Hepatic morphology and histochemistry of Wilson''s disease presenting as fulminant hepatic failure: a study of 11 cases

Eleven cases of Wilson's disease presenting as fulminant hepatic failure were analysed retrospectively to determine the specificity or otherwise of the histological findings. All cases were cirrhotic, eight with a micronodular pattern. There was marked parenchymal collapse with ductular proliferation and mild inflammation. Other features included cholestasis, hepatocyte necrosis, microvesicular fat and nuclear vacuolation. Orcein staining demonstrated copper-associated protein in the periphery of cirrhotic nodules in all cases and also variably within nodules in eight cases. Copper was demonstrable by the rhodanine method in similar locations but the staining reaction was qualitatively weaker in all cases. Characteristically, there was staining of both parenchymal and mononuclear phagocytic cells. This triad of cirrhosis, strong copper-associated protein deposition and copper positivity was not present in a control group of 20 cases of fulminant hepatic failure of other aetiology and with a similar clinical presentation. It is concluded that in the clinical context of fulminant hepatitis the presence of cirrhosis should raise the suspicion of Wilson's disease and that, with routinely processed and stained tissue, including autopsy tissue, the diagnosis can be made histologically.     

Cytologic diagnosis of vulvar Paget's disease by means of brushing smear: Report of a case

Paget's disease of the vulva is a rare entity; since it may show the same clinical symptoms as benign chronic vulvitis, it may result in a delayed diagnosis. A 63‐year‐old woman was found to have an eczematoid pink to red lesion located in the vulva. Scraping cytology of the vulva showed isolated malignant cells of Paget type. The patient underwent wide local excision of the vulvar tumor and histopathological examination of resected specimens revealed that Paget cells were distributed singly or tended to form small nests in the epidermis. We consider vigorous brushing cytology to be a useful initial study for cancer screening of patients for any suspicious vulvar lesions. Diagn. Cytopathol. 2010. © 2009 Wiley‐Liss, Inc.     

Serum thrombomodulin-a reliable marker of disease activity in systemic lupus erythematosus (SLE): advantage over established serological parameters to indicate disease activity

To date no specific serological parameter is available to assess disease activity in SLE. Soluble serum thrombomodulin is a new marker of endothelial cell injury and vasculitis. The objective of this study was to compare in vivo soluble thrombomodulin as marker of disease activity in SLE with established and recent serological parameters. One hundred and twenty-four sera of 30 patients with proven SLE with different disease activities were tested for serum levels of thrombomodulin, intercellular adhesion molecule-1 (ICAM-1), E-selectin, vascular cell adhesion molecule-1 (VCAM-1), IL-2R, IL-6, IL-10, dsDNA by ELISA and dsDNA additionally by radioimmunoassay (RIA). C-reactive protein (CRP), complement component C3, IgG, creatinine, anti-nuclear antibodies (ANA) and intermediate filament antibodies were measured by standard laboratory tests. The clinical disease activity was evaluated by the Systemic Lupus Activity Measure (SLAM). Correlations of the different serological SLE disease activity parameters with the SLAM scores revealed the highest significance for serum thrombomodulin (correlation coefficient 0.82). This was further confirmed by the intra-individual analysis of follow-up sera. In addition, a moderate correlation could be found for IL-6, IL-10, ICAM-1, CRP and erythrocyte sedimentation rate (ESR). In summary, soluble thrombomodulin is the most important serological parameter of disease activity in SLE currently available, as shown by the in vivo studies. Soluble thrombomodulin might be a valuable serological parameter for therapeutical considerations.     

Fine-needle aspiration of histiocytic necrotizing lymphadenitis (Kikuchi's disease)

Fine-needle aspiration (FNA) of the lymph node was done in five patients with histiocytic necrotizing lymphadenitis (Kikuchi's disease). In four patients, the aspirates were found to have many small and large atypical lymphocytes, some reactive, phagocytic histiocytes, and intense extracellular debris. Neutrophils, plasma cells, or multinucleated giant cells were not seen. These cytologic findings were considered diagnostic for Kikuchi's disease. In one patient, the aspirate did not show significant histiocytosis or tissue necrosis and was considered nondiagnostic. In patients with both typical clinical features and characteristic cytologic findings in the lymph node aspirates, FNA of the lymph node alone will suffice for diagnosis. In those patients with typical clinical features but nondiagnostic findings in the FNA aspirates, the diagnosis of Kikuchi's disease may have to be established either on repeated nodal FNA or on lymph node biopsy.     

Acute hemolytic crisis with fulminant hepatic failure as the first manifestation of Wilson's disease: a case report.

We report a 27-year-old woman who developed Coombs'' negative hemolytic anemia and fulminant hepatic failure as the initial manifestation of Wilson''s disease. Unmeasurably low level of serum alkaline phosphatase provided a clue to the diagnosis of Wilson''s disease. The diagnosis was established with the presence of Kayser-Fleischer ring, decreased serum ceruloplasmin level, and elevated urine and serum copper levels. In spite of repeated plasmapheresis, she died of multiorgan failure on the fifth hospital day.     

Proliferating cell nuclear antigen (PCNA) expression in Hodgkin's disease.

Previous studies of the proliferating cell fraction in Hodgkin's disease (HD) have been directed towards the classical Hodgkin and Reed-Sternberg cells (HRS) to the exclusion of the background population and have not included cases of nodular lymphocyte predominant Hodgkin's disease (NLPHD). Using an antibody to proliferating cell nuclear antigen (PCNA), we have determined the growth fraction of HRS cells and L&H cells in paraffin sections of 15 cases of classical HD [12 nodular sclerosis (NS), 3 mixed cellularity (MC)] and eight cases of NLPHD. By double staining with anti-PCNA and antibodies to B cells (CD20) and T cells (CD45RO), we also determined the growth fraction and immunophenotype of the background population in each case. In classical HD, 50.4 per cent of HRS cells were PCNA-positive and judged to be proliferating, which is comparable to previous studies, while in NLPHD 76.9 per cent of L&H cells were PCNA-positive. In both classical HD and NLPHD, the majority of PCNA-positive cells in the background were T cells, which showed a growth fraction of 57.8 and 68.5 per cent, respectively; in comparison, only 4 per cent of B cells were PCNA-positive in each type of HD. L&H cells are widely accepted to be B cells and there is growing evidence that HRS cells are also B cell-derived. Our results underline a relationship between classical HD and NLPHD and suggest that the characteristic histological features of both diseases may be caused by the production and release of cytokines from altered B cells.     

Interaction of endothelial cells and neutrophils in vitro: kinetics of thrombomodulin, intercellular adhesion molecule-1 (ICAM-1), E-selectin, and vascular cell adhesion molecule-1 (VCAM-1): implications for the relevance as serological disease activity markers in vasculitides

Recently markers of endothelial cell activation or injury gained increasing interest as serological parameters of disease activation in vasculitides. Among these, soluble serum thrombomodulin, ICAM-1, VCAM-1 and E-selectin are of particular interest. However, only thrombomodulin showed the expected close correlation. The objective of this study was to investigate in vitro the kinetics of these endothelial cell receptors after interaction of unstimulated or cytokine-activated polymorphonuclear neutrophils (PMN) and endothelial cells in order to find evidence explaining these different clinical findings. Over the time period of up to 48 h of incubation the kinetics of thrombomodulin, ICAM-1, E-selectin, and VCAM-1 levels in the supernatant of endothelial cells in co-culture with neutrophils were determined in vitro by ELISA under basal and partially cytokine-activated (tumour necrosis factor-alpha) conditions. Increased levels of ICAM-1, E-selectin and VCAM-1 were already found due to cytokine activation of endothelial cells alone. This increase was augmented after coincubation with neutrophils. In contrast, a significant increase of thrombomodulin in the supernatant was only found due to cell injury after cell-cell interaction of cytokine-activated endothelial cells with neutrophils. In conclusion, this in vitro model of the kinetics of soluble endothelial cell receptors after cell-cell interaction of cytokine-activated PMN and endothelial cells underlines the advantage of thrombomodulin in contrast to the adhesion molecules as a marker of endothelial damage. Therefore, soluble thrombomodulin seems to be a promising, valuable serological disease activity marker in vasculitides.     

Dipeptidyl carboxypeptidase 1 (DCP1) and butyrylcholinesterase (BCHE) gene interactions with the apolipoprotein E epsilon4 allele as risk factors in Alzheimer's disease and in Parkinson's disease with coexisting Alzheimer pathology

Alzheimer's disease (AD) and Parkinson's disease (PD) are genetically heterogeneous. Dipeptidyl carboxypeptidase 1 (DCP1) and butyrylcholinesterase (BCHE) genes may modify the risk of these disorders. We investigated whether common polymorphisms present in these genes operate as risk factors for AD and PD in Finnish subjects, independently or in concert with the apolipoprotein E ε4 allele (APOE ε4). Eighty late onset sporadic AD patients, 53 PD patients (34 of whom had concomitant AD pathology), and 67 control subjects were genotyped for the insertion (I)/deletion (D) polymorphism of DCP1 and the K variant of BCHE. In logistic regression analysis, the DCP1 *I allele in combination with APOE ε4 significantly increased the risk of AD (OR 30.0, 95% CI 7.3-123.7), compared to subjects carrying neither of the alleles. Similar analysis showed that the risk of AD was significantly increased in subjects carrying both the BCHE wild type (*WT/*WT) genotype and ε4 (OR 9.9, 95% CI 2.9-33.8), compared to those without this BCHE genotype and ε4. Further, the risk of PD with AD pathology was significantly increased for carriers of DCP1 *I and ε4 (OR 8.0, 95% CI 2.1-31.1). We thus conclude that, in Finns, interaction between DCP1 *I and ε4 increases the risk of AD as well as of PD with coexisting Alzheimer pathology, which underlines the importance of the DCP1 I/D polymorphism in the development of Alzheimer neuropathology, whereas the wild type BCHE genotype in combination with ε4 had a combined effect with regard to the risk of AD.


Keywords: Alzheimer's disease; Parkinson's disease; dipeptidyl carboxypeptidase 1; butyrylcholinesterase     

Paget's disease of the breast masquerading as squamous cell carcinoma on cytology: A case report

Paget's disease is an uncommon manifestation of breast carcinoma occurring in 1–2% of female patients with breast cancer. Here, we present a case of Paget's disease of the breast, which was initially interpreted as squamous cell carcinoma on cytology. This case report raises two issues. First, histological and cytological specimens of Paget's disease show a mixed population of epithelial cells including squamous cells with reactive changes and malignant glandular cells. In the current case, a mixed population of atypical keratinizing and nonkeratinizing epithelial cells was initially interpreted as squamous cell carcinoma of cutaneous origin. The marked reactive changes in the squamous epithelium involved by Paget's disease should be recognized. Second, this case is an unusual clinical presentation for Paget's disease of the breast as the nipple‐areolar complex and underlying breast tissue were surgically absent at the time of diagnosis. Clinical suspicion, along with an awareness of the cytologic features and clinical presentation of Paget's disease, can help in reaching the correct diagnosis in a timely fashion. Diagn. Cytopathol. 2012. © 2011 Wiley Periodicals, Inc.     

IL-8 as an important chemoattractant for neutrophils in ulcerative colitis and Crohn's disease.

IL-8 is generating increasing interest as a powerful neutrophil chemoattractant and activator. To elucidate the mechanisms of neutrophil infiltration in inflammatory bowel disease, we examined 33 patients with ulcerative colitis (UC), 18 with Crohn's disease (CD), eight with some other type of colitis, and 18 normal control subjects for measurement of IL-8 in homogenates of colonic biopsy specimens. The affected colonic mucosa was found to contain significantly more IL-8 in patients with active inflammatory bowel disease than in patients with inactive disease (UC, P < 0.001; CD, P < 0.001), in patients with other types of colitis (UC, P < 0.05; CD, P < 0.01), or in normal control subjects (UC, P < 0.001; CD, P < 0.001). Colonic IL-8 levels correlated significantly with the macroscopic grade of local inflammation, especially in patients with UC (P < 0.001). Colonic IL-8 levels also correlated well with the neutrophil numbers in mucosal tissue (UC, r = 0.950, P < 0.001; CD, r = 0.940, P < 0.001), and with colonic IL-1 beta (r = 0.911, P < 0.001) and tumour necrosis factor-alpha (TNF-alpha) levels (r = 0.604, P < 0.001) in patients with these two conditions. These data suggest a potential role for IL-8 and its regulatory cytokines IL-1 and TNF-alpha in mediating neutrophil infiltration of the gut wall in inflammatory bowel disease.     

Pulmonary tumor thrombotic microangiopathy associated with extramammary Paget's disease: An autopsy case report

Pulmonary tumor thrombotic microangiopathy (PTTM) is histologically characterized by micro tumor cell embolism and intimal fibrocellular proliferation of pulmonary arteries or arterioles. We report a secondary case of PTTM associated with extramammary Paget's disease (EMPD). The patient was a 72‐year‐old man with exertional dyspnea. Clinical examinations found he had pulmonary hypertension and multiple osteolytic lesions of vertebra. Cytological analysis of pulmonary wedge artery sample detected malignant cells and he was dead before treatment was started. Multiple tumor embolisms (>17) were identified in pulmonary arteries or arterioles at autopsy, consistent with PTTM. Metastatic nodules were found in liver and lymph node. Furthermore, disseminated carcinomatosis of the bone marrow (DCBM) was seen. Immunostaining results pointed out that tumor cells possessed mammary gland phenotype. He had 4‐years history of EMPD in the left axilla without recurrence, and immunohistochemistry results were the same as the autopsy specimen. Thus, we diagnosed the primary site of PTTM to be EMPD. Our case highlights the usefulness of the recent proposed classification of PTTM, potential association between PTTM and DCBM, and the necessity for long‐term follow‐up in EMPD. EMPD can rarely cause PTTM to manifest as a paraneoplastic syndrome.     

Cytologic diagnosis and monitoring of Hodgkin's disease in cerebrospinal fluid: a case report

Central nervous system (CNS) involvement in Hodgkin's disease is rare, but when the tumor extends into the CNS the route of tumor spread is similar to that seen in non-Hodgkin's lymphoma. Reed-Sternberg cells were identified in the cerebrospinal fluid (CSF) of a patient with Hodgkin's disease involving the CNS. Sequential cytologic examination of the CSF proved valuable in evaluating the efficacy of therapy. The ability to identify Reed-Sternberg cells in the CSF makes CSF cytology a useful adjunct in the management of patients with established or suspected CNS involvement of Hodgkin's disease.     

Brain metastasis from cutaneous squamous cell carcinoma coexistent with extramammary Paget's disease: A case report

We report a case of cutaneous squamous cell carcinoma (CSCC), initially coexisting with invasive extramammary Paget's disease (EMPD), in the scrotum of an 84‐year‐old man. The patient initially had a rash and pruritus before presenting with a pedunculated scrotal mass surrounded by widespread erythema. He underwent total gastrectomy for adenocarcinoma 1 year previously and had been receiving TS‐1 (Tegafur/Gimeracil/Oteracil pottasium) orally. Histopathologically, the tumor consisted of invasive SCC, with invasive EMPD in the erythematous region. From the clinical presentation and histopathological findings, we assumed that CSCC developed in the background of the EMPD. The CSCC metastasized to several inguinal lymph nodes and to the brain in the following years. While the histogenesis of each of the tumors remains to be elucidated, the fact that the CSCC rather than the EMPD metastasized to a distant site in this patient is to be noted for future treatment considerations.     

Cytodiagnosis of Ollier's disease: A case report

Ollier's disease is a rare nonhereditary condition where patients present with multiple enchondromas involving usually the small bones of the hands and feet. We report the case of a 17‐year‐old girl who presented with multiple osteolytic lesions involving almost all phalanges of both her hands. Fine‐needle aspiration cytology (FNAC) was performed from her left index finger. Smears showed mostly chondroid matrix with singly scattered cells showing binucleation and mild atypia at places. A diagnosis of enchondroma was offered in view of the cytologic and radiological findings. The dysplastic cartilage in Ollier's disease may show features similar to well differentiated chondrosarcoma. It is important not to overdiagnose such cases with atypia as low grade chondrosarcomas. Radiological appearances must be taken into account. FNAC is helpful as an outpatient diagnostic procedure when it obviates surgical intervention as most lesions tend to regress asthe skeleton matures. Diagn. Cytopathol. 2009. © 2009 Wiley‐Liss, Inc.     

Congenital pulmonary lymphangiectasis: Report of an autopsy case masquerading as pulmonary interstitial emphysema

We describe the clinicopathologic features of a case of congenital pulmonary lymphangiectasis (CPL). A male Japanese infant born prematurely at 34 weeks of gestation developed a severe moaning sound, dyspnea, and prominent respiratory acidosis about 10 min after delivery. A chest X-ray film showed bilateral frosted glass-like infiltrates with an air bronchogram and an air leak around the cardiac shadow, suggesting pneumomediastinum. The patient died of hypoxemic respiratory failure 13 h after birth. The death was complicated by bilateral pneumothorax, despite the initiation of artificial ventilation and administration of a surfactant. At autopsy, small cystic lesions were noted in the visceral pleura, interlobular septa, and hilum of both lungs. A histologic examination of the lungs showed diffuse and marked dilation of the lymphatic channels in the subpleural, peribronchial, interlobular, and hilar areas. The channels were lined with flattened endothelium, which was immunohistochemically positive for D2-40. In addition, lymphangiectasis was found around the thymus and intra-abdominal organs, but no cardiovascular anomalies were seen. The findings conformed to a primary form of CPL, Noonan Group 3. Although pulmonary interstitial emphysema (PIE) was considered an important differential diagnosis because of the overlapping clinicopathologic features, a giant cell reaction surrounding the interstitial cystic lesions, a histologic hallmark of PIE, was absent in the present case.     

Hyaline vascular Castleman's disease (HVCD) mimicking lung metastasis of renal carcinoma: A case report and literature review

Castleman's disease (CD) is a rare lymphoproliferative disorder characterized by atypical lymph node follicular hyperplasia. Subsequential occurrence of CD and cancers has been rarely reported and interpretations of the relationship are contentious. An asymptomatic 70-year-old man was found to have a left-sided hilar mass during routine follow-up after a radical right nephrectomy for clear cell carcinoma, raising suspicions of lung metastasis. Because there was no sign of recurrence in the original operative region, he underwent wedge resection of the left lung and lymph nodes dissection. Histology showed typical features of HVCD. Herein, we emphasize careful histopathology and complete resection of CD. We speculate that subsequential occurrence of CD and cancers may not be coincidental and warrants further exploration.     

Cytomorphologic manifestations of Alzheimer's disease using brain squash smears: An autopsy study with histology–cytology correlation

Alzheimer's disease (AD) is the most common form of dementia. The cardinal histopathologic features include senile plaques (SPs) and neurofibrillary tangles (NFTs), and in addition, granulovacuolar degeneration (GVD) and Hirano bodies (HBs) are frequently observed in the hippocampus. We studied hippocampal cytological features of AD, compared with controls. Hippocampal squash smears were prepared from 26 autopsy brains and stained with three different solutions, including Papanicolaou stain (Pap‐s). The smears were evaluated for the aforementioned four structures and gliosis, and their frequency was compared between AD (n = 15) and control (n = 11) groups. Hippocampal smears of all AD cases revealed NFTs and gliosis. NFTs were light gray with thick flame‐like structures on Pap‐s. GVD was identified in the majority of AD cases and was most easily observed on Pap‐s. SPs were difficult to identify and were seen only in AD cases. HBs were rarely identified as long light eosinophilic hyaline structures on Pap‐s. Cytological findings of hippocampi reflect the characteristic histological features of AD with the exception of HBs, which are difficult to identify on smears. NFTs and gliosis, and SPs seem to be sensitive and specific cytologic markers in hippocampal smears for AD, respectively. Diagn. Cytopathol. 2009. © 2009 Wiley‐Liss, Inc.     

Diagnosis and classification of Goodpasture's disease (anti-GBM)

Goodpasture's disease or anti-glomerular basement membrane disease (anti-GBM-disease) is included among immune complex small vessel vasculitides. The definition of anti-GBM disease is a vasculitis affecting glomerular capillaries, pulmonary capillaries, or both, with GBM deposition of anti-GBM autoantibodies. The disease is a prototype of autoimmune disease, where the patients develop autoantibodies that bind to the basement membranes and activate the classical pathway of the complement system, which start a neutrophil dependent inflammation. The diagnosis of anti-GBM disease relies on the detection of anti-GBM antibodies in conjunction with glomerulonephritis and/or alveolitis. Overt clinical symptoms are most prominent in the glomeruli where the inflammation usually results in a severe rapidly progressive glomerulonephritis. Despite modern treatment less than one third of the patients survive with a preserved kidney function after 6 months follow-up. Frequencies vary from 0.5 to 1 cases per million inhabitants per year and there is a strong genetic linkage to HLA-DRB1¹1501 and DRB1¹1502. Essentially, anti-GBM disease is now a preferred term for what was earlier called Goodpasture's syndrome or Goodpasture's disease; anti-GBM disease is now classified as small vessel vasculitis caused by in situ immune complex formation; the diagnosis relies on the detection of anti-GBM in tissues or circulation in conjunction with alveolar or glomerular disease; therapy is effective only when detected at an early stage, making a high degree of awareness necessary to find these rare cases; 20–35% have anti-GBM and MPO-ANCA simultaneously, which necessitates testing for anti-GBM whenever acute test for ANCA is ordered in patients with renal disease.     

Wilson's disease: an analysis of 28 Brazilian children

OBJECTIVES:

Clinical-laboratory and evolutionary analysis of twenty-eight patients with Wilson''s disease.

METHODS:

Twenty-eight children (twelve females and sixteen males) with Wilson''s disease were evaluated retrospectively between 1987 and 2009, with a follow-up of 72 months (1 – 240 months). The clinical, laboratory, and histologic features at diagnosis were recorded at the end of the study.

RESULTS:

The median age at diagnosis was 11 years (2 – 18 years). Twelve patients were asymptomatic, seven had hepatitis symptoms, five had raised aminotransferase levels, three had hepatomegaly associated with neurological disorders, one had fulminant hepatitis with hemolytic anemia, and six patients presented with a Kayser-Fleischer ring. A histological analysis revealed that six children had chronic hepatitis, seven had cirrhosis, two had steatosis, one had portal fibrosis, and one had massive necrosis. The treatment consisted of D-penicillamine associated with pyridoxine for 26 patients. Adverse effects were observed in the other two patients: one presented with uncontrollable vomiting and the other demonstrated elastosis perforans serpiginosa. At the end of the study, all 26 treated patients were asymptomatic. Twenty-four of the patients were treated with D-penicillamine and pyridoxine, and two were treated with trientine and zinc sulfate. A liver transplant was performed in one patient with fulminant hepatitis, but the final patient died 48 hours after admission to the intensive care unit.

CONCLUSIONS:

Family screenings associated with early treatment are important in preventing Wilson''s disease symptoms and potentially fatal disease progression. The study suggests that Wilson''s disease must be ruled out in children older than two years presenting with abnormal levels of hepatic enzymes because of the heterogeneity of symptoms and the encouraging treatment results obtained so far.     

Induction and maintenance treatment of inflammatory bowel disease: A comprehensive review

Ulcerative colitis (UC) and Crohn's disease (CD) are the two major types of inflammatory bowel disease (IBD). We conducted a comprehensive review of meta-analyses to summarize the reported effectiveness of different drugs for IBD. We performed a literature search and a total of 110 meta-analyses from 66 articles were summarized and re-analyzed (62 in UC and 48 in CD). In summary, 5-ASA was more effective than placebo in both induction and maintenance treatment of UC, but there were conflicting results on the effect of 5-ASA on the induction treatment or relapse of CD. The use of immunomodulatory agents in the induction or maintenance phase of UC and CD using immunomodulators appeared to be more effective than placebo, but the results were impacted by small number of patients, discordant results with the largest study and risk of biases. Anti-TNF-α and anti-integrin therapeutic antibodies in both, induction and maintenance, showed a better efficacy than placebo in a large proportion of patients analyzed. Other agents, such as probiotics, antibiotics, omega-3, were shown to be more effective than placebo, but the same issues arose as stated above with the use of immunomodulatory agents. In conclusion, we performed a comprehensive review of meta-analysis on comparative efficacy of pharmacotherapy used in the management of IBD. Our review will augment our understanding of the treatment of UC and CD by providing a guideline for interpreting the statistically significant findings and discusses the optimal choice for IBD treatment.