Shigetaka Yamasaki

c-erbB-2 oncoprotein expression related to chemoradioresistance in esophageal squamous cell carcinoma

PURPOSE Esophageal carcinoma is a challenging target for radiotherapy. To improve treatment efficacy, an investigation of a predictive factor is desirable. In this study, we evaluated the significance of apoptosis and immunohistochemical staining for p53, Ki-67, c-erbB-2 (HER-2/neu), Ku (p70/p80), and DNA-PKcs for predictive markers of the responsiveness to chemoradiotherapy in esophageal squamous cell carcinoma. MATERIALS AND METHODS This retrospective analysis consisted of 34 patients with esophageal squamous cell carcinoma in whom tumor biopsy was performed before treatment. They were divided into chemoradiosensitive (n = 13) and chemoradioresistant (n = 21) groups according to the tumor response evaluated at a total radiation dose of 40 Gy. The biopsy samples were examined with immunohistochemical staining for various factors and with an in situ nick end labeling method for apoptosis. The examined data were compared between the two groups. RESULTS The difference in the Ki-67, p53, Ku (p70/p80), DNA-PKcs labeling indexes and the apoptosis index in tumor cells between the chemoradiosensitive and chemoradioresistant groups was not statistically significant. The expression of c-erbB-2 oncoprotein was statistically significant in the chemoradioresistant group (p = 0.02), although it did not correlate with survival. CONCLUSIONS c-erbB-2 immunostaining is useful for the prediction of chemoradioresistance in esophageal squamous cell carcinoma.

Fibrosis and smooth muscle metaplasia in rectovaginal endometriosis

Rectovaginal (RV) endometriosis presents with a nodular lesion composed of fibromuscular and endometriotic tissue, and the fibromuscular tissue is the major component in the severe stage. The purpose of our study was to examine the extending process of fibromuscular tissue in RV endometriosis. Histological examinations using immunostains, were performed in 90 RV tissue specimens from 37 women. Fibrosis was present in 89 specimens. In each specimen, the intensity of the fibrosis differed from area to area: in mildly fibrotic areas, the collagen fibers were present around the endometriotic tissue, and in severely fibrotic areas, the fibrosis widely extended into fat and connective tissus as well as within the endometriotic tissue. In the 60 specimens containing endometriotic tissue, the increase in the amount of endometriotic tissue significantly correlated to the increase in degree of fibrosis in the entire tissue. The presence of aggregated smooth muscles, unassociated with blood vessels, was defined as smooth muscle metaplasia (SMM), which was always present within the fibrotic areas, and was observed in 80 specimens. The degree of SMM in the entire tissue was significantly correlated with the degree of fibrosis. From these findings, the following was hypothesized. Initially, endometriotic tissue was present sporadically and fibrosis was present around the endometriotic tissue. Thereafter, proliferation of endometriotic tissue and an increase in fibrosis occur consecutively. The SMM was present within the fibrotic areas, and it became more severe, correlating with the increase in fibrosis. In conclusion, this is the first report describing the extending process of the fibromuscular tissue of RV endometriosis from a histological viewpoint, and we think that recognization of this process is useful for histological diagnosis and clinical management of RV endometriosis.

Duodenal somatostatinoma: A case report and review of 31 cases with special reference to the relationship between tumor size and metastasis

Somatostatinomas are rare functioning neoplasms usually arising in the pancreas and duodenum. We report a case of somatostatinoma in a 42‐year‐old male with neither neurofibromatosis nor somatostatinoma syndrome. A large tumor in the descending duodenum had given rise to multiple lymph node metastases. An additional 31 duodenal somatostatinoma cases were also reviewed. Most originated in the descending part of the duodenum, with the ampulla and peri‐ampullary area as the most common sites (60%). Frequent manifestations were abdominal pain (25%), jaundice (25%), or cholelithiasis (19%), the latter two reflecting obstruction of the bile duct by tumors. Only two cases showed a possible somatostatinoma syndrome (6%). The tumors with metastases, lymph nodes (10) and liver (2), were significantly larger than average than those without (2.91 ± 1.49 cm vs 1.36 ± 0.71 cm, P< 0.05). With a cut‐off point of 2.0 cm, diagnostic accuracy for metastasis was 77.78% with 87.50% specificity and 63.64% sensitivity. The smallest tumor with metastases was 0.8 cm and the largest without metastases was 3.0 cm. These results indicate that duodenal somatostatinomas are malignant by nature and the risk of metastasis significantly increases with tumors larger than 2.0 cm.

Autoimmune hepatitis in primary Sjögren's syndrome: Pathological study of the livers and labial salivary glands in 17 patients with primary Sjögren's syndrome

Although primary Sjögrens syndrome (pSS) is an autoimmune exocrinopathy, the involvement of liver has been reported. Because no study focusing on autoimmune hepatitis (AIH) in pSS has been published, the purpose of the present study was to perform a clinical and histological examination of the liver, focusing on AIH, in 17 pSS patients. The patients had liver enzyme abnormalities without hepatitis virus infection. In all cases, biopsied livers were examined, and in 10 cases biopsied labial salivary glands were also examined histologically. Based on the authors’ diagnostic criteria for AIH in pSS, the liver diseases consisted of AIH (eight cases, 47%), primary biliary cirrhosis (PBC; six cases, 35%), non‐specified chronic hepatitis (two cases, 12%) and acute hepatitis (one case, 6%). Lymphoplasmacytic infiltrate, with predominancy of CD3+ T cells, was noted in both the liver and salivary glands in the patients with AIH. The patients with AIH with severe interface hepatitis had a good response to immunosuppressive therapy. The comparison of liver histology between the PBC with pSS group and the PBC without pSS group showed that the incidence of lymphoid non‐suppurative cholangitis was higher in PBC with pSS. In conclusion, the present study offers new information on the relatively common occurrence, diagnostic criteria and treatment effects of AIH in pSS.

B-cell lymphoma of mucosa-associated lymphoid tissue of the thymus: A report of two cases with a background of sjogren's syndrome and monoclonal gammopathy☆

Two rare cases of low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) arising in the thymus are reported. Both patients (a 61-year-old man and a 75-year-old woman) were suffering from Sjögrens syndrome and immunoglobulin (Ig)A kappa monoclonal gammopathy. Mixed IgA-IgG cryoglobulinemia was also present in the male case. Tumor cells expressed IgA and kappa antibody reactive proteins identical with serum IgA kappa M. Moreover, we could demonstrate rearrangements of the immunoglobulin heavy and light chain genes, which supported the monoclonal origin of tumor cells. Immunological abnormalities improved after thymectomy in one case in which the tumor cells were confined to the thymus, but not the other with regional lymph node involvement, suggesting a causal role for the tumor. MALT lymphomas of the thymus thus appear to be associated with immunological disorders such as Sjögrens syndrome or monoclonal gammopathy.

Detection of Epstein–Barr virus-encoded small RNA-expressed myofibroblasts and IgG4-producing plasma cells in sclerosing angiomatoid nodular transformation of the spleen

Sclerosing angiomatoid nodular transformation (SANT) of the spleen is a rare inflammatory tumor-like lesion composed of vascular nodules and non-neoplastic stroma including spindle cells and inflammatory cells. The focus of our study was on the stromal proliferating process in SANT. Nine cases of SANT were examined. All cases showed α-smooth muscle actin (α-SMA) and vimentin on the spindle cells but not CD21, CD31, CD34, CD68, desmin, S100, human herpes virus-8, or anaplastic lymphoma kinase-1. In one case, 20–30% of the myofibroblasts in Epstein–Barr-virus (EBV)-positive spindle cells were detected using double-labeling immunohistochemistry for α-SMA and EBV-encoded small RNA in situ hybridization. A quantitative analysis of IgG and IgG4-positive plasma cells (pPCs) in SANT was performed. The median densities of IgG-pPCs and IgG4-pPCs in SANT were approximately four-fold and 13-fold higher than those in the normal spleens, respectively. In addition, there was a statistically significant increase of IgG4/IgG-pPCs ratio in SANT in comparison to the control specimens. In conclusion, the fibrogenesis in a subset of SANT may be associated with EBV-infected myofibroblasts in an overlapping immune reaction indicated by the presence of infiltrating IgG4-pPCs. Further investigation is needed to elucidate the association between SANT and IgG4-related sclerosing disease.

Different patterns of p16INK4A and p53 protein expressions in intraductal papillary-mucinous neoplasms and pancreatic intraepithelial neoplasia.

Objectives: To examine aberrations and differences of cell cycle regulatory proteins between intraductal papillary-mucinous neoplasms (IPMNs) and pancreatic intraepithelial neoplasias (PanINs). Methods: In total, 47 IPMN lesions and 42 PanIN lesions were obtained from 26 patients with IPMN and 16 patients who underwent pancreatic surgery for invasive pancreatic ductal cancer or other diseases. They were subjected to conventional hematoxylin-eosin staining and immunostaining for p16INK4A and p53. The percentages of immunohistochemical positivity or negativity were compared between IPMN and PanIN, in accordance with the same histological grade of atypia. The Ki-67 labeling index was also counted in each lesion. Results: Either the loss of p16INK4A expression or the overexpression of p53 was much more frequently observed among PanIN-3 than among carcinoma in situ in IPMN (P = 0.046 and 0.008, respectively). The Ki-67 labeling index was correlated with the histological grades of both PanINs and IPMNs (P = 0.0001 and P = 0.0001, respectively). Conclusions: There are different immunohistochemical expression patterns of p16INK4A and p53 between IPMNs and PanINs. These may substantiate their different genetic progressions to invasive carcinoma.Abbreviations: IPMN - intraductal papillary-mucinous neoplasia, PanIN - pancreatic intraepithelial neoplasia

Intraductal Spread of Pancreatic Cancer

Background: Invasive ductal adenocarcinoma of the pancreas (IDAP) also spreads through the pancreatic ductal tree. The aim of this study was to clarify the clinicopathologic features of IDAP with intraductal spread. Methods: We studied the intraductal spread of IDAP and its correlation with clinicopathologic parameters in a surgical series of 54 patients. The pancreatic ducts were analyzed by confirmation of mural elastic fibers with elastica van Gieson stain. Results: Intraductal spread of carcinoma was identified in 37 patients (69%). Such spread was frequent in well-differentiated IDAP (93%), and the number of intraductal carcinoma foci was correlated with the grade of tumor differentiation (p < 0.001). The large branch ducts were the main route of intraductal spread (64.1%). The proliferation index, evaluated using Ki67, was lower in the intraductal carcinoma components than in the associated infiltrating carcinoma components (p < 0.001). The presence or absence of intraductal spread was not correlated with age, sex, tumor location, tumor size, or stage. IDAP with intraductal spread showed a tendency, although it was not significant (p = 0.092), to be associated with longer survival compared with IDAP without intraductal spread. Conclusion: IDAP, especially of the well-differentiated type, has a tendency to spread intraductally. The difference between the Ki67 labeling indexes in the intraductal and associated infiltrating carcinoma components suggests that these components show different biological behaviors.

Pancreatic, hepatic, splenic, and mesenteric mucinous cystic neoplasms (MCN) are lumped together as extraovarian MCN

Mucinous cystic neoplasms (MCN) of the pancreas are mucin‐producing cystic tumors with an ovarian‐like stroma (OLS). In the present study MCN were obtained from 27 patients. These MCN were derived from 22 pancreas, three livers, spleen, and mesentery. MCN in various organs have common clinicopathological profiles, being unilocular or multilocular cystic tumors, with a fibrous capsule and lined by mucin‐secreting epithelium associated with an underlying subepithelial OLS. The OLS showed strong positivity for α‐smooth muscle actin (α‐SMA) and vimentin and weak, focal positivity for desmin. Both estrogen receptors and progesterone receptors were expressed in the nuclei of OLS cells. In addition, 20 ovarian MCN and 13 normal ovaries were studied with particular attention to the stroma. The stroma of ovarian MCN was strongly immunopositive for α‐SMA and vimentin and focally positive for desmin, whereas normal ovarian stroma was immunonegative for both α‐SMA and desmin. The OLS of MCN mentioned here was similar to the septa of ovarian MCN but not to ovarian stroma. In conclusion, MCN in various organs should be lumped together as ‘extraovarian’ MCN. The OLS was identified on the basis of myofibroblastic proliferation both in response to neoplastic development and dependent on hormones.

Exposure to a high total dosage of glucocorticoids produces non-alcoholic steatohepatits.

To the Editor: Non-alcoholic steatohepatitis (NASH) is a disease involving histological changes similar to those in alcoholic liver disease in patients without alcohol abuse. NASH occasionally progresses to liver cirrhosis, and is commonly associated with obesity, diabetes and hyperlipidemia. As for druginduced NASH, Farrell, and Stavitz and Sanyal reported that glucocorticoids induce NASH, based on a case report published in 1977 describing NASH in a patient with systemic lupus erythematosus (SLE) who had received long-term glucocorticoid therapy. After that case report, two further case reports describing the occurrence of NASH in SLE patients were published. In those cases the duration of corticosteroid therapy differed, that is, short-term in one and long-term in another. Therefore, it became important to clarify the relationship between the duration of glucocorticoid therapy (or total dosage of administered glucocorticoids) and the occurrence of NASH in SLE. Our previous study of hepatic lesions in 52 SLE cases indicated that exposure to a high total dosage of glucocorticoids is related to the occurrence of severe fatty liver, but we did not address NASH in that study. Therefore, the present study examined relationships between the administration of glucocorticoids and the occurrence of NASH in two groups of 48 SLE cases (31 autopsy cases and 17 liver biopsy cases), consisting of the low total dosage group (14 cases; total dosage of prednisolone <3 g, duration of prednisolone administration 2 months-1 year) and the high total dosage group (34 cases; total dosage of prednisolone >10 g, duration of prednisolone administration 2–20 years). The diagnosis of SLE was based on the criteria of the American College of Rheumatology for SLE. NASH was present in two patients in the high total dosage group, producing a 6% incidence of NASH in that group (Table 1). The two patients with NASH had neither obesity, diabetes nor hyperlipidemia. In one of those two patients with NASH, the liver had severe steatosis, ballooning of many hepatocytes and many Mallory bodies, associated with focal perisinusoidal fibrosis and focal portal fibrosis histologically (Fig. 1). The histological diagnosis of NASH was grade 3 and stage 2. In the other patient with NASH, the liver had severe steatosis, ballooning of many hepatocytes and focal perisinusoidal fibrosis histologically. The histological diagnosis of NASH in that patient was grade 2 and stage 1. In addition, severe steatosis was present only in the high total dosage group (Table 1). The present study concluded that exposure to a high total dosage of glucocorticoids induces NASH because in the low total dosage group there was neither NASH nor severe steatosis. Also, severe steatosis occurred in the high total dosage group, and two patients with NASH belonged to the high total dosage group and they had severe steatosis. Moreover, they had not major factors for the occurrence of NASH, such as obesity, diabetes mellitus or hyperlipidemia. In addition, severe steatosis frequently occurs in NASH. The mechanism of glucocorticoid-induced steatosis and steatohepatitis is considered as follows. The glucocorticoids inhibit mitochondrial b oxidation, and decreases hepatic triglyceride secretion from the liver, which result in steatosis. Induction of lipid peroxidation in the liver by the repeated administration of glucocorticoids also produces steatosis. The mechanism by which steatosis evolves into steatohepatitis in some patients receiving glucocorticoids remained unexplored, but probably involves an exacerbating pathogenetic mechanism underlying NASH. We therefore think that exposure to a high total dosage of glucocorticoid may produce exacerbation of the pathogenetic mechanism underlying NASH. However, more studies are needed to confirm the mechanism of glucocorticoidinduced NASH.