Toshiharu Matsumoto

The liver in systemic lupus erythematosus: pathologic analysis of 52 cases and review of Japanese autopsy registry data

We present pathologic findings for 52 livers (51 autopsy specimens and one wedge biopsy specimen) from patients with systemic lupus erythematosus (SLE). Hepatic congestion was the most common disease (40 livers), followed by fatty liver (38), arteritis (11), cholestasis (nine), peliosis hepatis (six), chronic persistent hepatitis (six), nonspecific reactive hepatitis (five), cholangiolitis (four), nodular regenerative hyperplasia of the liver (three), and hemangioma (three). The data obtained here suggest that arteritis of the SLE liver is more common than has been recognized previously. One patient had hepatic infarction complications induced by arteritis. On the basis of the findings in the present study and a review of the literature, we suggest that hepatic infarction resulting from arteritis is rare in SLE. On the other hand, while occurrence of nodular regenerative hyperplasia of the liver in SLE patients has been considered to be rare, our findings suggest that it may be more common than has been recognized previously. Although congestion and cholestasis may be acute terminal illnesses, fatty change is considered to be specific to the SLE liver. Statistical analysis indicates that exposure to a large dosage of glucocorticoids is a significant factor in the etiology of severe fatty liver. In addition, our review of Japanese autopsy registry data for 1,468 patients with SLE indicates that the incidence of chronic liver diseases in SLE autopsy cases is as follows: chronic hepatitis, 2.4%; cirrhosis, 1.1%; and liver fibrosis, 0.8%.

Application of a new histological staging and grading system for primary biliary cirrhosis to liver biopsy specimens: Interobserver agreement

Recently the authors proposed a new staging and grading system for primary biliary cirrhosis (PBC) that takes into account necroinflammatory activity and histological heterogeneity. Herein is proposed a convenient version of this system. Scores for fibrosis, bile duct loss, and chronic cholestasis were combined for staging: stage 1, total score of 0; stage 2, score 1–3; stage 3, score 4–6; and stage 4, score 7–9. Cholangitis activity (CA) and hepatitis activity (HA) were graded as CA0–3, and HA0–3, respectively. Analysis of interobserver agreement was then conducted. Digital images of 62 needle liver biopsy specimens of PBC were recorded as virtual slides on DVDs that were sent to 28 pathologists, including five located overseas. All participants were able to apply this version in all 62 cases. For staging, kappa was 0.385 (fair agreement) and the concordance rate was 63.9%. For necroinflammatory activity, the kappa and concordance rate were 0.110 (slight agreement) and 36.9% for CA, and 0.197 (slight agreement) and 47% for HA, respectively. In conclusion, this new staging and grading system for PBC seems to be more convenient and practical than those used at present, but more instruction and guidance are recommended for the grading of necroinflammatory activity in practice.

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.

The lung in polyarteritis nodosa: A pathologic study of 10 cases

Polyarteritis nodosa (PAN) is characterized by necrotizing arteritis of medium-sized and small arteries in various organs. Pulmonary artery involvement in PAN has been considered rare. Previously, it also has been thought that patients with PAN do not have interstitial pneumonitis and fibrosis. A detailed pathologic analysis of pulmonary diseases associated with PAN was made in 10 autopsy cases of PAN. Arteritis affecting bronchial arteries was present in seven patients (70%). The data obtained suggest that arteritis in the lung in patients with PAN is more common than has been recognized previously. Diffuse alveolar damage (DAD) involving all lobes bilaterally was present in five patients; it was acute in two patients and organizing in three. In the patients with organizing DAD the degree of fibrosis in the interstitium differed among the lobes, and the fibrosis was more severe in the lower lobe than in the other lobes. Two patients presented with interstitial fibrosis with honeycomb lung of the posterior and lateral basal segments of the lower lobes of both lungs; in one of these patients interstitial fibrosis was present in an area of organizing DAD. Five patients died of respiratory failure resulting from DAD. In conclusion, it is important to consider DAD and interstitial fibrosis as complications of PAN.

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.

Placental pathology in systemic lupus erythematosus with antiphospholipid antibodies

Systemic lupus erythematosus (SLE) is associated with a poor pregnancy outcome. Antiphospholipid antibodies (APL), which include lupus anticoagulant (LAC) and anticardiolipin antibodies (aCL), are frequently found in patients with SLE, and their presence has been associated with fetal loss. To examine placental pathologic features of SLE patients with APL, we performed a pathologic study on 47 placental tissue samples from 47 pregnant SLE patients with APL (15 patients; four LAC single‐positive patients, seven aCL single‐positive patients, four LAC and aCL double‐positive patients) and without APL (32 LAC and aCL double‐negative patients). The incidence of extensive infarction, decidual vasculopathy, decidual thrombosis and perivillous fibrinoid change, which have been thought to be characteristic lesions of APL placenta, was significantly higher in the LAC and aCL double‐positive patients than in the patients without APL. Conversely, the above‐mentioned lesions between the LAC or aCL single‐positive patients and the APL negative patients did not differ significantly. Among the 15 patients with APL, two of the three patients with both decidual vasculopathy and thrombosis had extensive infarction associated with fetal death. Moreover, the patients having fetal death showed LAC and aCL double‐positivity. In conclusion, this study indicated that the LAC and aCL double‐positivity is an important factor for extensive infarction resulting from decidual vasculopathy and decidual thrombosis in the SLE placenta. Moreover, it was indicated that LAC and aCL double‐positivity is an important risk factor for fetal death in the SLE patient.

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.

Grading system of lymphatic invasion according to D2-40 immunostaining is useful for the prediction of nodal metastasis in squamous cell carcinoma of the uterine cervix

Aims To determine the relationship between lymphatic invasion detected by D2‐40 immunostaining and nodal metastasis in squamous cell carcinoma (SCC) of the cervix.

Relationship between the histological degrees of hepatitis and the postoperative recurrence of hepatocellular carcinoma in patients with hepatitis C

The relationship between the recurrence of hepatocellular carcinoma (HCC) and the degree of inflammation was evaluated in resected livers with the hepatitis C virus (HCV) -associated HCC. Seventy-three patients with HCV-associated HCC who were followed up for more than 2 years were selected for this study. In these cases, the degree of chronic hepatitis in noncancerous regions at the time of surgery was classified according to the New Inuyama Classification as follows, the degree of necroinflammatory activity (Grading) was graded from A0 to A3, and the degree of fibrosis (Staging) was staged on F0-F4. In addition, among these patients, 41 patients who were followed by blood tests every 3 months were divided into two groups (high or low group) according to annual average levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), the platelet counts (Plt), and alpha-fetoprotein (AFP). As a result, cancer-free survival rate was significantly lower in the high-grade group (A3) than in the low-grade group (A1 or 2) (P=0.01). The high ALT (>80 IU) group and the high AFP (>20 mg/ml) group also had significantly worse cancer-free survival rate than the low ALT group and the low AFP group (P=0.04 for ALT, P=0.03 for AFP). A multivariate analysis for the prognostic values revealed the AFP level (P=0.02) and the Grading (P=0.04) were useful as independent prognostic factors concerning recurrence. In conclusion, the degree of inflammatory activity (Grading) is considered to be a useful factor regarding recurrence after liver resection in patients with HCC. Furthermore, the inhibition of inflammation in remnant liver may also contribute to the prevention of recurrence.