPT) of the pancreas to be made. The pathological appearance of the liver and lung tumors was similar to that of the pancreatic tumor. This is the first report of a case of pancreatic SPT that showed lung metastasis. It should be kept in mind that pancreatic SPT may take such an aggressive clinical course, although they are usually benign in nature.

Differential diagnosis of benign or malignant intraductal papillary mucinous neoplasm of the pancreas by multidetector row helical computed tomography: evaluation of predictive factors by logistic regression analysis.

Objective: The purpose of this study is to evaluate predictive factors for discriminating benign from malignant intraductal mucin-producing neoplasm (IPMN) of the pancreas on multidetector row computed tomography (MDCT). Materials and Methods: Fifty-three patients with IPMN underwent MDCT, and the imaging and pathological findings were evaluated. In patients with branch duct-type tumors, sex and age of the patient, location, shape, size and multiplicity of the cystic lesion, presence of mural nodule, and maximum diameter of main pancreatic duct (MPD) dilatation were evaluated by logistic regression analysis. Results: Tumors were classified as main duct-type (n = 7) and branch duct-type (n = 46). Among main duct-type tumors, all 7 lesions were diagnosed as malignant. Among 46 lesions of branch-type IPMN, 8 lesions were malignant, and 38 lesions were benign. On adjusted logistic regression analysis, combination factor of main duct dilatation and mural nodule or large cystic size had statistical significance for the risk of malignancy in branch duct-type IPMN. Conclusions: Main duct-type IPMN is highly suggestive for malignancy. Combination factors of main ductal dilation and mural nodule, and main ductal dilation, and large cystic tumor size are thought to be predictive factors for malignant branch-type IPMN.

Myolipoma of the retroperitoneum

A case of retroperitoneal myolipoma is reported. A 55‐year‐old woman with the main complaint of an abdominal mass was admitted to Teikyo University Hospital, Tokyo, Japan. Retroperitoneal liposarcoma was suspected based on magnetic resonance imaging, and the tumor was resected. The resected tumor was well encapsulated and 30 × 15 × 8 cm in size. Histologically, it consisted of mature adipose cells and smooth muscle cells. Neither nuclear atypia nor mitosis was observed in either component. The tumor was pathologically diagnosed as myolipoma of the retroperitoneum. Retroperitoneal myolipoma is often misdiagnosed radiologically as liposarcoma because the overwhelming majority of large retroperitoneal tumor containing fat is liposarcoma, however, the clinical course of myolipoma is quite different from that of liposarcoma. Although myolipoma is very rare, pathologists should consider it in the differential diagnosis of fat‐containing retroperitoneal masses.

Genetic and epigenetic aberrations occurring in colorectal tumors associated with serrated pathway

To clarify molecular alterations in serrated pathway of colorectal cancer (CRC), we performed epigenetic and genetic analyses in sessile serrated adenoma/polyps (SSA/P), traditional serrated adenomas (TSAs) and high‐methylation CRC. The methylation levels of six Group‐1 and 14 Group‐2 markers, established in our previous studies, were analyzed quantitatively using pyrosequencing. Subsequently, we performed targeted exon sequencing analyses of 126 candidate driver genes and examined molecular alterations that are associated with cancer development. SSA/P showed high methylation levels of both Group‐1 and Group‐2 markers, frequent BRAF mutation and occurrence in proximal colon, which were features of high‐methylation CRC. But TSA showed low‐methylation levels of Group‐1 markers, less frequent BRAF mutation and occurrence at distal colon. SSA/P, but not TSA, is thus considered to be precursor of high‐methylation CRC. High‐methylation CRC had even higher methylation levels of some genes, e.g., MLH1, than SSA/P, and significant frequency of somatic mutations in nonsynonymous mutations (p < 0.0001) and insertion/deletions (p = 0.002). MLH1‐methylated SSA/P showed lower methylation level of MLH1 compared with high‐methylation CRC, and rarely accompanied silencing of MLH1 expression. The mutation frequencies were not different between MLH1‐methylated and MLH1‐unmethylated SSA/P, suggesting that MLH1 methylation might be insufficient in SSA/P to acquire a hypermutation phenotype. Mutations of mismatch repair genes, e.g., MSH3 and MSH6, and genes in PI3K, WNT, TGF‐β and BMP signaling (but not in TP53 signaling) were significantly involved in high‐methylation CRC compared with adenoma, suggesting importance of abrogation of these genes in serrated pathway.

Methylation epigenotypes and genetic features in colorectal laterally spreading tumors

Aberrant DNA methylation plays an important role in genesis of colorectal cancer (CRC). Previously, we identified Group 1 and Group 2 methylation markers through genome‐wide DNA methylation analysis, and classified CRC and protruded adenoma into three distinct clusters: high‐, intermediate‐ and low‐methylation epigenotypes. High‐methylation epigenotype strongly correlated with BRAF mutations and these aberrations were involved in the serrated pathway, whereas intermediate‐methylation epigenotype strongly correlated with KRAS mutations. Here, we investigated laterally spreading tumors (LSTs), which are flat, early CRC lesions, through quantitative methylation analysis of six Group 1 and 14 Group 2 methylation markers using pyrosequencing. Gene mutations in BRAF, KRAS and PIK3CA, and immunostaining of TP53 and CTNNB1 as well as other clinicopathological factors were also evaluated. By hierarchical clustering using methylation information, LSTs were classified into two subtypes; intermediate‐methylation epigenotype correlating with KRAS mutations (p = 9 × 10−4) and a granular morphology (LST‐G) (p = 1 × 10−7), and low‐methylation epigenotype correlating with CTNNB1 activation (p = 0.002) and a nongranular morphology (LST‐NG) (p = 1 × 10−7). Group 1 marker methylation and BRAF mutations were barely detected, suggesting that high‐methylation epigenotype was unlikely to be involved in LST development. TP53 mutations correlated significantly with malignant transformation, regardless of epigenotype or morphology type. Together, this may suggest that two molecular pathways, intermediate methylation associated with KRAS mutations and LST‐G morphology, and low methylation associated with CTNNB1 activation and LST‐NG morphology, might be involved in LST development, and that involvement of TP53 mutations could be important in both subtypes in the development from adenoma to cancer.

TP53 mutation at early stage of colorectal cancer progression from two types of laterally spreading tumors

Although most sporadic colorectal cancers (CRC) are thought to develop from protruded adenomas through the adenoma–carcinoma sequence, some CRC develop through flat lesions, so‐called laterally spreading tumors (LST). We previously analyzed epigenetic aberrations in LST and found that LST are clearly classified into two molecular subtypes: intermediate‐methylation with KRAS mutation and low‐methylation with absence of oncogene mutation. Intermediate‐methylation LST were mostly granular type LST (LST‐G) and low‐methylation LST were mostly non‐granular LST (LST‐NG). In the present study, we conducted a targeted exon sequencing study including 38 candidate CRC driver genes to gain insight into how these genes modulate the development of LST. We identified a mean of 11.5 suspected nonpolymorphic variants per sample, including indels and non‐synonymous mutations, although there was no significant difference in the frequency of total mutations between LST‐G and LST‐NG. Genes associated with RTK/RAS signaling pathway were mutated more frequently in LST‐G than LST‐NG (P = 0.004), especially KRAS mutation occurring at 70% (30/43) of LST‐G but 26% (13/50) of LST‐NG (P < 0.0001). Both LST showed high frequency of APC mutation, even at adenoma stage, suggesting its involvement in the initiation stage of LST, as it is involved at early stage of colorectal carcinogenesis via adenoma‐carcinoma sequence. TP53 mutation was never observed in adenomas, but was specifically detected in cancer samples. TP53 mutation occurred during development of intramucosal cancer in LST‐NG, but during development of cancer with submucosal invasion in LST‐G. It is suggested that TP53 mutation occurs in the early stages of cancer development from adenoma in both LST‐G and LST‐NG, but is involved at an earlier stage in LST‐NG.

Discrimination of fibrotic staging of chronic hepatitis C using multiple fibrotic markers

In order to evaluate and judge a fibrotic stage of patients with chronic hepatitis C, multivariate regression analysis was performed using multiple fibrotic markers.

A case of β-catenin-positive hepatocellular adenoma with MR imaging sign of diffuse intratumoral fat deposition

Hepatocellular adenoma (HCA) is a rare primary benign tumor of the liver, which occurs predominantly in young and middle-aged women. Recently, the subclassification of HCA was proposed by the Bordeaux group. Subsequently, characteristic radiological and clinical features have been revealed in each HCA subtype. According to the previous literature, diffuse intratumoral fat deposition is a very common finding in hepatocyte nuclear factor 1α-negative HCA, but this finding has been reported in β-catenin-positive HCA in the literature for only one case. In this case report, we report the second case of β-catenin-positive HCA with MR imaging sign of diffuse intratumoral fat deposition, confirmed immunohistologically on the basis of a surgical specimen. In addition, our case showed hypovascularity and isointensity on the hepatobiliary phase which have been reported as characteristic findings in β-catenin-positive HCA. Diffuse intratumoral fat deposition can be observed in β-catenin-positive HCA, which has a greater probability of malignant transformation than other types of HCA.

Glomus tumor of the liver presenting as a cystic lesion

To the Editor: Glomus tumors are rare mesenchymal neoplasms, originally described in 1924 by Masson, which commonly occur in the skin or superficial soft tissues, especially in the distal extremities. Cases of glomus tumors occurring in visceral organs have rarely been reported. Moreover, only three cases of glomus tumors in the liver have been reported in the English literature, and no such cases exist in the Japanese literature. Herein, we report on the fourth case of a glomus tumor in the liver, which was unique in that the tumor comprised a large monolocular lesion. A 63-year-old man with epigastric pain and hiccups for 8 months had been previously diagnosed with gastroesophageal reflux. Proton pump inhibitors were prescribed, but his symptoms did not improve. Abdominal computed tomography (CT) revealed a hepatic cystic mass, and the patient was subsequently admitted to the NTT Medical Center Tokyo for evaluation. Further CT examinations revealed a monolocular cystic mass, 13 cm in diameter, in the right lobe of the liver (Fig. 1a). The cystic wall was smooth and well defined, and a 2-cm mural nodule was present on the left side of the cyst. Upon right lobectomy of the liver, a 20 × 15 × 8 cm large specimen with a smooth surface was excised. On gross appearance, the cystic mass was 12 × 10 × 8 cm large with 1000 mL of dark red fluid. On cross-section, the cyst was found to be monolocular (Fig. 1b). The inner surface was grayish-white, slightly rough, and showed focal hemorrhage. A 2-cm mural nodule, which had been detected on preoperative CT, was noted. Microscopically, cuboidal or polygonal tumor cells were found to proliferate in the cystic wall and mural nodule (Fig. 2a). The tumor cells had well-defined cell membranes, and uniform round or oval nuclei, which were centrally located in the eosinophilic cytoplasm of the cells (Fig. 2b). The nuclei were uniform, and no atypia was observed. The tumor had thin-walled small vessels. The cyst was surrounded by a hyalinized fibrous capsule with focal hemosiderin deposition and hemorrhage. The inner surface was covered by fibrous tissue, and tumor cells were focally observed, whereas no epithelial or endothelial lining of the inner surface was observed. The mitotic rate was 2/50 highpower fields. On the basis of these histological findings, a glomus tumor was strongly suspected. Because of morphological similarity, however, we had to rule out several differential diagnoses, including hemangiopericytoma, hemangioendothelioma, perivascular epithelioid cell tumor, carcinoid tumor, epithelioid gastrointestinal stromal tumor, and hepatocellular adenoma, among others. Accordingly, we performed immunohistochemical analyses. The tumor cells stained positive for alphasmooth muscle actin (Fig. 2c), vimentin, and type IV collagen, which surrounded the cells (Fig. 2d). Immunostaining for cytokeratin, epithelial membrane antigen, desmin,

Fibrosis score consisting of four serum markers successfully predicts pathological fibrotic stages of chronic hepatitis B.

In order to evaluate and judge a fibrotic stage of patients with chronic hepatitis B, multivariate regression analysis was performed using multiple fibrosis markers.