Modern Pathology (2007) 20, 405–415 & 2007 USCAP, Inc All rights reserved 0893-3952/07 $30.00 www.modernpathology.org Benign extramedullary myeloid proliferations Dennis P O’Malley US Labs, Irvine, CA, USA Extramedullary proliferations of bone marrow elements are infrequently encountered in routine pathology practice. On occasion, they can present diagnostic difficulties when seen in unusual or unanticipated sites. This review serves to cover aspects of underlying embryogenesis of myeloid elements, as well as sites and circumstance of benign proliferations of myeloid elements along with their occasional confusion with neoplastic myeloid proliferations. Benign proliferations associated with hematologic disorders and hemato- poietic growth factors are discussed. Immunohistochemical evaluation of myeloid proliferations is considered as well. Modern Pathology (2007) 20, 405–415. doi:10.1038/modpathol.3800768; published online 2 March 2007 Keywords: extramedullary hematopoiesis; spleen; lymph node; myelolipoma; myeloid sarcoma; diagnosis The production of blood cells by the bone marrow is epididymis, ovaries and endometrium.1,2 It is these the basic function of the hematopoietic system. The circumstances and the proliferation of marrow appropriate proliferation and production of marrow elements in extramedullary sites that are the focus elements is fundamental to the control of numerous of this review. Evaluation of neoplastic myeloid body systems, because of the far-reaching effects of proliferations (NMP), in the context of differential the hematologic elements. Oxygen transport by red diagnosis, will also be briefly discussed. cells, coagulation by platelets and the nonspecific immune responses by granulocytes and monocytes are the essential functions, but there are numerous Benign other, more subtle functions of the hematopoietic system as well. Embryology The embryologic development of the hematopoie- To understand better the development of extrame- tic system is exceedingly complex and relies on dullary hematopoiesis (EMH), a brief review of close interaction with other systems of the body. The normal hematopoietic development is necessary. delicate orchestration of development can be seen as The derivation and ultimate construction of an the primary site of hematopoiesis changes from yolk intact hematologic system from the embryo to its sac to liver and finally within the marrow cavity. adult form is a complex process with many steps Under normal circumstances after birth, there is and numerous molecular and cellular interactions. little proliferation of hematopoietic elements out- In the earliest stages of embryo development, the side the marrow. However, in a variety of pathologic yolk sac is the earliest site of primordial develop- conditions, marrow elements will be present, and ment of the hematopoietic system.3 Aggregates of sometimes proliferate, outside the relatively specific mesodermal cells condense and form vascular environment of the bone marrow. Myeloid prolifera- elements within the yolk sac. Clusters of primitive tions have been reported in a wide variety of sites mesodermal cells that develop into hematopoietic including lymph nodes, mediastinum, breast, cen- cells develop in close association to these blood tral nervous system, peripheral nerves, orbit, middle vessels and are termed blood islands. These early ear, pancreas, urethra, oropharynx, nasopharynx, hematopoietic elements begin to circulate in the pleura and lungs, pericardium, heart, gastrointest- embryo as soon as the vascular elements allow inal tract, peritoneum, thyroid gland, skin, subcuta- (approximately 20 days). In parallel to development neous tissue, kidney, adrenal gland, prostate gland, of hematopoiesis in the yolk sac, the rudimentary liver develops. In the fetal liver, hematopoietic progenitor cells are not produced, but are colonized Correspondence: Dr DP O’Malley, MD, US Labs, 2601 Campus by circulating hematopoietic precursors, which Drive, Irvine, CA 92612, USA. E-mail: [email protected] proliferate and differentiate in the liver parenchy- Received 20 October 2006; revised 03 January 2007; accepted 17 ma. At approximately day 30, the liver is the January 2007; published online 2 March 2007 primary site of hematopoiesis (but not generation Extramedullary myeloid proliferations DP O’Malley 406 The first cause, filtration, is mostly seen in marrow disorders with mobilization of increased numbers of immature hematopoietic precursor cells (such as chronic idiopathic myelofibrosis). The second circumstance, compromise of, or damage to the marrow space, can be caused by a variety of neoplastic and nonneoplastic and stromal disorders affecting the marrow. The third cause, generation of hematopoietic growth-stimulating factors, may oc- cur independently, as a result of hematopoietic growth factors production by tumor or at sites of tissue damage and repair. It should be noted that although some cases may be caused by one of these factors, it is likely more than one factor contributes in most circumstances. In a large study, Koch et al1 found that 78% of cases of nonhepatosplenic EMH were symptomatic. Pleural effusion, ascites, neurologic deficit, cardiac tamponade, chronic renal failure, acute respiratory Figure 1 Microscopic image of fetal liver showing intrasinusoidal failure, orbital proptosis, subglottic stenosis are development of hematopoietic cells; the predominant cell type is among the symptoms associated with EMH. erythroid. Tissue biopsy, fine needle aspiration, radionucleo- tide scanning have all been used as diagnostic of hematopoietic stem cells, as described above) techniques to evaluate extramedullary myeloid dis- (Figure 1). Besides the yolk sac, hematopoietic stem ease.1 The radiologic appearance of myeloid sarcoma cells are also produced from the aorta–gonads– can be distinctive enough for a presumptive diagnosis.5 mesonephros region. The aorta–gonads–mesone- Localized irradiation, red blood cell transfusions, phros is an important transient site of development surgical excision, decompressive laminectomy and of stem cells, which populate the marrow. The bone chemotherapy including hydroxyurea are most com- marrow forms relatively late in embryogenesis, and monly used in therapy for extramedullary myeloid establishment of hematopoietic elements in the diseases.1 Localized therapy has no apparent effect medullary cavities of bone occurs at approximately on long-term outcomes, independent of systemic 8 weeks of development. By 11 weeks, a stromal therapy. Jenkin et al6 recommended that localized environment and hematopoietic cells are estab- irradiation should be limited to cases where there is lished in the marrow cavity and produce, primitive, imminent compromise or critical organ damage (eg but identifiable blood components. Spleen plays a eye, brain, spinal cord and kidney). minor role as a site of hematopoiesis, predominantly of erythroid elements. At each step of development, a complex interaction of local stroma, cell–cell Pediatric interactions and the influence of cytokines and The finding of EMH in infants is not unusual. The hematopoietic growth factors play a central role.3 most common sites are liver, spleen and lymph nodes, but EMH can be found in other sites as well (Figure 2). It is expected that as the infant develops General, Benign EMH in age, extramedullary sites would regress. Un- doubtedly, premature births or a perinatal period In general, there are three circumstances which associated with physiologic stress would have the underlie the abnormal, extramedullary proliferation potential for persistence of EMH. This EMH would of normal hematopoietic elements: (1) filtration, serve the biologic purpose of producing more where immature cells are trapped by the spleen or hematopoietic elements, in response to whatever other sites (such as in cases of acquired or functional pre- or perinatal stress was present. It is easy to hyposplenism) and proliferate; (2) inadequate mar- conceive that a variety of causes would induce row space to produce appropriate numbers of retention or expansion of the hematologic elements. marrow elements (owing to compromise of marrow These would include bleeding, infections, hypoxia cavity, eg myelophthisis, or overproduction of and a wide variety of congenital defects of heart, marrow elements) or damage to the bone marrow lungs, kidneys and other organs and systems. microenvironment leading to increased numbers of circulating hematopoietic stem cells;4 (3) abnormal cytokine or other circulating hematopoietic growth Hematologic Disorders factors causing stem cell differentiation to hemato- poietic cells or local effects simulating the marrow Benign hematologic disorders are a well-known microenvironment.1 cause of expansion of the hematopoietic-producing Modern Pathology (2007) 20, 405–415 Extramedullary myeloid proliferations DP O’Malley 407 Figure 2 Myeloid proliferations in lymph node. (a) Image from an enlarged node in a 6-week-old premature infant. This benign proliferation consists of predominantly myeloid elements including numerous eosinophil precursors. (b) Enlarged lymph node from an adult with a long history of chronic idiopathic myelofibrosis. Under this circumstance the proliferation is neoplastic and the proliferation consists of dysplastic megakaryocytes and immature myeloid elements. space beyond the confines of the marrow cavity. The relative erythroid hyperplasia seen in the bone most common of these disorders include thalasse- marrow. However, if the