Well differentiation and intact Smad4 expression are specific features of groove pancreatic ductal adenocarcinomas.

OBJECTIVES: We aimed to select true groove pancreatic ductal adenocarcinomas (GPDACs) and define their specific features. METHODS: We performed histopathologic and immunohistochemical comparisons of 6 GPDACs with 6 duodenal adenocarcinomas (DACs) and 24 conventional pancreatic ductal adenocarcinomas (cPDACs). Both groups were adjusted to ensure similar mean tumor size. RESULTS: Representative loupe image showed prominent duodenal invasion and slight pancreatic invasion. Groove pancreatic ductal adenocarcinomas exhibited different mucins and cytokeratin profiles in DACs, but cPDACs and small branch pancreatic ducts had the same profiles. Histopathologic analysis of GPDACs showed a significantly higher incidence of duodenal invasion and well differentiation than cPDACs, although the incidences of lymph node metastasis, angiolymphatic invasion, and neural invasion were similar. Immunohistochemical analysis of GPDACs showed a significantly lower frequency of abnormal Smad4 immunolabeling, and fewer GPDAC samples exhibited abnormal immunolabeling for MUC1, p16, Smad4, and p53 than cPDACs. CONCLUSIONS: These results suggest that GPDACs arise from small branch pancreatic ducts around accessory pancreatic duct penetrating the groove and duodenum and are distinguishable from DACs. Molecular immunohistochemistry suggests the accumulation of genetic abnormalities during tumor progression is slow in comparison with cPDACs. Thus, the site of PDAC occurrence, such as the border or inner area of the pancreas head, may determine genetic progressivity.

Association of higher methotrexate dose with lymphoproliferative disease onset in rheumatoid arthritis patients.

OBJECTIVE: Methotrexate (MTX) is used as an anchor drug for rheumatoid arthritis (RA). Lymphoproliferative disease (LPD) occasionally develops in patients treated with MTX, and is known as MTX-associated LPD (MTX-LPD). Although MTX-LPD occurs mainly in RA patients, it has not been established if MTX administration is an independent risk factor for LPD in RA patients. We examined the clinical characteristics of MTX-LPD in Japanese RA patients and attempted to determine the risk factors for MTX-LPD development. METHODS: We performed a nested case-control study on RA patients. We enrolled 5,753 RA patients from Kagawa, Japan. In age- and sex-matched patients, we separated patients who did not develop LPD under MTX treatment (MTX non-LPD group) from those that did (MTX-LPD group) and conducted a comparative examination. We used multivariate analysis to determine the independent risk factors for MTX-LPD onset. RESULTS: There were 28 patients in the MTX-LPD group and 125 patients in the MTX non-LPD group. Multivariate analysis of the parameters extracted by univariate analysis revealed that the mean MTX dose was a risk factor for MTX-LPD after adjusting for age; therefore, higher MTX dose is associated with LPD onset in RA patients. CONCLUSION: MTX is an independent risk factor for LPD onset in Japanese RA patients.

Well-differentiated pancreatic ductal adenocarcinomas measuring ≤ 1 cm exhibit early features of tumor progression: a report of five lesions and a comparative study with advanced lesions.

PURPOSE: The purpose of this study was to clarify whether the features of well-differentiated pancreatic ductal adenocarcinomas (PDACs) measuring ≤ 1 cm are the same as those of early PDACs. METHODS: Five well-differentiated PDACs measuring ≤ 1 cm were clinicopathologically compared with 19 ≥ 2 cm PDACs. Additionally, an immunohistochemical analysis for abnormalities in the expression of five molecular parameters: MUC1, p16, p53, Smad4 and sonic hedgehog, which are associated with tumor progression, was performed. RESULTS: The clinicopathological comparison revealed that well-differentiated PDACs measuring ≤ 1 cm were detected significantly more often without angiolymphatic invasion and with a sparse presence of cancer cells than were the ≥ 2 cm PDACs. On the other hand, in well-differentiated PDACs measuring ≤ 1 cm, the incidence of abnormal immunolabeling for MUC1, p16, p53 and sonic hedgehog was similar to that in ≥ 2 cm PDACs. However, the incidence of diffusely positive immunolabeling for MUC1 and the mean number of abnormally immunolabeled samples for the five parameters were significantly lower in well-differentiated ≤ 1 cm PDACs (20 % and 3 ± 1) than in ≥ 2 cm PDACs (90 % and 4 ± 1). CONCLUSION: The current study revealed that as the tumor size increases, molecular abnormalities are accumulated, suggesting that well-differentiated PDACs measuring ≤ 1 cm are in an earlier stage of genetic progression than are ≥ 2 cm PDACs, and these lesions may exhibit early features of invasive PDACs.

Video-assisted thoracic resection for intralobar pulmonary sequestration.

We present a case in which video-assisted thoracic resection for intralobar pulmonary sequestration (ILPS) was successfully performed. A 36-year-old woman had repeated pneumonia. Chest computed tomography (CT) showed a round mass in the right lower lobe of the lung. Subsequent three-dimensional CT revealed that a large anomalous artery arising from the descending thoracic aorta was distributing to the posterior basal segment containing the lesion and was draining into the inferior pulmonary vein. The patient was diagnosed with ILPS and underwent surgery. The anomalous artery was divided, and the sequestered segment was completely resected by video-assisted thoracic surgery (VATS). We think that VATS resection for ILPS is feasible and is a major therapeutic option as noninvasive surgery.

A minute pancreatic ductal adenocarcinoma with lipomatous pseudohypertrophy of the pancreas.

CONTEXT: This report describes a minute pancreatic ductal adenocarcinoma which appeared to be in early stage tumor progression based on the study of its molecular abnormalities. In addition, it was associated with lipomatous pseudohypertrophy, a rare disease. CASE REPORT: A 78-year-old male presented to our department with an incidental pancreatic tumor. Abdominal dynamic computed tomography showed an enlarged pancreas, and diffuse fat density in the entire pancreas was demonstrated. In the pancreatic body, a slightly enhanced early phase 10 mm mass was detected. He underwent a distal pancreatectomy. The histological features of the tumor revealed abundant fibrosis and duct lesions with various atypia. Duct lesions equivalent to well-differentiated adenocarcinoma were shown sparsely, but no vessel or lymphatic permeation nor perineural invasion were observed. In the background of the pancreas, diffuse fatty infiltrations which were composed of abundant normal adipose tissue and scattered pancreatic parenchyma were observed. The results of immunolabeling for MUC1, p16, p53 and Smad4 demonstrated that there is the possibility of coexistence of precancerous duct lesions and cancerous lesions in the genetic progression of pancreatic cancer. CONCLUSION: The above results suggested that this pancreatic ductal adenocarcinoma with lipomatous pseudohypertrophy might be an example of very early stage tumor progression.

Large Intrahepatic Cholangiocarcinoma with Tumor Infiltrative Lymphocytes and Autoimmune Hepatitis-Like Features.

The development of a primary hepatic tumor associated with autoimmune hepatitis (AIH) has been rarely reported. This report describes a rare case of intrahepatic cholangiocarcinoma (ICC) that accompanied tumor infiltrative lymphocytes (TIL) and AIH-like features. Moreover, multiple early gastric cancers were recognized in synchrony. An 81-year-old male was admitted due to liver dysfunction. His laboratory data on admission showed an elevation of immunoglobulin G and a positive titer of antinuclear antibody. Biological tests for HBV and HCV were negative. Computed tomography showed a well-enhanced hepatic tumor and gastrointestinal fiberscopy revealed two early gastric cancers with mucosal invasion. Biopsies were obtained from the background liver and the hepatic tumor. Histologically, the tumor revealed adenocarcinoma and the liver showed piecemeal necrosis and interface hepatitis with lymphoplasmacytic infiltration. The patient underwent hepatectomy and distal gastrectomy. Finally, he was diagnosed to have a mass forming type ICC and early gastric cancers. Moreover, prominent TIL in the ICC was revealed. An analysis of the infiltrating lymphocytes by immunohistochemical staining suggested that there was a difference in the local immune response between the tumor and the background liver. Review of the literature showed that there are only three reports of ICC associated with AIH, if including the current case.

Resection of four synchronous invasive ductal carcinomas in the pancreas head and body associated with pancreatic intraepithelial neoplasia: report of a case.

This report describes a very rare case of four synchronous invasive ductal carcinomas (IDCs) in the pancreas head and body with possible multicentricity. The patient was a 75-year-old woman. Abdominal dynamic computed tomography showed four low-density masses (25 mm, 20 mm, 10 mm, and 10 mm in diameter) in the pancreas head and body. The patient underwent a pylorus-preserving subtotal pancreatoduodenectomy. Histologically, the discontinuity between the four tumors was confirmed; one tumor (20 mm) was moderately differentiated tubular adenocarcinoma, and the others (25 mm, 10 mm, and 10 mm) were papillary adenocarcinomas. Two smaller papillary adenocarcinomas were composed of abundant fibrosis, pancreatic intraepithelial neoplasia (PanIN) 2-3, and IDC with stromal invasion. PanIN-1-2 lesions proximal to the four IDCs were evident. The immunohistochemical staining by CK20, MUC1, and Ki-67 revealed apparently different features for 2 IDCs (25 mm and 20 mm) and somewhat differential features for three papillary adenocarcinomas. Therefore, the progression of PanIN to IDC and multicentric occurrences of these four IDCs were possible. In this report, we show that immunohistochemistry and the confirmation of the presence of PanINs in IDC were useful to some extent for the study of multiple pancreatic cancers.

Immunohistochemically detected expression of p27(Kip1) and Skp2 predicts survival in patients with intrahepatic cholangiocarcinomas.

In intrahepatic cholangiocarcinomas (ICCs), the prognostic significance of p27(Kip1), a cyclin-dependent kinase inhibitor, remains controversial, and there have been no studies of degradation pathway associated proteins, S-phase kinase-interacting protein (Skp2), and Jun activation domain-binding protein-1 (Jab1). In the present study of 74 patients with ICC-mass forming type (ICC-MF) undergoing radical surgery, we determined immunohistochemical expression of p27(Kip1), Skp2, and Jab1 and examined relationships with clinicopathologic findings and patient survival. On the basis of the average of labeling indices, we set cutoff values to define high and low expressors and divided the cases into two groups. A statistically significant correlation was found between low p27(Kip1) expression and lymph node metastasis (P = .009). Patient survival in the low p27(Kip1) expression group (n = 25) was also significantly worse than that in the high p27(Kip1) expression group (n = 49, P = .0007). A significant inverse correlation was found between p27(Kip1) and Skp2 expression (P = .016). High Skp2 expression (n = 36) was significantly associated with poor prognosis (P = .0046). High Jab1 expression was observed in 32 cases, but there was no statistically significant relationship with clinicopathologic findings or patient survival. The multivariate analysis revealed that low p27(Kip1) and high Skp2 expression are independent and significant factors of poor prognosis. The results suggest that low p27(Kip1) and high Skp2 expression are associated with aggressive tumor behavior, and these cell-cycle regulators are useful markers to predict outcome of patients with ICC-MF.

Diffuse large B-cell lymphoma presenting with hypercalcemia and multiple osteolysis.

Osteolysis and hypercalcemia are observed in 5-15%, and 10%, respectively, of malignant lymphoma patients during their clinical course. However, both osteolysis and hypercalcemia are uncommon at onset of the disease. We encountered a 24-year-old male non-Hodgkin's lymphoma patient who had multiple osteolytic lesion from the onset of the disease and repeated episodes of hypercalcemia during the clinical course. The patient died with refractory disease. We studied the expression of chemokines which might affect bone resorption using the reverse transcriptase-polymerase chain reaction (RT-PCR) method. Increased expressions of MIP-1alpha, MIP-1beta and RANKL, which are osteoclast-activating factors, were observed in the RNA derived from the patient's lymphoma cells. The secretion of osteoclast-activating factors such as MIP-1alpha by the tumor cells (and/or bone marrow stromal cells) might be involved in the etiology of osteolysis and hypercalcemia in some malignant lymphoma cases.

Peripheral T-cell lymphoma presenting with rapidly progressing myelofibrosis.

Myelofibrosis following peripheral T-cell lymphoma has rarely been reported. Described here is a case of peripheral T-cell lymphoma with myelofibrosis and elevated transforming growth factor beta (TGF-beta). A 69 years old male was admitted due to anemia and thrombocytopenia. His bone marrow showed fibrosis and was infiltrated with small lymphoid cells and a few residual normal hematopoietic cells. He had presented with hepatosplenomegaly and left inguinal lymph node swelling. Biopsy of the left inguinal lymph node revealed diffuse mature small lymphoid cells with atypical nuclei. Immunophenotyping of the small lymphoid cells were positive for CD3, CD8, TCR alphabeta and HLA-DR and were negative for CD4, CD19, CD20 and CD56. T-cell receptor beta-chain gene was rearranged in bone marrow cells. He was diagnosed as having peripheral T-cell lymphoma complicated with myelofibrosis. Chemotherapy was administrated which improved his pancytopenia and symptoms. Two years later, anemia and thrombocytopenia developed rather quickly, he died because of progression of myelofibrosis with severe pancytopenia.