"Plasma cell hepatitis" in liver allografts: identification and characterization of an IgG4-rich cohort.

Plasma cell hepatitis (PCH), also known as "de novo autoimmune" hepatitis, is an increasingly recognized, but suboptimally named and poorly understood, category of late allograft dysfunction strongly resembling autoimmune hepatitis (AIH): They share plasma-cell-rich necro-inflammatory activity on biopsy, autoantibodies and steroid responsiveness, but overlap with rejection is problematic. A retrospective study of clinical, serological, histopathological and IgG4 immunohistological features of PCH (n = 20) in liver allograft recipients, native liver AIH (n = 19) and plasma-cell-rich renal allograft rejection (n = 20) showed: (1) high frequency (44%) of HLA-DR15; (2) less female predominance (p = 0.03) and (3) n = 9/20 PCH recipients showed >25 IgG4+ plasma cells/high-power field (IgG4+ PCH) versus AIH (n = 1/19, p = 0.008) or plasma-cell-rich kidney rejection (n = 2/20, p = 0.03). The IgG4+ PCH (n = 9) subgroup showed lower alanine transaminase (ALT) (p < 0.01) and aspartate transaminase (AST) (p < 0.05) at index biopsy but (a) higher plasma cell number/percentage, (b) more aggressive-appearing portal/periportal and perivenular necro-inflammatory activity and (c) more severe portal/periportal fibrosis than IgG4- PCH (n = 11). Significant demographic, histopathologic and plasma cell phenotype differences between PCH and AIH suggest distinct pathogenic mechanisms for at least the IgG4+ PCH subgroup likely representing an overlap between allo- and auto-immunity. IgG4+ PCH was associated with fibrosis, but also highly responsive to increased immunosuppression.

Re-examination of the lymphocytotoxic crossmatch in liver transplantation: can C4d stains help in monitoring?

C4d-assisted recognition of antibody-mediated rejection (AMR) in formalin-fixed paraffin-embedded tissues (FFPE) from donor-specific antibody-positive (DSA+) renal allograft recipients prompted study of DSA+ liver allograft recipients as measured by lymphocytotoxic crossmatch (XM) and/or Luminex. XM results did not influence patient or allograft survival, or cellular rejection rates, but XM+ recipients received significantly more prophylactic steroids. Endothelial C4d staining strongly correlates with XM+ (<3 weeks posttransplantation) and DSA+ status and cellular rejection, but not with worse Banff grading or treatment response. Diffuse C4d staining, XM+, DSA+ and ABO- incompatibility status, histopathology and clinical-serologic profile helped establish an isolated AMR diagnosis in 5 of 100 (5%) XM+ and one ABO-incompatible, recipients. C4d staining later after transplantation was associated with rejection and nonrejection-related causes of allograft dysfunction in DSA- and DSA+ recipients, some of whom had good outcomes without additional therapy. Liver allograft FFPE C4d staining: (a) can help classify liver allograft dysfunction; (b) substantiates antibody contribution to rejection; (c) probably represents nonalloantibody insults and/or complete absorption in DSA- recipients and (d) alone, is an imperfect AMR marker needing correlation with routine histopathology, clinical and serologic profiles. Further study in late biopsies and other tissue markers of liver AMR with simultaneous DSA measurements are needed.

A critical appraisal of methods to grade transplant glomerulitis in renal allograft biopsies.

Transplant glomerulitis is an increasingly recognized lesion in renal transplant biopsies. To develop a refined grading system, we defined glomerulitis by the presence of ≥5 leukocytes/glomerulus and evaluated 111 biopsies using three different grading systems: (i) percentage of glomerular involvement, (ii) peak inflammation in the most severely affected glomerulus and (iii) presence/absence of endocapillary occlusion by inflammatory cells. Endocapillary occlusion had no impact on graft survival, but was associated with increased serum creatinine, proteinuria and subsequent transplant glomerulopathy. Grading based on either percent or peak glomerular involvement correlated with graft failure and peritubular capillaritis. However, the percent glomerular involvement method had the additional advantage of displaying associations with: concurrent proteinuria, focal or diffuse immunoperoxidase peritubular capillary C4d staining, 1-year postbiopsy serum creatinine, subsequent detection of donor-specific antibody and development of transplant glomerulopathy. Patients with >75% glomerular involvement also revealed persistent high-grade glomerulitis on follow-up biopsies despite antirejection treatment. In conclusion, grading of glomerulitis is a meaningful exercise, and a quantification system based on percentage of glomerular involvement shows the most robust associations with clinical parameters and prognosis.

DNA mismatch repair deficiency in curatively resected sextuple primary cancers in different organs: a molecular case report.

A male patient synchronously or metachronously underwent six curative resections after diagnoses of cancers in the rectum, urinary bladder, stomach, colon, liver and lung. Five cancers, excluding early colon cancer, were analyzed for instability in seven microsatellite markers and in transforming growth factor beta type II receptor, insulin-like growth factor II receptor and BAX. All analyzed cancers had replication errors and instability in at least one target gene. These results suggest that abnormal DNA mismatch repair system plays a major role in the occurrence of multiple primary cancers in this case.

A novel microdissection and genotyping of follicular-derived thyroid tumors to predict aggressiveness.

Distinguishing thyroid follicular adenoma from minimally invasive or encapsulated angioinvasive carcinoma can be diagnostically challenging. In some cases, tumors are distorted, fragmented, or stripped of their capsule, and a definitive diagnosis becomes nearly impossible. In other cases, the foci of capsular and/or vascular invasion are subtle, thus making the diagnosis of carcinoma difficult. We developed a microdissection genotyping assay for assessing a panel of tumor-suppressor genes for loss of heterozygosity mutations. The frequency of allelic loss (FAL) in follicular-derived neoplasms correlates with the histologic aggressiveness of the tumor. Furthermore, we calculated the amount of genetic heterogeneity within each tumor, as a second important measure of a tumor's ability for clonal expansion and a surrogate marker for its malignant potential. The follicular adenomas had a low FAL (average 9%) and low intratumoral heterogeneity (5% variability). The minimally invasive and encapsulated angioinvasive carcinomas had an intermediate FAL (average 30%) and intermediate intratumoral heterogeneity (10% variability). The widely invasive carcinomas had a high FAL (average 53%) and high intratumoral heterogeneity (24% variability). Although a larger retrospective study is needed to correlate genotyping studies with patient outcome and prognosis, our results indicate that performing a mutational genotyping assay can stratify tumors into the histologically well-defined categories of adenomas, minimally invasive/angioinvasive carcinomas, and widely invasive follicular carcinomas.

Multinucleated variant endothelial cells (MVECs) of human aorta: expression of tumor suppressor gene p53 and relationship to atherosclerosis and aging.

Multinucleated variant endothelial cells (MVECs) generally exist in atherosclerotic human aorta and even in nonatherosclerotic aorta. Because the number of nuclei is increased in every MVEC, and because DNA instability was suspected, a series of oncogene expressions was conducted to clarify the nature of nuclear abnormality. The tumor suppressor gene p53 was found to be specifically expressed in the multinuclei of MVECs, while double nuclei were sometimes positive, and mononuclear typical endothelial cells were always negative for p53. Polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) revealed extra bands in exons 5 and 7 of the p53 gene, but no additional band in exons 6 and 8. In a BCL family, BCL-2 was coexpressed in one or two nuclei in the perinuclear space of the multinuclei of MVECs, whereas MCL-1, BCL-XS/L, and BAX were all negative, indicating that the BCL-2 coding gene is expressed only in the corresponding one or two nuclei of the multinuclei. Another oncogene, c-MET (hepatocyte growth factor receptor), was universally expressed in either type of endothelial cells, but other oncogenes, k-RAS and c-ERBB2, were not expressed in either type. MVECs were derived from human aorta and therefore non-tumorous somatic cells. No morphologic evidence of apoptosis was found. Although it is unclear that the extra bands came from the MVECs or just from ECs associated with atherosclerosis, combined immunocytological studies and PCR analysis suggest that MVECs express mutant type p53.

Phlegmonous colitis: a specific and severe complication of chronic hepatic disease.

Phlegmonous colitis (PC) is an acute infectious entity caused by bacteria. In this study, we reviewed 8,822 autopsy cases and found 13 cases of PC (0.15%). PC affected 2.43% of patients with hepatic cirrhosis or subacute liver atrophy, both of which were considered to be due to hepatitis viral infection. Before autopsy, none of the cases studied was suspected to involve PC, irrespective of the immediate cause of patient death. Thirteen autopsy cases showed some or all of the following pathohistologic characteristics: (1) involvement of the cecum (9 cases, 76.9%), (2) phlegmonous inflammatory changes and edema in the submucosa (100%), (3) bacterial infection (100%), (4) no microscopically detectable mucosal injuries (12 cases, 92.3%), and (5) acute serositis (peritonitis) (2 cases, 15.4%). These results suggest that PC is an unrecognized, but fatal complication of patients with some hepatic diseases and that PC has pathohistologic characteristics in common with previously reported spontaneous bacterial peritonitis in animal models. PC probably arises due to spontaneous infection in patients with hepatic cirrhosis.

Expression of c-Met in laryngeal carcinoma.

Expression of c-Met, a gene for the hepatocyte growth factor/scatter factor (HGF/SF) receptor, is known to be associated with tumour development in several human carcinomas. The expression of c-Met was examined using immunohistochemistry in 82 cases of primary laryngeal carcinoma to evaluate the tissue distribution of c-Met and the clinicopathological significance of c-Met expression. In normal larynx, c-Met expression was observed only in some minor salivary glands. Positive reaction for c-Met in neoplastic epithelium was noted in 45 out of 82 (54.9%) cases. In 44 cases, structures adjacent to the carcinoma (noncancerous squamous epithelium, some stromal fibroblastic cells, and endothelial cells) showed positive reaction for c-Met. c-Met expression in cancerous epithelium was significantly correlated with lymph node status (P<0.04) and proliferating activity expressed by the Ki-67 labelling index (P<0.02). There was no correlation between c-Met expression and age, sex, histological type, T category, distant metastasis or clinical stage. The data suggest that overexpression of c-Met in laryngeal carcinomas represents a growth advantage for cancer cells, which may be conferred by the mitogenic effect of HGF/SF. Simultaneous c-Met expression in noncancerous components of the larynx may represent a paracrine modification of c-Met.

Increased mast cell infiltration in varicose veins of the lower limbs: a possible role in the development of varices.

BACKGROUND: This study shows increased infiltration of mast cells in the walls of varicose veins in the lower limbs as an explanation of the pathogenesis of varix formation. METHODS: Great saphenous veins exhibiting varicosity were histologically examined after vein stripping surgery, and the numbers of mast cells in the varicose lesions were estimated in 20 high-power fields (x400). Normal-looking regions of the veins were referred to as controls, and normal saphenous veins were prepared during coronary artery bypass grafting and designated baseline controls. RESULTS: The varicose lesions showed a greater extent of mast cell infiltration (15.0 +/- 8.4 cells; mean +/- standard deviation), whereas control veins (5.9 +/- 4.0) and baseline control veins (4.4 +/-2.9) had a smaller number of mast cells. CONCLUSIONS: The study suggests that increased mast cell infiltration contributes to the development of varicose veins.

Polypoid adenomyoma of the gallbladder.

We describe a distinctive polypoid lesion of the gallbladder (16 mm in diameter) at the fundus, associated with a granulomatous mass in the liver adjacent to the gallbladder fossa, in a 64-year-old Japanese woman. Preoperatively, the lesion was diagnosed as advanced gallbladder cancer infiltrating the liver, and hepatopancreato-duodenectomy was performed. In the resected specimen, the polyp was round and pedunculate in shape, and, microscopically, it consisted of a mixture of small glandular and surrounding muscular elements, but atypia was not noted. The constituent elements were identical with those of adenomyoma, but the polypoid appearance was unusual. The hepatic lesion proved to be a foreign body granuloma containing multiple barium fragments and giant cells. A deep gastric ulcer, which penetrated into the gallbladder fossa, was also noted, near the granuloma. The histologic features indicate that the polypoid appearance of the tumor was due to a secondary modification of pre-existing adenomyoma by hepatic granuloma. To our knowledge, this is the second reported case of an adenomyomatous lesion of the gallbladder with a polypoid appearance.

Expression of Trk tyrosine kinase receptor is a biologic marker for cell proliferation and perineural invasion of human pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a widely known severe malignancy with a poor prognosis. Perineural invasion extending to the extra-pancreatic nerve plexus, a significant concern in the treatment is frequently present in this cancer. We analyzed immunohistochemical expression of neurotrophins (NGF, BDNF, NT-3) and the cognate receptors, Trk tyrosine kinase receptor family (TrkA, B, C) and p75NGFR in 28 surgically resected PDAC specimens. A comparative study between several clinicopathologic factors and Trk receptors revealed a significant correlation between increased expression of TrkA and cancer proliferation, as well as TrkC and cancer invasion, including venous and perineural invasion. The present findings revealed a novel mechanism in PDAC progression that is mediated via a NTs-Trk interaction.

Critical role of type IV collagens in the growth of bile duct carcinoma. In vivo and in vitro studies.

Most extrahepatic bile duct carcinomas (EBDC) are characterized by a striking stromal response (desmoplasia). Our previous studies showed deposition of type IV collagen in the desmoplastic stroma beyond the basement membrane. Although type IV collagen is expressed in EBDC, little is known about the pattern of deposition in tumor stroma and how this matrix component influences the behavior of tumor cells. With the progression of desmoplasia in EBDC, different changes occurred in the quantity and localization of type IV collagen from that of type I collagen. Type I collagen was diffusely distributed in the stroma and appeared to be concentrated in the center of the tumors. In contrast, type IV collagen was deposited in the interstitium alongside carcinoma cells at the tumors' periphery. Weak or no type IV collagen deposition was detected in the more central portion of the tumors containing sclerotic collagens. To investigate the role of stromal type IV collagen in tumor cell proliferation, EBDC cell lines were cultured in a three-dimensional matrix containing varying compositions of type I collagen and type IV collagen. They were also assayed for cell adhesion and migration using in vitro models. Type IV collagen more extensively stimulated tumor cell proliferation, adhesion and migration in a dose-dependent manner than did type I collagen. All of these results suggest that modified tumor stroma with the presence of type IV collagen in EBDC provides a better environment for tumor growth and invasion.

Phlegmonous colitis in a patient with liver cirrhosis, hepatocellular carcinoma and acute promyelocytic leukemia.

We describe a case of phlegmonous colitis occurring in a 70-year-old man with liver cirrhosis, hepatocellular carcinoma and acute promyelocytic leukemia. He developed an acute abdominal emergency and died during the first day of admission. Autopsy revealed a colon lesion characterized by suppurative inflammation associated with marked edema and hemorrhage in the submucosa. These findings were identical both macroscopically and microscopically to those of phlegmonous colitis.

Development of colonic necrosis following severe acute pancreatitis.

We herein describe a 70-year-old male patient who developed colonic necrosis following severe acute pancreatitis. He was referred to our hospital with a diagnosis of acute pancreatitis. In the course of the disease, he developed sudden and massive hematochezia and died. The autopsy findings revealed large bowel ischemia with transmural infarction. The possible pathogenic mechanisms of colonic ischemia are also discussed.

Granular cell tumor in the ascending colon.

We describe a case of multiple polypoid lesions that occurred in the colon of a 62-year-old man. Eight of the lesions were demonstrated by barium enema, and five were examined histologically. A small nodule in the submucosa of the ascending colon was histologically identical to granular cell tumor, characterized by nested growth of large tumor cells with ample granular cytoplasm and small round nuclei. Immunohistochemically, the cells were positive for S-100, neuron-specific enolase and vimentin, and negative for alpha-smooth muscle actin and desmin.

Hepatopancreatoduodenectomy for squamous and adenosquamous carcinoma of the gallbladder.

The characteristics of squamous or adenosquamous cell carcinoma of the gallbladder differ quite markedly from those of adenocarcinoma, although the incidence is extremely low. Recently, we encountered both of the former types of gallbladder carcinoma: a 77-year-old man with squamous cell carcinoma and a 70-year-old man with adenosquamous cell carcinoma of the gallbladder. Both had a large mass in the gallbladder fossa region with infiltration to the liver and invasion of the duodenum. Hepatopancreatoduodenectomy was performed on both of these patients. The TNM stage of the former was IV (T4N0M0) and of the latter IV (T4N0M0) and of the latter IV (T4N1bM0). The former has remained well without recurrence for about 1 year and 4 months after the operation, while the latter died of recurrent disease 6 months after operation. The true reason for the difference in the prognosis of these two patients was not known. However, hepatopancreatoduodenectomy is considered to be a most adaptable operative procedure for squamous or adenosquamous cell carcinoma of the gallbladder in view of their mode of spread, and the presence of lymph node metastasis might be a factor of poor prognosis.

Radiographic observation of a case of gastrointestinal stromal tumor in stomach.

A case of gastrointestinal stromal tumor (GIST) in stomach was presented. Serial barium meal x-ray examinations revealed an enlarging elevated lesion on the fornix of the stomach. Tumor volume doubling time was found to be 299 days. Microscopic and immunohistochemical studies of the resected tumor disclosed GIST, uncommitted type, low grade malignant/potentially malignant. A radiographic feature of this rare type of gastric submucosal tumor was demonstrated in this report.

[Intra-arterial chemotherapy with granulocyte colony-stimulating factor for breast cancer before surgical treatment].

Intra-arterial chemotherapy (IAC) for far advanced breast cancer is now performed as a routine adjuvant chemotherapy before surgical treatment. However, the following problems remain unsolved; (1) serious adverse reactions such as myelosuppression, (2) unsuccessful insertion of catheter into the internal thoracic artery, and (3) long waiting-period from IAC to surgical treatment. The present studies were conducted to evaluate the utility of a one-route IAC, in which the subclavian artery alone is used, and the efficacy of granulocyte colony-stimulating factor (G-CSF). There was no significant difference in the antitumor effect between the patients with two-route IAC, in which both internal thoracic artery and subclavian artery are used, and the patients with one-route IAC. Administration of G-CSF in combination with IAC reduced both the frequency and the severity of IAC-induced side effects. G-CSF administration during IAC was more effective than after IAC. G-CSF prevented IAC-induced myelo-suppression and/or accelerated recovery from this complication and thus reduced significantly the waiting-period before surgical treatment.

[A comparative study on the serum and tissue 5-FU concentrations in patients with hepatocellular carcinoma after preoperative oral administration of UFT and 5'-DFUR].

UFT or 5'-DFUR was orally administered to the patients with hepatocellular carcinoma preoperatively and the concentrations of these drugs and 5-FU in the serum, liver tissue and cancer tissue obtained at the time of operation were measured. The unchanged 5'-DFUR was not detected in any of these samples. The concentration of 5-FU in cancer tissue was significantly higher in UFT treated group (0.409 microgram/g) than that in 5'-DFUR group (0.040 microgram/g). However, the 5-FU levels in the serum and noncancerous liver tissue were also higher than those in the patients with other organ cancers. Although UFT is a useful drug for the adjuvant chemotherapy of hepatocellular carcinoma, the dose was considered to be minimized to avoid the side effects since the activity of drug-metabolizing enzymes may be decreased in hepatocellular carcinoma complicated with liver cirrhosis.