Research Article: Macrophage activation syndrome in a patient with pulmonary inflammatory myofibroblastic tumour

Date Published: May 20, 2012

Publisher: BioMed Central

Author(s): Christoph Kuppe, Saskia Westphal, Eva Bücher, Marcus J Moeller, Bernhard Heintz, Marion E Schneider, Jürgen Floege.


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.

Partial Text

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 [4]. 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 [5].

The patient, a 27 year-old male, presented initially to his general practitioner because of increasing back pain. As an electrical mechanic he traveled extensively from Germany to China, Russia and South Korea and was mainly involved in the installation of electronic devices in newly built tunnels. Due to back pain and an evolving neurological deficit of the lower extremities, the patient was admitted to an external orthopaedic department. A magnetic resonance imaging (MRI) of the spine revealed an atypical tumour in the left upper lung lobe encasing the vertebrae Th3-Th4. A computerized tomography (CT) of the thorax revealed a mass of 3.9 cm x 2.9 cm in the left upper lung lobe (Figure1A, B, arrows). Histological examination of a biopsy of the mass showed an IPT with large amounts of histiocytes, lymphocytes and plasma cells (Figure1C, D). After neurosurgical therapy, the neurological deficit in the lower extremities improved and the patient was discharged. In a second operation, the lung tumour was removed. Histological examination of this material also revealed an IPT. Given the extensive travel history of the patient, various infectious agents were excluded (mycobacteria, legionella, Borrelia burgdorferi, pneumocystis, Epstein-Barr virus (EBV), herpes simplex virus, human immunodeficiency virus-1/2, parvovirus, respiratory viruses, cytomegalovirus (CMV) and other bacteria, stool pathogens and urinary histoplasma antigen). During the following two years, the patient was intermittently treated with corticosteroids, and low-dose radiation therapy was performed in order to control tumour growth locally, as recommended previously [10].

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 [12]. 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 [13]. 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 [5]. 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.

Written informed consent was obtained from the patient for publication of this case report.

The authors declare that they have no competing interests.

BH and JF diagnosed the case and planned the treatment and medical follow up. CK gathered the patient’s history and drafted the manuscript and the subsequent revisions. MJ and JF participated in manuscript revision. SW carried out immunohistochemistry. MS carried out FACS and in-vitro studies. All authors read and approved the final manuscript




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