Case Report
PAS-positive macrophages—not always infection
Lancet 2011; 377: 1890
Department of General Internal
Medicine (W Meersseman MD),
Department of Rheumatology
(P Verschueren MD),
Department of Morphology
and Molecular Pathology
(T Tousseyn MD, R De Vos PhD),
and Department of Hepatology
(D Cassiman MD), University
Hospital Gasthuisberg,
Leuven, Belgium
Correspondence to:
Dr Wouter Meersseman,
University Hospital Gasthuisberg,
Department of General Internal
Medicine, 3000 Leuven, Belgium
wouter.meersseman@
uzleuven.be
See Online for webappendix
Figure: PAS stain of bone marrow showing macrophages with PAS-positive granules
An increased number of lipid-laden macrophages (arrow) can be seen as intracytoplasmatic granules with PAS
staining with and without diastase pretreatment.
1890
Wouter Meersseman, Patrick Verschueren, Thomas Tousseyn, Rita De Vos, David Cassiman
In April, 2009, a 30-year old man of Turkish origin was
referred to our hospital with a 5-year history of asthenia
and arthralgias. 2 years earlier he had been diagnosed
with rheumatoid arthritis, which did not respond to
non-steroidal anti-inflammatory drugs. On examination,
he had unexplained splenomegaly (span 22 cm).
Laboratory tests showed thrombocytopenia (92 × 10⁹/L),
and a normal ESR. Immunological tests including
antibodies to cyclic citrullinated protein were inconclu-
sive. Ultrasonography of the knee joints showed bilateral
synovial proliferation. His knees were not red, hot, or
painful, and there was no tumour.
Our differential diagnosis included chronic infection
and lymphoma. PET with labelled 18-fluorodeoxyglucose
did not reveal inflammatory spots in joints or muscles.
There was also no increased uptake in the spleen, making
the diagnosis of lymphoma less likely. A bone-marrow
biopsy sample showed infiltration of foamy, vacuolated
macrophages with granules positive for periodic-acid-
Schiff (PAS) (figure). The material was also highlighted
by a Grocott silver stain, which raised the suspicion of
histoplasmosis, and he was treated with itraconazole.
However, after 4 months of treatment, there was no
resolution of symptoms, and thrombocytopenia and
splenomegaly persisted. A new biopsy sample of bone
marrow was taken. Ultrastructural examination of the
macrophages revealed cytoplasmatic lamellar lysosomal
inclusions as described in lysosomal storage disorders
with splenomegaly such as Gaucher disease, cholesterol
ester storage disease, and Niemann-Pick disease
(webappendix).1 Peripheral leucocyte enzyme assay
showed pronounced sphingomyelinase deficiency
(1·7 nmol/mg, normal 5·1–18·7), which accords with a
diagnosis of Niemann-Pick type B disease. Sequence
analysis of the SMPD1 coding region revealed a
homozygous mutation (p.Leu163Pro), which has not
been described previously. When PAS is found in
macrophages, the most common underlying diagnosis is
infection (eg, Whipple’s disease, leishmaniasis, endemic
mycoses).2 However, the patient never had abnormal
inflammatory indices. He had not travelled to a region
endemic for histoplasmosis. Moreover, on Giemsa
staining, the foamy macrophages had a sea-blue
appearance, characteristic of Niemann-Pick disease.
When last seen in February, 2011, our patient was well,
without pulmonary symptoms.
Niemann-Pick type B disease is a rare autosomal-
recessive lysosomal storage disorder (incidence
1 in 250 000), which results from the deficiency of acid
sphingomyelinase and the accumulation of lysosomal
sphingomyelin in the lysosomes of cells of the monocyte–
macrophage system. The histological hallmark of the
disease is the foam cell, also known as the Niemann-Pick
cell, in affected tissues. Biochemical abnormalities
include dyslipidaemia (low HDL-cholesterol) and
thrombocytopenia. The diagnosis of type B disease is
usually made in childhood after splenomegaly is found.
Survival well into adulthood is common; the oldest
patient alive is 65 years old. In contrast to types A and C
of the disease, neurological features are rare. Frequent
symptoms include bleeding (49%), pulmonary infections
and shortness of breath due to interstitial lung disease
(42%), and joint or limb pain (39%)3, which was the main
complaint in our patient. Growth can be delayed during
adolescence, and studies with standard questionnaires
report only mild impairment of quality of life.3 Premature
coronary artery disease can occur because of the abnormal
lipid profiles.3 There is currently no available treatment
for this disease. Clinical trials with enzyme replacement
therapy are planned for the near future.4 Close follow-up
is needed because of the risk of interstitial lung disease
and premature coronary artery disease.5 Our patient’s
case illustrates that some cases of apparent infections,
presenting with PAS-positive macrophages, spleno-
megaly, and arthralgia actually represent a type of
lysosomal storage disease. Correct diagnosis allows
genetic counselling and avoids unnecessary treatment
References
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3 McGovern MM, Wasserstein MP, Giugliani R, et al. A prospective,
cross-sectional survey study of the natural history of Niemann-Pick
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4 Beck M. Emerging drugs for lysosomal storage diseases.
Expert Opin Emerg Drugs 2010; 15: 495–507.
5 Simpson WL, Mendelson D, Wasserstein MP, et al. Imaging
manifestations of Niemann-Pick disease type B. Am J Roentgenol
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