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Neuropathology 2014; 34, 547–553
doi:10.1111/neup.12135
C a se Repor t
Methotrexate myelopathy with extensive transverse necrosis: Report of an autopsy case Masayuki Shintaku,1 Nao Toyooka,2 Takashi Koyama,3 Shunsuke Teraoka2 and Mitsuru Tsudo2 Departments of 1Pathology, 2Hematology and 3Diagnostic Radiology, Osaka Red Cross Hospital, Osaka, Japan
The patient was a 70-year-old woman with lymphoplasmacytic lymphoma which showed a predominantly diffuse involvement of the bone marrow and kidney. Because atypical lymphocytes appeared in the cerebrospinal fluid, the intrathecal administration of methotrexate (MTX) and cytosine arabinoside (Ara-C) was repeated several times. The patient developed flaccid paraplegia 8 months after the beginning of intrathecal administration, and died 4 months later. Autopsy demonstrated extensive transverse necrosis involving the lower thoracic cord and marked vacuolar degeneration of the white matter of the cervical, upper thoracic and lumbo-sacral cord. Focal vacuolar degeneration of the white matter was also noted in the left parietal lobe. Although vacuolar degeneration of the white matter is a common feature in MTX myelopathy, extensive transverse necrosis is rare. In the present case, an overlapping of two mechanisms, that is, injury of vascular endothelial cells and the direct toxic effect of MTX and Ara-C on the white matter, probably played a crucial role in the pathogenesis of severe myelopathy. Because severe myelopathy occurs infrequently, considering the large number of patients receiving the intrathecal administration of MTX, it is possible that a constitutional predisposition or abnormal sensitivity to MTX was involved in the pathogenesis in the present patient. Key words: cytosine arabinoside, methotrexate, myelopathy, pathogenesis, transverse necrosis.
INTRODUCTION Methotrexate (MTX) is a folic acid antagonist widely employed for the treatment of hematological malignancies, particularly for the treatment or prophylaxis of CNS
Correspondence: Masayuki Shintaku, MD, Department of Pathology, Osaka Red Cross Hospital, Tennoji, Osaka 543-8555, Japan. Email: [email protected] Received 8 April 2014; revised and accepted 8 May 2014.
© 2014 Japanese Society of Neuropathology
involvement of acute childhood lymphoblastic leukemia.1,2 It is well known that, particularly when applied intrathecally, MTX infrequently induces severe neurological complications which cause very severe sequelae in some cases.1–3 Among these neurological complications, disseminated necrotizing leukoencephalopathy (DNL)1,2,4 and MTX myelopathy5–7 are two major entities which are frequently fatal. While DNL has been widely investigated clinically and also neuropathologically,1,2,4,8,9 reports on the neuropathological findings of MTX myelopathy are relatively rare, and the previously documented findings vary from vacuolar degeneration of the lateral and posterior funiculi5,7 to complete transverse necrosis of the spinal cord.6,10 We report an autopsy case of MTX myelopathy in which the spinal cord showed transverse necrosis involving the lower thoracic cord, in addition to marked vacuolar degeneration of the white matter of the cervical, upper thoracic and lumbo-sacral cord.
CASE REPORT The patient, a previously healthy 70-year-old woman, presented to our hospital with a headache that had exacerbated for 1 month. MRI demonstrated multiple osteolytic lesions in the clivus, sphenoid bone and mandible, and positron emission tomography performed 2 months later revealed additional multifocal lesions involving the bilateral kidneys, bone marrow, pancreas and subcutaneous tissue. Needle biopsies of the renal lesion and bone marrow confirmed a diagnosis of malignant lymphoma of the B-cell type. Generalized lymph node swelling was not found. Blood analyses revealed hypergammaglobulinemia, but monoclonal gammopathy was not demonstrated throughout the clinical course. Although the patient did not have any neurological symptoms on admission, CSF examination demonstrated an increased white blood cell count (478/mm3, mostly atypical lymphocytes) and in addition to the intravenous administration of multiple anti-neoplastic drugs, the intrathecal administration of MTX (at a dose of 15 or
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Fig. 1 (a) MRI of the spinal cord at about two and a half months before death. Swelling of the spinal cord below the level of T4 is seen and the swollen portion of the spinal cord was not enhanced by contrast medium (left, T2-weighted image; right, fat-suppression T1-weighted image with contrast enhancement). (b) CT of the brain at about 2 months before death showing a diffuse low density area spreading over the bilateral deep cerebral white matter.
Fig. 2 (a) The bone marrow at autopsy showing a proliferation of lymphoma cells forming many large nodules. (b) Higher magnification of lymphoma cells showing plasmacytic differentiation (a, HE stain; ×10, b, HE stain, ×100).
12 mg) and cytosine arabinoside (Ara-C, at a dose of 40 or 30 mg) was started two months after the first admission. Atypical lymphocytes in the CSF transiently disappeared after intrathecal administration but appeared repeatedly following the interruption of the administration. The intrathecal administration was repeated 17 times during the subsequent 8 months, and the total doses of MTX and Ara-C amounted to 243 and 640 mg, respectively. Monitoring of the concentration of MTX and Ara-C in the CSF was not performed. Seven months after the beginning of intrathecal administration, fever, weakness of the lower extremities and unsteady gait developed, and many atypical lymphocytes appeared in the peripheral blood. In the next month, flaccid paraplegia and urinary and fecal incontinence appeared, and MRI demonstrated a swelling of the spinal cord below the level of T4 (Fig. 1a). The intrathecal administration was immediately discontinued. Diffuse lowdensity areas were also demonstrated in the bilateral cerebral white matter on CT examination (Fig. 1b). Two months later, the spinal cord lesions had progressed to the lower thoracic level, and disorientation also appeared. The
consciousness level of the patient gradually deteriorated, and she died the following month, about 14 months after the onset of her illness and about 4 months after the onset of neurological symptoms. Autopsy demonstrated lymphoplasmacytic lymphoma which predominantly showed diffuse involvement of the bilateral kidneys (each weighed 190 g) and bone marrow (Fig. 2a,b). Microscopic lymphomatous involvement was also found in the liver, spleen, adrenals, pancreas, uterus and lymph nodes. Other pathological findings included pulmonary aspergillosis (in the right upper lobe), transfusional hemosiderosis and adrenocortical atrophy.
NEUROPATHOLOGICAL FINDINGS Prominent pathological changes were found in the spinal cord (Fig. 3). They consisted of almost complete transverse necrosis (myelomalacia) involving the lower thoracic cord and vacuolar degeneration of the white matter in the cervical, upper thoracic and lumbo-sacral cord (Fig. 4). © 2014 Japanese Society of Neuropathology
Methotrexate myelopathy
Fig. 3 Schematic drawing of the spinal cord lesions. Areas of vacuolar degeneration are indicated by stippling and hatched areas show necrosis or severe disintegration of the tissue.
Fig. 4 Sections of the spinal cord at the levels of C7, Th4, Th10 and L4. Note almost complete transverse necrosis at the thoracic cord and peripherally accentuated vacuolar degeneration of the white matter at the cervical and lumbar cord (Luxol fast blue-PAS stain).
Fig. 5 Coarsely vacuolar degeneration of the peripheral region of the lateral funiculus at the level of C7 (a, HE stain, ×25; b, Luxol fast blue-PAS stain, ×25).
© 2014 Japanese Society of Neuropathology
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Fig. 6 (a) Many axonal spheroids were seen within the lateral funiculus at the level of C3. (b) The gray matter of the spinal cord was relatively well preserved, but some anterior horn cells showed chromatolytic changes. (c) A small focus of vacuolation and rarefaction of the deep white matter of the parietal lobe, comprising a lesion resembling that seen in disseminated necrotizing leukoencephalopathy. (d) Scattered axonal spheroids within the lesion (a, modified Bielschowsky stain, ×50; b, C8, Luxol fast blue-PAS stain, ×50; c, HE stain, ×25; d, modified Bielschowsky stain, ×25).
The lower thoracic cord was swollen and showed marked softening. The tissue architecture of the spinal cord had disappeared and been replaced by an amorphous, necrotic tissue mass covered by the fibrotic pia mater. The infiltration of foamy macrophages was mild, reflecting the interruption of the blood stream, within the necrotic tissue. Only a small portion of the white matter showing marked vacuolar degeneration remained chiefly in the marginal, subpial regions. Neither intravascular thrombosis nor vascular occlusion was seen, and pathological changes of the vascular wall, such as fibrinoid necrosis, vasculitis, fibrohyalinous thickening and calcification, were also not observed in the spinal cord. In the cervical, upper thoracic and lumbo-sacral cord, the bilateral posterior and lateral funiculi exhibited marked, coarsely vacuolar degeneration (Fig. 5a,b). The degeneration was particularly marked in the marginal, subpial regions and accompanied by an infiltration of numerous foamy macrophages. In the degenerated areas, myelin sheaths were almost completely absent.Axons were preserved in comparison with myelin sheaths, and the remaining axons were occasionally situated in the center of vacuoles. From this finding, the vacuolar degeneration was considered most likely to be formed by splitting of the lamellae of myelin sheaths. Axonal spheroids were found in the lateral funiculi of the cervical cord (Fig. 6a). Many foamy macrophages infiltrated the white matter, but no infiltration of other inflammatory cells was found. The pia mater showed fibrous thickening, but small and mediumsized arteries in the subarachnoid space did not show any
stenotic or obstructive lesions. The infiltration of a small number of residual lymphoma cells was noted within the fibrotic pia mater of the lumbo-sacral cord.The gray matter was relatively well preserved, but large anterior horn cells showing central chromatolysis were scattered (Fig. 6b). The brain weighed 1280 g and showed no apparent gross abnormalities except a small focus of hemorrhagic infarct due to aspergillosis in the left occipital lobe. Microscopically, the cerebral cortex showed no marked changes. The white matter of the cerebral hemispheres demonstrated slight edema and rarefaction, and myelin sheaths had been slightly and diffusely lost. Neither axonal swelling nor loss was apparent. The subcortical white matter and corpus callosum were well preserved. The immunohistochemical study demonstrated a mild but diffuse proliferation of CD68-positive microglia/macrophages and mild astrocytosis in the cerebral white matter. Small arteries of the white matter showed mild sclerotic changes. In the left parietal white matter, a small focus of vacuolar degeneration was found (Fig. 6c), which contained several axonal spheroids (Fig. 6d). The basal ganglia, thalamus, brain stem and cerebellum showed no pathological changes, except for vacuolar degeneration of the posterior funiculi in the lower medulla oblongata and of the cerebellar dentate nucleus.
DISCUSSION The intrathecal administration of MTX has been widely employed for the treatment or prophylaxis of CNS involvement of hematological malignancies, particularly acute © 2014 Japanese Society of Neuropathology
Methotrexate myelopathy childhood lymphoblastic leukemia.1,2,4 The occurrence of neurological complications caused by intrathecal MTX administration is well known, but most patients with these complications recover from the transient neurological symptoms, mostly due to aseptic meningitis. However, in a small percentage permanent and occasionally severe neurological sequelae occur.1–4 The development of CNS damage is considered to be independent from the cumulative dose of intrathecal MTX, but dependent on continuous exposure to the drug over a prolonged period.1,11 Most patients with severe neurological complications due to MTX also have a history of cranio-spinal radiation, and a synergistic effect of MTX and radiation is considered a potent pathological mechanism leading to severe damage of CNS tissue.1–5,12,13 Serious myelopathy also occurs due to radiation alone (delayed radiation myelopathy),14–16 and the damage to vascular endothelial cells,15 direct injury of oligodendroglia and myelin sheaths,16 and disturbance of the intraspinal venous drainage due to lesions of the venous walls14 are considered important pathogenetic factors by various investigators. However, as exemplified in the present case, CNS damage can occur due to the administration of MTX alone without radiation.8,9 Among the serious neurological sequelae induced by the systemic or intrathecal administration of MTX, DNL1,2,4 and MTX myelopathy5–7 comprise two major disease entities. Other rare variants include disseminated demyelinating leukoencephalopathy,8,9 parenchymatous degeneration with gliosis and axonal dystrophy17 (or “multifocal axonopathy”),13 and diffuse or focal subpial necrosis of the gray matter.18 MTX myelopathy clinically manifests as paraplegia in most patients.7 Pathological alterations mainly affect the marginal regions of the spinal cord in a circumferential manner, and coarsely vacuolar degeneration of the white matter in association with severe loss of axons and myelin sheaths is a characteristic finding.5,7,19,20 The gray matter is relatively well preserved. It is usually accompanied by the infiltration of foamy macrophages and reactive astrocytosis, and dystrophic calcification is also frequently observed. The lesions involve the brain stem upward to the level of the midbrain in some cases.20 Reznik reported a rare case of acute ischemic necrosis which involved the anterior horn of the entire length of the spinal cord in a girl with acute lymphocytic leukemia, although the pathogenesis of this gray matter lesion remained unknown.21 Transverse necrosis of the thoracic cord, which is similar to that seen in the present case, has been reported by Grisold et al.10 and von der Weid et al.6 in patients with acute lymphoblastic leukemia. The pathogenesis of MTX myelopathy has yet to be fully elucidated. It is probably multifactorial, but two major mechanisms are considered to exist. One is an injury to endothelial cells of venules and capillaries of the spinal cord © 2014 Japanese Society of Neuropathology
551 which causes alterations of the blood-brain barrier, an increase in vascular permeability, and the insinuation of plasma proteins into the vascular wall.3,12,22 These factors lead to degeneration and necrosis of the vascular wall and cause vacuolar degeneration of the white matter due to anoxia. The vascular injury also allows MTX to diffuse into the CNS parenchyma and, as described next, to directly exert toxic effects. These mechanisms resemble those operating in delayed radiation myelopathy,14–16 but as seen in the present case, pathological changes of the intraspinal vascular wall are usually not prominent in MTX myelopathy, at least at a light microscopic level. The other major mechanism is a direct toxic effect on the pia mater and white matter caused by intrathecal administration, which leads to disruption of the pia-glial barrier and injury to myelin sheaths and oligodendrocytes.3,6,7,18,22 MTX is a folic acid-antagonist which inhibits DNA synthesis through competitive inhibition of the action of dihydrofolate reductase. Metabolic disturbance of folic acid induced by MTX also indirectly inhibits the synthesis of methionine, which is necessary for the formation and maintenance of myelin sheaths, and finally leads to vacuolar degeneration of the white matter.7,23 These pathomechanisms have something in common with those of subacute combined degeneration of the spinal cord due to vitamin B12 deficiency.24 In the case of MTX myelopathy, the constitutional predisposition or abnormal sensitivity to MTX (idiosyncrasy) of patients, such as genetic polymorphisms or mutations concerning methionine metabolism,23,25,26 is also probably involved in the pathogenesis, because the reported frequency of severe MTX myelopathy is disproportionately low, considering the large number of patients receiving intrathecal MTX administration. In the present case, these multiple mechanisms are considered to have overlapped and caused extensive transverse necrosis of the lower thoracic cord and vacuolar degeneration of the white matter. In addition, both the neurotoxicity of the intrathecally administered Ara-C and the presence of lymphoma cells within the subarachnoid space probably exerted deleterious effects to aggravate the spinal cord lesions. Myelopathic changes induced by the intrathecal administration of Ara-C, which inhibits DNA synthesis by competitively inhibiting the action of DNA polymerase, are rarely known to occur,27 and in some reported cases of MTX myelopathy, Ara-C was administered in addition to MTX.6,19 The presence of lymphoma or leukemic cells in the subarachnoid space or leptomeninges is known to impair the transport of MTX from the CSF to systemic circulation.11 In our case, the presence of lymphoma cells within the subarachnoid space might have been one of the factors causing the aggravation of the spinal cord lesions.
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The reason why the lesions in the present case were most severe at the level of the lower thoracic cord can be partly explained by the fact that the lower thoracic cord is most vulnerable to circulatory disturbance or venous congestion.28 In addition to the primary lesions due to MTX myelopathy, secondary (Wallerian) degeneration of the descending and ascending fiber tracts probably contributed to the formation of the white matter lesions of the spinal cord in the present case, but the differentiation of secondary degeneration from the primary MTX lesions was difficult in the sections. The present patient had lymphoplasmacytic lymphoma. Lymphoplasmacytic lymphoma is occasionally associated with IgM monoclonal gammopathy (Waldenström’s macroglobulinemia), and Scheithauer et al. reported a case in which multiple plaque-like demyelinating lesions were found in the cerebral white matter.29 The topographical relationship between the demyelinating lesions, perivascular extravasation of IgM-containing plasma protein and lymphomatous infiltration was apparent in their case.29 In our case, monoclonal gammopathy was not demonstrated during the clinical course, and it is unlikely that abnormal hypergammaglobulinemia exerted a deleterious effect to aggravate the pathogenesis of the spinal cord lesions. In conclusion, MTX myelopathy is, although occurring only infrequently, a grave and often fatal complication of the intrathecal administration of MTX. Meticulous neurological observation and the sequential monitoring of MTX concentration in the CSF are probably the most important procedures to prevent the occurrence of this complication.
REFERENCES 1. Price RA, Jamieson PA. The central nervous system in childhood leukemia. II. Subacute leukoencephalopathy. Cancer 1975; 35: 306–318. 2. Liu HM, Maurer HS, Vongsvivut S, Conway JJ. Methotrexate encephalopathy. A neuropathologic study. Hum Pathol 1978; 9: 635–648. 3. Perry A, Schmidt RE. Cancer therapy-associated CNS neuropathology: an update and review of the literature. Acta Neuropathol 2006; 111: 197–212. 4. Rubinstein LJ, Herman MM, Long TF, Wilbur JR. Disseminated necrotizing leukoencephalopathy. A complication of treated central nervous system leukemia and lymphoma. Cancer 1975; 35: 291–305. 5. Clark AW, Cohen SR, Nissenblatt MJ, Wilson SK. Paraplegia following intrathecal chemotherapy. Neuropathologic findings and elevation of myelin basic protein. Cancer 1982; 50: 42–47.
6. von der Weid NX, de Crousaz H, Beck D, Deonna T, Miklossy J, Janzer RC. Acute fatal myeloencephalopathy after combined intrathecal chemotherapy in a child with acute lymphoblastic leukemia. Med Pediatr Oncol 1991; 19: 192–198. 7. Honda D, Ochiai J, Ujihira N, Yoshida M, Sobue G. Methotrexate myelopathy. Neurol Med (Tokyo) 2012; 77: 35–42. 8. Matsubayashi J, Tsuchiya K, Matsunaga T, Mukai K. Methotrexate-related leukoencephalopathy without radiation therapy. Distribution of brain lesions and pathological heterogeneity on two autopsy cases. Neuropathology 2009; 29: 105–115. 9. Yokoo H, Nakazato Y, Harigaya Y, Sasaki N, Igeta Y, Itoh H. Massive myelinolytic leukoencephalopathy in a patient medicated with low-dose oral methotrexate for rheumatoid arthritis. An autopsy report. Acta Neuropathol 2007; 114: 425–430. 10. Grisold W, Lutz D, Wolf D. Necrotizing myelopathy associated with acute lymphoblastic leukemia. Acta Neuropathol 1980; 49: 231–235. 11. Bleyer WA, Drake JC, Chabner BA. Neurotoxicity and elevated cerebrospinal-fluid methotrexate concentration in meningeal leukemia. N Engl J Med 1973; 289: 770–773. 12. Suzuki K, Takemura T, Okeda R, Hatakeyama S. Vascular changes of methotrexate-related disseminated necrotizing leukoencephalopathy. Acta Neuropathol 1984; 65: 145–149. 13. Shibutani M, Okeda R, Hori A, Schipper H. Methotrexate-related multifocal axonopathy. Report of an autopsy case. Acta Neuropathol 1989; 79: 333– 335. 14. Okeda R. Two autopsy cases of radiation myelopathy. Consideration about the pathogenesis. Adv Neurol Sci (Tokyo) 1971; 15: 619–639. 15. Jellinger K, Sturm KW. Delayed radiation myelopathy in man. Report of twelve necropsy cases. J Neurol Sci 1971; 14: 389–408. 16. Burns RJ, Jones AN, Robertson JS. Pathology of radiation myelopathy. J Neurol Neurosurg Psychiat 1972; 35: 888–898. 17. Hendin B, DeVivo DC, Torack R, Lell ME, Ragab AH, Vietti TJ. Parenchymatous degeneration of the central nervous system in childhood leukemia. Cancer 1974; 33: 468–482. 18. Skullerud K, Halvorsen K. Encephalomyelopathy following intrathecal methotrexate treatment in a child with acute leukemia. Cancer 1978; 42: 1211– 1215. 19. Saiki JH, Thompson S, Smith F, Atkinson R. Paraplegia following intrathecal chemotherapy. Cancer 1972; 29: 370–374. © 2014 Japanese Society of Neuropathology
Methotrexate myelopathy 20. Tomonaga M, Takeno Y, Ishii N, Okayama M. Paraplegia following intrathecal methotrexate. Adv Neurol Sci (Tokyo) 1978; 22: 1204–1211. 21. Reznik M. Acute ascending poliomyelomalacia after treatment of acute lymphocytic leukemia. Acta Neuropathol 1979; 45: 153–157. 22. Shibutani M, Okeda R. Experimental study on subacute neurotoxicity of methotrexate in cats. Acta Neuropathol 1989; 78: 291–300. 23. Linnebank M, Pels H, Kleczar N et al. MTX-induced white matter changes are associated with polymorphisms of methionine metabolism. Neurology 2005; 64: 912–913. 24. Pant SS, Asbury AK, Richardson EP Jr. The myelopathy of pernicious anemia. A neuropathological reappraisal. Acta Neurol Scand 1968; 44 (Suppl. 35): 1–36. 25. Linnebank M, Moskau S, Jürgens A et al. Association of genetic variants of methionine metabolism with
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methotrexate-induced CNS white matter changes in patients with primary CNS lymphoma. Neuro-oncol 2009; 11: 2–8. Ackermann R, Semmler A, Maurer GD et al. Methotrexate-induced myelopathy responsive to substitution of multiple folate metabolites. J Neurooncol 2010; 97: 425–427. Breuer AC, Pitman SW, Dawson DM, Schoene WC. Paraparesis following intrathecal cytosine arabinoside. A case report with neuropathologic findings. Cancer 1977; 40: 2817–2822. Wolf HK, Anthony DC, Fuller GN. Arterial border zone necrosis of the spinal cord. Clin Neuropathol 1990; 9: 60–65. Scheithauer BW, Rubinstein LJ, Herman MM. Leukoencephalopathy in Waldenström’s macroglobulinemia. Immunohistochemical and electron microscopic observations. J Neuropathol Exp Neurol 1984; 43: 408–425.
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Neuropathology 2014; 34, 547–553
doi:10.1111/neup.12135
C a se Repor t
Methotrexate myelopathy with extensive transverse necrosis: Report of an autopsy case Masayuki Shintaku,1 Nao Toyooka,2 Takashi Koyama,3 Shunsuke Teraoka2 and Mitsuru Tsudo2 Departments of 1Pathology, 2Hematology and 3Diagnostic Radiology, Osaka Red Cross Hospital, Osaka, Japan
The patient was a 70-year-old woman with lymphoplasmacytic lymphoma which showed a predominantly diffuse involvement of the bone marrow and kidney. Because atypical lymphocytes appeared in the cerebrospinal fluid, the intrathecal administration of methotrexate (MTX) and cytosine arabinoside (Ara-C) was repeated several times. The patient developed flaccid paraplegia 8 months after the beginning of intrathecal administration, and died 4 months later. Autopsy demonstrated extensive transverse necrosis involving the lower thoracic cord and marked vacuolar degeneration of the white matter of the cervical, upper thoracic and lumbo-sacral cord. Focal vacuolar degeneration of the white matter was also noted in the left parietal lobe. Although vacuolar degeneration of the white matter is a common feature in MTX myelopathy, extensive transverse necrosis is rare. In the present case, an overlapping of two mechanisms, that is, injury of vascular endothelial cells and the direct toxic effect of MTX and Ara-C on the white matter, probably played a crucial role in the pathogenesis of severe myelopathy. Because severe myelopathy occurs infrequently, considering the large number of patients receiving the intrathecal administration of MTX, it is possible that a constitutional predisposition or abnormal sensitivity to MTX was involved in the pathogenesis in the present patient. Key words: cytosine arabinoside, methotrexate, myelopathy, pathogenesis, transverse necrosis.
INTRODUCTION Methotrexate (MTX) is a folic acid antagonist widely employed for the treatment of hematological malignancies, particularly for the treatment or prophylaxis of CNS
Correspondence: Masayuki Shintaku, MD, Department of Pathology, Osaka Red Cross Hospital, Tennoji, Osaka 543-8555, Japan. Email: [email protected] Received 8 April 2014; revised and accepted 8 May 2014.
© 2014 Japanese Society of Neuropathology
involvement of acute childhood lymphoblastic leukemia.1,2 It is well known that, particularly when applied intrathecally, MTX infrequently induces severe neurological complications which cause very severe sequelae in some cases.1–3 Among these neurological complications, disseminated necrotizing leukoencephalopathy (DNL)1,2,4 and MTX myelopathy5–7 are two major entities which are frequently fatal. While DNL has been widely investigated clinically and also neuropathologically,1,2,4,8,9 reports on the neuropathological findings of MTX myelopathy are relatively rare, and the previously documented findings vary from vacuolar degeneration of the lateral and posterior funiculi5,7 to complete transverse necrosis of the spinal cord.6,10 We report an autopsy case of MTX myelopathy in which the spinal cord showed transverse necrosis involving the lower thoracic cord, in addition to marked vacuolar degeneration of the white matter of the cervical, upper thoracic and lumbo-sacral cord.
CASE REPORT The patient, a previously healthy 70-year-old woman, presented to our hospital with a headache that had exacerbated for 1 month. MRI demonstrated multiple osteolytic lesions in the clivus, sphenoid bone and mandible, and positron emission tomography performed 2 months later revealed additional multifocal lesions involving the bilateral kidneys, bone marrow, pancreas and subcutaneous tissue. Needle biopsies of the renal lesion and bone marrow confirmed a diagnosis of malignant lymphoma of the B-cell type. Generalized lymph node swelling was not found. Blood analyses revealed hypergammaglobulinemia, but monoclonal gammopathy was not demonstrated throughout the clinical course. Although the patient did not have any neurological symptoms on admission, CSF examination demonstrated an increased white blood cell count (478/mm3, mostly atypical lymphocytes) and in addition to the intravenous administration of multiple anti-neoplastic drugs, the intrathecal administration of MTX (at a dose of 15 or
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Fig. 1 (a) MRI of the spinal cord at about two and a half months before death. Swelling of the spinal cord below the level of T4 is seen and the swollen portion of the spinal cord was not enhanced by contrast medium (left, T2-weighted image; right, fat-suppression T1-weighted image with contrast enhancement). (b) CT of the brain at about 2 months before death showing a diffuse low density area spreading over the bilateral deep cerebral white matter.
Fig. 2 (a) The bone marrow at autopsy showing a proliferation of lymphoma cells forming many large nodules. (b) Higher magnification of lymphoma cells showing plasmacytic differentiation (a, HE stain; ×10, b, HE stain, ×100).
12 mg) and cytosine arabinoside (Ara-C, at a dose of 40 or 30 mg) was started two months after the first admission. Atypical lymphocytes in the CSF transiently disappeared after intrathecal administration but appeared repeatedly following the interruption of the administration. The intrathecal administration was repeated 17 times during the subsequent 8 months, and the total doses of MTX and Ara-C amounted to 243 and 640 mg, respectively. Monitoring of the concentration of MTX and Ara-C in the CSF was not performed. Seven months after the beginning of intrathecal administration, fever, weakness of the lower extremities and unsteady gait developed, and many atypical lymphocytes appeared in the peripheral blood. In the next month, flaccid paraplegia and urinary and fecal incontinence appeared, and MRI demonstrated a swelling of the spinal cord below the level of T4 (Fig. 1a). The intrathecal administration was immediately discontinued. Diffuse lowdensity areas were also demonstrated in the bilateral cerebral white matter on CT examination (Fig. 1b). Two months later, the spinal cord lesions had progressed to the lower thoracic level, and disorientation also appeared. The
consciousness level of the patient gradually deteriorated, and she died the following month, about 14 months after the onset of her illness and about 4 months after the onset of neurological symptoms. Autopsy demonstrated lymphoplasmacytic lymphoma which predominantly showed diffuse involvement of the bilateral kidneys (each weighed 190 g) and bone marrow (Fig. 2a,b). Microscopic lymphomatous involvement was also found in the liver, spleen, adrenals, pancreas, uterus and lymph nodes. Other pathological findings included pulmonary aspergillosis (in the right upper lobe), transfusional hemosiderosis and adrenocortical atrophy.
NEUROPATHOLOGICAL FINDINGS Prominent pathological changes were found in the spinal cord (Fig. 3). They consisted of almost complete transverse necrosis (myelomalacia) involving the lower thoracic cord and vacuolar degeneration of the white matter in the cervical, upper thoracic and lumbo-sacral cord (Fig. 4). © 2014 Japanese Society of Neuropathology
Methotrexate myelopathy
Fig. 3 Schematic drawing of the spinal cord lesions. Areas of vacuolar degeneration are indicated by stippling and hatched areas show necrosis or severe disintegration of the tissue.
Fig. 4 Sections of the spinal cord at the levels of C7, Th4, Th10 and L4. Note almost complete transverse necrosis at the thoracic cord and peripherally accentuated vacuolar degeneration of the white matter at the cervical and lumbar cord (Luxol fast blue-PAS stain).
Fig. 5 Coarsely vacuolar degeneration of the peripheral region of the lateral funiculus at the level of C7 (a, HE stain, ×25; b, Luxol fast blue-PAS stain, ×25).
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Fig. 6 (a) Many axonal spheroids were seen within the lateral funiculus at the level of C3. (b) The gray matter of the spinal cord was relatively well preserved, but some anterior horn cells showed chromatolytic changes. (c) A small focus of vacuolation and rarefaction of the deep white matter of the parietal lobe, comprising a lesion resembling that seen in disseminated necrotizing leukoencephalopathy. (d) Scattered axonal spheroids within the lesion (a, modified Bielschowsky stain, ×50; b, C8, Luxol fast blue-PAS stain, ×50; c, HE stain, ×25; d, modified Bielschowsky stain, ×25).
The lower thoracic cord was swollen and showed marked softening. The tissue architecture of the spinal cord had disappeared and been replaced by an amorphous, necrotic tissue mass covered by the fibrotic pia mater. The infiltration of foamy macrophages was mild, reflecting the interruption of the blood stream, within the necrotic tissue. Only a small portion of the white matter showing marked vacuolar degeneration remained chiefly in the marginal, subpial regions. Neither intravascular thrombosis nor vascular occlusion was seen, and pathological changes of the vascular wall, such as fibrinoid necrosis, vasculitis, fibrohyalinous thickening and calcification, were also not observed in the spinal cord. In the cervical, upper thoracic and lumbo-sacral cord, the bilateral posterior and lateral funiculi exhibited marked, coarsely vacuolar degeneration (Fig. 5a,b). The degeneration was particularly marked in the marginal, subpial regions and accompanied by an infiltration of numerous foamy macrophages. In the degenerated areas, myelin sheaths were almost completely absent.Axons were preserved in comparison with myelin sheaths, and the remaining axons were occasionally situated in the center of vacuoles. From this finding, the vacuolar degeneration was considered most likely to be formed by splitting of the lamellae of myelin sheaths. Axonal spheroids were found in the lateral funiculi of the cervical cord (Fig. 6a). Many foamy macrophages infiltrated the white matter, but no infiltration of other inflammatory cells was found. The pia mater showed fibrous thickening, but small and mediumsized arteries in the subarachnoid space did not show any
stenotic or obstructive lesions. The infiltration of a small number of residual lymphoma cells was noted within the fibrotic pia mater of the lumbo-sacral cord.The gray matter was relatively well preserved, but large anterior horn cells showing central chromatolysis were scattered (Fig. 6b). The brain weighed 1280 g and showed no apparent gross abnormalities except a small focus of hemorrhagic infarct due to aspergillosis in the left occipital lobe. Microscopically, the cerebral cortex showed no marked changes. The white matter of the cerebral hemispheres demonstrated slight edema and rarefaction, and myelin sheaths had been slightly and diffusely lost. Neither axonal swelling nor loss was apparent. The subcortical white matter and corpus callosum were well preserved. The immunohistochemical study demonstrated a mild but diffuse proliferation of CD68-positive microglia/macrophages and mild astrocytosis in the cerebral white matter. Small arteries of the white matter showed mild sclerotic changes. In the left parietal white matter, a small focus of vacuolar degeneration was found (Fig. 6c), which contained several axonal spheroids (Fig. 6d). The basal ganglia, thalamus, brain stem and cerebellum showed no pathological changes, except for vacuolar degeneration of the posterior funiculi in the lower medulla oblongata and of the cerebellar dentate nucleus.
DISCUSSION The intrathecal administration of MTX has been widely employed for the treatment or prophylaxis of CNS involvement of hematological malignancies, particularly acute © 2014 Japanese Society of Neuropathology
Methotrexate myelopathy childhood lymphoblastic leukemia.1,2,4 The occurrence of neurological complications caused by intrathecal MTX administration is well known, but most patients with these complications recover from the transient neurological symptoms, mostly due to aseptic meningitis. However, in a small percentage permanent and occasionally severe neurological sequelae occur.1–4 The development of CNS damage is considered to be independent from the cumulative dose of intrathecal MTX, but dependent on continuous exposure to the drug over a prolonged period.1,11 Most patients with severe neurological complications due to MTX also have a history of cranio-spinal radiation, and a synergistic effect of MTX and radiation is considered a potent pathological mechanism leading to severe damage of CNS tissue.1–5,12,13 Serious myelopathy also occurs due to radiation alone (delayed radiation myelopathy),14–16 and the damage to vascular endothelial cells,15 direct injury of oligodendroglia and myelin sheaths,16 and disturbance of the intraspinal venous drainage due to lesions of the venous walls14 are considered important pathogenetic factors by various investigators. However, as exemplified in the present case, CNS damage can occur due to the administration of MTX alone without radiation.8,9 Among the serious neurological sequelae induced by the systemic or intrathecal administration of MTX, DNL1,2,4 and MTX myelopathy5–7 comprise two major disease entities. Other rare variants include disseminated demyelinating leukoencephalopathy,8,9 parenchymatous degeneration with gliosis and axonal dystrophy17 (or “multifocal axonopathy”),13 and diffuse or focal subpial necrosis of the gray matter.18 MTX myelopathy clinically manifests as paraplegia in most patients.7 Pathological alterations mainly affect the marginal regions of the spinal cord in a circumferential manner, and coarsely vacuolar degeneration of the white matter in association with severe loss of axons and myelin sheaths is a characteristic finding.5,7,19,20 The gray matter is relatively well preserved. It is usually accompanied by the infiltration of foamy macrophages and reactive astrocytosis, and dystrophic calcification is also frequently observed. The lesions involve the brain stem upward to the level of the midbrain in some cases.20 Reznik reported a rare case of acute ischemic necrosis which involved the anterior horn of the entire length of the spinal cord in a girl with acute lymphocytic leukemia, although the pathogenesis of this gray matter lesion remained unknown.21 Transverse necrosis of the thoracic cord, which is similar to that seen in the present case, has been reported by Grisold et al.10 and von der Weid et al.6 in patients with acute lymphoblastic leukemia. The pathogenesis of MTX myelopathy has yet to be fully elucidated. It is probably multifactorial, but two major mechanisms are considered to exist. One is an injury to endothelial cells of venules and capillaries of the spinal cord © 2014 Japanese Society of Neuropathology
551 which causes alterations of the blood-brain barrier, an increase in vascular permeability, and the insinuation of plasma proteins into the vascular wall.3,12,22 These factors lead to degeneration and necrosis of the vascular wall and cause vacuolar degeneration of the white matter due to anoxia. The vascular injury also allows MTX to diffuse into the CNS parenchyma and, as described next, to directly exert toxic effects. These mechanisms resemble those operating in delayed radiation myelopathy,14–16 but as seen in the present case, pathological changes of the intraspinal vascular wall are usually not prominent in MTX myelopathy, at least at a light microscopic level. The other major mechanism is a direct toxic effect on the pia mater and white matter caused by intrathecal administration, which leads to disruption of the pia-glial barrier and injury to myelin sheaths and oligodendrocytes.3,6,7,18,22 MTX is a folic acid-antagonist which inhibits DNA synthesis through competitive inhibition of the action of dihydrofolate reductase. Metabolic disturbance of folic acid induced by MTX also indirectly inhibits the synthesis of methionine, which is necessary for the formation and maintenance of myelin sheaths, and finally leads to vacuolar degeneration of the white matter.7,23 These pathomechanisms have something in common with those of subacute combined degeneration of the spinal cord due to vitamin B12 deficiency.24 In the case of MTX myelopathy, the constitutional predisposition or abnormal sensitivity to MTX (idiosyncrasy) of patients, such as genetic polymorphisms or mutations concerning methionine metabolism,23,25,26 is also probably involved in the pathogenesis, because the reported frequency of severe MTX myelopathy is disproportionately low, considering the large number of patients receiving intrathecal MTX administration. In the present case, these multiple mechanisms are considered to have overlapped and caused extensive transverse necrosis of the lower thoracic cord and vacuolar degeneration of the white matter. In addition, both the neurotoxicity of the intrathecally administered Ara-C and the presence of lymphoma cells within the subarachnoid space probably exerted deleterious effects to aggravate the spinal cord lesions. Myelopathic changes induced by the intrathecal administration of Ara-C, which inhibits DNA synthesis by competitively inhibiting the action of DNA polymerase, are rarely known to occur,27 and in some reported cases of MTX myelopathy, Ara-C was administered in addition to MTX.6,19 The presence of lymphoma or leukemic cells in the subarachnoid space or leptomeninges is known to impair the transport of MTX from the CSF to systemic circulation.11 In our case, the presence of lymphoma cells within the subarachnoid space might have been one of the factors causing the aggravation of the spinal cord lesions.
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The reason why the lesions in the present case were most severe at the level of the lower thoracic cord can be partly explained by the fact that the lower thoracic cord is most vulnerable to circulatory disturbance or venous congestion.28 In addition to the primary lesions due to MTX myelopathy, secondary (Wallerian) degeneration of the descending and ascending fiber tracts probably contributed to the formation of the white matter lesions of the spinal cord in the present case, but the differentiation of secondary degeneration from the primary MTX lesions was difficult in the sections. The present patient had lymphoplasmacytic lymphoma. Lymphoplasmacytic lymphoma is occasionally associated with IgM monoclonal gammopathy (Waldenström’s macroglobulinemia), and Scheithauer et al. reported a case in which multiple plaque-like demyelinating lesions were found in the cerebral white matter.29 The topographical relationship between the demyelinating lesions, perivascular extravasation of IgM-containing plasma protein and lymphomatous infiltration was apparent in their case.29 In our case, monoclonal gammopathy was not demonstrated during the clinical course, and it is unlikely that abnormal hypergammaglobulinemia exerted a deleterious effect to aggravate the pathogenesis of the spinal cord lesions. In conclusion, MTX myelopathy is, although occurring only infrequently, a grave and often fatal complication of the intrathecal administration of MTX. Meticulous neurological observation and the sequential monitoring of MTX concentration in the CSF are probably the most important procedures to prevent the occurrence of this complication.
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