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Cite this article: Guzey FK, Hıtay Y, Isler C, Tas A, Aktas O, et al. (2015) Primary Spinal Intramedullary Lymphoma: A Case Report and Review of the Litera-ture. JSM Neurosurg Spine 3(1): 1049.

*Corresponding authorFeyza Karagoz Guzey, Topkapi Mahallesi, Kahalbagi Sokak 46/2 Fatih Istanbul, Turkey, 34093, Tel: 905326334032; Email:

Submitted: 28 November 2014

Accepted: 05 January 2015

Published: 08 January 2015

Copyright© 2015 Guzey et al.

OPEN ACCESS

Keywords•Central nervous system lymphoma•Lymphoma•Nonhodgkin lymphoma•Spinal intramedullary lymphoma•Spinal intramedullary tumor

Case Report

Primary Spinal Intramedullary Lymphoma: A Case Report and Review of the LiteratureFeyza Karagoz Guzey1*, Yucel Hıtay1, Cihan Isler1, Abdurrahim Tas1, Ozgur Aktas1, Azmi Tufan1, Mustafa Vatansever1 and Aslı Kahraman Akkalp2

1Department of Neurosurgery, Bagcilar Research and Training Hospital, Turkey2Department of Neurosurgery and Pathology, Bagcilar Research and Training Hospital, Turkey

Abstract

Background: Primary spinal intramedullary lymphoma is a very rare lesion. It has not specific laboratory or radiologic findings. Therefore false and late diagnosis is frequent.

Case Report and Literature Review: A 55 year-old lady with multifocal primary spinal intramedullary B-cell non-Hodgkin’s lymphoma was reported. Review of literature yielded 45 cases with primary spinal intramedullary lymphoma and clinical and radiological characteristics of these 46 cases were evaluated.

Results: Male/female ratio was 24/22. Median age of the patients was 51.5 years for all cases except a series consisting 14 cases to be reported in an article in which detailed data case by case was not given. Median age of those 14 cases was 62.5. Most of the cases were localized in the cervical and then thoracic segments. Multifocal spinal tumors were found in 12 patients. Most of the patients were admitted with rapidly progressing myelopathy symptoms and signs. Most frequently seen magnetic resonance appearance was T2 hyperintensity and dense and homogeneous contrast enhancement with spinal cord enlargement. Misdiagnosis was frequent (23 cases) and certain diagnosis could be provided with autopsy in 5 cases. Tissue sampling was performed mostly with spinal cord biopsy (27) and brain biopsy (10 cases). Most of the cases had B-cell lymphoma (26 cases). Patients were treated with various types of chemotherapy, radiotherapy or combination of them. Twenty-six cases were died during follow-up median 16.5 months (for 10 cases of the largest series consisting 14 cases) and 10 months (for other cases) after onset of symptoms and signs.

Survival time was significantly different between neither cell types (B cell and other lymphomas) nor initial treatment modalities (chemotherapy, radiotherapy or combined of them).

Conclusions: Primary spinal intramedullary lymphoma diagnosis is difficult, and misdiagnosis is frequent. It must be kept in mind for differential diagnosis especially in middle aged patients with rapidly progressing myelopathy findings. Prognosis is poor despite aggressive treatment.

INTRODUCTIONPrimary central nervous system (CNS) lymphoma sourced

from brain, leptomeninges, eyes or spinal cord is an uncommon type of extranodal non-Hodgkin’s lymphoma which constitutes only 1% of all lymphomas in the body [1]. Patients are classified as “primary” if there is no evidence of systemic lymphoma by screening at the time of diagnosis [2]. Spinal cord lymphomas may be primary and originate in the spinal cord or accompany

other CNS sites sequentially or concurrently [2]. It is not a rare event in the patients with brain lesions because of spread via direct invasion from the medulla oblongata or dissemination with cerebrospinal fluid (CSF) [3]. Kawasaki et al [4] reported that there was spinal cord involvement in 4 of 14 cases with primary brain lymphomas. However, isolated spinal cord involvement is exceedingly rare and observed in 1-3.3% of all cases of primary CNS lymphomas [5,6].

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Because of rarity of these lesions, primary intramedullary lymphomas (PIML) are usually not suggested in differential diagnosis in the patients with spinal intramedullary masses. Therefore, delayed diagnosis and misdiagnosis is very frequent. However, early diagnosis is important because effective treatment in early period of the disease may provide quite long survival.

We reported a case with primary spinal intramedullary B-cell lymphoma and also we found 45 cases with detailed data in literature. Characteristics of these 46 cases were discussed.

CASE REPORTA 55 year-old lady who had not any disease previously was

referred to our clinic for spinal intramedullary mass at the lumbar segments of the spinal cord and conus region. She had a monoparesis of her left leg for one month. On her physical examination, there was a left leg paresis with 1-2/5 strength on proximal and 3/5 strength on distal muscles. There was not hypoesthesia or sphincteric disturbances. Spinal magnetic resonance imaging (MRI) revealed an intramedullary mass, 41x14 mm in size, locating in the lumbar segments of the spinal cord and conus medullaris at T12 to L1 levels. It extended into the left neural foramen along with spinal root. The mass was hypointense on T1-weighted, and slightly hyperintense on T2-weighted sections and it was enhanced homogeneously after intravenous contrast injection (Figure 1 a-d). In addition, there was a small mass with same imaging characteristics in the filum terminale at L2 level (Figure 1 c). Brain, cervical and thoracic MRIs did not reveal other pathologies.

Routinely performed blood biochemical parameters, infection markers and peripheral blood cell counts were at normal levels and serologic tests including human immunodeficiency virus (HIV) and hepatitis viruses were negative. Abdominal and thoracic computerized tomography and breast investigations performed for primary tumor screening were also normal.

She operated on for especially histological diagnosis. The intramedullary tumor was infiltrative and it had not distinct borders intraoperatively. Only biopsy and decompressing duraplasty could be performed. On the day of surgery, prednisolone 250 mg intravenously was performed and it was continued for the day after and then gradually decreased. Just after operation, her leg paresis partly improved. Pathological investigation showed that the tumor was large B-cell lymphoma (Figure 2). Bone marrow aspiration and thorax and abdomen computerized tomographies revealed no pathology. The tumor was accepted as a PIML. It could not be find any immunological risk factor.

Her treatment was continued in an oncology center. She was treated with whole craniospinal radiotherapy (RT) consisting 36 grays in 20 fractions and additional doses to the posterior fossa (9 grays in 5 fractions) and to the operation site (T12-L2) (9 grays in 5 fractions). However she died because of dissemination of the disease after 3 months from operation (4 months from onset of the disease).

REVIEW OF LITERATUREMedline were searched for PIML. All found papers were

evaluated. Cases with previously known lymphoma story or

Figure 1a Lumbar T1 (a) weighted sagittal and T2 weighted axial.

Figure 1b MRI sections showed an intramedullary mass with T1 iso and T2 hyperintensity.

Figure 1c

systemic disease during first admission were not included into the study. The cases that had been reported in CNS lymphoma series were introduced into the study only if their detailed characteristics had been reported in the articles. Forty-five cases found in the literature [2,3,6-34] and total 46 cases with our one were evaluated for their clinical and radiological characteristics

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Figure 1d It had indistinct borders and enhanced homogeneously after intravenous contrast injection (c and d). In addition, there was a second small mass with similar characteristics in the filum terminale at L2 level (c).

Figure 2 Diffuse and strong CD20 immunoreactivity in the neoplastic cells (CD20 X400).

(Table 1). Intravascular lymphoma cases [26,27] were not excluded in spite of some peculiar characteristics of this entity because there were 3 cases with intravascular B cell lymphoma in the series of Flanagan et al [2]. Also, two cases with primary spinal intramedullary histiocytic lymphoma without systemic involvement [9,32] were included into the study. One case [15] was included into the study despite the paper could not be found. However, characteristics of that case were given in detail in other papers.

Fourteen of these 46 cases were reported in a series by Flanagan et al [2]. In these series, characteristics of the patients were given altogether without detailed in case by case. Therefore, some data were given separately for Flanagan’s series and other cases in our review.

STATISTICAL EVALUATIONThe relationships of metric independent parameters were

evaluated with Student-t independent test and nonmetric independent parameters were evaluated with chi-square and Fisher’s exact tests according to the subject numbers. Survival was demonstrated as Kaplan-Meier curves according to the cell type and treatment modalities. Survival time of patients with different cell type and treatment modalities was compared by Wilcoxon test. It was accepted as significant if p value was <0,05.

Literature Year n

Herbst et al [7] 1976 1

Bruni et al [8] 1977 1

Mitsumoto et al [9] 1980 1

Slager et al [10] 1982 1

Hautzer et al [11] 1983 1

Itami et al [12] 1986 1

Landan et al [13] 1987 1

Bluemke and Wang [14] 1990 1

Slowik et al [3] 1990 1

Nakao et al [15] 1994 1

Schild et al [16] 1995 1

McDonald et al [17] 1995 1

Urasaki et al [18] 1996 1

Kim et al [19] 1996 1

Caruso et al [20] 1998 1

Drouet et al [21] 1999 1

Pels et al [22] 2000 1

Thurnher et al [23] 2000 1

Bekar et al [24] 2001 1

Nakamizo et al [25] 2002 2

Herrlinger et al [26] 2002 1

Legais et al [27] 2002 1

Schwarz et al [28] 2002 1

Lee et al [29] 2002 1

Machiya et al [30] 2007 1

Peltier et al [31] 2007 1

Toshkezi et al [32] 2010 1

Flanagan et al [2] 2011 14

Lin et al [33] 2012 1

Sato et al [6] 2013 1

Bhushanam et al [34] 2014 1

Our case 2014 1

Total 46

Table 1: Articles reporting the cases with primary spinal intramedullary lymphoma.

n: number of patients reported in articles

RESULTSMale/female ratio was 24/22. Ages of the patients were

between 11-82 years with a 62.5 years median age for Flanagan’s series and 51.5 years median age for other cases (Table 2).

Clinical picture

All patients had an initial neurologic presentation of progressive myelopathy according to the level of their lesions except one who had conus medullaris symptoms and signs (Table 2). Symptom onset was subacute (>8 weeks) in 21 (46.6%) and insidious (<8 weeks) in 24 cases (53.3%). In one case there was not adequate data in the article [23].

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Risk factors

There were some immune disorders such as acquired immune deficiency syndrome (AIDS), or myasthenia gravis in 7 patients [2,3,11,12,18,23]. Pathological types were not mentioned in 2 of them [2], however, other 5 cases had non-B-cell type lymphomas. These patients with immunological risk factors was significantly younger than the immunocompetent patients (p=0,023).

Localization and dissemination of the tumor

In the Flanagan’s series detailed tumor localization data were not given. In 6 of those cases, the lesion was located in the conus medullaris, however the localization of the 8 intramedullary lesions was not mentioned. In the other 32 cases, tumor localizations were listed in Table 2.

Lesions were multicentric in the spinal cord/ filum terminale or spinal leptomeninges in 12 cases [2,20,28,our case]. In 26 cases, the disease disseminated to other sites of CNS (in 21 cases) or outside of the CNS (in 5 cases) (Table 2). In 2 of them, CNS [11] or abdominal lymph node [26] involvement were diagnosed during postmortem examination. In other 24 cases, dissemination was diagnosed during the first diagnosis (limited to the CNS) in 9 patients, or after median 3 (1 to 18) months from onset of symptoms in the others.

Radiological examinations

In 38 cases out of 46, diagnosis was made with MRI, and in 7 cases with myelography. In one case, it was not mentioned in the article [19].

In most of the cases, there was a typical appearance on MRI: Iso-hypointensity on T1-weighted sections, hyperintensity on T2-weighted sections, dense and usually homogeneous contrast enhancement with spinal cord enlargement and edema. Masses usually had indistinct borders. However these findings were not rule, and this typical appearance had been shown in 19 cases (Table 3). Tumor might not be enhanced [14,27], or it might have central hypointense area in the contrast enhancement [32], or spinal cord enlargement might not be seen [21].

In 24 cases there were some misdiagnoses prior certain diagnosis (Table 4). In 5 cases, certain diagnosis could be made after death [2,8,10,11,13]. Four of them were from pre-MRI era and were evaluated with myelography.

Other investigations

Blood chemistry and cell counts of all patients with adequate data in the papers were normal on admission except one with myasthenia gravis whose immunoglobulin G and M levels were high [11].

Cerebrospinal fluid results were reported in 33 cases including 12 cases from Flanagan’s series. In 5 of them, CSF findings had been reported as “normal”. In other cases, protein level and cell count were high (Table 5). There were malignant cells in CSF in only 4 patients [2,19].

Tests for screening of systemic malignancy such as thorax or abdomen computerized tomography and bone marrow biopsy were negative in all patients.

Demographic data Gender#: 24 male/ 22 female Age: Median 51.5 and mean±SD 50.41±16.03 (11-77) years* and median 62.5 (41-82) years&

Clinical pictures* Paraparesis/tetraparesis: 26 cases Hemiparesis/leg monoparesis: 5 cases Conus syndrome: 1 case Duration of the symptoms from onset to admission: Median 1, mean±SD 3.27±4.95 month (5 days-23 months)Localization*α Cervical 13; Thoracic 10; Lumbar 2; Conus 3; Longer segments 7Dissemination#

Multiple spinal lesions: 12 (9 cases from Flanagan’s series, 3 cases from other reports) CNS involvement: 21 (9 cases from Flanagan’s series, 12 cases from other reports) Systemic dissemination: 5

Table 2: Demographic data and clinical pictures of the patients and localizations of the tumors.

#All cases;*32 cases other than the cases of Flanagan’s series [2];α3 cases of 32 had multiple spinal lesions&14 cases reported by Flanagan et al.

T2 signal characteristics n

Hyperintense: 27

Hypointense 4*

Isointense 2

NM 6

Expansion of spinal cord

Positive 27

Negative 7

NM 2

Contrast enhancement

Positive 35

Negative 0

NM 1

Typical MRI appearance(T2 hyperintensity,

cord expansion and contrast enhancement 19

Table 3: MRI findings of 34 patients investigated with MRI except one whose detailed MRI data were not mentioned in the article [19].

n: number of patientsNM: not mentioned in the article*in 3 of those 4 cases (from Flanagan’s series) there were multiple lesions, and some of them were hyperintense on T2 weighted MRI.

Tissue diagnosis

Tissue diagnosis was provided with spinal cord in 27 cases, with brain biopsy in 10 cases. In one case [23], type of tissue sampling was not mentioned in the article, in 3 cases diagnosis could be performed with CSF cytology [2,19], and in 5 cases it could be performed with autopsy [2,8,10,11,13].

There were several histological diagnoses from general terms such as non-Hodgkin lymphoma to very detailed ones such as B-cell perivascular low grade lymphoma. In 26 cases, tumor was

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from B-cell lineage (5 of them had intravascular lymphomas), and in 7 cases from T-cell lineage consistent to the rate of cell type reported in literature for CNS lymphomas [35] (Table 6).

Histological types did not show statistically significant differences according to the gender or age of the patients (p=0,08 and p=0,94, respectively).

Treatment

It is well known that steroid treatment may result marked improvement of clinical picture in cases with CNS lymphoma. In 16 out of 46 cases, steroid was administered prior to certain diagnosis, and 14 of them were improved dramatically for a while [2,6,9,26,27,32,our case].

None of the cases whose diagnosis was provided with spinal cord biopsy deteriorated after surgery. In 4 of these 27 cases subtotal resection was also added to the biopsy and in our case, a wide duraplasty was also performed.

In 38 patients whose diagnosis could be performed in vivo and whose treatment data were adequate in articles, various types of radiotherapy (RT), chemotherapy (CT), or combination of them were performed after staging of the disease (Table 7).

Outcome

In Flanagan’s series [2] outcome of the patients and results of treatment modalities were not given case by case. In this series, 10 patients died (median duration symptom onset to death, 16.5 months; range 2–97), and 4patients remained living at last follow-up (median 59 months from symptom onset; range 3–138). In 3 cases from other reports, there was not follow-up data in the articles [23,30,33]. In other 29 cases, median duration of follow-up from onset of the symptoms was 17 (range 4- 60) months, and 17 cases died median 10 (range 4- 30) months after first symptoms. Kaplan-Meier curves of those 29 cases were shown in Figure 3.

Outcome and survival times of the various treatment groups were shown in Table 7. There was no statistically significant

Misdiagnoses Number of patients

Transverse miyelitis 5

Multiple sclerosis 5

Syringomyelia 3

Chronic demyelinating disease 3

Disk disease 2

Disseminated encephalomyelitis 2

Infectious myelitis 1

Sarcoidosis 1

Neuromyelitis optica 1

Total 23

Table 4: Misdiagnoses of the patients.

CSF findings Level (median/interval)

Protein 110&/70.75* (24-466) mg/dlCell count (mainly polyclonal lymphocyte) 92&/48* (2-369)/mm3

Table 5: CSF findings of the patients.

&12 cases of Flanagan et al; *16 cases from other series except 5 cases whose CSF findings had been reported as “normal”

Histological type Number of patients Gender*α

male/femaleAge (year)* α

Median (interval)Outcome on last fu* fu (month)

median (interval) &Alive Dead NM

B cell 26 9/5 51.5 (11-77) 6 7 1 17 (4-60)Non B cell (T cell) (Other)

20(7)(13)

5/13 52.5 (24-75) 6 10 2 16.5 (4.5-48)

Total 46 32 32

Table 6: Histological type and their outcome.

Fu: Follow-up*Except 14 cases of Flanagan et al [2]; &except cases of Flanagan et al [2] and without adequate dataαThere was not statistically significant difference between patients with B cell lymphomas and non-B cell lymphomas

Treatment Number of patientsOutcome on last fu* fu time (month)

median (interval) *&Alive Dead

CT (with 3 salvage RT) 17 3 2 19 (8-60)

RT (With 1 salvage CT) 10 3 7 22 (4-48)

Combined CT/RT 11 6 4 16 (6-42)

Not mentioned 3

Diagnosis after death 5

Total 46

Table 7: Treatment modalities after tissue diagnosis and their outcome.

CT: Chemotherapy; RT: Radiotherapy; fu: follow-up*Except 12 cases of Flanagan et al [2] and 1 case without adequate data&Median time from onset to death or last fu

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difference between treatment groups (p=0,681), and between histological types (p=0,715).

DISCUSSIONMalignant lymphoma of the CNS usually occurs in the brain

tissue. Patients were classified as “primary” if there was no evidence of systemic lymphoma by screening in use at the time of diagnosis. Dissemination of the disease to the spinal cord is not a rare event during follow-up of these cases however PIML on admission of the patient is quite rare [3,36]. It must be primary and originate in the spinal cord and symptoms and signs must be related to the involvement of spinal cord, however, other CNS sites involvement may accompany sequentially or concurrently [2]. We could find only 45 cases with PIML in literature with detailed data and added a new case.

Because of its rarity, diagnosis is difficult in this disease and there may be an important delay in both diagnosis and treatment even in the MRI era. However some clinical, laboratory and radiological clues that may provide to suggest lymphoma possibility in differential diagnosis were determined in this review.

It was not shown any difference between genders for development of PIML. Most of the patients were pooled in the middle aged groups (40 to 60) although there were patients from all age groups between 11 to 82 years.

Presence of immunological disorders in the patients is also a warning sign for lymphoma diagnosis. In 7 out of 46cases in this series, there was one of various immunological problems (15.2%). There has been a dramatic increase in the incidence of primary CNS lymphoma in the setting of AIDS in last a few decades [37]. However, there were only 2 cases related to AIDS in this series [2,23].

Clinical picture was related to localization of the tumor in the spinal cord, and there were not any specific symptoms or signs. However, these tumors were quickly progressive, and the time

between onset of symptoms to the admission was quite short (median 1.5 months).

The most important diagnostic technique for this disease is MRI. There is a typical appearance in most of cases: hyperintensity on T2-weighted sections, dense and usually homogeneous contrast enhancement, indistinct tumor borders, and spinal cord enlargement. However, these characteristics are not specific for PIML. Various pathologies such as astrocytomas, metastatic tumors or neurosarcoidosis may cause similar appearances [1,2,26]. In addition, PIMLs in some cases have not these typical characteristics. Tumor may have not hyperintensity on T2-weighted sections, it may have central hypointensity or there may not be spinal cord enlargement [21]. Presence of multiplicity, brain involvement and leptomeningeal involvement may support lymphoma diagnosis. Therefore, whole spinal and brain examination with MRI should be performed for differential diagnosis of spinal intramedullary masses.

Neurologically well response of the patients to steroid therapy that is given for various reasons is a very important sign that must be suggested lymphoma. Even unexpected remissions may be observed on MRI after steroid treatment [24]. In this review series also, 14 out of 16 cases who were treated with steroid therapy for especially misdiagnoses such as demyelinating diseases improved dramatically at least for a few days.

Although CSF cytology was generally negative (only 8, 8% positivity), protein level and cell count in CSF were usually higher than normal levels in these patients. The sensitivity of CSF cytology in CNS lymphoma other than intramedullary tumors is reported 26%–31% but the addition of flow cytometry and repeated CSF examinations may further increase diagnostic yield [2].

For certain diagnosis, tissue sampling is mandatory if CSF cytology was negative. If there are concomitant brain lesions, diagnosis may be performed with brain biopsy that is safer than spinal cord biopsy. However, spinal cord biopsy was necessary

Figure 3 Kaplan-Meier curves according to the cell types of tumors (a) and initial treatment types (b) of the patients by other reports than Flanagan’s.

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in most of cases in this review. It was not reported neurological deterioration in any of the patients due to spinal cord biopsy. In addition, decompression with laminectomy and duraplasty in the patients with rapidly progressing neurological deficits may provide quick improvement until definitive treatment with CT or RT as in our case.

The interpretation of histological findings was difficult in this review, because different classification systems were used in the articles. It is known that primary CNS lymphomas show histological and immunologic similarities to systemic lymphomas [9], but they have a larger cytological diversity than extraneural tumors [3]. Although histological types of some cases were not mentioned in the articles, most of the cases had B-cell lymphomas (56.5%) consistently other CNS primary lymphomas [22].

The most important steps in the approach to spinal cord lymphoma are biopsy and histological diagnosis, followed by treatment with CT, RT or combination of these. Although comparison was difficult because various treatment protocols were used for both RT and CT in the cases of this review, survival results of treatment modalities were not different. Herrlinger et al [26] recommended CT including high-dose methotrexate alone or in combination with local RT according to the general guideline for treatment of other primary CNS lymphomas.

Unfortunately, prognosis of PIML is poor despite aggressive treatment. Primary CNS lymphomas are radiosensitive tumors, and the use of high-dose methotrexate combined with whole-brain radiation increases median survival to 36–60 months [38]. However, in PIML cases in this review it was found that median survival was only 3 months (rang 0-138) in Flanagan’s series, and 17 months (range 4-60) in other cases.

CONCLUSIONSPrimary spinal intramedullary lymphoma is a rare lesion. It

has not specific laboratory or radiologic findings. Therefore false and late diagnosis is frequent. It must be kept in mind especially in middle aged patients with rapidly progressing myelopathy findings. Prognosis is poor despite aggressive treatment with RT, CT or combination of them.

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Guzey FK, Hıtay Y, Isler C, Tas A, Aktas O, et al. (2015) Primary Spinal Intramedullary Lymphoma: A Case Report and Review of the Literature. JSM Neurosurg Spine 3(1): 1049.

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