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Central Nervous System Angiocentric, Angiodestructive T-Cell Lymphoma (Lymphomatoid Granulomatosis) B.K. Kleinschmidt-DeMasters, M.D., Christopher M. Filley, M.D., and Mitchell A. Bitter, M.D. Departments of Pathology and Neurology, University of Colorado Health Sciences Center, Denver, Colorado
Kleinschmidt-DeMasters BK, Filley CM, Bitter MA. Central nervous system angiocentric, angiodestructive T-cell lymphoma (lymphomatoid granulomatosis). Surg Neurol 1992;37:130-7.
Most neurosurgeons and neurologists still consider lymphomatoid granulomatosis (LG) as a type of central nervous system (CNS) vasculitis. However, new insights, primarily from the hematologic literature, have cast doubt on the benign character of this disorder. In this article we (1) report a case of an 18-year-old woman with diffuse CNS disease and no mass lesion who developed multiple small cortical infarcts and dementia secondary to multifocal angiocentric, angiodestructive lymphoma; we (2) review other cases of LG with predominant CNS involvement; we (3) summarize the current understanding of LG, which is now considered to be a premalignant or overt angiocentric, angiodestructive T-cell lymphoma rather than a nonneoplastic vasculitis: the importance to neurologic surgeons and neurologists is that while pulmonary involvement in LG is generally the most prominent finding, patients may present with early or dramatic CNS disease; and we (4) note that although dementia is uncommon in young adults, this report adds yet another rare condition to the long differential list of dementia in this age group. KEY WORDS: Dementia; Multiinfarct; Angiocentric; T-cell; Lymphorna
The entity lymphomatoid granulomatosis (LG) is undergoing reevaluation. "Angiocentric immunoproliferative lesion" (ALL) [9,18] has been coined in the hematologic literature to encompass LG, and it better describes an angiocentric, angiodestructive disease that is characterized neither by multinucleated giant cells nor by true granulomas [20,23]. LG lies at the higher grade end of this hematologic spectrum of AIL. Many hematopatholAddress reprint requests to: B.K. Kleinschmidt-DeMasters, Departments of Pathology and Neurology, University of Colorado Health Sciences Center, 4200 East Ninth Avenue (B216), Denver, Colorado 80262-0216. Received August 5, 1991; accepted August 19, 1991.
~:) 1992 by Elscvier Science PublishingCo., Inc.
ogists feel LG should be considered a malignant angiocentric, angiodestructive lymphoma from onset [9,18]. Recent investigations using immunophenotyping and molecular techniques in LG lying outside the central nervous system (CNS) have demonstrated the T-cell nature of AIL/LG [5,11,13,24,26,34,36], its premalignant or overtly lymphomatous character (angiocentric Tcell lymphoma) [11,13,18,26,34,36], its clonality [13,36], and its association, in some cases, with Epstein-Barr virus [25]. Although the disease mostly involves the lungs and extrapulmonary sites such as the upper respiratory tract, skin, kidney, and peripheral nervous system [20,23], the CNS is involved in approximately 30% of cases [20] and has generated special interest and diagnostic difficulties. Even if disputed cases of CNS AIL/LG [2,7,17] are eliminated, no single clinical presentation has been characteristic. Patients may display varied neurologic deficits secondary to the seemingly random involvement of one or more CNS sites. We document an unusual case with multiinfarct dementia and review previously reported cases of AIL/LG with predominant CNS involvement as well as recent literature on AIL/LG.
Case Report A 22-year-old right-handed woman had been in good health except for scoliosis until she began to experience memory loss, emotional lability, and tremor at age 18. These problems progressed slowly, and at age 19 she noted that her left leg was slightly weaker than the right. Examination at that time disclosed poor recent m e m o r y (one of five objects at 5 minutes), dyscalculia, concrete proverb interpretation, a fine postural tremor o f the hands, and impaired heel-to-shin testing of the left lower extremity. A computed tomography (CT) scan of the brain showed a hypodense lesion in the right putamen and enlargement of the right sylvian fissure; magnetic resonance imaging (MRI) revealed right putamenal hyperintensity on T2-weighted images and mild generalized atrophy. An electroencephalogram (EEG) disclosed 0090 ~019/92/$3.00
Angiocentric, Angiodestructive Lymphoma
generalized high-amplitude sharp waves, often with a right predominance. The results of bilateral internal carotid and left vertebral arteriography were normal. Neuropsychological testing found that she had significant verbal and nonverbal memory deficits, a tendency toward anger and irritability, and generalized intellectual decline (Full Scale IQ 76, Verbal IQ 78, and Performance IQ 86). At age 20 she was admitted to a psychiatric hospital for disinhibited behavior. Examination showed poor recent memory (one of four words at 5 minutes), impulsivity, distractibility, tremor, and an equivocal left upgoing toe. MRI was unchanged, but the EEG now showed right temporal spikes. Visual, auditory, and somatosensory evoked potentials were all normal. Lumbar puncture produced clear fluid with a glucose of 55 mg/100 mL, protein of 47 mg/100 mL, 2 mononuclear cells, 0 red blood cells/uL, negative Gram stain and cryptococcal antigen, nonreactive venereal disease research laboratories, and 2 oligoclonal bands. Blood chemistry survey, complete blood count, erythrocyte sedimentation rate, antinuclear antibody, urinalysis, thyroid function tests, vitamin B12 and folate levels, and a test for human immunodeficiency virus (HIV) all produced negative or unremarkable results. A chest roentgenogram disclosed scoliosis and Harrington rods that had been placed at age 13. Results of a slit lamp examination and serum ceruloplasmin level were normal. Administration of carbamazepine led to minimal improvement in her frequent irritable outbursts. A neuropsychological evaluation documented deterioration in memory and behavior and recorded a Full Scale IQ of 73 (Verbal IQ 76, Performance IQ 72). Generalized myoclonic jerks began, followed by complex partial and generalized seizures soon thereafter. Left hemiparesis became evident, and a wheelchair was necessary. Arterial lactate and urinary organic acid levels were normal. Antibody titers against measles, rubella, mumps, herpes simplex, varicella zoster, and parainfluenza 1 and 2 were all 1 : 20 or less. An echocardiogram found mitral and tricuspid prolapse without valvular insufficiency. The findings of nerve conduction studies and electromyography were normal. Brain biopsy from the right insular cortex was performed 2 years after the onset of symptoms and disclosed an angiocentric lymphoma, characterized by gray matter vascular permeation. The lymphomatous infiltrate was composed of medium-sized cells with convoluted nuclei, admixed with small numbers of histiocytes and nonneoplastic-appearing lymphocytes. Vascular thrombi were not present. A needle biopsy of the adjacent putamenal biopsy showed reactive astrocytosis, perivascular lymphocytes, and hemosiderin pigment but no infarct. Individual neoplastic cells infiltrated between involved blood
Surg Neurol 1992;37:130-7
131
F i g u r e 1. T2-weighted M R I scan at age 22 demonstrating bioccipital cortica] hyperintensity but no mass or white matter involvement. A n unrelated, clinically subtle subdura/ hematoma, probably sustained during a seizure with head injury, is also shown on the left (TR = .7,000. TE =
40~.
vessels, but no cohesive mass was present. Immunophenotypmg was unsuccessful owing to the focal nature of the process and tissue exhaustion. A trial of 80 mg/day prednisone for 3 weeks with 2 weeks of tapering doses produced no benefit. At that point, 3000 cGy of wholebrain irradiation was administered over 15 sessions, and marked improvement was apparent. The patient was able to walk without assistance, and the tremor abated. Chemotherapy with cis-platin, cytarabine, and dexamethasone resulted in no further improvement, and in part because of leukopenia this regimen was terminated. The patient then remained stable for the next 18 months, continuing to walk without assistance and with much improved behavioral control. Two to four seizures per month were noted, most of which were of a complex partial nature. Four years after the onset of symptoms, at age 22, she had an MRI scan (Figure 1) that disclosed bioccipital hyperintensity on T2-weighted images, which is consistent with recent infarction. A repeat biopsy, this time of the right occipital lobe, was carried out, and a grade III angiocentric immunoproliferative lesion [24] (angiocentric lymphoma) was identified, which was histologically similar to the first biopsy and involved gray matter blood vessels and leptomeninges. Recent small
132
Surg Neurol 1992;37:130-7
Figure 2. Low-powerphotomicrograph taken from the secondbrain biopsy illustrating the angiocentricity of the neoplastic infiltrate in the upper half of the illustration. The pale, vacuolatedarea in the lower half of the photo is acute infarction. Hematoxylin and eosin stain × 230.
cortical infarcts were noted near vessels involved by the angiocentric, angiodestructive lymphoma (Figure 2). Occasional small cortical vessels contained thrombi and fibrinoid necrosis. Remote cavitated cortical infarcts were also present but not intimately associated with lymphoma. N o cohesive lymphomatous mass was found. Cytologically malignant cells with convoluted hyperchromatic nuclei were again admixed with smaller numbers of nonneoplastic lymphocytes, plasma cells, and histiocytes (Figure 3). Immunophenotyping was carried out on frozen, B-5, and formalin-fixed tissue and showed the lymphoma to be of a T < e l l origin (see Table 1). The pan T-cell antigens CD5 and CD7 were not expressed, as is characteristic of many T-cell lymphomas [30]. T d T was also not expressed, which is consistent with a more mature, nonlymphoblastic T-cell lymphoma. The result of H I V testing was again negative, as it was for testing for the human T-lymphocytic virus, type I
Kleinschmidt-DeMasters et al
(HTLV-I). Testing for Epstein-Barr virus revealed a viral capsular antigen IgG titer o f 1 : 640, Epstein-Barr nuclear antigen titer of 1 : 3 2 0 , and envelope antigen and viral capsular antigen titer
Surg Neurol 1992;37:130-7
Central Nervous System Angiocentric, Angiodestructive T-Cell Lymphoma (Lymphomatoid Granulomatosis) B.K. Kleinschmidt-DeMasters, M.D., Christopher M. Filley, M.D., and Mitchell A. Bitter, M.D. Departments of Pathology and Neurology, University of Colorado Health Sciences Center, Denver, Colorado
Kleinschmidt-DeMasters BK, Filley CM, Bitter MA. Central nervous system angiocentric, angiodestructive T-cell lymphoma (lymphomatoid granulomatosis). Surg Neurol 1992;37:130-7.
Most neurosurgeons and neurologists still consider lymphomatoid granulomatosis (LG) as a type of central nervous system (CNS) vasculitis. However, new insights, primarily from the hematologic literature, have cast doubt on the benign character of this disorder. In this article we (1) report a case of an 18-year-old woman with diffuse CNS disease and no mass lesion who developed multiple small cortical infarcts and dementia secondary to multifocal angiocentric, angiodestructive lymphoma; we (2) review other cases of LG with predominant CNS involvement; we (3) summarize the current understanding of LG, which is now considered to be a premalignant or overt angiocentric, angiodestructive T-cell lymphoma rather than a nonneoplastic vasculitis: the importance to neurologic surgeons and neurologists is that while pulmonary involvement in LG is generally the most prominent finding, patients may present with early or dramatic CNS disease; and we (4) note that although dementia is uncommon in young adults, this report adds yet another rare condition to the long differential list of dementia in this age group. KEY WORDS: Dementia; Multiinfarct; Angiocentric; T-cell; Lymphorna
The entity lymphomatoid granulomatosis (LG) is undergoing reevaluation. "Angiocentric immunoproliferative lesion" (ALL) [9,18] has been coined in the hematologic literature to encompass LG, and it better describes an angiocentric, angiodestructive disease that is characterized neither by multinucleated giant cells nor by true granulomas [20,23]. LG lies at the higher grade end of this hematologic spectrum of AIL. Many hematopatholAddress reprint requests to: B.K. Kleinschmidt-DeMasters, Departments of Pathology and Neurology, University of Colorado Health Sciences Center, 4200 East Ninth Avenue (B216), Denver, Colorado 80262-0216. Received August 5, 1991; accepted August 19, 1991.
~:) 1992 by Elscvier Science PublishingCo., Inc.
ogists feel LG should be considered a malignant angiocentric, angiodestructive lymphoma from onset [9,18]. Recent investigations using immunophenotyping and molecular techniques in LG lying outside the central nervous system (CNS) have demonstrated the T-cell nature of AIL/LG [5,11,13,24,26,34,36], its premalignant or overtly lymphomatous character (angiocentric Tcell lymphoma) [11,13,18,26,34,36], its clonality [13,36], and its association, in some cases, with Epstein-Barr virus [25]. Although the disease mostly involves the lungs and extrapulmonary sites such as the upper respiratory tract, skin, kidney, and peripheral nervous system [20,23], the CNS is involved in approximately 30% of cases [20] and has generated special interest and diagnostic difficulties. Even if disputed cases of CNS AIL/LG [2,7,17] are eliminated, no single clinical presentation has been characteristic. Patients may display varied neurologic deficits secondary to the seemingly random involvement of one or more CNS sites. We document an unusual case with multiinfarct dementia and review previously reported cases of AIL/LG with predominant CNS involvement as well as recent literature on AIL/LG.
Case Report A 22-year-old right-handed woman had been in good health except for scoliosis until she began to experience memory loss, emotional lability, and tremor at age 18. These problems progressed slowly, and at age 19 she noted that her left leg was slightly weaker than the right. Examination at that time disclosed poor recent m e m o r y (one of five objects at 5 minutes), dyscalculia, concrete proverb interpretation, a fine postural tremor o f the hands, and impaired heel-to-shin testing of the left lower extremity. A computed tomography (CT) scan of the brain showed a hypodense lesion in the right putamen and enlargement of the right sylvian fissure; magnetic resonance imaging (MRI) revealed right putamenal hyperintensity on T2-weighted images and mild generalized atrophy. An electroencephalogram (EEG) disclosed 0090 ~019/92/$3.00
Angiocentric, Angiodestructive Lymphoma
generalized high-amplitude sharp waves, often with a right predominance. The results of bilateral internal carotid and left vertebral arteriography were normal. Neuropsychological testing found that she had significant verbal and nonverbal memory deficits, a tendency toward anger and irritability, and generalized intellectual decline (Full Scale IQ 76, Verbal IQ 78, and Performance IQ 86). At age 20 she was admitted to a psychiatric hospital for disinhibited behavior. Examination showed poor recent memory (one of four words at 5 minutes), impulsivity, distractibility, tremor, and an equivocal left upgoing toe. MRI was unchanged, but the EEG now showed right temporal spikes. Visual, auditory, and somatosensory evoked potentials were all normal. Lumbar puncture produced clear fluid with a glucose of 55 mg/100 mL, protein of 47 mg/100 mL, 2 mononuclear cells, 0 red blood cells/uL, negative Gram stain and cryptococcal antigen, nonreactive venereal disease research laboratories, and 2 oligoclonal bands. Blood chemistry survey, complete blood count, erythrocyte sedimentation rate, antinuclear antibody, urinalysis, thyroid function tests, vitamin B12 and folate levels, and a test for human immunodeficiency virus (HIV) all produced negative or unremarkable results. A chest roentgenogram disclosed scoliosis and Harrington rods that had been placed at age 13. Results of a slit lamp examination and serum ceruloplasmin level were normal. Administration of carbamazepine led to minimal improvement in her frequent irritable outbursts. A neuropsychological evaluation documented deterioration in memory and behavior and recorded a Full Scale IQ of 73 (Verbal IQ 76, Performance IQ 72). Generalized myoclonic jerks began, followed by complex partial and generalized seizures soon thereafter. Left hemiparesis became evident, and a wheelchair was necessary. Arterial lactate and urinary organic acid levels were normal. Antibody titers against measles, rubella, mumps, herpes simplex, varicella zoster, and parainfluenza 1 and 2 were all 1 : 20 or less. An echocardiogram found mitral and tricuspid prolapse without valvular insufficiency. The findings of nerve conduction studies and electromyography were normal. Brain biopsy from the right insular cortex was performed 2 years after the onset of symptoms and disclosed an angiocentric lymphoma, characterized by gray matter vascular permeation. The lymphomatous infiltrate was composed of medium-sized cells with convoluted nuclei, admixed with small numbers of histiocytes and nonneoplastic-appearing lymphocytes. Vascular thrombi were not present. A needle biopsy of the adjacent putamenal biopsy showed reactive astrocytosis, perivascular lymphocytes, and hemosiderin pigment but no infarct. Individual neoplastic cells infiltrated between involved blood
Surg Neurol 1992;37:130-7
131
F i g u r e 1. T2-weighted M R I scan at age 22 demonstrating bioccipital cortica] hyperintensity but no mass or white matter involvement. A n unrelated, clinically subtle subdura/ hematoma, probably sustained during a seizure with head injury, is also shown on the left (TR = .7,000. TE =
40~.
vessels, but no cohesive mass was present. Immunophenotypmg was unsuccessful owing to the focal nature of the process and tissue exhaustion. A trial of 80 mg/day prednisone for 3 weeks with 2 weeks of tapering doses produced no benefit. At that point, 3000 cGy of wholebrain irradiation was administered over 15 sessions, and marked improvement was apparent. The patient was able to walk without assistance, and the tremor abated. Chemotherapy with cis-platin, cytarabine, and dexamethasone resulted in no further improvement, and in part because of leukopenia this regimen was terminated. The patient then remained stable for the next 18 months, continuing to walk without assistance and with much improved behavioral control. Two to four seizures per month were noted, most of which were of a complex partial nature. Four years after the onset of symptoms, at age 22, she had an MRI scan (Figure 1) that disclosed bioccipital hyperintensity on T2-weighted images, which is consistent with recent infarction. A repeat biopsy, this time of the right occipital lobe, was carried out, and a grade III angiocentric immunoproliferative lesion [24] (angiocentric lymphoma) was identified, which was histologically similar to the first biopsy and involved gray matter blood vessels and leptomeninges. Recent small
132
Surg Neurol 1992;37:130-7
Figure 2. Low-powerphotomicrograph taken from the secondbrain biopsy illustrating the angiocentricity of the neoplastic infiltrate in the upper half of the illustration. The pale, vacuolatedarea in the lower half of the photo is acute infarction. Hematoxylin and eosin stain × 230.
cortical infarcts were noted near vessels involved by the angiocentric, angiodestructive lymphoma (Figure 2). Occasional small cortical vessels contained thrombi and fibrinoid necrosis. Remote cavitated cortical infarcts were also present but not intimately associated with lymphoma. N o cohesive lymphomatous mass was found. Cytologically malignant cells with convoluted hyperchromatic nuclei were again admixed with smaller numbers of nonneoplastic lymphocytes, plasma cells, and histiocytes (Figure 3). Immunophenotyping was carried out on frozen, B-5, and formalin-fixed tissue and showed the lymphoma to be of a T < e l l origin (see Table 1). The pan T-cell antigens CD5 and CD7 were not expressed, as is characteristic of many T-cell lymphomas [30]. T d T was also not expressed, which is consistent with a more mature, nonlymphoblastic T-cell lymphoma. The result of H I V testing was again negative, as it was for testing for the human T-lymphocytic virus, type I
Kleinschmidt-DeMasters et al
(HTLV-I). Testing for Epstein-Barr virus revealed a viral capsular antigen IgG titer o f 1 : 640, Epstein-Barr nuclear antigen titer of 1 : 3 2 0 , and envelope antigen and viral capsular antigen titer
