Int J Hematol (2008) 88:294–298 DOI 10.1007/s12185-008-0159-3
CASE REPORT
Spinal cord compression in an adolescent with relapsed B-precursor acute lymphoblastic leukemia and mental neuropathy Elpis Mantadakis Æ Aspasia Katragkou Æ Eufrosini Papadaki Æ Stefanos Papadhimitriou Æ George Paterakis Æ Eftichia Stiakaki Æ Maria Kalmanti
Received: 15 July 2008 / Revised: 27 July 2008 / Accepted: 1 August 2008 / Published online: 18 September 2008 Ó The Japanese Society of Hematology 2008
Abstract The authors report a case of intraspinal mass associated with recurrence of B-precursor acute lymphoblastic leukemia in an adolescent male who presented with numb chin syndrome at initial diagnosis of the leukemia. The patient developed sensory changes, later on motor weakness, and eventually paraplegia. An emergent MRI scan showed an intraspinal mass at the level of T9 vertebra. Biopsy obtained during laminectomy revealed a mass composed of lymphoblasts immunophenotypically identical to the patient’s known leukemia. Surgical decompression and dexamethasone were ineffective in restoration of the neurological deficits. Intraspinal extramedullary relapses should be considered in the differential diagnosis of leukemic patients with neurological symptoms.
1 Introduction Leptomeningeal relapse is common in patients with acute lymphoblastic leukemia (ALL), but a solid intraspinal mass with spinal cord compression as a site of extramedullary relapse is very uncommon [1–3]. We present an adolescent male with multiply relapsed Bprecursor ALL who developed acute paraplegia due to an intraspinal mass with the same immunophenotypic features with the underlying leukemia. Interestingly, the patient presented with numb chin syndrome at initial diagnosis of the leukemia and had a very short first remission despite early response to induction chemotherapy. The etiology of mental neuropathy and the management of malignant spinal cord compression are discussed.
Keywords Acute lymphoblastic leukemia Spinal cord compression Numb chin syndrome 2 Case presentation E. Mantadakis A. Katragkou E. Stiakaki M. Kalmanti (&) Department of Pediatric Hematology/Oncology, University Hospital of Heraklion, 71 110 Heraklion, Crete, Greece e-mail:
[email protected] E. Papadaki Department of Radiology, University Hospital of Heraklion, Heraklion, Crete, Greece S. Papadhimitriou Department of Hematology, General District Hospital of Athens ‘‘G. Gennimatas’’, Athens, Greece G. Paterakis Department of Immunology, General District Hospital of Athens ‘‘G. Gennimatas’’, Athens, Greece
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A 17-year-old male presented to the emergency department of our hospital due to weakness, arthralgias, and lip numbness for 1 week. On physical examination, he had hepatosplenomegaly, few scattered petechiae, and decreased sensation confined to the skin and mucous membrane of the lower lip and the skin of the chin. A hemogram demonstrated leukocytes 133,000/ll (85% blasts), hemoglobin 13.9 g/dl and platelets 55,000/ll. The blasts were CD19?, CD10?, Tdt?, cl-, consistent with common B-ALL (B2-ALL according to the classification of the European Group for the Immunological characterization of leukemias) [4]. Examination of cerebrospinal fluid (CSF) on admission showed mild pleocytosis (8 nucleated cells/ll) with blasts. Cytogenetic analysis revealed two abnormal clones 46,XY,del(9)(p22.1),add(16)(q22) and 46,XY,add(9) (p22.1),del(9)(p11.2)add(16)(q22)], while FISH analysis
Spinal cord compression and mental neuropathy in ALL
demonstrated homozygous deletion of 9p21 and no evidence of TEL/AML1, BCR/ABL or MLL gene rearrangements. The patient who had two matched sibling donors (MSD) was treated according to the high-risk dexamethasone arm of the BFM 2000 protocol [5]. A magnetic resonance imaging (MRI) scan of the brain that was performed after the end of the prednisone prophase was unremarkable. The lower lip and chin numbness subsided quickly after the first 4 days of therapy. The patient was a good prednisone responder, i.e., he had \1,000 blasts/ll in the peripheral blood after one intrathecal injection of methotrexate on days 1 and 7 of oral prednisone, while he had no detectable minimal residual disease (MRD) by flow cytometry on a bone marrow aspirate performed on day 15. Despite achieving hematological remission on day 33 and receiving intensive chemotherapy without delays, he relapsed in the bone marrow after only 5 months of remission. He achieved a second complete hematological remission documented morphologically and by flow cytometry with modified hyperCVAD [6]. At that time he underwent hematopoietic stem cell transplantation from one of his MSD, preceded by conditioning with total body irradiation (TBI) and cyclophosphamide. Unfortunately, he relapsed again 2 months after transplantation, despite the development of mild graft versus host disease (GVHD) with skin and gut involvement. Although the use of clofarabine was considered at this point [7], the drug was not unavailable to us. Hence, he received again modified hyperCVAD achieving a third hematological remission. Four months later he had an isolated leptomeningeal CNS relapse, when due to sensory disturbances of the lower extremities, he underwent a lumbar puncture that demonstrated CSF with 728 nucleated cells/ll (predominantly blasts) and 48 red cells/ll. A computed tomography (CT) scan of the head and spine at that time was negative for mass lesions. Although liposomal cytarabine for intrathecal therapy was considered at this point [8], this drug is not commercially available in Greece. Hence, he received intensive triple intrathecal chemotherapy and additional craniospinal irradiation to the spinal cord tolerance dose and achieved blast clearance of the CSF. Unfortunately, three months later he underwent an isolated extramedullary relapse on the right arm (painful solid mass) confirmed by needle biopsy, for which he was receiving outpatient palliative radiation therapy and analgesics. Halfway through this treatment, the patient complained about progressive difficulty in walking and diffuse pain. His transdermal fentanyl patch was increased, but 2 days later he had difficulty in urinating, and 1 day later he developed weakness and later on inability to move his legs. On physical examination, he had remarkable muscle weakness with absent deep tendon reflexes in the lower extremities, and sensory loss below the waist along with a distended bladder. At that time, he had mild peripheral
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blood cytopenias with leukocytes 2,400/ll with no circulating blasts, hemoglobin 10.3 g/dl and platelets 79,000/ll. An emergent lumbar puncture was performed and yielded with difficulty 1 ml of CSF with five nucleated cells with blasts and 4,960 red cells/ll. An emergent MRI scan of the thoracic and lumbar spine was performed after the lumbar puncture and revealed an extradural, intraspinal mass at the level of T9 vertebra, arising from the adjacent left paraspinal space and extending into the spinal canal through the adjacent T9–T10 distended intervertebral foramen. The mass occupied most of the spinal canal displacing the spinal cord anteriorly and to the right. At this level the spinal cord appeared deformed with a slight increase of signal intensity on T2 sequences due to compression (Figure 1). The mass lesion infiltrated also the left posterior aspect of the T9 vertebra and the heads of the left ninth and tenth ribs, while a similar right paraspinal mass infiltrated the head of the right ninth rib. A similar but smaller mass was also recognized at the level of the T10–T11 (not shown), infiltrating the left intervertebral foramen and extending into the spinal canal without any spinal cord compression. Bolus dexamethasone 10 mg intravenously was urgently administered and the patient underwent emergency laminectomy and partial removal of the intraspinal mass for decompression of the displaced spinal cord. Biopsies obtained at the time of surgery confirmed the presence of a mass composed of lymphoblasts with the same immunophenotypic features with the patient’s known ALL. Mobility and sensory disturbances did not substantially recover after surgery. No additional chemotherapy or radiation was administered due to the patient’s pre-terminal
Fig. 1 Axial T2-weighted MRI at the level of the T9 vertebra demonstrates an extradural mass (thick arrow) arising from the adjacent left paraspinal space and extending into the spinal canal, where it displaces and deforms the spinal cord (thin arrow)
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condition. The patient died 3 weeks later in florid hematological relapse. Circulating blasts to the peripheral blood were seen only 3 days prior to his death.
3 Discussion We present the unusual case of a patient with precursor BALL, who despite high-risk features (age [10 years, leukocyte count at diagnosis [100,000/ll, CNS disease at diagnosis) showed an early response to induction chemotherapy. The initial early bone marrow relapse in our patient was unexpected, since despite the high-risk features of the leukemia, he was a good prednisone responder [9], and moreover, had no detectable MRD by flow cytometry at four consecutive measurements, including day 15, day 33 (end of induction), day 78 (end of consolidation), and also just prior to the administration of the third high-risk block of extra-compartment/intensified consolidation chemotherapy, according to BFM 2000. Recent data from the AIEOP-BFM 2000 study show that patients with precursor B-ALL and no detectable MRD on days 33 and 78 have a 92.5 and 87.7% 5-year progression free survival, respectively [5]. The patient had two MSD, but was not transplanted in first remission because he had none of the BFM criteria for allogeneic stem cell transplantation in first remission by a MSD, i.e., (a) poor prednisone response in addition to proB-ALL or M3 marrow on day 15 or leukocytes C100,000/ ll, (b) presence of t(9;22) or t(4;11), (c) MRD C 10-3 on day 78, and (d) no remission on day 33 [10]. Regarding the prognostic significance of the homozygous 9p21 deletion in the leukemic blasts, the genes including p16 at the INK4A/ARF locus located at 9p21 are frequently involved in ALL [11], but the independent prognostic significance of this deletion is debatable with both positive [12–15] and negative studies [16, 17]. Despite peripheral hematopoietic stem cell transplantation in second remission from his brother, our patient relapsed again two months later with leptomeningeal leukemia. Although he achieved clearance of the CSF with intensive, but palliative, intrathecal chemotherapy and additional craniospinal radiation, he suffered again an isolated extramedullary relapse in the right arm, and eventually developed paraplegia due to spinal cord compression from an intraspinal mass composed of lymphoblasts with the same immunophenotypic features with the underlying ALL. Evidence of bone marrow relapse became apparent only 3 days prior to his death. Liposomal cytarabine, a sustained-release formulation of cytarabine developed for intrathecal administration would have been a good therapeutic option in our patient, since limited data show significantly better response rates in
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patients with lymphomatous meningitis who received liposomal cytarabine compared with free cytarabine [18]. However, as previously said, this drug is not commercially available in Greece. The development of GVHD initially protected our patient from overt bone marrow relapse. It is well-known that GVHD after allogeneic hematopoietic stem cell transplantation has an anti-leukemic effect, that is, however, less effective in preventing extramedullary relapses [19]. The patient’s symptom at initial presentation of new onset numbness of the lip was indicative of what is known as numb chin syndrome or mental neuropathy, likely due to leukemic infiltration within the mental nerve pathway [20, 21]. The etiologies of mental neuropathy are diverse and include odondogenic problems (dental abscesses, facial trauma, mandibular osteomyelitis, etc.), systemic diseases like amyloidosis, sarcoidosis, syphilis, vasculitides, and diabetes mellitus, as well as neoplasias, both solid tumors (thyroid, head and neck, breast, lung, gastrointestinal, renal, and prostate carcinomas, sarcomas, melanomas), and hematological malignancies (multiple myeloma, leukemias, and lymphomas). Massey et al. described 19 patients with mental neuropathy secondary to systemic cancer. In nine of these patients, the numb chin was the presenting symptom of an underlying neoplasm, which was a lymphoreticular malignancy in nine cases [22]. Fenaux et al. described 18 adult patients with Burkitt lymphoma of whom 10 had mental neuropathy and Kuroda et al. described a single case of Burkitt leukemia presenting with bilateral numb chin syndrome as the initial symptom of the disease [23, 24]. Finally, Hiraki et al. described three more cases of ALL that presented with mental neuropathy as the initial symptom of the disease. This symptom heralded the initial progression of the disease in the first and second case, and the recurrence of the disease in the third case [25]. Hence, it seems that this neuropathy, a seemingly benign symptom that can be easily overlooked, may be a potentially serious sign of an underlying disease that must prompt the primary care physician towards a thorough investigation for a variety of diseases, including myeloproliferative ones. Although it has been suggested that mental neuropathy is a poor prognostic sign in patients with metastatic cancer, its true prognostic significance in patients with ALL remains unknown. Nevertheless, it appears to be more common in patients with advanced disease, large tumor burden and worse prognosis, and this likely means that its independent prognostic significance is doubtful. Our patient suffered a leptomeningeal relapse in the CNS after the transplantation, and pre-terminally developed an extradural, intraspinal mass that compressed the spinal cord. Spinal cord compression is a common presenting finding in children with malignancies occurring in 3% at diagnosis [26]. On the other hand, the prevalence of spinal cord
Spinal cord compression and mental neuropathy in ALL
compression is less well defined, but is probably higher in children and adolescents with refractory or relapsed malignancies, particularly neuroblastoma. When evaluating children with cancer and back pain, spinal cord compression should always be considered until proven otherwise. Although pain can be present for months prior to diagnosis, once neurologic symptomatology becomes apparent, paraplegia can develop rapidly and may be permanent, like in our patient. Several studies support irradiation of sub-clinical spinal cord compression, as a method of preserving neurological function in cases of malignant compression. However, our patient was irradiated in the past and could not receive additional radiation therapy. The role of corticosteroids in the management of malignant extradural spinal cord compression has been reviewed elsewhere [27]. High-dose intravenous dexamethasone appears to be slightly more effective, albeit much more toxic than moderate dose bolus dexamethasone. Hence, we used therapeutically moderate dose intravenous dexamethasone in addition to emergent laminectomy. Unfortunately, none of these measures proved effective into restoring ambulation. In conclusion, we present an adolescent male with multiply relapsed ALL and mental neuropathy at presentation, who developed paraplegia late into the course of his disease due to spinal cord compression by an extradural intraspinal mass composed of lymphoblasts with the same immunophenotypic features with the initially diagnosed leukemia. Although both dexamethasone and laminectomy proved ineffective in our patient, both should be considered early along with radiation therapy in the treatment of malignant extradural spinal cord compression. Finally, a detailed neurologic examination is of paramount importance for every patient with malignancy, including leukemia, and neurological symptoms.
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