Fine needle aspiration cytology of follicular dendritic cell sarcoma. Report of a case with cytologic detection in an extranodal site.

BACKGROUND: Follicular dendritic cell sarcoma (FDCS) is a rare malignancy of accessory immune cells that can present in both nodal and extranodal sites. Previous cytologic case reports of FDCS have focused on fine needle aspiration (FNA) findings in nodal sites with low grade morphology and indolent clinical courses. CASE: A 33-year-old female presented with a three-month history of abdominal distention, early satiety and nausea. Initial imaging studies showed a large abdominal mass, with subsequent studies showing lung, liver and lymph node metastases. Examination of primary and metastatic tumors by a combination of conventional histology, immunohistochemistry and FNA demonstrated an extranodal intraabdominal follicular dendritic cell sarcoma. CONCLUSION: FDCS demonstrates a characteristic cytologic picture on FNA, with important cytologic features, including both syncytial and discohesive large epithelioid to spindled malignant cells with intranuclear inclusions, nuclear grooves and a prominent, mature, lymphocytic inflammatory component. No evidence of morphologic tumor progression was noted in comparison of primary and metastatic tumors. To aid in the cytologic distinction of FDCS from other similar-appearing neoplasms, we recommend acquisition of material for immunohistochemical studies, recognition of diverse clinical presentations (including extranodal and aggressive) and acknowledgment of the range of tumor morphologic grades.

Hantavirus pulmonary syndrome is distinguishable from acute interstitial pneumonia.

CONTEXT: Hantavirus pulmonary syndrome (HPS) and acute interstitial pneumonia (AIP) can share similar clinical presentations. AIP is an acute, diffuse lung disease that has some clinical features suggesting a viral infection, although causative agent(s) have not been identified. OBJECTIVE: To clinically, histologically, and immunohistochemically compare cases of HPS to cases of AIP and to determine if any cases of AIP were actually examples of HPS. DESIGN: Seven cases of HPS and 9 cases of AIP were compared clinically and histologically by semiquantitative grading of features in lung tissue. The cases were also evaluated immunohistochemically for the presence of hantaviral antigens. RESULTS: Hantavirus pulmonary syndrome had a shorter clinical duration and more acute changes histopathologically; AIP was of longer clinical duration and was usually accompanied by histologic evidence of organization. Hantavirus pulmonary syndrome was distinguished by the presence of immature leukocytes in the pulmonary vasculature. No hantaviral antigens were identified immunohistochemically in the 9 case of AIP. Hantaviral antigens were identified in all 7 cases of HPS. CONCLUSION: Cases of AIP and fatal cases of HPS can generally be distinguished on clinical and histologic grounds, and this distinction can be further confirmed immunohistochemically.

Experimental infection model for Sin Nombre hantavirus in the deer mouse (Peromyscus maniculatus).

The relationship between hantaviruses and their reservoir hosts is not well understood. We successfully passaged a mouse-adapted strain of Sin Nombre virus from deer mice (Peromyscus maniculatus) by i.m. inoculation of 4- to 6-wk-old deer mouse pups. After inoculation with 5 ID(50), antibodies to the nucleocapsid (N) antigen first became detectable at 14 d whereas neutralizing antibodies were detectable by 7 d. Viral N antigen first began to appear in heart, lung, liver, spleen, and/or kidney by 7 d, whereas viral RNA was present in those tissues as well as in thymus, salivary gland, intestine, white fat, and brown fat. By 14 d nearly all tissues examined displayed both viral RNA and N antigen. We noted no consistent histopathologic changes associated with infection, even when RNA load was high. Viral RNA titers peaked on 21 d in most tissues, then began to decline by 28 d. Infection persisted for at least 90 d. The RNA titers were highest in heart, lung, and brown fat. Deer mice can be experimentally infected with Sin Nombre virus, which now allows provocative examination of the virus-host relationship. The prominent involvement of heart, lung, and brown fat suggests that these sites may be important tissues for early virus replication or for maintenance of the virus in nature.

Dermal lymphangiomata of the vulva and laser therapy: a case report and literature review.

Dermal lymphangioma of the vulva is a rare disorder of the lymphatic system. The mainstay of therapy has been vulvectomy. A 65-year-old woman with a remote history of cervical cancer who successfully underwent CO2 laser vaporization for extensive vulva lymphangiomata, and a literature review inclusive of all 28 previously reported cases are described. Ten (35.7%) of these patients had previously received pelvic radiation for cervical cancer, 8 of whom (80%) had also undergone radical hysterectomy. Including the present case, 5 patients, 3 of whom had previously received radiation therapy, have been treated successfully with laser therapy. These data support laser vaporization with retreatment of persistent or recurrent focal disease as the treatment of choice for dermal lymphangiomata. Surgical excision should be reserved for treatment failures. Radical hysterectomy in association with postoperative pelvic radiation therapy appears to be an important, previously unrecognized risk factor for its development.

Corpus gastritis is protective against reflux oesophagitis.

BACKGROUND: Gastric acid is important in the pathogenesis of reflux oesophagitis. Acid production by the gastric corpus is reduced in corpus gastritis. AIMS: To determine whether corpus gastritis protects against reflux oesophagitis. METHODS: Patients presenting for elective oesophagogastroduodenoscopy were studied. Two biopsy specimens were taken from the antrum, corpus, and cardia and stained with haematoxylin/eosin and Diff-Quick II stains. The presence and severity of gastritis were graded according to a modified updated Sydney classification. RESULTS: Of 302 patients, 154 had endoscopic signs of reflux oesophagitis. There was no difference between patients with and controls without oesophagitis in the overall infection rates with Helicobacter pylori. Acute or chronic corpus gastritis occurred less often in patients with than those without reflux oesophagitis. Compared with controls, corpus gastritis was less severe in patients with reflux oesophagitis. The presence of acute or chronic gastritis in the corpus was significantly correlated with either type of gastritis in other areas of the stomach. In a multivariate logistic regression, age, sex, smoking status, and the presence of chronic corpus gastritis all exerted a significant influence on the presence of reflux oesophagitis. Chronic corpus gastritis was associated with a 54% reduced risk for reflux oesophagitis. CONCLUSIONS: While infection with H pylori alone may not affect the occurrence of reflux oesophagitis, the development of chronic corpus gastritis seems to be protective.

Characteristics of intestinal metaplasia in the gastric cardia.

OBJECTIVE: Intestinal metaplasia of the gastroesophageal junction is frequently grouped together with Barrett's esophagus. The area of the gastroesophageal junction is comprised of the distal esophagus and the gastric cardia. The aim of the present study was to assess whether intestinal metaplasia in the distal esophagus and gastric cardia represent two different entities with a different set of risk factors. METHODS: Patients presenting for elective upper endoscopy were enrolled into a prospective study. The presence of gastritis and intestinal metaplasia was evaluated in gastric biopsies taken from the antrum, corpus, and cardia. Barrett's esophagus was defined by the presence of any length of columnar mucosa above the gastroesophageal junction. RESULTS: Of 302 patients, 50 patients had intestinal metaplasia of the gastric cardia, 73 Barrett's esophagus, and 116 erosive esophagitis. Men were more prone than women to develop Barrett's esophagus or erosive esophagitis. Both conditions were also more common among whites than nonwhites. Smoking was particularly common among patients with Barrett's esophagus. Patients with cardiac intestinal metaplasia did not share these demographic characteristics. The prevalence of daily reflux symptoms, erosive esophagitis, and Barrett's esophagus was similar among patients both with and without cardiac intestinal metaplasia. However, atrophy and intestinal metaplasia of the gastric antrum and corpus were found more frequently among patients with than without cardiac intestinal metaplasia. CONCLUSIONS: Intestinal metaplasia of the gastric cardia is different from Barrett's esophagus. Although cardiac intestinal metaplasia is closely associated with signs of gastritis in other parts of the stomach, gastroesophageal reflux disease does not seem to be a risk factor. A diagnosis of Barrett's esophagus should not be made based on the presence of intestinal metaplasia within the cardiac portion of the gastroesophageal junction.

The transcription factor E2F-1 in SV40 T antigen-induced cerebellar Purkinje cell degeneration.

Transgenic targeting of SV40 large T antigen (Tag) expression to murine cerebellar Purkinje cells induces these normally postmitotic neurons to undergo DNA synthesis and apoptosis. It has been proposed that these effects of Tag are due to the binding of Tag to pRb, which leads to the release and activation of the transcription factor E2F. Here it is reported that E2F and CDC2, the protein product of a gene regulated by E2F, were detectable in the Purkinje cell nuclei of Tag expressing transgenic animals. To directly test whether E2F-1 is part of the mechanism of Tag-induced Purkinje cell degeneration, transgenic mice that overexpress E2F-1 specifically in cerebellar Purkinje cells were generated. Although E2F-1 itself did not affect Purkinje cells, it did accelerate Tag-induced ataxia and Purkinje cell loss, suggesting that E2F-1 can contribute to the mechanism of Tag-induced Purkinje cell degeneration.

Progressive pan-colonic fibrosis secondary to oral administration of pancreatic enzymes.

Most patients with cystic fibrosis require oral administration of pancreatic enzymes to treat pancreatic insufficiency. Recent use of higher-strength enzyme preparations in large doses has been found to be associated with fibrotic strictures of the colon. We report a case of pancolonic fibrosis due to pancreatic enzyme use.

Cerebellar vascular and synaptic responses in normal mice and in transgenics with Purkinje cell dysfunction.

We used transgenic mice with Purkinje cell dysfunction (PO3 line) to study the role of these neurons in the increase in cerebellar blood flow (BFcrb) produced by stimulation of the cerebellar parallel fibers (PF). Mice (age 8-10 wk) were anesthetized (halothane) and artificially ventilated. Arterial pressure and end-tidal CO2 were monitored continuously. Arterial blood gases were measured. The PF were stimulated electrically (100 microA, 30 Hz; 40 s), and the increases in BFcrb were monitored by a laser-Doppler flow probe. First, we characterized the increases in BFcrb and the field potentials produced by PF stimulation in normal mice. PF stimulation evoked the typical field potentials and increased BFcrb by 60 +/- 4% (100 microA, 30 Hz; n = 10). The increases in BFcrb were attenuated by the broad-spectrum glutamate receptor antagonist kynurenate (-84 +/- 3%; P < 0.05 analysis of variance; n = 5), by the DL-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (-62 +/- 6%; P < 0.05; n = 5), and by the nitric oxide synthase inhibitor N omega-nitro-L-arginine (-46 +/- 7%; P < 0.05; n = 5). In PO3 transgenic mice, the increases in BFcrb produced by PF stimulation were reduced (P < 0.001) at every stimulus intensity and frequency tested (residual increase at 100 microA, 30 Hz: 19 +/- 2%; n = 6). The field potentials evoked by PF stimulation also were abnormal in that they lacked the late negative wave (n = 6), a finding consistent with lack of depolarization of Purkinje cells. The residual flow response in the transgenics was abolished by N omega-nitro-L-arginine (n = 5; P > 0.05). Ultrastructural studies showed that the density of PF-Purkinje cell synapses is reduced in PO3 mice, whereas the morphology of molecular layer interneurons (stellate cells) is normal. The findings suggest that Purkinje cells are responsible for a sizable component of the flow response whereas molecular layer interneurons mediate the remainder of the response. The study provides evidence that mouse mutants with spontaneous or genetically engineered cerebellar abnormalities could be useful to study the cellular and molecular correlates of functional hyperemia in the central nervous system.

Susceptibility to cell death induced by mutant SV40 T-antigen correlates with Purkinje neuron functional development.

Purkinje cells are uniquely susceptible to a number of physical, chemical, and genetic insults both during development and in the mature state. We have previously shown that when the postmitotic state of murine Purkinje cells is altered by inactivation of the retinoblastoma tumor susceptibility protein (pRb), immature as well as mature Purkinje cells undergo apoptosis. DNA synthesis and neuronal loss are induced in postmitotic Purkinje cells dependent upon the pRb-binding portion of SV40 large T antigen (T-ag). In the present study, Purkinje cell targeting of a mutant T-ag, PVU, which does not bind pRb, reveals disparate cerebellar phenotypes dependent upon temporal differences in transgene expression. Strong embryonic and postnatal transgene expression in three lines alters Purkinje cell development and function during the second postnatal week, causing ataxia without Purkinje cell loss. In contrast, two other transgenic lines reveal that PVU T-ag expression following normal Purkinje cell maturation causes rapid Purkinje cell degeneration. The second and third postnatal weeks of cerebellar development, which include the major period of synaptogenesis, appear to be the defining stage for the two PVU-induced phenotypes. These data indicate that Purkinje cell death susceptibility varies with developmental stage.

Phenotypic analysis of mice lacking the highly abundant Purkinje cell- and bipolar neuron-specific PCP2 protein.

The Purkinje cell protein-2 (Pcp2, also known as L7) gene is abundantly expressed only in Purkinje cells of the cerebellum and bipolar neurons of the retina. The spatio-temporal expression pattern of this gene suggests a role for PCP2 in Purkinje cell development or normal cell physiology. A PCP2-deficient mouse was created by gene targeting to test the hypothesis that it is required for Purkinje cell development or function. Although normally present in abundance, the absence of PCP2 in null animals caused no observable cerebellar abnormalities. Behavioral analysis reveals normal abilities for balance and coordination. Null cerebellum has normal Purkinje cell numbers, morphology, and ultrastructure. Retinal bipolar neurons appear similarly unaffected. Aged null animals (22 months) were also examined and no deficits were detected using the same behavioral and histologic analyses. Although the null animal does not reveal the function of PCP2, it does rule out an essential role for PCP2 in Purkinje cell development, in Purkinje cell survival, and in at least some aspects of cerebellar function.

The role of luminal nutrients in intestinal injury from mesenteric reperfusion and platelet-activating factor in the developing rat.

Necrotizing enterocolitis (NEC) develops primarily after the onset of enteral feeds in the premature infant. The purpose of this study was to evaluate the influence of intestinal luminal nutrients on histologic injury and the oxidant response in a rat model of NEC. On postnatal Days 10 and 35, Sprague-Dawley rats (total n = 81) underwent abdominal laparotomy. A control group received sham-injury only. The ischemia groups received a single intraluminal injection of 0.25 ml (Day 10) or 1.0 ml (Day 35) of lactose (8.6 g/dl), casein (2.2 g/dl), corn oil (4.4 g/dl), or infant formula (Similac; 20 g/dl). After injection of the nutrient solutions, ischemia groups underwent mesenteric occlusion for 1 hr and intraluminal injection of platelet-activating factor (50 microgram/kg). Necropsies were performed after 6 hr or at demise. Intestinal samples were taken for histology, total glutathione (GSH; an antioxidant), and conjugated dienes (a lipid peroxidation product). Histologic injury was scored from 0 (normal) to 5 (transmural necrosis). Microscopic injury scores in the oil group were significantly higher than the casein group (P < 0.05) and trended toward being higher in the formula group (P = 0.085) at age 10 days. Total GSH activity was significantly higher in the sham groups than all ischemia groups on Day 10 (P < 0.001) and than the corn oil group on Day 35 (P < 0.05). GSH activity did not differ among ischemia groups. Conjugated diene concentrations were significantly higher in the casein group than the lactose and sham groups at age 10 days (P < 0.05) only. We conclude that intraluminal lipids may augment intestinal ischemic injury in the newborn (age 10 days) but not the weanling rat. While oxygen-free radicals were present during injury, lipid peroxidation from oxygen radicals was not responsible for this increase in histologic injury.

EWS and WT-1 gene fusion in desmoplastic small round cell tumor of the abdomen.

Chromosome translocations found in neoplasms often result in the creation of hybrid genes encoding chimeric proteins. This case study describes a patient with desmoplastic small round cell tumor (DSRCT) of the abdomen, an aggressive neoplasm characterized by translocation of chromosomes 11 and 22. Southern hybridization showed that the Ewing sarcoma gene (EWS) gene was rearranged in the DSRCT. Reverse transcriptase-polymerase chain reaction analysis of tumor cell RNA revealed that exons 1 to 7 of the EWS gene were joined to exons 8 to 10 of the Wilms' Tumor-1 (WT-1) gene resulting in the production of a chimeric message. The WT-1 and EWS genes encode DNA and RNA binding proteins involved in Wilms' tumor and Ewing sarcoma pathogenesis, respectively. The fusion of these two genes in DSRCT results in the production of a putatively oncogenic protein composed of the zinc finger DNA binding domains of WT-1 linked to potential transcriptional regulatory domains of EWS. DNA sequencing revealed the genomic breakpoints of translocation on chromosomes 11 and 22. The genomic breakpoint on chromosome 22 occurred in EWS intron 7 just 2 nucleotides 3' of exon 7. Polymerase chain reaction-based assays were developed that could detect the fused genes in the DSRCT tumor using either RNA or genomic DNA. The potential diagnostic use of these assays is discussed.

SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat.

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant inherited disorder characterized by degeneration of cerebellar Purkinje cells, spinocerebellar tracts, and selective brainstem neurons owing to the expansion of an unstable CAG trinucleotide repeat. To gain insight into the pathogenesis of the SCA1 mutation and the intergenerational stability of trinucleotide repeats in mice, we have generated transgenic mice expressing the human SCA1 gene with either a normal or an expanded CAG tract. Both transgenes were stable in parent to offspring transmissions. While all six transgenic lines expressing the unexpanded human SCA1 allele had normal Purkinje cells, transgenic animals from five of six lines with the expanded SCA1 allele developed ataxia and Purkinje cell degeneration. These data indicate that expanded CAG repeats expressed in Purkinje cells are sufficient to produce degeneration and ataxia and demonstrate that a mouse model can be established for neurodegeneration caused by CAG repeat expansions.

Intrapulmonary lymph nodes masquerading as renal cell carcinoma metastases.

Clinically apparent intrapulmonary lymph nodes are rare but may be incorrectly diagnosed as pulmonary metastatic disease. We report on a 65-year-old man who presented with a left renal mass and left lower lobe pulmonary nodules that were interpreted radiographically to be consistent with metastatic disease. Surgical pathologic examination confirmed intrapulmonary lymph nodes and a Stage II renal cell carcinoma. Failure to diagnose intrapulmonary lymph nodes may result in erroneous diagnosis of metastatic disease and preclude potentially curative treatment.

A model of intestinal ischemia in the neonatal rat utilizing superior mesenteric artery occlusion and intraluminal platelet-activating factor.

The human premature newborn is susceptible to necrotizing enterocolitis (NEC) in the first 1 to 3 weeks of life, a time when the gastrointestinal tract is structurally and functionally premature. Studies of NEC are hampered by the lack of a standard, reproducible model in newborn animals. The purpose of this study was to produce a model for intestinal ischemic injury in newborn rats. On Days 14, 18, 22, and 26 of life, newborn rats (10/day) were subjected to 1 hr of superior mesenteric artery occlusion with a microaneurysm clip. Platelet activating factor (PAF, 50 micrograms/kg) was injected into the lumen of the proximal small intestine after occlusion was initiated. Control animals (10/day) underwent sham laparotomy on Days 14, 18, 22, and 26. Animals were autopsied upon demise (7.6 +/- 0.7 hr) or at 24 hr. The intestine was inspected for gross ischemic changes and samples were taken for histology and myeloperoxidase (MPO, an index of neutrophil infiltration). Ischemic injury was graded in a blinded fashion, by a pathologist, using a scale from 0 to 4 (0, no injury; 4, full-thickness necrosis). All animals in the experimental groups had evidence of histologic injury (mean +/- SEM) on Days 14 (1.0 +/- 0.0), 18 (2.5 +/- 0.5), 22 (3.6 +/- 0.3), and 26 (3.1 +/- 0.5). The sham-operated control animals had no injury (P < 0.0001). MPO levels (U/g protein) on Days 18 (27.2 +/- 1.7 vs 13.9 +/- 2.3), 22 (40.9 +/- 5.4 vs 7.6 +/- 0.8), and 26 (29.3 +/- 4.4 vs 7.6 +/- 1.0) were significantly higher in experimental groups vs controls (P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

In vivo viability of postmitotic Purkinje neurons requires pRb family member function.

The product of the retinoblastoma susceptibility gene, pRb, is known to be an important regulator of cell division. Disrupted central nervous system development in RB null mice suggests a critical function for pRb in the proliferative arrest and initiation of terminal differentiation of certain neurons. Previously, we have shown that SV40 T-ag expression targeted to Purkinje neurons in transgenic mice causes cell-specific death. Here we describe that T-ag expression induces DNA synthesis and results in DNA fragmentation in Purkinje neurons. Characterization of transgenic mouse lines expressing mutant T-ags demonstrate that the pRb binding domain of T-ag is required for induction of Purkinje cell loss. These findings indicate that a pRb function is required well beyond the completion of Purkinje neuron differentiation and provide a link between cell cycle regulation and neurodegeneration in vivo.

Hantavirus pulmonary syndrome. Pathogenesis of an emerging infectious disease.

A recent outbreak of a severe pulmonary disease in the southwestern United States was etiologically linked to a previously unrecognized hantavirus. The virus has been isolated from its major reservoir, the deer mouse, Peromyscus maniculatus, and recently named Sin Nombre virus. Clinically, the disease has become known as the hantavirus pulmonary syndrome (HPS). Since May 1993, 44 fatal cases of HPS have been identified through clinicopathological review and immunohistochemical (IHC) testing of tissues from 273 patients who died of an unexplained noncardiogenic pulmonary edema. In 158 cases for which suitable specimens were available, serological testing and/or reverse transcription-polymerase chain reaction (RT-PCR) amplification of extracted RNA was also performed. IHC, serological, and PCR results were concordant for virtually all HPS and non-HPS patients when more than one assay was performed. The prodromal illness of HPS is similar to that of many other viral diseases. Consistent hematological features include thrombocytopenia, hemoconcentration, neutrophilic leukocytosis with a left shift, and reactive lymphocytes. Pulmonary histopathological features were similar in most of the fatal HPS cases (40/44) and consisted of an interstitial pneumonitis with a variable mononuclear cell infiltrate, edema, and focal hyaline membranes. In four cases, however, pulmonary features were significantly different and included diffuse alveolar damage and variable degrees of severe air space disorganization. IHC analysis showed widespread presence of hantaviral antigens in endothelial cells of the microvasculature, particularly in the lung. Hantaviral antigens were also observed within follicular dendritic cells, macrophages, and lymphocytes. Hantaviral inclusions were observed in endothelial cells of lungs by thinsection electron microscopy, and their identity was verified by immunogold labeling. Virus-like particles were seen in pulmonary endothelial cells and macrophages. HPS is a newly recognized, often fatal disease, with a spectrum of microscopic morphological changes, which may be an important cause of severe and fatal illness presenting as adult respiratory distress syndrome.