Pathology of Whipple Disease
Pathology
Small Intestine
The histopathologic features of intestinal Whipples disease are quite distinctive. At gross inspection, most patients have abnormal mucosa in the distal duodenum and jejunum. Whitish to yellow plaque-like patches are observed in approximately three fourths of patients alternatively, the mucosa may appear pale yellow. Abnormal villous structure and mild mucosal flattening become evident using magnifying optics. Viewed with light microscopy, the visible patches reflect lipid deposits or lymphangiectasia, whereas villous distension results from infiltration by macrophages in the lamina propria. The swollen cytoplasm of macrophages appears foamy when stained with hematoxylin-eosin, but numerous granular particles become visible when the PAS stain is used. These particles correspond to lysosomes filled with numerous T. whippelii, and the positive reaction with PAS reflects the glycoprotein content of the bacterial cell walls. Single extracellular bacteria are barely visible with conventional light microscopy due to their size, but they become evident in the mucosal stroma with high-resolution light microscopy and electron microscopy . Their number varies greatly among patients.
Electron microscopic studies have revealed uniformity in the size of the rod-shaped bacteria, with an external diameter of 0.2 to 0.25 m and a length of up to 2.5 m. There is an electron-dense outer layer that is not found in other bacteria; some have speculated this unusual membrane may be of host origin.Most of the structurally intact bacteria, including dividing forms, are found outside of host cells in the lamina propria . In contrast, the intracellular bacteria in macrophages are often found in various stages of degradation. Findings based on fluorescent in situ hybridization using specific T. whippelii 16S rDNA probes support and extend the findings derived from electron microscopy ; the 16S rRNA signal from metabolically active bacteria is found in the intestinal lamina propria, just beneath the basement membrane, but is absent from the PAS-positive macrophages. Thus, T. whippelii appears to prefer extracellular environments within the host, despite its association with eukaryotic cells.
Mucosal infiltration is usually diffuse, but in some patients patchy lesions may be present.The inflammatory reaction is generally dominated by macrophages, whereas neutrophils and eosinophils are more scarce, as are lymphocytes and plasma cells. This cellular composition is unusual for an invasive bacterial infection, a feature that suggests a disturbance of mobilization and chemotaxis of leukocytes.
Variants of the usual histologic findings occur in some patients. These include rare cases with PAS-positive macrophages that are located exclusively in the submucosa and rare cases with epithelioid granulomas in the affected mucosa.Taken together, the intestinal histopathology of Whipples disease demonstrates some heterogeneity.
During treatment, the histologic findings in the intestinal mucosa change substantially but slowly over several months or more. In addition to a continuous decrease in the number of PAS-positive macrophages, the pattern of cellular infiltration of the mucosa changes with time from diffuse to patchy. This feature demands multiple biopsies during follow-up examinations. Mucosal infiltration shifts from the upper portion (i.e., involving villi) to the lower part of the mucosa (i.e., pericryptal lamina propria) and submucosa. More significantly, the cytologic aspects of the PAS-positive macrophages undergo changes. Before treatment, most macrophages have numerous granular particles in the cytoplasm that stain intensely red with PAS (type 1 macrophages ). Within 1 to 6 months of treatment, the percentage of type 1 macrophages gradually decreases, and in parallel, cells prevail with only some coarse granular inclusions and a background of diffuse or fine granular more faintly PAS-positive cytoplasm (type 2 macrophages). After 6 to 15 months, most macrophages that are still present have diffuse and faintly PAS-positive material in their cytoplasm but lack granular inclusions (type 3 macrophages). Type 3 macrophages contain only filamentous remnants of bacteria. Thus, their positive PAS reaction reflects the presence of glycoprotein residue of degraded bacterial cell wall. In patients with adequate therapy, some type 3 macrophages usually persist, even for more than 10 years; in fact, the finding of type 3 macrophages alone is consistent with intestinal remission. On the other hand, despite documented clinical remission of intestinal disease, some patients may still harbor T. whippelii and may later develop extraintestinal Whipples disease. Thus, the prognostic value of intestinal histology during the follow-up of patients is limited.
Extraintestinal Pathology
Autopsy reports in untreated patients have illustrated involvement of virtually any organ and tissue in Whipples disease.As with intestinal disease, the histologic hallmark of extraintestinal involvement is the presence of intracellular PAS-positive granular particles. However, the diagnostic significance of these lesions in extraintestinal tissues is limited, and additional evidence is required for the diagnosis of Whipples disease. Rod-shaped bacteria have been documented by electron microscopy in many extraintestinal organs, including colon, liver, heart, lung, brain, eye, lymph node, bone marrow, and spleen.
Two different types of lymph node lesions are common in Whipples disease. Abdominal nodes generally contain lipid deposits that induce a granulomatous foreign body type of reaction.Peripheral lymph nodes (inguinal, axillary, cervical) generally do not contain lipids but feature a toxoplasmosis-like lymphadenitis with small clusters of epithelioid macrophages, some of which have PAS-positive particles that correspond to inclusions with T. whippelii. Rarely, a third type of lymph node reaction may be observed that resembles sarcoidosis; it occurs most commonly in the mediastinum.
Whipples disease affects diverse regions of the brain. Most commonly, perivascular infiltrates of PAS-positive macrophages are present, as well as tumor-like granulomas of variable size, consisting of glial cells with intensely PAS-positive granular particles. Occasionally, granulomas in the ventricular system cause occlusive hydrocephalus. Floating PAS-positive macrophages can frequently be detected in the CSF, even in patients without neurologic or psychiatric symptoms
Small Intestine
The histopathologic features of intestinal Whipples disease are quite distinctive. At gross inspection, most patients have abnormal mucosa in the distal duodenum and jejunum. Whitish to yellow plaque-like patches are observed in approximately three fourths of patients alternatively, the mucosa may appear pale yellow. Abnormal villous structure and mild mucosal flattening become evident using magnifying optics. Viewed with light microscopy, the visible patches reflect lipid deposits or lymphangiectasia, whereas villous distension results from infiltration by macrophages in the lamina propria. The swollen cytoplasm of macrophages appears foamy when stained with hematoxylin-eosin, but numerous granular particles become visible when the PAS stain is used. These particles correspond to lysosomes filled with numerous T. whippelii, and the positive reaction with PAS reflects the glycoprotein content of the bacterial cell walls. Single extracellular bacteria are barely visible with conventional light microscopy due to their size, but they become evident in the mucosal stroma with high-resolution light microscopy and electron microscopy . Their number varies greatly among patients.
Electron microscopic studies have revealed uniformity in the size of the rod-shaped bacteria, with an external diameter of 0.2 to 0.25 m and a length of up to 2.5 m. There is an electron-dense outer layer that is not found in other bacteria; some have speculated this unusual membrane may be of host origin.Most of the structurally intact bacteria, including dividing forms, are found outside of host cells in the lamina propria . In contrast, the intracellular bacteria in macrophages are often found in various stages of degradation. Findings based on fluorescent in situ hybridization using specific T. whippelii 16S rDNA probes support and extend the findings derived from electron microscopy ; the 16S rRNA signal from metabolically active bacteria is found in the intestinal lamina propria, just beneath the basement membrane, but is absent from the PAS-positive macrophages. Thus, T. whippelii appears to prefer extracellular environments within the host, despite its association with eukaryotic cells.
Mucosal infiltration is usually diffuse, but in some patients patchy lesions may be present.The inflammatory reaction is generally dominated by macrophages, whereas neutrophils and eosinophils are more scarce, as are lymphocytes and plasma cells. This cellular composition is unusual for an invasive bacterial infection, a feature that suggests a disturbance of mobilization and chemotaxis of leukocytes.
Variants of the usual histologic findings occur in some patients. These include rare cases with PAS-positive macrophages that are located exclusively in the submucosa and rare cases with epithelioid granulomas in the affected mucosa.Taken together, the intestinal histopathology of Whipples disease demonstrates some heterogeneity.
During treatment, the histologic findings in the intestinal mucosa change substantially but slowly over several months or more. In addition to a continuous decrease in the number of PAS-positive macrophages, the pattern of cellular infiltration of the mucosa changes with time from diffuse to patchy. This feature demands multiple biopsies during follow-up examinations. Mucosal infiltration shifts from the upper portion (i.e., involving villi) to the lower part of the mucosa (i.e., pericryptal lamina propria) and submucosa. More significantly, the cytologic aspects of the PAS-positive macrophages undergo changes. Before treatment, most macrophages have numerous granular particles in the cytoplasm that stain intensely red with PAS (type 1 macrophages ). Within 1 to 6 months of treatment, the percentage of type 1 macrophages gradually decreases, and in parallel, cells prevail with only some coarse granular inclusions and a background of diffuse or fine granular more faintly PAS-positive cytoplasm (type 2 macrophages). After 6 to 15 months, most macrophages that are still present have diffuse and faintly PAS-positive material in their cytoplasm but lack granular inclusions (type 3 macrophages). Type 3 macrophages contain only filamentous remnants of bacteria. Thus, their positive PAS reaction reflects the presence of glycoprotein residue of degraded bacterial cell wall. In patients with adequate therapy, some type 3 macrophages usually persist, even for more than 10 years; in fact, the finding of type 3 macrophages alone is consistent with intestinal remission. On the other hand, despite documented clinical remission of intestinal disease, some patients may still harbor T. whippelii and may later develop extraintestinal Whipples disease. Thus, the prognostic value of intestinal histology during the follow-up of patients is limited.
Extraintestinal Pathology
Autopsy reports in untreated patients have illustrated involvement of virtually any organ and tissue in Whipples disease.As with intestinal disease, the histologic hallmark of extraintestinal involvement is the presence of intracellular PAS-positive granular particles. However, the diagnostic significance of these lesions in extraintestinal tissues is limited, and additional evidence is required for the diagnosis of Whipples disease. Rod-shaped bacteria have been documented by electron microscopy in many extraintestinal organs, including colon, liver, heart, lung, brain, eye, lymph node, bone marrow, and spleen.
Two different types of lymph node lesions are common in Whipples disease. Abdominal nodes generally contain lipid deposits that induce a granulomatous foreign body type of reaction.Peripheral lymph nodes (inguinal, axillary, cervical) generally do not contain lipids but feature a toxoplasmosis-like lymphadenitis with small clusters of epithelioid macrophages, some of which have PAS-positive particles that correspond to inclusions with T. whippelii. Rarely, a third type of lymph node reaction may be observed that resembles sarcoidosis; it occurs most commonly in the mediastinum.
Whipples disease affects diverse regions of the brain. Most commonly, perivascular infiltrates of PAS-positive macrophages are present, as well as tumor-like granulomas of variable size, consisting of glial cells with intensely PAS-positive granular particles. Occasionally, granulomas in the ventricular system cause occlusive hydrocephalus. Floating PAS-positive macrophages can frequently be detected in the CSF, even in patients without neurologic or psychiatric symptoms
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