台灣癌症醫誌 (J. Cancer Res. Pract.) 29(4), 212-220, 2013 Case Report journal homepage:www.cos.org.tw/web/index.asp Vanishing Tumor of Brain:Administration of Corticosteroids Followed by Disappearance of Primary Central Nervous System Lymphoma Yun-Kai Chan 1, Cheng-Kuei Chang 2,3, Cheng-Chia Tsai 1,2 * 1 Department of Neurosurgery, Mackay Memorial Hospital, Taipei, Taiwan 2 Graduate Institute of Injury Prevention and Control, Taipei Medical University, Taipei, Taiwan 3 Department of Neurosurgery, Taipei Medical University - Shuang Ho Hospital, Taipei, Taiwan Abstract. We report a case of primary central nervous system lymphoma (PCNSL) of the right cerebellar hemisphere, which vanished after the use of corticosteroids for 14 days. Because of the disappearance of the tumor, the pathologic examination after stereotactic biopsy revealed no evidence of malignancy. After corticosteroids were stopped, the tumor recurred 12 days later. A suboccipital craniectomy with partial removal of the right cerebellar tumor was then performed. The pathologic examination revealed diffuse large B-cell lymphoma of activated B-cell type. After high-dose Methotrexate, Methylprednisolone, Rituximab, and whole-brain radiation therapy, the right cerebellar PCNSL resolved in 8 months. Corticosteroids are frequently used in patients with intracranial neoplasms. The tumor which spontaneously disappears before definitive diagnosis and treatments (other than corticosteroids) is called a vanishing tumor. The possible diagnoses of vanishing tumors include lymphoma, germinoma, multiple sclerosis, neurosarcoidosis, localized cerebral infarction and focal encephalitis. We suggest that if PCNSL is suspected on non-enhanced and contrast-enhanced cranial CT scanning or MRI, we should not use corticosteroid until tissue has been obtained for diagnosis. Otherwise, it may lead to misdiagnosis or a delayed diagnosis. 病例報告 Keywords : primary central nervous system lymphoma (PCNSL), corticosteroid 腦部的消失腫瘤 : 在原發性中樞神經淋巴癌之病人使用皮質類固醇 詹雲凱 1 張丞圭 2,3 蔡承嘉 1,2 * 1 臺北馬偕紀念醫院外科部神經外科 2 臺北醫學大學傷害防治學研究所 3 行政院衛生署雙和醫院外科部神經外科 中文摘要我們報告一個右側小腦原發性中樞神經淋巴癌的病例, 病人在使用了皮質類固醇十四天之後, 腫瘤消失不見了 因為腫瘤消失不見, 在立體定位腦部切片中所取出的組織, 病理檢查之中並沒有看到任何惡性的細胞 停止了皮質類固醇之後十二天, 腫瘤復發了
Y. K. Chan et al./jcrp 29(2013) 212-220 213 因此, 我們後續安排了下枕部顱骨切除術合併部份移除右側小腦腫瘤, 病理檢查顯示是瀰漫性大 B 細胞淋巴癌 經過確診後, 使用了高劑量 Methotrexate Methylprednisolone Rituximab 以及全腦放射線治療, 右側小腦的腫瘤在手術後八個月消失不見 皮質類固醇很常使用在腦部腫瘤的患者, 而腫瘤在明確的診斷以及治療 ( 除了皮質類固醇 ) 之前, 就自行不見的情況下, 稱之為 消失的腫瘤 這種腫瘤的可能診斷包括淋巴癌 生殖細胞瘤 多發性硬化症 神經系統結節病 局部腦梗塞 以及局部腦炎 我們認為, 當我們在腦部的電腦斷層或是磁振造影的影像上懷疑到原發性中樞神經淋巴癌的病灶, 在獲得組織以確定病理診斷之前, 建議避免使用皮質類固醇 否則, 將會導致誤診或延遲診斷 關鍵字 : 原發性中樞神經淋巴癌 皮質類固醇 INTRODUCTION Corticosteroids are often prescribed immediately after an intracranial mass is diagnosed on cerebral computed tomography (CT) or magnetic resonance imaging (MRI). However, if primary CNS lymphoma (PCNSL) is suspected, corticosteroids must be withheld until the diagnosis has been established by pathological examination. We report our clinical experience and review the literature with regard to presentation, evaluation, radiological findings, and treatments of primary CNS lymphoma (PCNSL). CASE REPORT A 63-year-old woman was brought to our Neurology Clinic because of headache, dizziness, unsteady gait, impaired writing, slurred speech, nausea, and vomiting for 2 days. She denied head injury, convulsion, jerking posture, choking, and water drooling. Upon physical examination, the patient was oriented, and her Glasgow coma scale was E4M6V5. The pupils were isocoric, and cranial nerves were normal. Muscle power of the four extremities was full. The deep tendon reflex was normal for the four extremities. An unsteady gait, however, was noted. Besides, a fin- *Corresponding author: Cheng-Chia Tsai M.D., Ph.D. * 通訊作者 : 蔡承嘉醫師 Tel: +886-2-28094661 Fax: +886-2-28094679 E-mail: angle@ms1.mmh.org.tw ger-nose-finger test revealed dysmetria of her right hand. The non-enhanced and contrast-enhanced cranial CT scanning disclosed a homogenously enhancing tumor with perifocal edema in the right cerebellar hemisphere (Figure 1). After admission, Dexamethasone (5 mg) was administrated intravenously three times a day, starting the next day. The cranial MRI revealed an isointense right cerebellar lesion on T1WI, a slightly hyperintense lesion with perifocal edema on T2WI, and a homogenously enhancing lesion on T1WI with Gd enhancement. Besides, magnetic resonance spectroscopy (MRS) revealed an elevated Cho/NAA ratio (Figure 2). Malignant neoplasm was strongly suspected. We also performed CSF analysis, chest CT scanning, and abdominal echography. The results were all negative. We checked several tumor markers, and the reports were within normal limits. Fourteen days after admission, stereotactic biopsy of the right cerebellar tumor through a right suboccipital burr hole was performed for diagnosis. The pre-operative navigation contrast-enhanced cranial CT scanning had disclosed tumor shrinkage (Figure 3). Frozen section showed a benign lesion. Pathologic examination revealed no evidence of malignancy (Figure 4). We stopped Dexamethasone 12 days after surgery. She was discharged in stable general condition 18 days after surgery. Six days after discharge, severe headache, dizziness, and unsteady gait were noted. She was brought to our emergency department, and was admitted again.
214 Y. K. Chan et al./jcrp 29(2013) 212-220 Figure 1. Non-enhanced (Figure 1a) and contrast-enhanced (Figure 1b) cranial CT scanning disclosed a homogenously enhancing tumor with perifocal edema in right cerebellum The non-enhanced and contrast-enhanced cranial CT scanning revealed an enhanced mass lesion involving the right cerebellar hemisphere with compression of the 4th ventricle and brainstem and another hyperdense lesion with minimal enhancement in the left basal ganglion region (Figure 5). Cranial MRI revealed a hypointense right cerebellar lesion and isointense left basal ganglion lesion on T1WI, hyperintense right cerebellar lesion with perifocal edema, slightly hyperintense left basal ganglion lesion on T2WI, homogenously enhancing right cerebellar lesion, and slightly enhancing left basal ganglion lesion on T1WI with Gd enhancement. MRS still revealed elevated Cho/NAA ratio (Figure 6). Suboccipital craniectomy with partial removal of the right cerebellar tumor was performed for tumor decompression. Frozen section suggested lymphoma. Pathologic examination revealed diffuse large B-cell lymphoma of activated B-cell type (Figure 7). A whole abdominal CT scan was performed post-operatively, and the results were negative. A GA-67 tumor survey revealed residual right cerebellar tumor without abnormal tracer uptake elsewhere. Afterwards, she received chemotherapy with high-dose Methotrexate, Methylprednisolone, and Rituximab for 4 courses, and whole-brain radiation therapy with 36 GY for 5 months. Cranial MRI, 6 months after surgery, revealed a right cerebellar hypointense signal on T1WI, hyperintense signal on T2WI, and hypointense signal on T1WI with Gd enhancement (Figure 8). Focal encephalomalacia and good tumor control were noted. We also followed up with GA-67 tumor survey 8 months after surgery, which disclosed resolution of previous lymphoma in the right cerebellum. This patient was still in a good condition without any neurological deficits at present. DISCUSSION Primary central nervous system lymphoma (PCNSL)
Y. K. Chan et al./jcrp 29(2013) 212-220 215 Figure 2. Non-enhanced and Gadolinium-enhanced cerebral MRI revealed isointense right cerebellar lesion on T1WI (Figure 2a), slightly hyperintense lesion with perifocal edema on T2WI (Figure 2b), homogenously enhancing lesion on T1WI with Gd enhancement (Figure 2c), and MRS revealed elevated Cho/NAA ratio (Figure 2d) is an uncommon variant of extranodal non-hogkin lymphoma (NHL). PCNSL can affect the neuraxis, including the eyes, brain, cranial nerves, leptomeninges, spinal cord, and cerebrospinal fluid. This type of lymphoma represents about 3~4% of brain tumors, and 4~6% of all extranodal lymphomas. About 90% of PCNSLs are diffuse large B-cell lymphoma (DLBCL), and the remaining 10% are poorly characterized low-grade lymphoma, Burkitt s lymphoma, and T-cell lymphoma. DLBCL of PCNSL is composed of im-
216 Y. K. Chan et al./jcrp 29(2013) 212-220 Figure 3. Pre-operative navigation contrast-enhanced cranial CT scanning disclosed tumor shrinkage munoblasts or centroblasts which have a predilection for blood vessels, resulting in lymphoid clustering around small cerebral vessels. PCNSL is a lategerminal center or post-germinal center lymphoid neoplasm. The symptoms include focal neurological deficits, neuropsychiatric signs, increased intracranial pressure, seizure, headache, ocular symptoms, confusion, lethargy, and cerebellar signs. Compared with other forms of NHL, B symptoms such as fever, weight loss, or night sweats are rarely noted [1-5]. Corticosteroids are frequently used in patient with intracranial neoplasms. In patients with PCNSL, corticosteroids may result in rapid resolution of the cerebral mass and dramatic clinical improvement. In 40~ 85% of patients with PCNSL, corticosteroids can cause cell lysis and regression of tumor. Corticosteroids induce lympholytic effects. The binding of corti- Figure 4. Unremarkable architecture of cerebellar cortex positive for GFAP (Figure 4b) and composed of outer molecular layer and inner granular layer with Purkinge cells in between (Figure 4a), focal scattered increase CD68(+) macrophages (Figure 4c) and LCA(+) small lymphocytes (Figure 4d), and Ki-67 revealed no increase nuclear staining (Figure 4e)
Y. K. Chan et al./jcrp 29(2013) 212-220 217 Figure 5. Non-enhanced (Figure 5a and 5c) and contrast-enhanced cranial CT scanning revealed an enhanced mass lesion involving right cerebellar hemisphere with compression of 4th ventricle and brainstem (Figure 5a and 5b), and another hyperdense lesion with minimal enhancement in left basal ganglia (Figure 5c and 5d) costeroids to the cytoplasmic steroid receptor translocates the receptor to the nucleus, where it is bound with DNA, regulating target gene expression and signaling apoptosis. Therefore, apoptosis of lymphoid cells induced by corticosteroids does not require wild-type p53 activity. But the effect is short-lived, and the tumor will recur within weeks to months after tapering of corticosteroids. Thus, corticosteroids
218 Y. K. Chan et al./jcrp 29(2013) 212-220 Figure 6. Cerebral MRI revealed hypointense right cerebellar lesion and isointense left basal ganglion lesion on T1WI (Figure 6a), hyperintense right cerebellar lesion with perifocal edema and slightly hyperintense left basal ganglion lesion on T2WI (Figure 6b), homogenously enhancing right cerebellar lesion and slightly enhancing left basal ganglion lesion on T1WI with Gd enhancement (Figure 6c), and MRS revealed elevated Cho/NAA ratio (Figure 6d) Figure 7. Brain tissue infiltrated by monomorphic large lymphoid cells (Figure 7a and 7b). The tumor cells showed prominent nucleoli and frequent mitoses, strongly positive for Mum-1, Bcl-2, and CD20, and negative for CD30, ALK, and Bcl-6. (Figure 7c, 7d, 7e, 7f, 7g, and 7h)
Y. K. Chan et al./jcrp 29(2013) 212-220 219 Figure 8. Cerebral MRI revealed right cerebellar hypointense signal on T1WI (Figure 8a), hyperintense signal on T2WI (Figure 8b), and hypointense signal on T1WI with Gd enhancement (Figure 8c) should be withheld in patients suspected of PCNSL until tissue has been obtained for diagnosis, or the lympholytic effect may obscure the diagnosis of PCNSL [1,5-7]. The tumor which spontaneously disappears before definitive diagnosis and treatments (other than corticosteroids) is called a vanishing tumor, tumor regression, ghost tumor, or burned-out tumor. If the enhancing lesion has disappeared on the images, it may lead to misdiagnosis or a delayed diagnosis. But is a lesion that rapidly diminishes or disappears after a few doses of corticosteroids pathognomonic of PCNSL? Unfortunately not. Some other intracranial lesions, such as germinoma, multiple sclerosis, neurosarcoidosis, localized cerebral infarction, focal encephalitis, not only can mimic PCNSL radiographically but also respond to corticosteroids. Hence, corticosteroids should not be used as a diagnostic tool. Lumbar puncture, slit-lamp examination, and vitrectomy may be necessary for diagnosis sometimes [1,7,8]. For neurosurgeons, it is important to identify PCNSL on the images before administration of corticosteroids. The imaging modality of choice is non-enhanced and contrast-enhanced cranial MRI. Sometimes, cranial CT scanning has to be used in patients who cannot undergo MRI, for example patients with a cardiac pacemaker. In immunocompetent patients with PCNSL, lesions are solitary in 65% and multifocal in 35%, and are located in cerebral hemispheres (38%), thalamus/basal ganglia (16%), corpus callosum (14%), periventricular region (12%), and cerebellum (9%). PCNSL is usually isodense to hyperdense on CT images. On non-enhanced MRI, lesions are homogenously isointense or hypointense to cortex on T1-weighted images, and isointense to hypointense with variable surrounding edema on T2- weighted images. On contrast-enhanced MRI, tumors show homogenous enhancement. Besides, PCNSL is hyperintense on diffusion weighted imaging (DWI), and hypointense on the DWI-derived apparent diffusion coefficient (ADC maps). These findings are contributed by high cell density and scant cytoplasm. On the other hand, lesions are usually multiple with ring-enhancement in immunocompromised patients [1-5,9]. In PCNSL patients, resection of tumor does not
220 Y. K. Chan et al./jcrp 29(2013) 212-220 increase survival, and sometimes causes neurologic deterioration due to the usually deep location of the lesions. Therefore, stereotactic biopsy of tumors, including histopathology with immunohistochemical staining, is the standard diagnostic procedure for patients suspected of CNS lymphoma. Rarely, resection of tumor is needed for patients with brain herniation due to the mass effect of the tumor. Combinedmodality therapy (whole-brain radiation therapy plus chemotherapy) is the treatment of choice for patients with PCNSL. In patients with advanced systemic NHL, the CHOP regimen (Cyclophosphamide HCl, Doxorubicin, Vincristine, and Prednisone) is the optimal combination for the treatment. But these drugs produce poor results in PCNSL patients because of limited blood-brain barrier (BBB) penetration. Methotrexate, a folate antagonist that interrupts DNA biosynthesis, is the backbone of chemotherapy for PCNSL patients. But due to its high degree of ionization at physiologic ph, Methotrexate is also associated with poor penetration of the BBB. Therefore, highdose Methotrexate (HD-MTX) (8 g/m 2 ) is used for adequate BBB penetration. Besides, Rituximab, a humanized monoclonal antibody against the CD20 antigen on B lymphoma cells, is also used for selected PCNSL patients. But it is not yet known whether Rituximab will improve outcomes. PCNSL is a radiosensitive tumor, and whole-brain radiation therapy (WBRT) will improve survival. But if patients are more than 60 years old, we should watch for neurotoxic effects, including ataxia, incontinence, cognitive, motor, and autonomic dysfunctions. Neurotoxic effects have a negative impact on quality of life. Currently, complete remission rates of PCNSL are 30~ 87% and 5-year overall survival rates 30~ 50% [1-5,7, 9]. In conclusion, PCNSL is an uncommon variant of extranodal non-hogkin lymphoma. When PCNSL is suspected on non-enhanced and contrast-enhanced cranial CT scanning or MRI, corticosteroids should be withheld until tissue has been obtained for diagnosis. After making definitive diagnosis, HD-MTX, Rituximab, and WBRT will improve the chances of survival. REFERENCES 1. Nasir S, DeAngelis LM. Update on the management of primary CNS lymphoma. Oncology 14(2): 228-237, 2000. 2. Gerstner ER, Batchelor TT. Primary central nervous system lymphoma. Arch Neurol 67 (3): 291-297, 2010. 3. Ferreri AJ. How I treat primary CNS lymphoma. Blood 118: 510-522, 2011. 4. Batchelor T, Loeffler JS. Primary CNS lymphoma. J Clin Oncol 24 (8): 1281-1288, 2006. 5. DeAngelis LM, Hormigo A. Treatment of primary central nervous system lymphoma. Semin Oncol 31: 684-692, 2004. 6. Weller M. Glucocorticoid treatment of primary CNS lymphoma. J Neurooncol 43: 237-239, 1999. 7. Hunt MA, Jahnke K, Murillo TP, et al. Distinguishing primary central nervous system lymphoma from other central nervous system diseases: a neurosurgical perspective on diagnostic dilemmas and approaches. Neurosurg Focus 21 (5): E3, 2006. 8. Okita Y, Narita Y, Miyakita Y, et al. Long-term follow-up of vanishing tumors in the brain: How should a lesion mimicking primary CNS lymphoma be managed? Clin Neurol Neurosurg 114: 1217-1221, 2012. 9. Baraniskin A, Deckert M, Schulte-Altedorneburg G, et al. Current strategies in the diagnosis of diffuse large B-cell lymphoma of the central nervous system. Br J Haematol 156 (4): 421-432, 2012.