Marcia R. Gottfried

Gastrointestinal pathology in patients with common variable immunodeficiency and X-linked agammaglobulinemia

Review of the medical records of 43 patients with common variable immunodeficiency (CVID) and 23 patients with X-linked agammaglobulinemia (XLAG) revealed a high incidence of chronic gastrointestinal complaints, most commonly diarrhea. Thirty-eight biopsies, four small-bowel resection specimens, and one autopsy from 10 patients with CVID and one patient with XLAG showed a wide range of abnormalities. A pattern resembling acute graft-versus-host disease, with apoptotic bodies and lymphocytes in crypts, was seen in the stomach (four patients), small bowel (three patients), and colon (three patients). Small-bowel specimens from three CVID patients with malabsorption showed mild to severe villous atrophy. Three CVID patients had Giardia in biopsies. Two cases of small bowel lymphoma associated with nodular lymphoid hyperplasia were identified in CVID patients. One patients small bowel contained foamy histiocytes in the lamina propria, resembling Whipples disease or chronic granulomatous disease, with numerous apoptotic bodies in crypts. Ultrastructurally, the histiocytes contained cellular debris. The patient with XLAG had recurrent fissuring necrosis of small bowel resembling Crohns disease; a patient with CVID had colitis with features similar to ulcerative colitis. Poorly formed granulomas were seen in the stomach (one CVID patient) and the colon (two CVID patients). Lymphocyte populations were dominated by T cells; B cells were scarce except in lymphoid follicles in CVID patients with nodular lymphoid hyperplasia. Patients with CVID and XLAG manifest a spectrum of abnormalities in the gastrointestinal tract, with patterns superficially resembling graft-versus-host disease, inflammatory bowel disease, and Whipples disease, but often lacking some of the diagnostic features of the diseases. Many of the CVID patients with chronic gastrointestinal complaints (62%) also had evidence of autoimmune phenomena, suggesting that in some patients the inflammatory process in the gastrointestinal tract has an autoimmune component.

Early diagnosis of columnar-lined esophagus: a new endoscopic diagnostic criterion

The relationship between the proximal margins of the gastric mucosal folds and the squamocolumnar mucosal junction (SCMJ) in normal subjects and in patients with columnar-lined esophagus (CLE) was studied. Results indicate that in the normal esophagus, the SCMJ is located within 2 cm of the proximal margin of the gastric folds. The proximal margin of the gastric folds in a hiatal hernia pouch provide a fixed, reproducible, anatomic landmark at endoscopy, which designates the junction of the muscular wall of the esophagus and stomach and permits one to predict the expected normal location of the SCMJ. The diagnosis of CLE should be considered at endoscopy when either the SCMJ is located or columnar epithelium is obtained by biopsy at a site greater than 2 cm above the proximal margin of the gastric folds located within a hiatal hernia pouch. This study provides an endoscopic criterion to permit a more accurate diagnosis of CLE in its earliest stages and may permit a better assessment of its prevalence.

Neoadjuvant chemoradiation for localized adenocarcinoma of the pancreas.

AbstractBackground: The use of neoadjuvant preoperative chemoradiotherapy CRT for pancreatic cancer has been advocated for its potential ability to optimize patient selection for surgical resection and to downstage locally advanced tumors. This article reports our experience with neoadjuvant CRT for localized pancreatic cancer. Methods: Since 1995, 111 patients with radiographically localized, pathologically confirmed pancreatic adenocarcinoma have received neoadjuvant external beam radiation therapy EBRT; median, 4500 cGy with 5-flourouracil–based chemotherapy. Tumors were defined as potentially resectable PR, n = 53 in the absence of arterial involvement and venous occlusion and locally advanced LA, n = 58 with arterial involvement or venous occlusion by CT. Results: Five patients 4.5% were not restaged due to death n = 3 or intolerance of therapy n = 2. Twenty-one patients 19% manifested distant metastatic disease on restaging CT. Twenty-eight patients with initially PR tumors 53% and 11 patients with initially LA tumors 19% were resected after CRT. Histologic examination revealed significant fibrosis in all resected specimens and two complete responses. Surgical margins were negative in 72%, and lymph nodes were negative in 70% of resected patients. Median survival in resected patients has not been reached at a median follow-up of 16 months. Conclusions: Neoadjuvant CRT provided an opportunity for patients with occult metastatic disease to avoid the morbidity of resection and resulted in tumor downstaging in a minority of patients with LA tumors. Survival after neoadjuvant CRT and resection appears to be at least comparable to survival after resection and adjuvant postoperative CRT.

Glycogenic hepatopathy: an underrecognized hepatic complication of diabetes mellitus.

Reported are the clinical and pathologic features of glycogenic hepatopathy, a pathologic overloading of hepatocytes with glycogen that is associated with poorly controlled diabetes mellitus. Fourteen cases were studied by stains, including hematoxylin and eosin, trichrome, periodic acid–Schiff, and periodic acid–Schiff with diastase. Ultrastructural analysis was performed in 2 cases. Medical records were reviewed for clinical presentations, laboratory findings, and clinical outcomes. The individuals ranged from 8 to 25 years of age. All had type I diabetes mellitus with poor glycemic control. The clinical presentations included hepatomegaly, abdominal pain, and elevated transaminases (range, 50–1600 IU/L). The transaminases were dramatically elevated in 3 cases to greater than 10 times the upper limit of normal. All biopsies showed diffusely pale staining hepatocytes on hematoxylin and eosin stains, with excessive glycogen accumulation demonstrated by periodic acid–Schiff stains. Ultrastructural examination revealed marked glycogen accumulation in the cytoplasm and nuclei. Most cases showed no evidence for fatty liver disease: steatosis was absent in 12 of 14 cases, simple steatosis was seen in 1 of 14 cases, and mild steatohepatitis was present in 1 of 14 cases. Mallory hyaline was absent in all cases, acidophil bodies were only rarely seen, and inflammation was absent or minimally present. Fibrosis was typically absent, with only 2 cases demonstrating focal mild fibrosis. Three patients had adequate follow-up and demonstrated improvement of liver enzyme levels with control of blood glucose. We conclude that glycogenic hepatopathy can cause hepatomegaly and significant transaminase elevations in individuals with type I diabetes mellitus. The pathology is distinct from steatohepatitis.

Significance of Histological Response to Preoperative Chemoradiotherapy for Pancreatic Cancer

BackgroundNeoadjuvant (preoperative) chemoradiotherapy (CRT) for pancreatic cancer offers theoretical advantages over the standard approach of surgery followed by adjuvant CRT. We hypothesized that histological responses to CRT would be significant prognostic factors in patients undergoing neoadjuvant CRT followed by resection. MethodsSince 1994, 193 patients with biopsy-proven pancreatic adenocarcinoma have completed neoadjuvant CRT, and 70 patients have undergone resection. Specimens were retrospectively examined by an individual pathologist for histological responses (tumor necrosis, tumor fibrosis, and residual tumor load) and immunohistochemical staining for p53 and epidermal growth factor receptor. Factors influencing overall survival were analyzed with the Kaplan-Meier (univariate) and Cox proportional hazards (multivariate) methods.ResultsThe estimated overall survival (median ± SE) in the entire group of patients undergoing resection was 23 ± 4.2 months, with an estimated 3-year survival of 37% ± 6.6% and a median follow-up of 28 months. Complete histological responses occurred in 6% of patients. Overexpression of p53 was more common in patients with large residual tumor loads. Tumor necrosis was an independent negative prognostic factor, as were positive lymph nodes, a large residual tumor load, and poor tumor differentiation.ConclusionsHistological response to neoadjuvant CRT—as measured by residual tumor load—may be useful as a surrogate marker for treatment efficacy. Characterization of the tumor cells that survive neoadjuvant CRT may help us to identify new or more appropriate targets for systemic therapy.

The Significance of c- erb B-2 and p53 Immunoreactivity in Patients with Adenocarcinoma of the Esophagus

ObjectiveStudies in breast cancer suggest that p53 and c-erb B2 protein overexpression are predictive of outcome. The authors determined whether these molecular markers correlated with treatment response and survival in patients with adenocarcinoma of the esophagus and esophagogastric junction. BackgroundImmunostaining for p53 and c-erb B2 was performed on paraffin-embedded specimens from 42 patients with esophageal adenocarcinoma. All patients received neoadjuvant chemotherapy (cisplatin and fluorouracil [5-FU] X 3 cycles) and irradiation (4500 rads) followed by resection. ResultsIn this cohort of patients, 79% (33/42) were positive for p53, and 43% (18/42) were positive for c-erb B2. p53 positivity correlated with residual disease in the resection specimen but not with disease-free survival. Although c-erb B2 negativity correlated with residual disease after resection and a 5-year survival of 10%, c-erb B2 positivity was associated with a 5-year actuarial survival of 60%. ConclusionsAlthough p53 protein overexpression is commonly observed in adenocarcinoma of the esophagus, its prognostic value appears limited. In contrast, c-erb B2 protein expression predicts a favorable response to therapy and improved survival.

Safety and efficacy of India ink and indocyanine green as colonic tattooing agents

BACKGROUND Controversy exists concerning the safety and efficacy of colonic tattooing for the intraoperative identification of polypectomy sites. The purpose of this study was to determine (1) the concentrations of India ink and indocyanine green that resulted in high-visibility tattoos without significant tissue inflammation and (2) the India ink injection volume that produces best visibility at colonoscopy, laparoscopy, and laparotomy. METHODS Twenty-two New Zealand white rabbits (2 kg) were anesthetized and injected with India ink (undiluted 1:10, 1:50, 1:100, 1:1000, 1:10,000) and indocyanine green as an undiluted, concentrated formulation (25 mL/2 mL solvent) or in a diluted form (25 mg/5 mL solvent) at various concentrations (1:10, 1:50, 1:100). Tuberculin syringes were used to create a 0.1 mL serosal bleb at two injection sites 2 cm apart. Laparotomy was repeated at days 1, 3, and 7 after injection. Additionally, 16 rabbits were injected with India ink at laparotomy and re-explored at 1 and 5 months. Twelve mongrel dogs (20 kg) were injected with 1.0 mL volumes. Re-exploration by colonoscopy, laparoscopy, and laparotomy was done at 7 days and 1 month. Tattoo visibility at re-exploration in both animal models was graded on a scale (0 = agent not seen, 1 = seen with difficulty, 2 = easily seen). Histology in the rabbit was judged by degrees of inflammation (0 = no inflammation, 2 = mild inflammation, 4 = moderate inflammation, 6 = severe inflammation). RESULTS The concentrated indocyanine green solution was easily visible only on day 1 in the rabbit. Injections of both concentrated and diluted indocyanine green caused mucosal ulceration and moderate to severe inflammation. India ink studied at 7 days, 1 month, and 5 months after injection in the rabbit model was visible at all concentrations. The undiluted and 1:10 concentrations were easily seen and showed evidence of mucosal ulceration. Tattoos produced with all other India ink concentrations were visible without gross inflammation. India ink was also studied at 7 days and 1 month in dogs. The tattoo with the 1:100 concentration at 0.5 mL was seen consistently at colonoscopy, laparoscopy, and laparotomy with only a mild submucosal reaction at 7 days. The tattoos produced with the 1:100 and 1:1000 concentrations at 0.5 mL and 1.0 mL injection volumes were easily seen by all methods of intraabdominal visualization at 1 month with similar histology. CONCLUSION Indocyanine green was an ineffective colonic tattooing agent. India ink was an effective colonic tattooing agent. Dilute concentrations that caused little to no inflammation could be visualized at 7 days and 1 month in rabbits and dogs and at 5 months in rabbits. India ink, at appropriated concentrations, appears to be a safe short- and long-term colonic tattooing agent.

Clinical utility of positron emission tomography in the diagnosis and management of periampullary neoplasms.

Background This study examined the effect that 18-fluorodeoxyglucose positron emission tomography (18FDG-PET) imaging had on the clinical management of patients with suspected periampullary malignancy.

Expression of the cell adhesion molecule CD44 in gastric adenocarcinomas

CD44, an integral membrane glycoprotein expressed by many cell types, serves as the principal transmembrane hyaluronate receptor and may be a determinant of metastatic and invasive behavior in carcinomas. The expression of CD44 in 23 gastric adenocarcinoma and 12 peptic ulcer disease (PUD) resection specimens and gastric carcinoma cell lines HS746t and KATO III was examined by immunohistochemistry using the murine monoclonal antibody A3D8 on formalin-fixed, paraffin-embedded tissue or cells. Western blot analysis of whole cell lysates of KATO III and HS746t cells showed protein bands at 85 to 90 kd with KATO III cells expressing an additional band at 145 kd. In normal stomach gastric epithelium was negative. In PUD foveolar epithelium was focally positive, but staining did not correlate with the extent of gastritis. In carcinoma cases intensity of staining was progressively stronger comparing intestinal metaplasia with dysplasia with intramucosal carcinoma. Invasive carcinoma was invariably more strongly positive than dysplasia or intramucosal carcinoma. Twelve adenocarcinomas were weakly positive and 11 were strongly positive. The staining intensity of metastases (12 cases) was the same or weaker than the primary tumor. For the 12 patients whose carcinomas were weakly positive, mean length of survival for the six who died was 23.3 months. Five of the 11 patients whose carcinomas strongly expressed CD44 died within the study period with a mean length of survival of 11.0 months. A key consequence of CD44 overexpression in gastric carcinomas may be development of the invasive phenotype and strong expression may indicate a poorer prognosis.

Evaluation of porcine-derived small intestine submucosa as a biodegradable graft for gastrointestinal healing.

High-risk anastomoses in the gut may benefit from the application of a synthetic reinforcement to pre vent an enteric leak. Recently a porcine-derived small intestine submucosa (SIS) was tested as a bioscaffold in a number of organ systems. The aim of this study was to evaluate the effectiveness of SIS in stimulating healing in the stomach. Twelve rats underwent surgical removal of a full-thickness gastric defect (1 cm) and subsequent repair with a double-layer patch of porcine-derived SIS. The graft was secured with interrupted sutures placed within 1 mm of the edge of the graft. After 21 days, the animals were killed and their stomachs harvested for histologic examination. Cross sections were processed for paraffin embedding and 4-micron sections were stained with hematoxylin and eosin. All animals survived, gained weight, and demonstrated no signs of peritonitis over the 3-week postoperative period. On postmortem examination, the defect was completely closed in all animals by granulation tissue and early fibrosis. Although most of the luminal surface of the grafted areas remained ulcerated, early regeneration of normal gastric mucosa was seen at the periphery of the defect. SIS may act as an effective scaffolding agent for intestinal mucosa and may offer protection in high-risk anastomoses.