H1-antihistamines exacerbate high-fat diet-induced hepatic steatosis in wild-type but not in apolipoprotein E knockout mice.

We examined the effects of two over-the-counter H1-antihistamines on the progression of fatty liver disease in male C57Bl/6 wild-type and apolipoprotein E (ApoE)-/- mice. Mice were fed a high-fat diet (HFD) for 3 mo, together with administration of either cetirizine (4 mg/kg body wt) or fexofenadine (40 mg/kg body wt) in drinking water. Antihistamine treatments increased body weight gain, gonadal fat deposition, liver weight, and hepatic steatosis in wild-type mice but not in ApoE-/- mice. Lobular inflammation, acute inflammation, and necrosis were not affected by H1-antihistamines in either genotype. Serum biomarkers of liver injury tended to increase in antihistamine-treated wild-type mice. Serum level of glucose was increased by fexofenadine, whereas lipase was increased by cetirizine. H1-antihistamines reduced the mRNA expression of ApoE and carbohydrate response element-binding protein in wild-type mice, without altering the mRNA expression of sterol regulatory element-binding protein 1c, fatty acid synthase, or ApoB100, in either genotype. Fexofenadine increased both triglycerides and cholesterol ester, whereas cetirizine increased only cholesterol ester in liver, with a concomitant decrease in serum triglycerides by both antihistamines in wild-type mice. Antihistamines increased hepatic levels of conjugated bile acids in wild-type mice, with the effect being significant in fexofenadine-treated animals. The increase was associated with changes in the expression of organic anion transport polypeptide 1b2 and bile salt export pump. These results suggest that H1-antihistamines increase the progression of fatty liver disease in wild-type mice, and there seems to be an association between the severity of disease, presence of ApoE, and increase in hepatic bile acid levels.

Progressive nodular histiocytosis with normal karyotypic analysis.

Non-Langerhans cell histiocytoses (NLH) comprise a spectrum of diseases that includes sinus histiocytosis with massive lymphadenopathy, hemophagocytic lymphohistiocytosis, xanthogranuloma, and reticulohistiocytoma. Progressive nodular histiocytosis (PNH) is a rare NLH that microscopically mimics juvenile xanthogranuloma but presents with disseminated persistent and progressive papulonodules in adults. Herein, we describe a case of PNH presenting as diffuse, progressively enlarging papules, nodules, and pedunculated tumors in a 38-year-old male. The diagnosis is supported microscopically by the morphologic and immunohistochemical findings. Whereas conventional cytogenetic analysis of Langerhans cell histiocytosis and juvenile xanthogranuloma has previously been described, there are no reports of the karyotype of PNH. In our patient, conventional cytogenetic analysis of the tumor revealed a normal karyotype. Although these results may represent the overgrowth of normal stromal cells rather than lesional cells, we believe this to be an important finding, indicating karyotypic analysis will not allow for distinction between PCH and other NLH or Langerhans cell histiocytoses.

Greater interobserver agreement by endoscopic mucosal resection than biopsy samples in Barrett's dysplasia.

BACKGROUND & AIMS: Endoscopic mucosal resection (EMR) is an important diagnostic, staging, and therapeutic tool for patients with Barrett's esophagus (BE)-associated neoplasia. We analyzed the histopathologic characteristics of specimens collected during EMR compared with biopsy specimens from patients with BE and assessed interobserver variability in pathologists' assessment of EMR and biopsy specimens. METHODS: We evaluated EMR (n = 251) and biopsy (n = 269) specimens collected from patients with BE at 2 tertiary referral centers. A detailed histologic analysis was performed for each EMR and biopsy specimen to determine the grade of dysplasia, depth of the specimen, proportion of specimen with dysplasia, and quality of samples. Interobserver agreement for both biopsy and EMR specimens (among 4 experienced pathologists) was calculated by using kappa statistics. RESULTS: Histologic analysis showed that submucosa was present in the majority of EMRs, compared with biopsy specimens (88% vs 1%, P < .0001). Almost all biopsy specimens (99%) included lamina propria. However, the muscularis mucosa was observed in only 58% of biopsy specimens. For both EMR and biopsy specimens, the highest grade of dysplasia comprised < or =25% of the total area in >50% of the specimens. Interobserver agreement on the diagnosis of dysplasia was significantly greater for EMR specimens than biopsy specimens (low-grade dysplasia, 0.33 vs 0.22, P < .001; high-grade dysplasia, 0.43 vs 0.35, P = .018). CONCLUSIONS: Submucosa can be examined in most samples collected from EMR; the distribution of neoplasia is focal within biopsy and EMR specimens. There is more interobserver agreement among pathologists in the analysis of EMR samples than biopsy specimens for the diagnosis of dysplasia.

Amelanotic malignant melanoma: two collision tumors presenting as basal cell carcinoma and atypical fibroxanthoma.

Collision (contiguous) tumors of the skin can result in misleading clinicopathological presentations, and the choice of appropriate diagnostic techniques may prevent incomplete diagnosis and management. We report 2 cases of collision tumors involving amelanotic malignant melanoma of the back. One patient is a 79-yr-old male with an 8.7 x 5.5 x 4.5 cm polypoid lesion that on shave biopsy was diagnosed as basal cell carcinoma. Subsequent excision showed that the lesion was largely composed of amelanotic melanoma underlying a relatively small and thin basal cell carcinoma, and this probably would have been demonstrated in a punch (rather than shave) biopsy. The other patient is a 71-yr-old male with a 1 cm exophytic lesion on the back, which was determined microscopically to be melanoma, and a 0.6 cm papule on the back. This lesion was composed of 2 distinct contiguous neoplastic infiltrates, the predominant component being an atypical fibroxanthoma and the smaller component an amelanotic melanoma (primary vs metastatic), with diagnostic confirmation requiring multiple immunohistochemical stains.

Narrow-band imaging colonoscopy--a pilot feasibility study for the detection of polyps and correlation of surface patterns with polyp histologic diagnosis.

BACKGROUND: Colonoscopy is the preferred screening method for colorectal cancer. However, it has a substantial miss rate for colon polyps, and several techniques have been attempted to improve this limitation. Narrow-band imaging (NBI) is a novel technology that enhances the visualization of surface mucosal and vascular patterns. OBJECTIVE: The aim of this study was to determine the detection rate of additional polyps by NBI after removal of polyps visualized by standard white light colonoscopy (WLC) and to correlate the surface mucosal and vascular patterns with polyp histologic diagnosis. DESIGN: This was a prospective pilot feasibility study. SETTING: Kansas City Veterans Affairs Medical Center. PATIENTS: Subjects referred for screening colonoscopy were prospectively enrolled. METHODS: Subjects underwent colonoscopy after enrollment. After intubation of the cecum, colonic segments were sequentially examined, initially with WLC with removal of polyps followed by re-examination of the same segment with NBI. Additional polyps seen with NBI were photographed for their surface patterns and then removed. The total number of polyps visualized by WLC and NBI was calculated and the surface patterns were then correlated with polyp histologic features. RESULTS: Forty patients were enrolled in the study, all men, 32 white. The mean age was 62 years. A total of 72 polyps were detected by WLC (43 tubular adenoma, 28 hyperplastic polyps), whereas NBI detected an additional 51 polyps, of which 29 were tubular adenomas and 22 were hyperplastic. Five different surface/vascular patterns were observed: fine capillary network with absent mucosal pattern, circular pattern with dots, round/oval pattern, tubular pattern, and gyrus pattern. The sensitivity, specificity, and overall accuracy of the first two patterns for hyperplastic polyps were 86%, 96%, and 92%, respectively, and of the latter three patterns for tubular adenomas were 96%, 86%, and 92%, respectively. CONCLUSIONS: This pilot study demonstrates the feasibility of polyp detection and histologic correlation with NBI. These findings need to be confirmed in future randomized controlled trials.

Dose effect of soy supplementation in prostate cancer: a pilot study.

We performed a pilot study to determine the dose effect of soy supplement on serum hormonal levels, estrogen receptor alpha (ERalpha) and androgen receptor (AR) expression in patients scheduled to undergo prostatectomy. Cohorts of 3-4 eligible patients received escalating doses of a commercial soy supplement, Flav-ein, from the time of study enrollment until prostatectomy. Serum levels of prostate specific antigen (PSA), testosterone, and estrogen were measured at study enrollment and prior to prostatectomy. AR and ERalpha expression was evaluated in the pretreatment biopsy specimen and post-treatment prostatectomy specimen using immunohistochemical analysis. A total of 13 patients were enrolled in this pilot study and 11 patients were assessable for response. With soy supplementation, serum testosterone levels decreased in 9 of 11 patients and estrogen levels decreased in 8 of 10 patients in a dose-dependent manner. There was a variable effect on ERalpha expression with downregulation of receptor expression seen at the highest dose level. There was no effect on AR expression. In conclusion, supplementation with this commercial soy product produced a consistent decrease in serum sex hormone levels. Additional studies are needed to evaluate a potential dose effect on ERalpha expression.

The utility of a novel narrow band imaging endoscopy system in patients with Barrett's esophagus.

BACKGROUND: A narrow band imaging (NBI) endoscopy system has been developed that allows superficial surface imaging of esophageal tissue in vivo. OBJECTIVE: The objective was to assess the potential of NBI for prediction of histology during screening and surveillance endoscopy in patients with Barrett's esophagus (BE). DESIGN: A prospective cohort study. SETTING: Veterans Affairs Medical Center. PATIENTS: Fifty-one patients with known or suspected BE. METHODS: NBI images were graded according to mucosal pattern (ridge/villous, circular and irregular/distorted) and vascular pattern (normal and abnormal), and correlated with histology in a prospective, blinded manner. MAIN OUTCOME MEASUREMENTS: Biopsy-confirmed intestinal metaplasia (IM) and dysplasia were used as the outcome measures. RESULTS: Of 51 patients (mean BE length 3.5 cm), 28 had IM without dysplasia, 8 had low-grade dysplasia (LGD), 7 had high-grade dysplasia (HGD), and 8 had cardiac-type mucosa. The sensitivity, specificity, and positive predictive value of ridge/villous pattern for diagnosis of IM without HGD were 93.5%, 86.7%, and 94.7%, respectively. The sensitivity, specificity, and positive predictive value of irregular/distorted pattern for HGD were 100%, 98.7%, and 95.3%, respectively. If biopsies were limited to areas with irregular/distorted pattern, no patient with HGD would have been missed. However, NBI was unable to distinguish areas of IM from those with LGD. LIMITATIONS: The open study design without a control group was the main limitation. CONCLUSIONS: NBI is a novel diagnostic tool with a high degree of accuracy for the detection of metaplastic and dysplastic tissue within the BE segment.

Detection of Barrett's esophagus after endoscopic healing of erosive esophagitis.

BACKGROUND: The presence of erosive esophagitis (EE) in patients presenting for upper endoscopy may prevent the detection of underlying Barrett's esophagus (BE) in the distal esophagus. AIM: To prospectively determine the proportion of patients detected with BE upon repeat endoscopy after healing of EE. METHODS: Patients with endoscopically confirmed EE without BE were treated with standard doses of acid suppression therapy and a repeat endoscopy was performed to assess the presence of BE. If columnar mucosa was visualized in the distal esophagus, targeted biopsies were obtained and all biopsies were evaluated for the presence of intestinal metaplasia. BE was defined as columnar mucosa in the distal esophagus with intestinal metaplasia on biopsy. RESULTS: A total of 172 patients with reflux symptoms were diagnosed with EE without BE on initial endoscopy. They were treated with standard doses of proton pump inhibitor therapy, and after a mean duration of 11 wk (range 8-16 wk), a repeat endoscopy was performed to confirm healing of EE and to document the presence of BE. On repeat endoscopy, EE was completely healed in 116 patients (67%), and of those, BE was suspected in 32 patients (i.e., columnar-lined distal esophagus) and was confirmed in 16 patients (13.8%). In the 56 patients with persistent EE on repeat endoscopy, columnar mucosa in areas of previously healed esophagitis was visualized in 8 and confirmed in 5 patients (8.9% of nonhealed cases). Overall, 21 (12%) patients were confirmed with BE on repeat endoscopy; all men, mean age 61 yr with a median BE length of 0.5 cm (range 0.5-5 cm, interquartile range 0.5 cm). The majority of these patients (N = 19) had short segment Barrett's esophagus (SSBE) (i.e., length <3 cm). CONCLUSIONS: In patients with EE undergoing treatment with acid suppressive therapy, BE (mainly SSBE) is detected in approximately 12% of patients on repeat endoscopy. Patients with reflux symptoms undergoing endoscopy for the detection of BE (i.e., screening) should be treated with acid suppressive therapy prior to endoscopy to enhance the yield of BE. Alternatively, if the goal is to document BE and if EE is found at the initial endoscopy, then repeat endoscopy may be considered after acid suppressive therapy.

The frequency of Barrett's esophagus in high-risk patients with chronic GERD.

BACKGROUND: The reported frequency of Barrett's esophagus (BE) in patients with reflux symptoms varies from 5% to 15%. The exact frequency of long-segment BE (LSBE) (>3 cm) and short-segment BE (SSBE) (<3 cm) in patients with chronic symptoms of GERD is uncertain. The aim of this study was to determine the frequency of LSBE and SSBE in consecutive patients presenting for a first endoscopic evaluation with GERD as the indication. METHODS: Consecutive patients presenting to the endoscopy unit of a Veterans Affairs Medical Center for a first upper endoscopy with the indication of GERD were prospectively evaluated. Demographic information (gender, race, age), data on tobacco use and family history of esophageal disease, and body mass index (BMI) were recorded for all patients. Before endoscopy, all patients completed a validated GERD questionnaire. The diagnosis of BE was based on the presence of columnar-appearing mucosa in the distal esophagus, with confirmation by demonstration of intestinal metaplasia in biopsy specimens. All patients with erosive esophagitis on the initial endoscopy underwent a second endoscopy to document healing and to rule-out underlying BE. Patients with a history of BE, alarm symptoms (dysphagia, weight loss, anemia, evidence of GI bleeding), or prior endoscopy were excluded. RESULTS: A total of 378 consecutive patients with GERD (94% men, 86% white; median age 56 years, range 27-93 years) were evaluated. A diagnosis of BE was made in 50 patients (13.2%). The median length of Barrett's esophagus (BE) was 1.0 cm (range 0.5-15.0 cm). Of the patients with BE, 64% had short-segment BE (SSBE) (overall SSBE frequency 8.5%). The overall frequency of long-segment BE (LSBE) was 4.8%. A hiatal hernia was detected in 62% of the patients with BE. Of the 50 patients with BE (median age 62 years, range 29-81 years), 47 (94%) were men and 98% were white. Eighteen patients (36%) were using tobacco at the time of endoscopy; 23 (46%) were former users. The median body mass index (BMI) of patients with BE was 27.3 (overweight). There were no significant differences between patients with LSBE and SSBE with respect to age, gender, ethnicity, BMI, and GERD symptom duration. CONCLUSIONS: The frequency of BE in a high-risk patient group (chronic GERD, majority white men, age > 50 years) who sought medical attention is 13.2%, with the majority (64%) having SSBE. These data suggest that the frequency of BE in patients with GERD has not changed. The true prevalence of BE in the general population, including those who do not seek care, is undoubtedly lower, currently and historically. The majority of patients with BE are overweight and have a hiatal hernia. Demographic data for patients with LSBE and SSBE are similar, indicating that these are a continuum of the same process.

Development of Barrett's esophagus six months after total gastrectomy.

Barrett's esophagus (BE) is an acquired disease of the esophagus, in which esophageal squamous epithelium is changed by injury from reflux to metaplastic intestinal type columnar epithelium. BE is the premalignant lesion of adenocarcinoma of the esophagus. It is widely accepted that the long-standing reflux of gastric acid is a catalyst for the development of BE. More recent work points toward the reflux of duodenal secretions as a catalyst in this disease process as well. Moreover, the time course for the development of BE once a patient has reflux is not known. Our case challenges the currently defined time course of "long-standing" reflux symptoms for the development of BE, and supports the role of duodenal secretions alone in the development of BE. A 68-yr-old Caucasian man was admitted with weight loss, left upper quadrant pain, a hemoglobin of 6.8, and heme-positive stool. Esophagogastroduodenoscopy (EGD) revealed normal esophageal mucosa and a mass in the gastric cardia. Biopsies showed moderately differentiated gastric adenocarcinoma. The patient underwent a total gastrectomy, distal esophagectomy, and a Roux-en-Y esophagojejunostomy. Pathology confirmed gastric adenocarcinoma (T1 N0 Mx). The distal esophagus and gastroesophageal junction in the resected specimen were grossly and microscopically normal. Six months later an EGD, prompted by new complaints of regurgitation and dyspepsia, revealed distal esophageal mucosa lined by red-colored columnar tissue. Biopsies showed intestinal type epithelium. Thus, our case report's contribution to the current literature is twofold. It provides evidence of development of BE solely from duodenal reflux, and it documents a relatively short time span to development of BE.

Risk stratification of Barrett's esophagus: updated prospective multivariate analysis.

OBJECTIVES: Prospective evaluation of Barrett's esophagus (BE) in order to determine what demographic, endoscopic, and histologic features are predictive of the prevalence and incidence of Barrett's high-grade dysplasia (HGD) and adenocarcinoma (Ca). METHODS: Newly diagnosed BE patients were entered into and followed in a standardized surveillance protocol. The following features were examined using either forward, stepwise multiple regression analysis, or Cox proportional hazards to determine their ability to predict the presence of HGD or Ca at index BE diagnosis as well as their ability to predict progression of BE during follow-up: age, race, gender, length of BE in cm, size of a hiatal hernia, severity of dysplasia at index diagnosis as well as during surveillance, gastric Helicobacter pylori infection status, and type of medical acid-reflux treatment. RESULTS: A total of 550 patients were diagnosed with BE over the study period. Stepwise multiple regression analysis showed three factors significantly associated with index diagnosis of HGD or Ca: hiatal hernia (larger size), Barrett's length (longer length), and absence of H. pylori infection. Three hundred and twenty-four BE entered the surveillance protocol. Cox proportional hazards models revealed a significant and independent association for five factors predictive of the time to progression of BE: presence of dysplasia at index diagnosis (p < 0.001), severity of dysplasia during surveillance (p < 0.001), length of Barrett's epithelium (p= 0.012), size of hiatal hernia (p= 0.006), and gastric H. pylori infection status (p= 0.023). CONCLUSIONS: Endoscopic and histologic features of BE at initial diagnosis are predictive of index HGD and cancer as well as with risk of BE progression.

Hepatocellular carcinoma diagnosed by fine-needle aspiration of the parotid gland.

Hepatocellular carcinoma rarely metastasizes to the salivary glands. We report a case of a 47-yr-old man who presented with a right parotid lesion that was diagnosed by fine-needle aspiration (FNA) biopsy as a metastatic lesion suggestive of hepatocellular carcinoma with similar findings in a subsequent intraoral incisional biopsy. The patient's serum alpha-fetoprotein level was within normal limits at the time of diagnosis. CT scan revealed a mass in the liver, but a liver biopsy was not performed. The patient deteriorated rapidly and died about 4 mo later. An autopsy confirmed the presence of hepatocellular carcinoma with distant metastases to unusual sites, including the parotid gland, orbit, and calvarium, bypassing more common sites such as the lungs. This is the second known reported case in which hepatocellular carcinoma presented as a salivary gland metastasis. In both cases the diagnosis was made by FNA biopsy, illustrating the utility of this method for diagnosing uncommon metastatic salivary gland lesions.

Differential expression of neuropilin-1 in malignant and benign prostatic stromal tissue.

Neuropilin-1 (NRP-1), a co-receptor for VEGF165, is overexpressed in various prostate cancer cell lines and in advanced prostate tumors. However, distribution of the NRP-1 in prostate tumors has not yet been evaluated. Using immunohistochemical analysis, we evaluated 21 archival prostate tumors and 5 benign glands for the expression of NRP-1. In addition, we utilized a quantitative RT-PCR method to examine mRNA expression in 9 additional prostate tumors obtained from radical prostatectomy specimens and compared this expression to the adjacent normal tissue. The RT-PCR analyses demonstrated overexpression of NRP-1 mRNA in malignant tissue samples by 10.0-fold as compared to adjacent normal tissue. By immunohistochemistry, NRP-1 protein was undetected or minimally detected in the epithelial tumor cells. However, NRP-1 immuno-reaction was detected in the surrounding tumor stroma. Variable immuno-reaction for NRP-1 was also seen in the adjacent normal tumor stroma and the stroma of the benign prostate samples. These observations suggest that neuropilin-1 is expressed in the prostatic stromal cells, not epithelial tumor cells, and this expression is significantly increased in the malignant phenotype.

Yield of intestinal metaplasia in patients with suspected short-segment Barrett's esophagus (SSBE) on repeat endoscopy.

Biopsies from short segments of columnar appearing mucosa in the distal esophagus often fail to reveal intestinal metaplasia (IM). The yield of IM on repeat upper endoscopy (EGD) and biopsy in these patients is not known. Our aim was to prospectively evaluate the yield of IM on repeat EGD in patients with suspected SSBE (negative for IM on first EGD). Forty-three patients with suspected SSBE underwent repeat EGD with biopsy. This included 42 men and 1 woman, mean age 53 years (range: 45-90) with a mean columnar mucosa length of 1.26 cm (range: 0.5-2.5). On repeat EGD, 10 of 43 patients (23.2%) had evidence of IM. There was no statistically significant difference between the patients with proven SSBE on repeat EGD compared to those with persistent negative IM with regards to age, ethnicity, length of columnar mucosa, GERD symptoms, and hiatal hernia size. In conclusion, more than 20% of patients with suspected SSBE have evidence of IM (ie, proven SSBE) on repeat EGD. Thus repeat EGD with biopsy may be warranted in patients with tongues of columnar mucosa in the distal esophagus but no IM on the first biopsy to confirm the diagnosis of SSBE.

Neuropilin-1 is differentially expressed in myoepithelial cells and vascular smooth muscle cells in preneoplastic and neoplastic human breast: a possible marker for the progression of breast cancer.

The expression and distribution of neuropilin-1 (NRP-1) was examined in the samples of normal human breast tissues and in non-neoplastic and neoplastic areas of breast tissue removed for carcinoma using RT-PCR as well as conventional and tissue microarrays immunohistochemical analyses. The NRP-1 mRNA expression was significantly higher in neoplastic tissues as compared to normal breast samples. Immunohistochemically, the myoepithelial cells of the mammary ducts and lobules display positive reactions for NRP-1, whereas the inner ductal and lobular epithelial cell layers failed to react. The myoepithelial cells of ducts and lobules in both neoplastic and non-neoplastic tissue specimens displayed a stronger positive reaction for NRP-1 than those in the normal breast. A positive reaction for NRP-1, but with a gradual reduction in intensity, was observed in the myoepithelial cells of ducts with atypical epithelial hyperplasia and ductal carcinoma in situ (DCIS). The reaction was undetected or minimally detected in the areas of invasive carcinoma. NRP-1 positive immunolabeling was also localized in the vascular smooth muscle cells and in some endothelial cells of the blood vessels in normal, non-neoplastic and neoplastic breast tissue samples. In areas of breast carcinoma, NRP-1 immunolabeling was more prominent in both vascular smooth muscle cells and in some endothelial cells than in similar cells in normal breast. The specificity of the newly developed antibody for NRP-1 was confirmed by in situ hybridization with DIG-labeled PCR generated probe. These results suggest that NRP-1 may be a multiple function protein in human breast and may be involved in the induction of local invasiveness of neoplasia and angiogenesis and have direct relevance to the progression of breast cancer.