Case Report
A Rare Case of Primary High-Grade Large B-Cell Lymphoma of the Sciatic Nerve Pooja Advani,1 Aneel Paulus,2 Peter Murray,3 Liuyan Jiang,4 Ryan Goff,5 Robert Pooley,5 Manoj Jain,5 Hillary Garner,5 James Foran1 Clinical Practice Points Primary high-grade large B-cell lymphoma of the
sciatic nerve without any systemic or central nervous system manifestations is rare, and the natural history of the disease is reported to be aggressive. There is a paucity of data on the optimal treatment strategies for primary sciatic nerve lymphoma. Combined modality dose-adjusted R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) followed by involved field
radiation treatment to the sciatic nerve might result in functional and sustained complete remission and is an alternative treatment option. Neurolymphomatosis should be considered in the differential diagnosis of sciatic nerve tumors, and its accurate diagnosis is based on clinical features, expert hematopathology review, and functional imaging modalities including positron emission tomography-computed tomography scan.
Clinical Lymphoma, Myeloma & Leukemia, Vol. 15, No. 6, e117-20 ª 2015 Elsevier Inc. All rights reserved. Keywords: Diffuse Large B-cell Lymphoma, Neurolymphomatosis, Non-germinal center B-cell lymphoma, Primary sciatic nerve lymphoma, Sciatic nerve tumor
Introduction Nerve-seeking lymphomas are a unique clinicopathologic entity, with approximately 90% of cases classified as non-Hodgkin lymphoma (NHL) in origin. The remaining cases are attributed to various leukemias.1-4 Neurolymphomatosis (NL) is defined as localized invasion of the cranial nerves, peripheral nerves, roots, or cranial plexus by neurotropic tumor cells.1 Most NL cases are caused by malignant B-cell NHL (with some T and natural killer cell cases reported), which exhibits an aggressive disease behavior and is noted to cause systemic involvement in most patients.2 We report a rare case of primary high-grade B-cell NHL localized to the sciatic nerve without any systemic or central nervous system (CNS) involvement.
Case Report A 72-year-old white man presented to our hospital with a 2-year history of paresthesia, pain, and weakness in the sole of his left foot, 1
Division of Hematology and Medical Oncology Department of Cancer Biology Division of Orthopedics 4 Division of Pathology 5 Division of Radiology Mayo Clinic, Jacksonville, FL 2 3
Submitted: Sep 18, 2014; Revised: Nov 26, 2014; Accepted: Dec 6, 2014; Epub: Dec 11, 2014 Address for correspondence: James Foran, MD, Division of Hematology and Medical Oncology, Mayo Clinic, 4500 San Pablo Rd S, Jacksonville, FL 32224. E-mail contact: [email protected]
2152-2650/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2014.12.001
which gradually progressed to involve his posterior thigh and calf. He denied any history of back pain, trauma, immunosuppressive disorders, use of immunosuppressive medications, or B symptoms such as fever, night sweats, or significant weight loss. On clinical examination, he was noted to have an antalgic gait, weakness of the left gastrocnemius-soleus muscles, an inability to plantar flex the left foot, and sensory loss in the distribution of the S1-S2 dermatome. Nerve conduction studies showed an absent left lateral plantar response, absent left tibial H reflex, and mildly low amplitude at the ankle and popliteal fossa on left tibial motor study. This was associated with denervation changes in the gastrocnemius and soleus muscles on electromyography. A magnetic resonance imaging (MRI) scan of the lumbar spine showed multilevel lumbar spondylosis. He was treated conservatively with pain medications and epidural steroid injections without much benefit. Blood tests including complete blood counts, erythrocyte sedimentation rate, C-reactive protein, antinuclear antibody, rheumatoid factor, and lactate dehydrogenase levels were normal. An MRI scan of the left lower extremity with contrast showed a heterogeneously enhancing 1.4 1.3 6.3 cm fusiform elongated mass intimately associated with the distal sciatic nerve, which extended into the proximal tibial nerve and terminated approximately 9 cm above the level of the knee (Figure 1A and C). The patient subsequently underwent left sciatic nerve neurolysis and an open biopsy of the tumor showed an infiltrating high-grade large B-cell lymphoma. Immunohistochemistry analysis revealed tumor cells, diffusely and strongly positive for CD20 and multiple
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Large B-Cell Lymphoma of the Sciatic Nerve Figure 1 Magnetic Resonance Imaging (MRI) and Positron Emission Tomography-Computed Tomography (PET-CT) Images of the Left Lower Extremity. Fat-Saturated Post Gadolinium T1-Weighted Images of the Left Lower Extremity Reveals an Infiltrative Mass in the Region of the Left Sciatic Nerve in Coronal (A) and Axial (C) Sections, Indicated by the Arrows. Repeat MRI After 4 Cycles of Dose-Adjusted R-EPOCH (Rituximab, Etoposide, Prednisone, Vincristine, Cyclophosphamide, and Doxorubicin) Shows a Marked Decrease in the Size of the Mass; (B) and (D). On PET-CT Imaging, an Isolated Hypermetabolic Mass (Arrows) Along the Left Sciatic Nerve Is Seen on Coronal (E) and Axial (G) Sections. Repeat Imaging After 2 Cycles of DoseAdjusted R-EPOCH Shows a Complete Metabolic Response, Which Was Maintained After 4 Cycles to seen on coronal (F) and axial (H) sections
myeloma oncogene 1, with a subset noted to be positive for B-cell lymphoma 6 (Figure 2). Ki-67 immunostaining showed a proliferation index of 85% (Figure 2). The tumor cells were negative for CD3, CD10, TdT, and CD30. Based on the Han algorithm,5 the
patient received a final diagnosis of high-grade diffuse large B-cell lymphoma (DLBCL) of the non-germinal center B-cell (GCB) phenotype. FISH for c-Myc and B-cell lymphoma 2 (bcl-2) was within normal limits. No expansion form (full form) of c-Myc.
Figure 2 Histology Findings and Immunohistochemical Studies of Sciatic Nerve Biopsy. Hematoxylin and Eosin-Stained Sections Show Dense Proliferation of Neoplastic Large Lymphocytes Infiltrating the Sciatic Nerve Bundles (A, Magnification 34; B, Magnification 320). The Lymphoma Cells Are Diffusely and Strongly Positive for CD20 (C, Magnification 320) With a High Proliferative Rate (Approximately 80%) With Ki-67 (D, Magnification 320). The Stain of Ki-67 Also Highlights the Large Nuclei of the Neoplastic B Cells. The Arrow in (A) Indicates a Residual Uninvolved Nerve Bundle, and the Arrows in (B), (C), and (D) Indicate Schwann Cells With Spindle Wavy Nuclei, Which Are Negative for CD20 and Ki-67
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Pooja Advani et al Whole body positron emission tomography (PET)-computed tomography (CT) scan showed an isolated moderately hypermetabolic (standardized uptake value of 7.9) mass along the sciatic nerve in the mid to distal left thigh (Figure 1E and G). MRI of the brain and spine and cerebrospinal fluid (CSF) analysis was negative for lymphomatous involvement. A staging bone marrow aspiration and biopsy was also negative for involvement with B-cell lymphoma. As such, he was diagnosed with a stage IAE high-grade B-cell NHL, of low-intermediate risk according to the International Prognostic Index. Based on histopathologic findings, we treated our patient with 4 cycles of dose-adjusted R-EPOCH (rituximab with infusional etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin). Intrathecal methotrexate was also administered with each cycle. PET-CT scans after 2 cycles showed resolution of previously reported hypermetabolic activity in the region of the distal left sciatic nerve, consistent with a functional complete remission (CR) (Figure 1F and H). MRI of the lower extremities showed a marked interval decrease in the size of the mass. After completion of doseadjusted R-EPOCH chemotherapy, the patient proceeded to receive involved field radiation therapy (IFRT) to the distal left sciatic nerve (3600 centigray in 20 fractions). MRI of the lower extremities at the end of treatment demonstrated a continued decrease in the size of the mass to 0.7 0.4 cm, and a near complete resolution of the patchy marrow signal abnormalities and enhancement (Figure 1B and D). At a follow-up of 18 months, the patient continued to have a functional CR on imaging with a marked improvement in his pain and left leg paresthesia.
Discussion Diffuse large B-cell lymphoma is the most common form of B-cell NHL, with an incidence of approximately 7 per 100,000 per year in the United States.6 Typically these lymphomas arise from lymph nodes and other lymphatic tissues; however, approximately 40% of patients are known to present with extranodal disease.7 DLBCL is further comprised of 2 prognostically different subgroups with distinct gene expression profiles, GCBs and activated B-cells,8 or GCB and non-GCB, when evaluated using immunohistochemistry, with the latter having a more aggressive clinical course.9 Because of the rarity of the disease, the true incidence of NL has been difficult to define. The largest study conducted on the matter (by the International Primary CNS Lymphoma Collaborative Group) described the presentation, treatment, and outcome of 50 NL cases, diagnosed over a 16-year period (1993-2008). Further review (spanning cases from 2001-2008) identified an additional 44 patients with features consistent with a diagnosis of NL.2 Overall, NL was found to be the initial presentation of systemic lymphoma in 26% to 29.5% of cases. Incidence of peripheral nerve involvement was variable across all data sets reported (20%-66% of cases) with multiple other nervous tissue sites being afflicted simultaneously.2 Placed in perspective, our report, describing a case of isolated primary NL arising within the sciatic nerve without any systemic manifestations, is indeed unique. Only 13 cases of primary lymphoma of the sciatic nerve have been described in the literature to date, and of these, 12 cases were reported to be of B-cell lineage, with 1 instance of T-cell lymphoma.10-21 Isolated primary lymphoma of other peripheral nerves
such as the brachial plexus, sympathetic chain, radial, median, and ulnar nerves has also been reported.10 The precise reason for preferential involvement of the sciatic nerve is unknown. It is postulated that analogous to normal lymphoid cells, specific adhesion receptors present on lymphoma cells might determine their predilection toward particular tissues. However, the exact adhesion molecules for organ selectivity of NL remain to be identified.22 Diagnosis of NL is challenging because presentation of disease is often indolent and symptoms can mimic those of lumbar disc pathology. Involvement of the nerve due to lymphoma is often difficult to distinguish from Schwannoma on computerized axial tomography or MRI scans. More recently, fluorine-18 fluorodeoxyglucose PET is increasingly being used to assist in the diagnosis of NL, for staging purposes and in monitoring response to treatment.23 Because primary isolated lymphoma of the sciatic nerve is rare, optimal treatment and management are still under debate. However, therapeutic strategies can be judiciously tailored according to the tumor cell of origin. Considering the aggressive nature of nonGCB type DLBCL, we surmised that in our patient, dose-adjusted R-EPOCH and radiation therapy would be an appropriate treatment option. In general, the underlying malignant cells in previously reported sciatic nerve lymphomas exhibited an intermediate to high-grade histology, necessitating treatment approaches ranging from nerve resection, radiotherapy, and chemotherapy, alone or in combination.11,14 Chemotherapy regimens consisting of MACOPB (methotrexate, cytarabine, cyclophosphamide, vincristine, prednisone, and bleomycin),17 ProMACE-CytaBOM (prednisone, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine, methotrexate, and leucovorin),10 and relatively newer regimens, such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with or without rituximab, have been used.10,11 Sciatic nerve lymphomas appear to behave aggressively, with at least 4 of the previously reported patients dying of CNS and/or systemic disease 6 to 50 months after clinical onset of sciatic nerve lymphoma.10,16,17,21 One patient had evidence of systemic disease 36 months after clinical onset. Notably, the short follow-up period (10-48 months) for most cases described in the literature has made it difficult to evaluate the behavior of such tumors.10,11,14 The limited penetration of chemotherapeutic agents across the bloodenerve barrier might partially explain the poor outcomes in these patients. Keeping this in mind, and the high proliferation rate, non-GCB phenotype of DLBCL, and locally advanced lesion in our patient, we elected to treat our patient with combination chemotherapy consisting of dose-adjusted R-EPOCH. Based on the excellent results of the phase II study, this regimen has been shown to have particular benefit in patients in the low and intermediate International Prognostic Index subgroups of DLBCL.24 An alternate standard of care would be to consider full course systemic RCHOP alone or abbreviated R-CHOP with IFRT.25 Prophylactic treatment of the CNS might be required, even in the absence of initial involvement in view of the aggressive nature and high mortality of B-cell lymphoma of the sciatic nerve.16 It has been reported that localized radiation therapy in combination with systemic chemotherapy achieves good local control in patients with bulky localized disease.1
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Large B-Cell Lymphoma of the Sciatic Nerve Conclusion We report a rare case of primary DLBCL-NHL afflicting the sciatic nerve in the absence of systemic involvement. A sciatic nerve tumor should be in the differential diagnosis for patients who present with progressive paresthesia, pain, numbness, and weakness of the lower limb. Accurate diagnosis entails timely integration of clinical, radiographic, and pathologic findings, and the latter is most notably obtained from CSF, neural, and extraneural tissues. Electrophysiological studies, MRI, and PET-CT scan are useful diagnostic tools, and the latter can aid in staging the disease and monitoring treatment responses. Although the optimal treatment for these tumors is not known, an early and aggressive approach with resection, chemotherapy, and radiation therapy alone or in combination should be considered.
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Aregawi DG, Sherman JH, Douvas MG, Burns TM, Schiff D. Neuroleukemiosis: case report of leukemic nerve infiltration in acute lymphoblastic leukemia. Muscle Nerve 2008; 38:1196-200. 2. Grisariu S, Avni B, Batchelor TT, et al. Neurolymphomatosis: an International Primary CNS Lymphoma Collaborative Group report. Blood 2010; 115:5005-11. 3. Grisold W, Jellinger K, Lutz D. Human neurolymphomatosis in a patient with chronic lymphatic leukemia. Clin Neuropathol 1990; 9:224-30. 4. Kuroda Y, Nakata H, Kakigi R, Oda K, Shibasaki H, Nakashiro H. Human neurolymphomatosis by adult T-cell leukemia. Neurology 1989; 39:144-6. 5. Hans CP, Weisenburger DD, Greiner TC, et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 2004; 103:275-82. 6. Morton LM, Wang SS, Devesa SS, Hartge P, Weisenburger DD, Linet MS. Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001. Blood 2006; 107:265-76. 7. Krol AD, le Cessie S, Snijder S, Kluin-Nelemans JC, Kluin PM, Noordijk EM. Primary extranodal non-Hodgkin’s lymphoma (NHL): the impact of alternative
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8. 9.
10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25.
definitions tested in the Comprehensive Cancer Centre West population-based NHL registry. Ann Oncol 2003; 14:131-9. Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000; 403:503-11. Fu K, Weisenburger DD, Choi WW, et al. Addition of rituximab to standard chemotherapy improves the survival of both the germinal center B-cell-like and non-germinal center B-cell-like subtypes of diffuse large B-cell lymphoma. J Clin Oncol 2008; 26:4587-94. Misdraji J, Ino Y, Louis DN, Rosenberg AE, Chiocca EA, Harris NL. Primary lymphoma of peripheral nerve: report of four cases. Am J Surg Pathol 2000; 24:1257-65. Descamps MJ, Barrett L, Groves M, et al. Primary sciatic nerve lymphoma: a case report and review of the literature. J Neurol Neurosurg Psychiatry 2006; 77:1087-9. Preston DC, Shapiro BE. Lymphoma of the sciatic nerve. J Clin Neuromuscul Dis 2001; 2:227-8. Rojas-Marcos I, Montero-Perea E, Salinas-Martin MV, Encinas V, Pujol M, Martino M. Primary sciatic nerve lymphoma [in Spanish]. Neurologia 2010; 25:65-7. Strobel K, Fischer K, Hany TF, Poryazova R, Jung HH. Sciatic nerve neurolymphomatosis - extent and therapy response assessment with PET/CT. Clin Nucl Med 2007; 32:646-8. Kahraman S, Sabuncuoglu H, Gunhan O, Gurses MA, Sirin S. A rare reason of foot drop caused by primary diffuse large b-cell lymphoma of the sciatic nerve: case report. Acta Neurochir (Wien) 2010; 152:125-8. Quinones-Hinojosa A, Friedlander RM, Boyer PJ, Batchelor TT, Chiocca EA. Solitary sciatic nerve lymphoma as an initial manifestation of diffuse neurolymphomatosis. Case report and review of the literature. J Neurosurg 2000; 92:165-9. Roncaroli F, Poppi M, Riccioni L, Frank F. Primary non-Hodgkin’s lymphoma of the sciatic nerve followed by localization in the central nervous system: case report and review of the literature. Neurosurgery 1997; 40:618-21, discussion 618-21. Kanamori M, Matsui H, Yudoh K. Solitary T-cell lymphoma of the sciatic nerve: case report. Neurosurgery 1995; 36:1203-5. Pillay PK, Hardy RW Jr, Wilbourn AJ, Tubbs RR, Lederman RJ. Solitary primary lymphoma of the sciatic nerve: case report. Neurosurgery 1988; 23:370-1. Purohit DP, Dick DJ, Perry RH, Lyons PR, Schofield IS, Foster JB. Solitary extranodal lymphoma of sciatic nerve. J Neurol Sci 1986; 74:23-34. Eusebi V, Bondi A, Cancellieri A, Canedi L, Frizzera G. Primary malignant lymphoma of sciatic nerve. Report of a case. Am J Surg Pathol 1990; 14:881-5. Baehring JM, Damek D, Martin EC, Betensky RA, Hochberg FH. Neurolymphomatosis. Neuro Oncol 2003; 5:104-15. Salm LP, Van der Hiel B, Stokkel MP. Increasing importance of 18F-FDG PET in the diagnosis of neurolymphomatosis. Nucl Med Commun 2012; 33:907-16. Wilson WH, Dunleavy K, Pittaluga S, et al. Phase II study of dose-adjusted EPOCH and rituximab in untreated diffuse large B-cell lymphoma with analysis of germinal center and post-germinal center biomarkers. J Clin Oncol 2008; 26:2717-24. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Available at: http://www.nccn.org/professionals/physician_gls/f_ guidelines.asp. Accessed November 1, 2014.
A Rare Case of Primary High-Grade Large B-Cell Lymphoma of the Sciatic Nerve Pooja Advani,1 Aneel Paulus,2 Peter Murray,3 Liuyan Jiang,4 Ryan Goff,5 Robert Pooley,5 Manoj Jain,5 Hillary Garner,5 James Foran1 Clinical Practice Points Primary high-grade large B-cell lymphoma of the
sciatic nerve without any systemic or central nervous system manifestations is rare, and the natural history of the disease is reported to be aggressive. There is a paucity of data on the optimal treatment strategies for primary sciatic nerve lymphoma. Combined modality dose-adjusted R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) followed by involved field
radiation treatment to the sciatic nerve might result in functional and sustained complete remission and is an alternative treatment option. Neurolymphomatosis should be considered in the differential diagnosis of sciatic nerve tumors, and its accurate diagnosis is based on clinical features, expert hematopathology review, and functional imaging modalities including positron emission tomography-computed tomography scan.
Clinical Lymphoma, Myeloma & Leukemia, Vol. 15, No. 6, e117-20 ª 2015 Elsevier Inc. All rights reserved. Keywords: Diffuse Large B-cell Lymphoma, Neurolymphomatosis, Non-germinal center B-cell lymphoma, Primary sciatic nerve lymphoma, Sciatic nerve tumor
Introduction Nerve-seeking lymphomas are a unique clinicopathologic entity, with approximately 90% of cases classified as non-Hodgkin lymphoma (NHL) in origin. The remaining cases are attributed to various leukemias.1-4 Neurolymphomatosis (NL) is defined as localized invasion of the cranial nerves, peripheral nerves, roots, or cranial plexus by neurotropic tumor cells.1 Most NL cases are caused by malignant B-cell NHL (with some T and natural killer cell cases reported), which exhibits an aggressive disease behavior and is noted to cause systemic involvement in most patients.2 We report a rare case of primary high-grade B-cell NHL localized to the sciatic nerve without any systemic or central nervous system (CNS) involvement.
Case Report A 72-year-old white man presented to our hospital with a 2-year history of paresthesia, pain, and weakness in the sole of his left foot, 1
Division of Hematology and Medical Oncology Department of Cancer Biology Division of Orthopedics 4 Division of Pathology 5 Division of Radiology Mayo Clinic, Jacksonville, FL 2 3
Submitted: Sep 18, 2014; Revised: Nov 26, 2014; Accepted: Dec 6, 2014; Epub: Dec 11, 2014 Address for correspondence: James Foran, MD, Division of Hematology and Medical Oncology, Mayo Clinic, 4500 San Pablo Rd S, Jacksonville, FL 32224. E-mail contact: [email protected]
2152-2650/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2014.12.001
which gradually progressed to involve his posterior thigh and calf. He denied any history of back pain, trauma, immunosuppressive disorders, use of immunosuppressive medications, or B symptoms such as fever, night sweats, or significant weight loss. On clinical examination, he was noted to have an antalgic gait, weakness of the left gastrocnemius-soleus muscles, an inability to plantar flex the left foot, and sensory loss in the distribution of the S1-S2 dermatome. Nerve conduction studies showed an absent left lateral plantar response, absent left tibial H reflex, and mildly low amplitude at the ankle and popliteal fossa on left tibial motor study. This was associated with denervation changes in the gastrocnemius and soleus muscles on electromyography. A magnetic resonance imaging (MRI) scan of the lumbar spine showed multilevel lumbar spondylosis. He was treated conservatively with pain medications and epidural steroid injections without much benefit. Blood tests including complete blood counts, erythrocyte sedimentation rate, C-reactive protein, antinuclear antibody, rheumatoid factor, and lactate dehydrogenase levels were normal. An MRI scan of the left lower extremity with contrast showed a heterogeneously enhancing 1.4 1.3 6.3 cm fusiform elongated mass intimately associated with the distal sciatic nerve, which extended into the proximal tibial nerve and terminated approximately 9 cm above the level of the knee (Figure 1A and C). The patient subsequently underwent left sciatic nerve neurolysis and an open biopsy of the tumor showed an infiltrating high-grade large B-cell lymphoma. Immunohistochemistry analysis revealed tumor cells, diffusely and strongly positive for CD20 and multiple
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Large B-Cell Lymphoma of the Sciatic Nerve Figure 1 Magnetic Resonance Imaging (MRI) and Positron Emission Tomography-Computed Tomography (PET-CT) Images of the Left Lower Extremity. Fat-Saturated Post Gadolinium T1-Weighted Images of the Left Lower Extremity Reveals an Infiltrative Mass in the Region of the Left Sciatic Nerve in Coronal (A) and Axial (C) Sections, Indicated by the Arrows. Repeat MRI After 4 Cycles of Dose-Adjusted R-EPOCH (Rituximab, Etoposide, Prednisone, Vincristine, Cyclophosphamide, and Doxorubicin) Shows a Marked Decrease in the Size of the Mass; (B) and (D). On PET-CT Imaging, an Isolated Hypermetabolic Mass (Arrows) Along the Left Sciatic Nerve Is Seen on Coronal (E) and Axial (G) Sections. Repeat Imaging After 2 Cycles of DoseAdjusted R-EPOCH Shows a Complete Metabolic Response, Which Was Maintained After 4 Cycles to seen on coronal (F) and axial (H) sections
myeloma oncogene 1, with a subset noted to be positive for B-cell lymphoma 6 (Figure 2). Ki-67 immunostaining showed a proliferation index of 85% (Figure 2). The tumor cells were negative for CD3, CD10, TdT, and CD30. Based on the Han algorithm,5 the
patient received a final diagnosis of high-grade diffuse large B-cell lymphoma (DLBCL) of the non-germinal center B-cell (GCB) phenotype. FISH for c-Myc and B-cell lymphoma 2 (bcl-2) was within normal limits. No expansion form (full form) of c-Myc.
Figure 2 Histology Findings and Immunohistochemical Studies of Sciatic Nerve Biopsy. Hematoxylin and Eosin-Stained Sections Show Dense Proliferation of Neoplastic Large Lymphocytes Infiltrating the Sciatic Nerve Bundles (A, Magnification 34; B, Magnification 320). The Lymphoma Cells Are Diffusely and Strongly Positive for CD20 (C, Magnification 320) With a High Proliferative Rate (Approximately 80%) With Ki-67 (D, Magnification 320). The Stain of Ki-67 Also Highlights the Large Nuclei of the Neoplastic B Cells. The Arrow in (A) Indicates a Residual Uninvolved Nerve Bundle, and the Arrows in (B), (C), and (D) Indicate Schwann Cells With Spindle Wavy Nuclei, Which Are Negative for CD20 and Ki-67
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Pooja Advani et al Whole body positron emission tomography (PET)-computed tomography (CT) scan showed an isolated moderately hypermetabolic (standardized uptake value of 7.9) mass along the sciatic nerve in the mid to distal left thigh (Figure 1E and G). MRI of the brain and spine and cerebrospinal fluid (CSF) analysis was negative for lymphomatous involvement. A staging bone marrow aspiration and biopsy was also negative for involvement with B-cell lymphoma. As such, he was diagnosed with a stage IAE high-grade B-cell NHL, of low-intermediate risk according to the International Prognostic Index. Based on histopathologic findings, we treated our patient with 4 cycles of dose-adjusted R-EPOCH (rituximab with infusional etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin). Intrathecal methotrexate was also administered with each cycle. PET-CT scans after 2 cycles showed resolution of previously reported hypermetabolic activity in the region of the distal left sciatic nerve, consistent with a functional complete remission (CR) (Figure 1F and H). MRI of the lower extremities showed a marked interval decrease in the size of the mass. After completion of doseadjusted R-EPOCH chemotherapy, the patient proceeded to receive involved field radiation therapy (IFRT) to the distal left sciatic nerve (3600 centigray in 20 fractions). MRI of the lower extremities at the end of treatment demonstrated a continued decrease in the size of the mass to 0.7 0.4 cm, and a near complete resolution of the patchy marrow signal abnormalities and enhancement (Figure 1B and D). At a follow-up of 18 months, the patient continued to have a functional CR on imaging with a marked improvement in his pain and left leg paresthesia.
Discussion Diffuse large B-cell lymphoma is the most common form of B-cell NHL, with an incidence of approximately 7 per 100,000 per year in the United States.6 Typically these lymphomas arise from lymph nodes and other lymphatic tissues; however, approximately 40% of patients are known to present with extranodal disease.7 DLBCL is further comprised of 2 prognostically different subgroups with distinct gene expression profiles, GCBs and activated B-cells,8 or GCB and non-GCB, when evaluated using immunohistochemistry, with the latter having a more aggressive clinical course.9 Because of the rarity of the disease, the true incidence of NL has been difficult to define. The largest study conducted on the matter (by the International Primary CNS Lymphoma Collaborative Group) described the presentation, treatment, and outcome of 50 NL cases, diagnosed over a 16-year period (1993-2008). Further review (spanning cases from 2001-2008) identified an additional 44 patients with features consistent with a diagnosis of NL.2 Overall, NL was found to be the initial presentation of systemic lymphoma in 26% to 29.5% of cases. Incidence of peripheral nerve involvement was variable across all data sets reported (20%-66% of cases) with multiple other nervous tissue sites being afflicted simultaneously.2 Placed in perspective, our report, describing a case of isolated primary NL arising within the sciatic nerve without any systemic manifestations, is indeed unique. Only 13 cases of primary lymphoma of the sciatic nerve have been described in the literature to date, and of these, 12 cases were reported to be of B-cell lineage, with 1 instance of T-cell lymphoma.10-21 Isolated primary lymphoma of other peripheral nerves
such as the brachial plexus, sympathetic chain, radial, median, and ulnar nerves has also been reported.10 The precise reason for preferential involvement of the sciatic nerve is unknown. It is postulated that analogous to normal lymphoid cells, specific adhesion receptors present on lymphoma cells might determine their predilection toward particular tissues. However, the exact adhesion molecules for organ selectivity of NL remain to be identified.22 Diagnosis of NL is challenging because presentation of disease is often indolent and symptoms can mimic those of lumbar disc pathology. Involvement of the nerve due to lymphoma is often difficult to distinguish from Schwannoma on computerized axial tomography or MRI scans. More recently, fluorine-18 fluorodeoxyglucose PET is increasingly being used to assist in the diagnosis of NL, for staging purposes and in monitoring response to treatment.23 Because primary isolated lymphoma of the sciatic nerve is rare, optimal treatment and management are still under debate. However, therapeutic strategies can be judiciously tailored according to the tumor cell of origin. Considering the aggressive nature of nonGCB type DLBCL, we surmised that in our patient, dose-adjusted R-EPOCH and radiation therapy would be an appropriate treatment option. In general, the underlying malignant cells in previously reported sciatic nerve lymphomas exhibited an intermediate to high-grade histology, necessitating treatment approaches ranging from nerve resection, radiotherapy, and chemotherapy, alone or in combination.11,14 Chemotherapy regimens consisting of MACOPB (methotrexate, cytarabine, cyclophosphamide, vincristine, prednisone, and bleomycin),17 ProMACE-CytaBOM (prednisone, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine, methotrexate, and leucovorin),10 and relatively newer regimens, such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with or without rituximab, have been used.10,11 Sciatic nerve lymphomas appear to behave aggressively, with at least 4 of the previously reported patients dying of CNS and/or systemic disease 6 to 50 months after clinical onset of sciatic nerve lymphoma.10,16,17,21 One patient had evidence of systemic disease 36 months after clinical onset. Notably, the short follow-up period (10-48 months) for most cases described in the literature has made it difficult to evaluate the behavior of such tumors.10,11,14 The limited penetration of chemotherapeutic agents across the bloodenerve barrier might partially explain the poor outcomes in these patients. Keeping this in mind, and the high proliferation rate, non-GCB phenotype of DLBCL, and locally advanced lesion in our patient, we elected to treat our patient with combination chemotherapy consisting of dose-adjusted R-EPOCH. Based on the excellent results of the phase II study, this regimen has been shown to have particular benefit in patients in the low and intermediate International Prognostic Index subgroups of DLBCL.24 An alternate standard of care would be to consider full course systemic RCHOP alone or abbreviated R-CHOP with IFRT.25 Prophylactic treatment of the CNS might be required, even in the absence of initial involvement in view of the aggressive nature and high mortality of B-cell lymphoma of the sciatic nerve.16 It has been reported that localized radiation therapy in combination with systemic chemotherapy achieves good local control in patients with bulky localized disease.1
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Large B-Cell Lymphoma of the Sciatic Nerve Conclusion We report a rare case of primary DLBCL-NHL afflicting the sciatic nerve in the absence of systemic involvement. A sciatic nerve tumor should be in the differential diagnosis for patients who present with progressive paresthesia, pain, numbness, and weakness of the lower limb. Accurate diagnosis entails timely integration of clinical, radiographic, and pathologic findings, and the latter is most notably obtained from CSF, neural, and extraneural tissues. Electrophysiological studies, MRI, and PET-CT scan are useful diagnostic tools, and the latter can aid in staging the disease and monitoring treatment responses. Although the optimal treatment for these tumors is not known, an early and aggressive approach with resection, chemotherapy, and radiation therapy alone or in combination should be considered.
Disclosure The authors have stated that they have no conflicts of interest.
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