after allogeneic bone marrow transplantation from an. HLA-identical sibling. The excruciating and diffuse bone pain, fever and precipitous drop in peripheral.
Bone Marrow Transplantation, (1998) 22, 1125–1128 1998 Stockton Press All rights reserved 0268–3369/98 $12.00 http://www.stockton-press.co.uk/bmt
Case report Bone marrow necrosis in bone marrow transplantation: the role of MR imaging CS Chim1, C Ooi2, SK Ma3 and C Lam3 University Departments of 1Medicine, 2Radiology and 3Pathology, Queen Mary Hospital, University of Hong Kong, Hong Kong
Summary:
Case report
We describe an ALL patient who developed extensive bone marrow necrosis at the time of relapse 2 months after allogeneic bone marrow transplantation from an HLA-identical sibling. The excruciating and diffuse bone pain, fever and precipitous drop in peripheral blood counts were characteristic. This case illustrates the importance of repeat bone marrow biopsies for the diagnosis of disease relapse and the potential application of MR imaging in the assessment of patients with bone marrow necrosis. Keywords: bone marrow necrosis; ALL; magnetic resonance imaging
A 31-year-old man with pre-B acute lymphoblastic leukaemia (ALL) received an allograft from an HLA-identical sibling in first complete remission in August 1997 with Cy/TBI (cyclophosphamide 120 mg/kg; total body irradiation 12 Gy in six fractions) conditioning, and cyclosporin A and methotrexate, as graft-versus-host disease prophylaxis. Engraftment occurred on day 23 without acute graft-versus-host disease. Blood counts on discharge were within normal limits (Hb 13.3 g/dl, platelet 198 ⫻ 109/l and leucocyte 5.2 ⫻ 109/l) (normal range: Hb 11–16 g/dl; platelet 150–400 ⫻ 109/l; leukocyte 4–11 ⫻ 109/l). Bone marrow aspirate and biopsy on day 30 post-transplant confirmed complete remission. On day 80, he was admitted because of fever, sudden onset of excruciating pain over the pelvis, thighs and lower back. Complete blood picture revealed a precipitous drop in blood counts (Hb 8 g/dl; platelet 33 ⫻ 109/l; leucocyte 2.9 ⫻ 109/l) with a leukoerythroblastic blood picture. Prothrombin time, activated partial thromboplastin time and fibrinogen levels were within normal limits. Bone marrow aspirate on day 84 (Figure 1A) and trephine biopsy (Figure 1B and C) revealed extensive bone marrow necrosis. Alkaline phosphatase was 312 U/l (49–138 U/l). Serum calcium and phosphate levels were within normal limits. Lactate dehydrogenase was 1690 U/l (197–401 U/l). Despite repeatedly negative sepsis work-up (blood, urine and sputum cultures for bacteria and fungus), he was treated empirically with broad spectrum antibiotics. A repeat bone marrow biopsy performed on day 100 showed clusters of blast cells which were shown, by immunohistochemical study, to be recurrence of ALL. Radiographs of the pelvis and spine were normal but MR imaging (Figures 2 and 3) revealed changes consistent with BMN and malignant infiltration. He was started on ALL therapy (prednisolone ⫻ 28 days, weekly vincristine ⫻ 4, daunorubicin ⫻ 3 doses, l-asparaginase ⫻ days 15–28) and showed marked improvement with rapid resolution of fever and bone pain, and recovery of the blood counts. However, a post-chemotherapy bone marrow biopsy showed persistence of both blast cells and BMN. Although he received further chemotherapy (cytarabine and teniposide) and showed a transient response with respect to fever and bone pain, blast cells were persistently found in the bone marrow. His bone pain became excruciating and required mor-
Bone marrow necrosis (BMN) is a distinct pathologic entity associated with a wide variety of diseases.1–3 Antemortem diagnosis is rare and has been described in patients with sickle cell disease, leukaemias, lymphomas and neoplastic infiltration of the bone marrow.1–4 Patients usually present with fever, bone pain and tenderness. Bone marrow aspirate may yield a dry tap and trephine biopsy usually reveals necrotic marrow cells in a background of amorphous eosinophilic material.2,3 Associated underlying disease may occasionally be apparent in the trephine biopsy but multiple biopsies are usually required to confirm the diagnosis. Various risk factors including chemotherapy and radiotherapy have been implicated in BMN.2,3,5 The extent of necrosis is difficult to assess in living patients. However, magnetic resonance (MR) imaging is increasingly used to evaluate bone marrow involvement in haematological malignancies.6 While high-dose chemo-radiotherapy with stem cell rescue is a common treatment for patients with haematological malignancies worldwide, bone marrow necrosis has not been reported in this setting. Here, we describe a patient with acute lymphoblastic leukaemia who developed bone marrow necrosis after allogeneic bone marrow transplantation.
Correspondence: Dr CS Chim, University Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong Received 11 May 1998; accepted 15 July 1998
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Figure 1 (A) Trephine biopsy at the onset of bone marrow necrosis showing hypercellular marrow with an area of more advanced necrosis on the right and pyknotic cells with impending necrotic changes on the left. H&E ⫻ 60. (B) Besides bone marrow necrosis, there is also associated osteonecrosis as shown by loss of osteocytes giving rise to empty lacunae. (C) High power view of the same specimen showing faint outlines of dead cells admixed with scanty necrotic cells with pyknotic nuclei. H&E ⫻ 1000.
phine treatment. The patient is still alive with disease 4 months after the diagnosis of BMN. Pathology The bone marrow aspiration at the onset of symptoms (day 84) post-BMT (Figure 1A) showed cellular particles that contained only necrotic haemopoietic cells with ill-defined nuclear and cytoplasmic margins in a background of pale basophilic proteinaceous material. The day 84 trephine biopsy (Figure 1B and C) revealed extensive areas of coagulative necrosis with amorphous eosinophilic debris and vague cellular outlines. In areas where necrosis was not so advanced, marrow cells showed pyknotic nuclei and eosinophilic granular cytoplasm, which indicated impending necrosis. In addition, the bony trabeculae showed empty lacunae with loss of osteocytes, consistent with osteonecrosis. Reticulin fibres were diffusely coarsened. The absence of viable marrow tissue for examination precluded a definitive morphological diagnosis. The day 100 trephine biopsy showed persistent bone marrow necrosis with non-necrotic areas showing sheets of lymphoblasts. Immunohistochemical study on trephine biopsy demonstrated that these blasts were positive for terminal deoxynucleotidyl transferase (TdT), consistent with ALL in relapse. MR imaging MR imaging was performed with a 1.5-T system (Signa; GE Medical Systems, Milwaukee, WI, USA). The pelvis and lumbar spine were evaluated by spin echo (SE) T1weighted, fat-saturated fast spin echo (fat-sat FSE) T2weighted, and fat-sat SE T1-weighted gadolinium-DTPA (Gd-DTPA) sequences. Three distinct patterns of abnormal bone marrow were noted: the most common resembled avascular necrosis or bone infarctions. These were T1hypointense with central iso-/hyperintense zones on T2weighted images, surrounded by an inner hyperintense line which enhanced after Gd-DTPA administration, and an outer hypointense rim (Figure 2). There were also areas
of homogenous T1-and T2-hyperintensity which enhanced markedly after Gd-DTPA administration (Figure 3). These signal characteristics suggested blood or proteinaceous products within hyperaemic bone marrow. The least common bone marrow abnormality was T1-hypointense and T2hyperintense, with Gd-DTPA enhancement (Figure 2a, b), suggesting malignant infiltration. Based on these findings, the MR diagnosis was massive multifocal BMN with small islands of probable malignant infiltration. Discussion In brief, our patient developed extensive BMN associated with ALL relapse 2 months after high-dose chemo-radiotherapy without evidence of disseminated intravascular coagulation or sepsis. Extensive BMN is a rare finding in living patients and is seen predominately in malignant infiltration of the bone marrow such as ALL and lymphoma.1,2,7 The incidence has ranged from 0.15% (one in 664) to 0.4% (one in 202) of bone marrow biopsies over a period of 10 and 12 years, respectively.2,4 Besides the cardinal symptoms of bone pain and fever,2 our patient also had a precipitous drop in the blood counts. The shared laboratory abnormalities such as a leukoerythroblastic blood picture, raised alkaline phosphatase and LDH levels seen in others.1,2,7 However, abnormalities such as hypercalcaemia2 and disseminated intravascular coagulation2 were not evident. The extent of BMN is difficult to assess in living patients. In one study,2 extensive BMN was confirmed in six out of seven patients with BMN at autopsy. However focal BMN may occasionally occur.1,3 MR imaging is being increasingly used in bone marrow imaging6 due to its capability of evaluating large areas of bone marrow compared with bone marrow biopsies. Although the utility of MR imaging in the diagnosis of femoral head avascular necrosis is well-established,8,9 little is known about the MR features of BMN in haematological malignancies. Wedge-shaped and subchondral focal bone marrow ischaemia (T1-hypointense and T2-hyperintense) which
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Figure 2 (a and b) Coronal scans of the pelvis. (a) There are two hyperintense bands in the lateral aspects of the sacral ala (arrows) on fat-sat FSE T2-weighted scan. Marginated lesions with an inner hyperintense line and an outer hypointense rim are also noted in the body of the sacrum (arrowheads) and femoral heads (arrowheads). (b) Marked enhancement of the bands (arrows) and rim enhancement of the marginated lesions (arrowheads) are shown. Additional marginated lesions are now obvious in the iliac wings and ischium.
Figure 3 Another coronal section of the pelvis showing (a) a markedly hyperintense lesion in the left sacral ala (arrows) which remain hyperintense on fat-sat FSE T2-weighted images. The rest of the pelvis has been largely replaced by hypointense marrow. (b) On the fat-sat SE T1weighted Gd-DTPA image this lesion enhances markedly (arrows). Note marginated lesions with rim-enhancement in the rest of the pelvic bone.
resolve with time, have been described in haematological disorders.10 However, there has only been one report of BMN in which concurrent MR imaging was described together with histological data.11 In that paper, multifocal fluid-filled (T1-hypo and T2-hyperintense) and marginated lesions with a T1-hypointense rim were found in the pelvis and spine of three lymphoma patients.11 Our MR findings, however, differ in three respects: (1) there were no fluidfilled necrotic lesions; (2) well-marginated foci with a double-line sign on T2 images, typically seen in periarticular avascular necrosis,8 were the predominant abnormality; and (3) enhancing lesions with MR features of blood or proteinaceous material (markedly hyperintense on T1 and T2) were also present. Our MR findings suggest that BMN in haematological malignancies, at least on MR imaging, share similar fea-
tures with periarticular avascular necrosis. Features that distinguish the two are lesion site and distribution, with bone marrow necrosis diffusely affecting medullary bone of the pelvis and spine, and avascular necrosis being usually found at periarticular sites. The differences in MR features of bone marrow necrosis between our case and those of Weissman11 may be related to the different underlying diseases and the spectrum of evolutionary changes of necrotic bone marrow. It is likely that in our patient, the degree of marrow necrosis had not yet reached the final fluid-filled stage described by Weissman11 in two of his three cases. Our case also illustrates the usefulness of MR imaging in non-invasive evaluation of large areas of bone marrow, with possible differentiation between areas of necrosis and malignant infiltration.
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7 Nies BA, Kundel DW, Thomas LB, Freireich EJ. Leukopenia, bone pain, and bone necrosis in patient with acute leukemia. Ann Intern Med 1965; 62: 698–705. 8 Mitchell DG, Rao VM, Dalinka MK et al. Femoral head avascular necrosis: correlation of MR imaging, radiographic staging, radionuclide imaging, and clinical findings. Radiology 1987; 162: 709–715. 9 Mitchell DG, Steinberg ME, Dalinka MK et al. Magnetic resonance imaging of the ischemic hip. Clin Orthop Rel Res 1989; 244: 60–77. 10 Berg BV, Malghem J, Labaisse MA et al. Apparent focal bone marrow ischemia in patients with marrow disorders: MR studies. J Comp Assis Tomogr 1993; 17: 792–795. 11 Weissman DE, Negendank WG, Al-Katib AM, Smith MR. Bone marrow necrosis in lymphoma studied by magnetic resonance imaging. Am J Hematol 1992; 40: 42–46.
