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Neuropathology 2014; 34, 425–427
doi:10.1111/neup.12125
N eur opatho l o g y E d u ca t i o n
Multiple cerebral lesions in a 60-year-old female patient with a history of liver transplantation Ekkehard Hewer,1,4 Frauke Kellner-Weldon,2,4 Janine Abu-Isa3,4 and Anja M. Schmitt1,4 1
Institute of Pathology, Departments of 2Neuroradiology and 3Neurosurgery, Inselspital, Bern University Hospital, 4 University of Bern, Bern, Switzerland
CLINICAL COURSE A 60-year-old female patient presented with a 2-weeks history of progressive gait disturbance and fine motor movement deficits. Neurological examination showed a left-sided hemiparesis (grade 4) without further neurological deficits. MRI revealed multiple contrast-enhancing cerebral space-occupying lesions (Fig. 1). Her previous medical history was notable for orthotopic liver transplantation for autoimmune hepatitis performed 5 years earlier for which she was under immunosuppressive therapy with ciclosporin (2 × 100 mg/day) and mycophenolate mofetil. A navigation-assisted biopsy of a right frontal lesion was performed and histologically showed necrotizing granulomatous inflammation. Subsequently, an open excisional biopsy of this lesion was performed in order to retrieve sufficient tissue for microbiological studies. The specimen of the open biopsy was a whitish fragment of tissue measuring 1.2 × 0.8 × 0.7 cm. HE-stained sections revealed extensive necrotizing granulomatous inflammation (Fig. 1A,B) that was remarkable for an angiocentric pattern (Fig. 2C), while there was no evidence of vasculitis. The mixed inflammatory infiltrate included rare large atypical cells (Fig. 2D) resembling Reed-Sternberg cells. Immunohistochemical staining for GFAP highlighted the nodularity of the inflammatory infiltrate (Fig. 2E). Staining for CD68 labeled the abundant macrophages (Fig. 2F). The infiltrate included numerous small T lymphocytes (Fig. 2G–I) and a moderate number of B lymphocytes (Fig. 2J). The latter consisted of a spectrum of small, medium-sized and large cells (Fig. 2J,K) including the Reed-Sternberg-like cells. The medium-sized and large CD20-positive cells were also CD30-immunoreactive (Fig. 2M), strongly positive for Pax-5 and MUM-1(IRF-4),
Correspondence: Ekkehard Hewer, MD, Institute of Pathology, University of Bern, Murtenstrasse 31, 3010 Bern, Switzerland. Email: [email protected] Published online 17 April 2014.
© 2014 Japanese Society of Neuropathology
Fig. 1 T1-weighted gradient echo anatomical sequence (MPRage), contrast enhanced in the sagittal plane shows multiple ring-enhancing lesions.
but negative for CD15 (not shown). They were variably positive for Epstein-Barr virus-encoded RNA (EBER) by in situ hybridization (Fig. 2N). A CD138 staining showed scattered plasma cells and labeled rare medium-sized lymphoid cells. There was a high proliferative activity of the medium-sized and large cells (Ki-67/MIB-1; Fig. 2M). Special stains for microorganisms (Ziehl-Neelsen, PAS, Warthin-Starry, Grocott silver impregnation) yielded negative results as did extensive microbiological studies, including cultures for fungi and mycobacteriae as well as PCR for mycobacteriae. There was no clonal rearrangement of the immunoglobulin heavy chain or the T-cell receptor gamma chain genes. Staging did not reveal any extra-cerebral lesions. After the diagnostic work-up, the immunosuppressive medication was changed to everolimus and chemotherapy
426
E Hewer et al.
A
B
C
D
E
F
GFAP
G
H
CD3
I
CD4
K
J
CD20
CD30
CD8
L
CD20
N
M
CD68
CD138
O
EBER
MIB-1
Fig. 2 HE-stained slides showed extensive necrotizing granulomatous inflammation in an angiocentric distribution (A–C). Rare large cells resembling Reed-Sternberg cells were identified (arrows in D). GFAP staining highlighted the nodularity of the infiltrate (E). The infiltrate included abundant macrophages (CD68; F), numerous T cells (about equal numbers of CD4+ and CD8+ T cells; G–I) and a moderate number of B cells. The latter consisted of a spectrum of small to very large cells and included Hodgkin/Reed-Sternberg-like cells (J–K). In addition to scattered plasma cells, CD138 staining (L) labeled rare medium-sized lymphoid cells (arrow). The medium-sized and large B cells were CD30-positive (M), variably EBV-positive (N) and displayed high proliferative activity (MIB-1; O). Scale bar in (A) corresponds to 200 μm (A, G, J), 100 μm (B, E, F, H, I, L), and 50 μm (C, D, K, M–O), respectively.
© 2014 Japanese Society of Neuropathology
Post-transplant lymphoproliferative disorder was initiated.A control MRI 6 weeks after beginning of the induction chemotherapy showed complete remission of the cerebral lesions.
DIAGNOSIS Polymorphic post-transplant lymphoproliferative disorder (PTLD) confined to the CNS.
DISCUSSION The differential diagnosis of cerebral lesions in patients with a history of solid organ transplants is broad and includes a variety of infectious and neoplastic processes, especially conditions related to iatrogenic immunosuppression.1 The present case was diagnostically challenging for several reasons. (i) The extensive granulomatous inflammation suggested the possibility of an infectious process. (ii) The inflammatory infiltrate largely masked the actual neoplastic lesion. (iii) The occurrence of ReedSternberg-like cells might have led to a misdiagnosis as Hodgkin’s lymphoma. Given that special stains for microorganisms performed on histological sections are of limited sensitivity, negative results of cultures and PCR were critical in ruling out an infectious etiology of the granulomatous inflammation in the present case. Neurosarcoidosis as a differential diagnosis of granulomatous (meningo-)encephalitis was deemed unlikely because of the presence of necrosis. Imaging did not show pulmonary hilar lymph node involvement, further arguing against sarcoidosis. We interpret the granulomatous inflammation as a reactive change secondary to the lymphoproliferative disorder, similar to the granulomatous inflammation that accompanies a subset of Hodgkin’s lymphomas or the abundant macrophages in T-cell/histiocyte-rich large B-cell lymphoma. The distinction of the present findings from lymphomatoid granulomatosis (LG) is to some extent a semantic one, as the latter is associated with EBV, typically features an angiocentric histiocyte-rich infiltrate and may involve the CNS.2 A peculiarity of the present case was the population of scant atypical cells that resembled Reed-Sternberg cells of Hodgkin’s lymphoma. They shared immunoreactivity for CD30 and MUM1 with true Reed-Sternberg cells, but differed from them in that the B-cell expression pattern was not down-regulated (CD20 and CD79a were positive, and Pax-5 staining was as strong as that in small B lymphocytes) and that they were negative for CD15. This staining pattern is indeed characteristic of Reed-Sternberg-like cells occasionally observed in PTLD and allows for distinc-
© 2014 Japanese Society of Neuropathology
427 tion from classic Hodgkin’s lymphoma which also may occur in the post-transplant setting.3,4 PTLD are classified as monomorphic or polymorphic, respectively, depending on whether the lymphoproliferative process corresponds to a defined type of lymphoma or not. In the present case, the absence of a dominant B cell clone and the variability of EBER staining supported the interpretation as an oligoclonal B cell proliferation rather than an established lymphoma. By far the most common type of PTLD in the CNS is diffuse large B cell lymphoma.5 A recent large multi-center study has found the polymorphic type to account for 18% of all isolated PTLD of the CNS.6 In this study, 88% of PTLD cases were associated with EBV. The importance of a correct diagnosis of PTLD relates to its therapeutic implications. In fact, modification of the immunosuppressive may be sufficient to achieve remission in some patients, while others will require chemo- and/or radiotherapy or treatment with an anti-CD20 monoclonal antibody.7
REFERENCES 1. Martinez AJ. The neuropathology of organ transplantation: comparison and contrast in 500 patients. Pathol Res Pract 1998; 194: 473–486. 2. Nishihara H, Tateishi U, Itoh T, Nagashima K, Tanaka S. Immunohistochemical and gene rearrangement studies of central nervous system lymphomatoid granulomatosis. Neuropathology 2007; 27: 413–418. 3. Rohr JC, Wagner HJ, Lauten M et al. Differentiation of EBV-induced post-transplant Hodgkin lymphoma from Hodgkin-like post-transplant lymphoproliferative disease. Pediatr Transplant 2008; 12: 426–431. 4. Pitman SD, Huang Q, Zuppan CW et al. Hodgkin lymphoma-like posttransplant lymphoproliferative disorder (HL-like PTLD) simulates monomorphic B-cell PTLD both clinically and pathologically. Am J Surg Pathol 2006; 30: 470–476. 5. Suzuki M, Kosugi I, Terada T et al. A case of EpsteinBarr virus associated post-transplant lymphoproliferative disorder with CNS involvement: pathological findings at both biopsy and autopsy. Neuropathology 2011; 31: 440–445. 6. Evens AM, Choquet S, Kroll-Desrosiers AR et al. Primary CNS posttransplant lymphoproliferative disease (PTLD): an international report of 84 cases in the modern era. Am J Transplant 2013; 13: 1512–1522. 7. Kamdar KY, Rooney CM, Heslop HE. Posttransplant lymphoproliferative disease following liver transplantation. Curr Opin Organ Transplant 2011; 16: 274–280.
Neuropathology 2014; 34, 425–427
doi:10.1111/neup.12125
N eur opatho l o g y E d u ca t i o n
Multiple cerebral lesions in a 60-year-old female patient with a history of liver transplantation Ekkehard Hewer,1,4 Frauke Kellner-Weldon,2,4 Janine Abu-Isa3,4 and Anja M. Schmitt1,4 1
Institute of Pathology, Departments of 2Neuroradiology and 3Neurosurgery, Inselspital, Bern University Hospital, 4 University of Bern, Bern, Switzerland
CLINICAL COURSE A 60-year-old female patient presented with a 2-weeks history of progressive gait disturbance and fine motor movement deficits. Neurological examination showed a left-sided hemiparesis (grade 4) without further neurological deficits. MRI revealed multiple contrast-enhancing cerebral space-occupying lesions (Fig. 1). Her previous medical history was notable for orthotopic liver transplantation for autoimmune hepatitis performed 5 years earlier for which she was under immunosuppressive therapy with ciclosporin (2 × 100 mg/day) and mycophenolate mofetil. A navigation-assisted biopsy of a right frontal lesion was performed and histologically showed necrotizing granulomatous inflammation. Subsequently, an open excisional biopsy of this lesion was performed in order to retrieve sufficient tissue for microbiological studies. The specimen of the open biopsy was a whitish fragment of tissue measuring 1.2 × 0.8 × 0.7 cm. HE-stained sections revealed extensive necrotizing granulomatous inflammation (Fig. 1A,B) that was remarkable for an angiocentric pattern (Fig. 2C), while there was no evidence of vasculitis. The mixed inflammatory infiltrate included rare large atypical cells (Fig. 2D) resembling Reed-Sternberg cells. Immunohistochemical staining for GFAP highlighted the nodularity of the inflammatory infiltrate (Fig. 2E). Staining for CD68 labeled the abundant macrophages (Fig. 2F). The infiltrate included numerous small T lymphocytes (Fig. 2G–I) and a moderate number of B lymphocytes (Fig. 2J). The latter consisted of a spectrum of small, medium-sized and large cells (Fig. 2J,K) including the Reed-Sternberg-like cells. The medium-sized and large CD20-positive cells were also CD30-immunoreactive (Fig. 2M), strongly positive for Pax-5 and MUM-1(IRF-4),
Correspondence: Ekkehard Hewer, MD, Institute of Pathology, University of Bern, Murtenstrasse 31, 3010 Bern, Switzerland. Email: [email protected] Published online 17 April 2014.
© 2014 Japanese Society of Neuropathology
Fig. 1 T1-weighted gradient echo anatomical sequence (MPRage), contrast enhanced in the sagittal plane shows multiple ring-enhancing lesions.
but negative for CD15 (not shown). They were variably positive for Epstein-Barr virus-encoded RNA (EBER) by in situ hybridization (Fig. 2N). A CD138 staining showed scattered plasma cells and labeled rare medium-sized lymphoid cells. There was a high proliferative activity of the medium-sized and large cells (Ki-67/MIB-1; Fig. 2M). Special stains for microorganisms (Ziehl-Neelsen, PAS, Warthin-Starry, Grocott silver impregnation) yielded negative results as did extensive microbiological studies, including cultures for fungi and mycobacteriae as well as PCR for mycobacteriae. There was no clonal rearrangement of the immunoglobulin heavy chain or the T-cell receptor gamma chain genes. Staging did not reveal any extra-cerebral lesions. After the diagnostic work-up, the immunosuppressive medication was changed to everolimus and chemotherapy
426
E Hewer et al.
A
B
C
D
E
F
GFAP
G
H
CD3
I
CD4
K
J
CD20
CD30
CD8
L
CD20
N
M
CD68
CD138
O
EBER
MIB-1
Fig. 2 HE-stained slides showed extensive necrotizing granulomatous inflammation in an angiocentric distribution (A–C). Rare large cells resembling Reed-Sternberg cells were identified (arrows in D). GFAP staining highlighted the nodularity of the infiltrate (E). The infiltrate included abundant macrophages (CD68; F), numerous T cells (about equal numbers of CD4+ and CD8+ T cells; G–I) and a moderate number of B cells. The latter consisted of a spectrum of small to very large cells and included Hodgkin/Reed-Sternberg-like cells (J–K). In addition to scattered plasma cells, CD138 staining (L) labeled rare medium-sized lymphoid cells (arrow). The medium-sized and large B cells were CD30-positive (M), variably EBV-positive (N) and displayed high proliferative activity (MIB-1; O). Scale bar in (A) corresponds to 200 μm (A, G, J), 100 μm (B, E, F, H, I, L), and 50 μm (C, D, K, M–O), respectively.
© 2014 Japanese Society of Neuropathology
Post-transplant lymphoproliferative disorder was initiated.A control MRI 6 weeks after beginning of the induction chemotherapy showed complete remission of the cerebral lesions.
DIAGNOSIS Polymorphic post-transplant lymphoproliferative disorder (PTLD) confined to the CNS.
DISCUSSION The differential diagnosis of cerebral lesions in patients with a history of solid organ transplants is broad and includes a variety of infectious and neoplastic processes, especially conditions related to iatrogenic immunosuppression.1 The present case was diagnostically challenging for several reasons. (i) The extensive granulomatous inflammation suggested the possibility of an infectious process. (ii) The inflammatory infiltrate largely masked the actual neoplastic lesion. (iii) The occurrence of ReedSternberg-like cells might have led to a misdiagnosis as Hodgkin’s lymphoma. Given that special stains for microorganisms performed on histological sections are of limited sensitivity, negative results of cultures and PCR were critical in ruling out an infectious etiology of the granulomatous inflammation in the present case. Neurosarcoidosis as a differential diagnosis of granulomatous (meningo-)encephalitis was deemed unlikely because of the presence of necrosis. Imaging did not show pulmonary hilar lymph node involvement, further arguing against sarcoidosis. We interpret the granulomatous inflammation as a reactive change secondary to the lymphoproliferative disorder, similar to the granulomatous inflammation that accompanies a subset of Hodgkin’s lymphomas or the abundant macrophages in T-cell/histiocyte-rich large B-cell lymphoma. The distinction of the present findings from lymphomatoid granulomatosis (LG) is to some extent a semantic one, as the latter is associated with EBV, typically features an angiocentric histiocyte-rich infiltrate and may involve the CNS.2 A peculiarity of the present case was the population of scant atypical cells that resembled Reed-Sternberg cells of Hodgkin’s lymphoma. They shared immunoreactivity for CD30 and MUM1 with true Reed-Sternberg cells, but differed from them in that the B-cell expression pattern was not down-regulated (CD20 and CD79a were positive, and Pax-5 staining was as strong as that in small B lymphocytes) and that they were negative for CD15. This staining pattern is indeed characteristic of Reed-Sternberg-like cells occasionally observed in PTLD and allows for distinc-
© 2014 Japanese Society of Neuropathology
427 tion from classic Hodgkin’s lymphoma which also may occur in the post-transplant setting.3,4 PTLD are classified as monomorphic or polymorphic, respectively, depending on whether the lymphoproliferative process corresponds to a defined type of lymphoma or not. In the present case, the absence of a dominant B cell clone and the variability of EBER staining supported the interpretation as an oligoclonal B cell proliferation rather than an established lymphoma. By far the most common type of PTLD in the CNS is diffuse large B cell lymphoma.5 A recent large multi-center study has found the polymorphic type to account for 18% of all isolated PTLD of the CNS.6 In this study, 88% of PTLD cases were associated with EBV. The importance of a correct diagnosis of PTLD relates to its therapeutic implications. In fact, modification of the immunosuppressive may be sufficient to achieve remission in some patients, while others will require chemo- and/or radiotherapy or treatment with an anti-CD20 monoclonal antibody.7
REFERENCES 1. Martinez AJ. The neuropathology of organ transplantation: comparison and contrast in 500 patients. Pathol Res Pract 1998; 194: 473–486. 2. Nishihara H, Tateishi U, Itoh T, Nagashima K, Tanaka S. Immunohistochemical and gene rearrangement studies of central nervous system lymphomatoid granulomatosis. Neuropathology 2007; 27: 413–418. 3. Rohr JC, Wagner HJ, Lauten M et al. Differentiation of EBV-induced post-transplant Hodgkin lymphoma from Hodgkin-like post-transplant lymphoproliferative disease. Pediatr Transplant 2008; 12: 426–431. 4. Pitman SD, Huang Q, Zuppan CW et al. Hodgkin lymphoma-like posttransplant lymphoproliferative disorder (HL-like PTLD) simulates monomorphic B-cell PTLD both clinically and pathologically. Am J Surg Pathol 2006; 30: 470–476. 5. Suzuki M, Kosugi I, Terada T et al. A case of EpsteinBarr virus associated post-transplant lymphoproliferative disorder with CNS involvement: pathological findings at both biopsy and autopsy. Neuropathology 2011; 31: 440–445. 6. Evens AM, Choquet S, Kroll-Desrosiers AR et al. Primary CNS posttransplant lymphoproliferative disease (PTLD): an international report of 84 cases in the modern era. Am J Transplant 2013; 13: 1512–1522. 7. Kamdar KY, Rooney CM, Heslop HE. Posttransplant lymphoproliferative disease following liver transplantation. Curr Opin Organ Transplant 2011; 16: 274–280.
