Search

Tropical sprue is an acquired chronic diarrheal disorder of unclear etiology affecting residents of and visitors to tropical regions. Patients usually present with profuse diarrhea, weight loss, and malabsorption, notably of vitamin B12 and folate. The histologic changes typically resemble that of gluten-sensitive enteropathy. Reports of tropical sprue have become infrequent in the literature, and the diagnosis is often not considered either clinically or pathologically. This disease may, however, cause significant morbidity, although it is eminently treatable with broad-spectrum antibiotics. In this study, we report the clinical presentation of 12 tropical sprue patients along with the histologic changes of the intestinal mucosa and compare it with those of a series of 150 cases of gluten-sensitive enteropathy, the condition with which it is most frequently misdiagnosed. The cohort comprised 6 men and 6 women with a median age of 59 years (range, 38 to 78 y) with a history of residence or visitation in South Asia or Papua New Guinea. Partial villous blunting in the duodenal mucosa was present in 75% of cases, and a marked intraepithelial lymphocytosis was observed in all cases (mean per 100 epithelial cells 77.3; range, 42 to 124). A villous tip accentuation of intraepithelial lymphocytosis was not appreciable in most cases. No case of complete villous blunting (Marsh stage 3c) was identified in tropical sprue, contrasting with 25% in gluten-sensitive enteropathy cases. A duodenal mucosa eosinophil infiltrate was present in all cases with significantly higher counts compared with untreated gluten-sensitive enteropathy patients (26.6/HPF vs. 14.6/HPF; P=0.009). The ileal mucosa displayed more severe villous blunting with higher Marsh stages than in the corresponding duodenum from 5 patients. There was a mild intraepithelial lymphocytosis and eosinophil infiltrate in the colonic mucosa of half of the cases. Follow-up biopsies in 6 patients demonstrated a histologic response after oral folates and doxycycline treatment. In summary, tropical sprue is a pan-enteric inflammatory process often mistaken for gluten-sensitive enteropathy. Histologic findings suggesting tropical sprue in the appropriate clinical context include incomplete duodenal villous blunting without development of flat mucosa, frequent involvement of the terminal ileum with more marked inflammation and villous blunting than in the duodenum, and a conspicuous eosinophil infiltrate in the lamina propria. With the expansion of tourism and increasing employment opportunities in tropical regions, pathologists in the West are increasingly likely to encounter cases of tropical sprue and should be aware of this diagnosis.

Patients with long-standing chronic pancreatitis are thought to be at increased risk of developing pancreatic ductal adenocarcinoma, but the mechanism for this increased risk is unknown. Since increasing evidence supports the notion that infiltrating pancreatic ductal adenocarcinomas arise from pancreatic intraepithelial lesions (PanINs), we sought to determine if patients with chronic pancreatitis harbor PanINs with alterations in tumor suppressor genes that are associated with infiltrating pancreatic ductal adenocarcinoma. We identified 122 patients with a diagnosis of chronic pancreatitis and 29 patients with a well-differentiated pancreatic endocrine tumor that underwent pancreatic surgery at the Johns Hopkins Hospital from 1985 to 1999. PanINs from each resection specimen were identified, graded, counted, and correlated with smoking and alcohol history. The expression patterns of p16 and Smad4 were determined in a subset of PanINs by immunohistochemistry, and the pattern of labeling compared with that seen in PanINs associated with infiltrating adenocarcinoma of the pancreas as identified in prior studies, and to PanINs associated with pancreatic endocrine tumor. Duct lesions were present in 80 of the 122 pancreata with chronic pancreatitis (66%). Of 405 duct lesions identified in the chronic pancreatitis group, 7.6% were reactive changes, 65.5% were PanIN-1A, 18% were PanIN-1B, 7.4% were PanIN-2, and 1.5% were PanIN-3. Within the pancreatic endocrine tumor group, 22 PanINs were identified: 15 PanIN-1A, 4 PanIN-1B, and 3 PanIN-2. There were significantly fewer high-grade PanINs in the pancreata with chronic pancreatitis than in pancreata with pancreatic adenocarcinoma (P < 0.0001). Within the chronic pancreatitis group, the 80 patients with PanINs were significantly older than the 42 patients without PanINs (mean age 57.0 +/- 14.1 years vs. 50.9 +/- 14.7 years, P = 0.01). Smoking history was not associated with PanIN prevalence or grade, but patients who reported a history of excessive alcohol consumption had fewer PanINs (25 of 44 harbored PanINs, 57%) than those who did not (54 of 74, 73%, P = 0.07). In the chronic pancreatitis group, 0% of PanIN-1A, 11% of the PanIN-1B, 16% of the PanIN-2, and 40% of the PanIN-3 lesions showed loss of p16 expression, whereas all of the PanINs from patients with an pancreatic endocrine tumor retained p16 expression. All of the PanINs analyzed from patients with chronic pancreatitis retained normal Smad4 expression. We conclude that a significant minority of PanINs arising in patients with chronic pancreatitis show loss of p16 expression. This alteration, common to pancreatic cancer-associated PanINs, may contribute to the predisposition of patients with chronic pancreatitis to develop pancreatic ductal adenocarcinoma.