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Keywords:

  • Whipple's disease;
  • bone marrow;
  • PAS staining;
  • diagnosis

Abstract

  1. Top of page
  2. Abstract
  3. Case report
  4. Discussion
  5. References

Infection with Tropheryma whippelii, the causative agent of Whipple's disease, involves nearly every organ. Involvement of bone marrow may be an overlooked area of Whipple's disease. We report a case of lymphoma-like Whipple's disease with bone marrow involvement together with a brief review of the literature on this topic. Despite minimal documentation, bone marrow may be commonly involved in Whipple's disease and, although not specific, diastase-resistant periodic acid-Schiff (PAS)-positive macrophages in bone marrow may offer an important clue to diagnosis using PAS histology of upper endoscopic biopsies, polymerase chain reaction or electron microscopy.

Whipple's disease is a multisystemic bacterial infection caused by Tropheryma whippelii. Leading symptoms include weight loss, arthralgia, diarrhoea and abdominal pain. Less frequent are chills, fever, lymphadenopathy, skin hyperpigmentation and cardiovascular or neurological abnormalities. An important clue to the diagnosis is histological identification of periodic acid-Schiff (PAS)-positive, diastase-resistant and acid-fast negative material within macrophages. Indeed, the presence of numerous PAS-positive macrophages in the intestinal lamina propria of variously abnormal villi is pathognomonic. In other tissues, PAS-positive cells may be unspecific and misleading, and specific diagnostic tests such as electron microscopy (EM) or polymerase chain reaction (PCR) should be considered.

Gut involvement may be overt with episodic and watery diarrhoea, steatorrhoea, colicky abdominal pain, anorexia or gastrointestinal bleeding. However, it can be asymptomatic and require histological confirmation. Diagnosis is often delayed in patients without gastrointestinal symptoms, and lymphoma-like features of Whipple's disease such as constitutional symptoms, lymphadenopathy and organomegaly may result in initial referral to the haematologist for clinical evaluation and diagnostic work-up.

Characteristics of the peripheral blood count include anaemia, which is present in 90% of the patients and predominantly appears to be the result of chronic infection (iron deficiency is occasionally found; megaloblastic changes are rare), leucocytosis with neutrophilia in one-third of patients, occasional eosinophilia which may be prominent, and thrombocytosis. These findings are rather non-specific and barely of diagnostic value. Adenopathy, especially of mesenteric and retroperitoneal lymph nodes, with a characteristic histological appearance is noted in about one-half of patients. Hepatomegaly and splenomegaly are present in about 15% of cases (Dobbins, 1987; Marth, 2000).

An overlooked area of Whipple's disease may be the bone marrow involvement. Only a few studies have presented features intra vitam or at autopsy. Here, a case of lymphoma-like Whipple's disease with bone marrow involvement is presented together with a brief literature review. Although infrequently reported, bone marrow involvement may be common and the recognition of alterations suggestive of Whipple's disease may help establish the diagnosis.

Case report

  1. Top of page
  2. Abstract
  3. Case report
  4. Discussion
  5. References

A 42-year-old white man was admitted in May 1999 with mild periumbilical cramps, weight loss of 7 kg and night sweats since November 1998. A computerized tomography (CT) scan carried out prior to admission revealed hepatosplenomegaly and enlarged retroperitoneal and mesenteric lymph nodes. At presentation, the patient also had mild diarrhoea. He did not appear ill. An enlarged liver and spleen tip, but no peripheral lymphadenopathy, were palpable. An area of increased skin pigmentation (5 × 7cm) was noted on his back. Other physical findings were normal. The peripheral blood count showed microcytic anaemia [Hb 11·0 g/dl, mean corpuscular volume (MCV) 76·4 fl, mean corpuscular haemoglobin (MCH) 24·3 pg], a normal white blood cell count (5·41 × 109/l, with 26% bands and 49% segmented neutrophils), lymphopenia (0·75 × 109/l) and normal platelets (265 × 109/l). Eosinophils were 0·57 × 109/l.

The bone marrow showed markedly increased megakaryopoiesis with hyperfragmented forms and was remarkable for PAS-positive inclusions (Fig 1A), eosinophilia and increased iron stores. Other laboratory findings were: erythrocyte sedimentation rate (ESR) 12 mm/h, C-reactive protein (CRP) 45 mg/l (normal 0–3·0 mg/l), lactate dehydrogenase (LDH) 260 U/l and normal serumprotein electrophoresis. Human immunodeficiency virus (HIV)-serology was negative.

image

Figure 1. (A) Bone marrow specimen, PAS staining (original magnification 1000×). (B) Mesenteric lymph node, diastase-PAS staining. Left arrow: diastase-resistant PAS-positive granular material within extracellular spaces. Right arrow: partly granular, partly rod-shaped inclusions in macrophages (original magnification 800×).

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Diagnostic splenectomy was performed and turbid ascites was noted. The spleen was 560 g. Sparce multinucleated giant cells within non-caseating granulomas were seen in the white pulp and a few diastase–PAS-positive foamy macrophages were identified (not shown). The architecture of a mesenteric lymph node was vacuolated and barely preserved. Numerous histiocytes that partly condensed to granulomas were seen. Dense infitrates of granulocytes, including eosinophils, were scattered over the entire lymph node and formed local abscesses. Diastase-resistant PAS-positive material was found within inclusions in macrophages and in extracellular spaces (Fig 1B).

Duodenal biopsy showed abnormal villi and strongly PAS-positive rod-shaped organisms were seen within abundant foamy macrophages. PCR for Tropheryma whippelii was positive from the mesenteric lymph node, duodenal biopsy and ascites. PCR for mycobacteria was negative. Therapy with trimethoprim-sulphamethoxazole double-strength tablets b.i.d. was initiated and has been continued to date. The patient completely recovered and laboratory values normalized. Tissue biopsies have not yet been taken for control.

Discussion

  1. Top of page
  2. Abstract
  3. Case report
  4. Discussion
  5. References

In two out of five patients, focal bone marrow involvement with PAS-positive macrophages containing ‘sickle-form particles’ was found at autopsy (Sieracki & Fine, 1959). Similar findings were described in a 3-month-old child (Aust & Smith, 1962) and in a 75-year-old woman post mortem (Rausing, 1973). In an autopsy study on 15 cases, bone marrow sections were available in six patients and PAS-positive macrophages were found in four of these patients (Enzinger & Helwig, 1963). Some PAS-positive macrophages as well as reactive hyperplasia and slightly increased plasma cells were found retrospectively in bone marrow smears of a 58-year-old woman intra vitam (Remadi et al, 1992). Similarly, in the case reported by Rausing (1973), strongly PAS-positive cells with numerous intra- and extracellular rods were only seen retrospectively in sternal bone marrow smears taken several months before death. Prone et al (1999) presented eight patients. The bone marrow was assessed in only three of them, but two showed PAS-positive macrophages and a positive PCR and, in the remaining sample, very rare PAS-positive macrophages were detected but PCR was negative. The presence of the bacterium has been confirmed in bone marrow using EM at necropsy (Rausing, 1973) and in an aspirate taken intra vitam after 4 months of correct therapy (Tauris & Moesner, 1978). Unspecific findings include myeloid or myeloid and erythroid hyperplasia, extensive replacement by atypical mononuclear cells/myeloid metaplasia, or hypoplasia (Martel & Hodges, 1959; Dobbins, 1987). In only 9 out of 24 bone marrow specimens was morphology stated to be normal (Dobbins, 1987).

Granuloma formation has been observed repeatedly. Whereas some contained PAS-positive bacillary bodies (Jarolim et al, 1991), one PAS-negative non-caseating granuloma has been described by Wilcox et al (1987) in the bone marrow of a 58-year-old man in whom the diagnosis of Whipple's disease was confirmed by typical findings on duodenal biopsy with verification using EM. In the latter case, EM failed to show bacillary bodies in the bone marrow, whereas a small number of these could be seen in PAS-negative non-caseating granulomata within a lymph node (Wilcox et al, 1987).

Taken together, studies by Sieracki & Fine et al (1959), Enzinger & Helwig (1963) and Prone et al (1999), and data summarized by Dobbins (1987), suggest that bone marrow involvement by Whipple bacillus may be much more common than reflected by the paucity of reports. The presented case and literature overview emphasize the value of PAS-staining of bone marrow specimens in cases suspected to be Whipple's disease, in lymphoma-like or granulomatous diseases, or in chronic arthralgias (especially when of a migratory type). Although PAS-positive macrophages in bone marrow are not specific, they may offer an important clue to diagnosis which could be established by duodenal biopsy, PCR or EM.

References

  1. Top of page
  2. Abstract
  3. Case report
  4. Discussion
  5. References
  • Aust, C.H. & Smith, E.B. (1962) Whipple's disease in a 3-month old infant with involvement of the bone marrow. American Journal of Clinical Pathology, 37, 6674.
  • Dobbins, W.O. III (1987) Whipple's disease. Charles C Thomas, Springfield, Il.
  • Enzinger, F.M. & Helwig, E.B. (1963) Whipple's disease – a review of the literature and report of fifteen patients. Virchows Archiv A – Pathological Anatomy and Histopathology, 336, 238268.
  • Jarolim, D.R., Parker, G.A. & Sheehan, W.W. (1991) Bone marrow involvement by Whipple bacillus. Journal of Infectious Diseases, 163, 11701171.
  • Martel, W. & Hodges, F.J. (1959) The small intestine in Whipple's disease. American Journal of Roentgenology, 81, 623636.
  • Marth, T. (2000) Whipple's disease. In: Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases (ed. by G.L.Mandell, J.E.Bennett & R.Dolin), pp. 11701173. Churchill Livingstone, Philadelphia.
  • Prone, B., Poyart, C., Abachin, E., Fest, T., Belanger, C., Bonnet, C., Capelle, P., Bretagne, J.-F., Fabianek, A., Girard, L., Hagège, H. & Berche, P. (1999) Diagnosis and follow-up of Whipple's disease by amplification of the 16S rRNA gene of Tropheryma whippelii. European Journal of Clinical Microbiology and Infectious Diseases, 18, 6265.DOI: 10.1007/s100960050029
  • Rausing, A. (1973) Bone marrow biopsy in diagnosis of Whipple's disease. Acta Medica Scandinavica, 193, 58.
  • Remadi, S., Starobinski, M. & Wildgren, S. (1992) Atteinte de la moelle osseuse en cas de maladie de Whipple [Bone-marrow involvement in Whipple's disease]. Annales de Pathologie, 12, 188192.
  • Sieracki, J.C. & Fine, G. (1959) Whipple's disease: observation on systemic involvement. II. Gross and histologic observation. Archives of Pathology, 67, 8193.
  • Tauris, P. & Moesner, J. (1978) Whipple's disease. Clinical and histopathological changes during treatment with sulphamethoxazole-trimethoprim. Acta Medica Scandinavica, 204, 423427.
  • Wilcox, G.M., Tronic, B.S., Schecter, D.J., Arron, M.J., Righi, D.F. & Weiner, N.J. (1987) Periodic acid-Schiff-negative granulomatous lymphadenopathy in patients with Whipple's disease. Localization of the Whipple bacillus to noncaseating granulomas by electron microscopy. American Journal of Medicine, 83, 165170.