Macrophage activation syndrome in a patient with pulmonary inflammatory myofibroblastic tumour
© Kuppe et al.; licensee BioMed Central Ltd. 2012
Received: 5 March 2012
Accepted: 7 May 2012
Published: 20 May 2012
We describe for the first time a case of macrophage activation syndrome (MAS) in a patient with a history of inflammatory myofibroblastic tumour (inflammatory pseudotumour, IPT) of the lung and thoracic spine. The patient was admitted to the intensive care unit with a history of prolonged remitting fever, hepatosplenomegaly, bilaterally enlarged thoracic lymph nodes and an acute severe inflammatory response syndrome (SIRS). Up-regulated cytokine production (e.g. IL-1ß and IL-6), increased levels of ferritin and circulating soluble interleukin-2 receptor (sIL-2R, sCD25) led to the differential diagnosis of MAS. Bone marrow aspiration, the main tool for a definite diagnosis, revealed macrophages phagocytosing haematopoietic cells. Immunosuppressive therapy with corticosteroids and cyclosporine was an effective treatment in this patient.
KeywordsMacrophage activation syndrome Haemophagocytosis Pulmonary plasma cell granuloma
Macrophage activation syndrome (MAS) is a rare but potentially fatal disorder, characterized by combinations of pancytopoenia, liver failure, coagulopathy and organ dysfunction. It is thought to be caused by the activation and uncontrolled proliferation of CD8+ lymphocytes and well-differentiated macrophages, leading to haemophagocytosis and a so-called cytokine storm [1–3]. The term MAS describes a condition occurring in a broad spectrum of diseases, which belong to the histiocytic disorders, e.g. haemophagocytic lymphohistiocytosis (HLH). Familial or primary haemophagocytic lymphohistiocytosis has a known and well-characterized genetic basis, namely a mutation in the perforin gene . It results in the inability of cytotoxic T lymphocytes (CTLs) or natural killer (NK) cells to lyse target cells. Secondary HLH can be found in patients with infections, malignancies and inflammatory diseases such as juvenile idiopathic arthritis (JIA) or it may be an adverse effect of certain drugs .
Inflammatory myofibroblastic tumours are rare tumours with different invasive tendencies and growth capacity . In fact, this tumour entity represents the non-neoplastic unregulated growth of inflammatory cells and fibroblasts or myofibroblasts, irrespective of their organs of origin .
Pulmonary inflammatory myofibroblastic tumours usually consist of a mixed inflammatory infiltrate with a predominance of plasma cells . Two theories exist concerning the origin of IPTs. According to one theory, the tumour is in fact a regular inflammatory process, which follows interstitial pneumonia. Subsequently, it transforms into an organized pneumonia and, eventually, into an inflammatory myofibroblastic tumour. In support of this hypothesis, production of IL-6 mRNA and protein by tumour cells in IPT has been reported in some cases [8, 9]. Yet, according to another hypothesis, some plasma cell granulomas represent slow-growing mesenchymal tumours with secondary inflammatory changes.
In this report, we describe for the first time the occurrence of MAS in a patient with a history of an inflammatory myofibroblastic tumour of the lung and thoracic spine.
after 2 weeks
after 5 months
White-cell count (10^6/l)
Platelet count (10^6/l)
Prothombin time (INR)
Diagnostic criteria for HLH*
Manifestations in the patient described quotidian fever over several weeks
(3) Cytopenia involving two or more cell lines
haemoglobin < 9.0 d/dL, no other
(4) Hypertriglyceridaemia or hypofibrinogenaemia
(7) Low or absent natural killer cell activity
(8) Serum ferritin level > 500 μg
(9) Soluble CD25 (sIL-2 receptor) > 2500 U/ml
> 7200 U/ml
In acquired cases of macrophage activation syndrome (MAS), the clinical course is usually rapidly progressive with multi-system organ failure often occurring within weeks of the initial diagnosis of the syndrome. This syndrome is caused by dysregulated macrophage-lymphocyte interaction, which leads to uncontrolled proliferation of macrophages and CD8+ T-cells with up-regulated release of monokines, mainly of the interleukin-1 family (interleukin-1α and 1β and interleukin-18), whereas levels of T-cell–derived cytokines, such as interferon-γ, are much less increased . Recently, cell-type specific characteristics of ‘immature antigen presenting cells (APC)’ from patients with MAS have been described. It is known that tumours (especially fibroblasts) can express M-CSF, which could influence the development of immature phagocytic APCs . In our patient, fulminant MAS was present for approximately 3 weeks until the initiation of therapy. The standard definition of HLH requires the presence of at least five of nine clinical criteria. Our patient fulfilled seven of these criteria (Table2). Additionally, we could find an extramedullary manifestation of MAS, namely a proliferative (Ki-67-positive) histiocytic cell infiltrate in both elbows of the patient. Typically in the acute phase of the cytokine storm, lymphohistiocytic infiltrates can be found in the spleen, lymph nodes and bone marrow . A CD1a staining of the cubital veins remained negative, thus making the diagnosis of Langerhans-cell histiocytosis unlikely. In the absence of a clinically apparent malignancy, in addition to MAS, the differential diagnosis for fever with splenomegaly, liver failure and bilaterally enlarged lymph nodes includes premalignant, inflammatory, infectious, genetic and toxic causes. All of these could be ruled out on the basis of the history and laboratory studies. Acute EBV and CMV infections are associated with fever, pharyngitis, lymphadenopathy and fatigue and would likely have been self-limited. The differential diagnosis of sarcoidosis was mainly ruled out because no granulomas could be found in any of the biopsies. Furthermore, the bone marrow did not show any premalignant, infiltrative or infectious processes.
Several treatment options have been reported in the literature for MAS. A treatment protocol from the Histiocyte Society recommends a therapeutic regimen of etoposide, dexamethasone and cyclosporine . In other cases, high-dose steroids, cyclosporine, antihuman thymocyte globulin (ATG), intravenous immune globulin (IVIG), plasma exchange and allogeneic bone marrow transplantation have been described. Recently, treatment with an IL-1 beta receptor antagonist (anakinra) was successful in several cases of severe paediatric rheumatic disease-associated MAS [15, 16]. It can be speculated that other immunomodulatory therapies (alemtuzumab, infliximab, daclizumab, selective IL-1 and IL-6 antagonists) might influence the course of the disease beneficially, but clinical trials remain almost impossible due to the rare occurrence of the disease.
In summary, we describe the first patient with macrophage activation syndrome (MAS) and a history of an inflammatory myofibroblastic tumour, which could be controlled by immunosuppressive therapy including steroids and cyclosporine.
Written informed consent was obtained from the patient for publication of this case report.
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