Pulmonary Extramedullary Haematopoiesis After Allogeneic Stem-Cell Transplantation

Abstract

Practitioners performing stem-cell transplantation (SCT) sometimes experience temporary hypoxia during stem-cell infusion, which is recognized subjectively as chest discomfort and resolves completely after the infusion. Some physicians believe that this hypoxia is caused by a temporary embolism because of the presence of infused stem cells in the pulmonary artery. To the best of our knowledge, however, it remains unproven that stem cells aggregate in the small vessels of the pulmonary artery during stem-cell infusion. This infusion-related pulmonary event could be prevented by other interventions, such as filtration of the infusion stem cells to release cell clusters. A 52-year-old male aplastic anemia patient underwent allogeneic SCT from a sex-mismatched related donor. The stem-cell source was bone marrow from an human leukocyte antigen full-matched related donor with a conventional cyclophosphamide/total body irradiation regimen. Nine years after SCT, he suffered from late-onset noninfectious pulmonary complications constituting severe restrictive lung disease with pneumothorax. He underwent video-assisted thoracoscopic surgery for lung biopsy. Before video-assisted thoracoscopic surgery, his pulmonary function test showed a severe restrictive pattern, as following %VC was 45.8%, FEV1.0% was 100%, and FEV1.0 was 1.72 L. Chest x-ray photograph and chest computed tomography showed a broad low-attenuation area in the whole lung reflecting emphysema, and a reticulo-nodular shadow predominantly along the pleura. Computed tomography imaging specified bronchoectasia mainly in the bilateral upper lungs. Pathological findings of his right lung incidentally showed intravascular hematopoiesis containing immature granulocytes, erythrocytes, and megakaryocytes in his pulmonary artery (Fig. 1a). Evidence of the existence of stem cells was gained by partial staining by CD34 immunostaining in a few cells of the extramedullary hematopoiesis (EMH) site. The hematopoietic cells had XX signals detected by fluorescent in situ hybridization (Fig. 1b). There was no obvious hematological abnormality in his peripheral blood, and the proportion of XX and XY cells in the peripheral blood analyzed by fluorescent in situ hybridization revealed a 99.6% donor (XX) pattern with 0.0% XY signals. Bone marrow findings were normal, and no peripheral lymphadenopathy or hepatosplenomegaly was detected.FIGURE 1.: Pathological findings of lung biopsy (a) (×100) and sexual chromosome fluorescent in situ hybridization (FISH) in the same tissue (b) (×400). Extramedullary hematopoiesis (EMH) in the pulmonary artery was detected by XX chromosomal signals.EMH is a rare condition defined as the appearance of hematopoietic elements outside of the bone marrow. EMH is generally assumed to be a compensatory hyperplastic phenomenon when associated with anemia or space-occupying bone marrow disease (1). Though the presence of EMH in the lung is much less common (2), it is occasionally associated with traumatic events, such as a complicating bone fracture or cardiac surgery, leading to bone marrow embolism (3). In the present case, the patient’s aplastic anemia was in remission and the pathogenesis described above was not found. Peripherally transfused stem cells circulate to the lung arteries, where they may survive and continue hematopoiesis for several years after SCT. Spontaneous hypoxia during peripheral blood progenitor cell (PBPC) infusion may be recognizable if a massive cluster of stem cells occludes pulmonary circulation for a time and most of the cells recirculate while some stay to seed. Sale and Storb (4) reported the death of a dog due to extensive ossification of the lungs after dog leukocyte antigen-matched allograft transplantation. They explained that EMH needs not only hematopoietic cells but also an in vivo microenviroment including osteoblasts, fat cells, and fibroblasts. Mesenchymal cell growth could have resulted in the respiratory failure of the dog. This experimental phenomenon might provide the explanation for late-onset noninfectious pulmonary complications in the present case. And the early report concerning to the experimental model for chasing the transfused stem cells that initial sojourn of transplanted cells in the lungs last for 1 or 2 days (5). This might be associated to the early adverse events of respiratory system after transplantation. In conclusion, an influence of stem cells for lungs should be researched farther. To the best of our knowledge, this is the first documented case in the literature of isolated EMH in the lungs after SCT. Osamu Imataki Hiroaki Ohnishi Division of Haematology Department of Internal Medicine Faculty of Medicine Kagawa University Kagawa, Japan Yoshio Kushida Division of Pathology Kagawa University Hospital Kagawa, Japan Akira Kitanaka Department of Laboratory Medicine Faculty of Medicine Kagawa University Kagawa, Japan Yoshitsugu Kubota Transfusion Medicine Faculty of Medicine Kagawa University Kagawa, Japan