VOLUME
33
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NUMBER
19
䡠
JULY
1
2015
JOURNAL OF CLINICAL ONCOLOGY
D I A G N O S I S
O N C O L O G Y
sis of the left upper extremity as well as a bilateral defect of ocular abduction. Laboratory tests at the time of admission yielded the following results. Hematologic tests revealed a slightly elevated WBC count (10,400/L), with no abnormalities in the differential leukocyte count and no atypical cells. The soluble interleukin-2 receptor serum level was 362 U/mL, and the serum LDH level was 252 IU/L; serologic tests for HIV antibodies were negative. Bone marrow infiltration was absent. Tumor cells (82 cells/L) were found in the CSF. A brain magnetic resonance imaging examination (T1-weighted image) revealed a tumorous lesion (30 ⫻ 30 mm) showing a homogeneous and intense gadolinium enhancement in the right frontal to parietal lobe, surrounded by edema. Bleeding inside the tumor was also noted (Fig 1A, axial; Fig 1B, sagittal; Fig 1C, coronal). Contrast-enhanced computed tomography of the neck through pelvis revealed no tumorous lesions in any organs other than the CNS, suggesting that the tumor originated from the intracranial cavity. The patient was rated as low risk according to the IPI for primary CNS lymphoma (PCNSL). Flow cytometry of the brain tumor cells of this patient revealed expression of the chain, CD20, and CD19 on the cell membrane (Fig 2; FSC-H, forward scatter height values; IgM, immunoglobulin M; SSC-H, side scatter height values). Hematoxylin and eosin staining of the biopsy specimens from the brain tumor revealed tingible body macrophages (phagocytosing apoptotic tumor cells) at low magnification, whereas examination at higher magnification revealed that the tumor was primarily composed of medium- to large-sized lymphocytes (Fig 3A, ⫻100 magnification; Fig 3B, ⫻600 magnification). Immunostaining revealed that the brain tumor cells were medium sized, CD20⫹, CD3⫺, weakly CD5⫹, and CD10⫹, consistent with the findings of flow cytometry (Figs 3C to 3K, ⫻600 magnification; Fig 3C, CD20; Fig 3D, CD3; Fig 3E, CD5; Fig 3F, CD10; Fig 3G, cyclin D1; Fig 3H, Ki-67; Fig 3I, BCL2; Fig 3J, CD79a; Fig 3K, TdT, terminal deoxynucleotidyl transferase). Cyclin D1⫹ and BCL2⫹ are characteristic of MCL, whereas CD10⫹ is characteristic of Burkitt’s lymphoma (BL). The tumor cells were CD5⫹, CD10⫹, cyclin D1⫹, and BCL2⫹, with a high Ki-67 index; thus, they possessed the surface marker characteristics of both BL and MCL. Because a pooled biopsy
Primary CNS CCND1/MYC-Positive Double-Hit B-Cell Lymphoma: A Case Report and Review of the Literature Introduction Double-hit (DH) B-cell lymphomas are B-cell lymphomas that concurrently carry a chromosomal translocation involving MYC/ 8q24 as well as another chromosomal translocation, typically BCL2/ 18q21 (62%).1 The median age of patients with DH lymphomas is 51 to 65 years. This disease is often characterized by an abnormal elevation in the serum lactate dehydrogenase (LDH) level and tumor invasion of the bone marrow and CNS. According to the International Prognostic Index (IPI), this disease is often rated as having a poor prognosis. Doxorubicin-based chemotherapy, high-dose chemotherapy, and hematopoietic stem-cell transplantation have been used to treat this condition; however, the prognosis is quite poor, with a reported mean survival of 0.2 to 1.5 years. CCND1/MYC-positive DH lymphomas carrying chromosomal translocations involving CCND1/11q13 and MYC/8q24 are seen in approximately 5% to 10% of all patients with mantle-cell lymphoma (MCL). Many of these patients are leukemic and have a blastoid, pleomorphic, or even Burkitt’s-like morphology.2 We report a patient with CCND1/MYC-positive DH B-cell lymphoma of CNS origin who was recently treated at our facility. Case Report A 55-year-old man first became aware of paralysis of the left upper extremity and numbness of the left half of his body in midSeptember 2010 and visited the Department of Neurosurgery at our hospital (Juntendo University Urayasu Hospital). His past medical history and family history were not noteworthy. A brain tumor was suspected, and a craniotomy for a tumor biopsy was performed in October of the same year. At the time of admission, the patient’s mental acuity was normal. Superficial lymph nodes were not palpable. No skin lesions were noted. A neurologic examination revealed motor and sensory paraly-
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Fig 1. Journal of Clinical Oncology, Vol 33, No 19 (July 1), 2015: pp e79-e83
© 2014 by American Society of Clinical Oncology
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e79
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0.7
89.5
CD 19
1.2
λ-ch
FSC-H
98.6
0.0
κ-ch
SSC-H
Ig M
0.8
70.5
CD 5 0.4
CD 3
85.7
0.7
CD 10
0.7
CD 8
15.0
9.3
27.3
CD 20
0.0
CD 34
Fig 2.
specimen was not available, paraffin sections were used for paraffinembedded tissue section–fluorescent in situ hybridization. If we had used fusion probes for the biopsy, the separated red and green signals might have been mistaken as one yellow fusion signal if they overlapped because of the thickness (4 m) of the specimen. To avoid such false-positive results, a break-apart probe was selected for the biopsy
specimen. In this patient, the MYC split-signal positive rate was 75.0% (Fig 4A, MYC centromere [red arrows] and telomere [green arrows] probes). An analysis revealed negative results for both the CCND1 split signal and the BCL2 split signal (Fig 4B, CCND1 centromere [green arrows] and telomere [red arrows] probe; Fig 4C, BCL2 centromere [green arrows] and telomere [red arrows] probe), but the
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Fig 3. e80
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JOURNAL OF CLINICAL ONCOLOGY
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Diagnosis in Oncology
A
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Fig 4.
percentage of cells showing an excess on the telomere side of the CCND1/11q13 was 62%. These results mean that some reciprocal translocations with other unknown genes are likely to exist. Because tumor cell infiltration of the CSF was noted in this patient, a more specific fluorescent in situ hybridization using fusion probes was performed on a thin specimen (⬍ 1 m) in the CSF, revealing an MYCIgH fusion signal positive rate of 100% and a CCND1-IgH fusion signal positive rate of 99% (Fig 4D, MYC [red] and IgH [green] probes; Fig 4E, CCND1 [red] and IgH [green] probes, fusion signal [white arrows]). On the basis of these results, the tumor was diagnosed as a CCND1/MYC-positive DH lymphoma originating from the CNS. Chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone was begun in October 2010. Later, on the 20th hospital day, high-dose methotrexate plus high-dose cytarabine therapy was begun because of an elevated serum LDH level. However, the tumor did not diminish in size, and the patient began to develop seizures. From the 37th hospital day, chemotherapy with rituximab, cyclophosphamide, vincristine, doxorubicin, and dexamethasone was administered. A brain computed tomography scan obtained on the 73rd hospital day after two courses of this therapy revealed a tempo-
rary response to the treatment. However, in January 2011, bleeding inside the tumor recurred, and the tumor continued to increase in size, with the seizures becoming uncontrollable. The patient died in February 2011 (116th hospital day). No postmortem examination was performed. Discussion Imai et al3 reported 40 patients with PCNSL in their series; 12 patients (30%) were CD5⫹, whereas all of the patients were cyclin D1 negative. To our knowledge, only three patients with primary CNS MCL (including the patient presented here) have been reported to date, reflecting the extremely rare occurrence of this condition (Table 1).4,5 In all three reported patients, tumor infiltration of the CSF was noted, suggesting a poor prognosis for this disease. All three patients were rated as having a low to low-intermediate risk, according to the IPI. Only the first patient was rated as having a high risk according to the PCNSL IPI criteria.6 The first patient had a primary CNS MCL that was CD10⫺, suggesting that the tumor was unlikely to be a CCND1/ MYC-positive DH lymphoma.4 The second patient reported was 29 years old, which is relatively young for the onset of MCL. The second
Table 1. Summary of Primary CNS Mantle-Cell Lymphomas in the Literature Patient
Age (years)
Sex
Location
Markers
IPI
PCNSL IPI
Treatment
Outcome
Reference
1 2 3
74 29 55
F M M
Frontoparietal region/CSF CSF Frontal lobe/CSF
CD5⫹ CD20⫹ CD10⫺ CD23⫺ CD5⫹ CD20⫹ IgG⫹ CD5⫹ CD20⫹ CD10⫹ CCND1⫹
ⴱ
High Lowⴱ Low
MTX ASCT MTX, Ara-C
Dead, 1 month CR Dead, 4 months
4 5 Current article
LI Lowⴱ Low
Abbreviations: Ara-C, cytarabine; ASCT, autologous stem-cell transplantation; CCND1, cyclin D1; CR, complete remission; IgG, immunoglobulin G; IPI, International Prognostic Index; LI, low intermediate; MTX, methotrexate; PCNSL, primary CNS lymphoma. ⴱ Concerning.
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Sakurai et al
Table 2. Summary of Primary Cerebral Burkitt’s Lymphomas in the Literature Age Patient (years) Sex
HIV IPI
PCNSL IPI
ND
ND ND
ND
ND ND ND
ND ND ND ND ND ND
ND ND ND
Location
1
⬍1
M
2 3 4
11 55 5
M F M
Both temporal tips and partial temporal region Left temporo-occipital region Right temporoparietal region Frontal base dura and adjacent bone
5
6
F
CSF
6
40
M
7 8
15 49
9
Markers
ND
ND
Cerebellum and pons
CD19⫹ CD20⫹ CD10⫹ IgM⫹ ND
ND ND
ND
M F
Pituitary stalk Left parietal region
ND LCA⫹ CD19⫹
ND ND ⫺ ND
ND ND
8
M
ND
10
38
M
11
50
M
12 13
60 75
F F
Right lateral orbit and left temporal region Right front-temporoparietal subdural spade Central thalamus, right thalamus, and periventricular white matter Sellar region Intraventricular lesions
14
14
M
⫺
Adjuvant Treatment Chemotherapy ⫹ radiotherapy None None Chemotherapy ⫹ radiotherapy Chemotherapy
Outcome
Reference
Died, 20 months
7
Alive, 1 year Died, 1 month Better vision
8 9 10
CR, 2 years
11
ND
ND
Chemotherapy ⫹ radiotherapy Chemotherapy CHOP ⫹ craniospinal radiotherapy Chemotherapy
CD20⫹ CD79a⫹ CD10⫹ ⫹ ND BCL6⫹ CD20⫹ CD10⫹ ND ND
ND
None
Died, 11 days
16
ND
ND
ND
17
⫺
CD45⫹ CD79⫹ BCL 2⫺ LCA⫹ CD10⫹ CD20⫹ CD79a⫹ Right anterior horn and body of lateral CD20⫹ CD10⫹ CD79a⫹ BCL6⫹ ventricle
CR, 1 year
12
CR, 17 months DF, 6 months
13 14
Died, 11 months
15
⫺ ⫺
ND L
ND ND
ND Radiotherapy
ND Alive, 9 months
18 19
⫺
L
ND
Gamma knife ⫹ HDMTX ⫹ VP
CR, 18 months
20
Abbreviations: CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CR, complete remission; DF, disease free; HDMTX, high-dose methotrexate; IgM, immunoglobulin M; IPI, International Prognostic Index; L, low risk; LCA, leukocyte common antigen; ND, not described; PCNSL, primary CNS lymphoma; VP, vincristine plus prednisolone.
patient’s tumor was CD5⫹, CD19⫹, and CD20⫹; however, the diagnosis was questionable because of the lack of description regarding CD23 and histologic findings.5 On the basis of these findings and reports, the present is, to our knowledge, the first reported case of CCND1/MYC-positive DH lymphoma of CNS origin. Considering that primary CNS MCL follows a rapid clinical course and is likely to have a poor prognosis, as seen in the first patient case to be reported in the literature,4 the prognosis of CCND1/MYC-positive DH lymphoma of CNS origin is expected to be extremely poor. In fact, our patient died about 4 months after disease onset despite undergoing massive chemotherapy. To date, 14 cases of primary intracranial BL have been reported, and this disease is rare (Table 2).7-20 The age at onset of this disease shows two peaks (childhood and middle/advanced age). It is seen slightly more frequently in men. Although no prognostic factors for PCNSL have been identified, the responses of this disease to treatment can be divided in a rather clear-cut manner into a favorable group and an unfavorable group (Table 2). Information on CD5 expression was not available for any of the reported cases. Jiang et al21 published the first report on primary CNS B-cell lymphoma with features intermediate between those of diffuse large B-cell lymphoma and BL, stating that the patient showed excessive BCL2 expression but no t(14;18). Their report did not refer to cyclin D1, and additional details of this case remain obscure. In the present case, the disease was found to be therapy resistant on the 81st hospital day. Although high-dose chemotherapy was begun subsequently, the tumor tended to grow week after week, and the growth of the tumor, accompanied by bleeding inside the tumor, e82
© 2014 by American Society of Clinical Oncology
began to be visible 2 weeks after the start of this therapy. The growth of this tumor seemed to be difficult to suppress using the chemotherapy regimens that are conventionally used for PCNSL. In conclusion, the patient presented here had CCND1/MYCpositive DH lymphoma, which was morphologically akin to MCL (blastoid variant) originating from the CNS. To our knowledge, no previous report of a DH lymphoma of CNS origin has been published; the present patient case seems to be the first such case. The prognosis of this patient was predicted to be extremely poor, and in fact, the patient followed a rapid clinical course and died 4 months after the diagnosis. When dealing with such patients, chemotherapy that is conventionally used for PCNSL is unlikely to be sufficiently effective, and some modified treatment approaches are needed.
Hiroko Sakurai Juntendo University Urayasu Hospital, Chiba; Juntendo University, Tokyo, Japan
Kei-Ji Sugimoto Juntendo University Urayasu Hospital, Chiba, Japan
Asami Shimada Juntendo University Urayasu Hospital, Chiba; Juntendo University, Tokyo, Japan
Hidenori Imai, Mutsumi Wakabayashi, and Yasunobu Sekiguchi Juntendo University Urayasu Hospital, Chiba, Japan
Yasunori Ota and Koji Izutsu Toranomon Hospital, Tokyo, Japan JOURNAL OF CLINICAL ONCOLOGY
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Diagnosis in Oncology
Kengo Takeuchi The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
Norio Komatsu Juntendo University, Tokyo, Japan
Masaaki Noguchi Juntendo University Urayasu Hospital, Chiba, Japan
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest. REFERENCES 1. Aukema SM, Siebert R, Schuuring E, et al: Double-hit B-cell lymphomas. Blood 117:2319-2331, 2011 2. Hao S, Sanger W, Onciu M, et al: Mantle cell lymphoma with 8q24 chromosomal abnormalities: A report of 5 cases with blastoid features. Mod Pathol 15:1266-1272, 2002 3. Imai H, Shimada K, Shimada S, et al: Comparative clinicopathological study of primary CNS diffuse large B-cell lymphoma and intravascular large B-cell lymphoma. Pathol Int 59:431-437, 2009 4. Finsterer J, Lubec D, Jellinger K, et al: Recovery from coma caused by primary CNS mantle cell lymphoma presenting as encephalitis. Neurology 46:824-826, 1996 5. Trip SA, Wroe SJ, Davies G, et al: Primary CNS mantle cell lymphoma associated with an isolated CSF monoclonal IgG band. Eur Neurol 49:187-188, 2003 6. Ferreri AJ, Abrey LE, Blay JY, et al: Summary statement on primary central nervous system lymphomas from the Eighth International Conference on Malignant Lymphoma, Lugano, Switzerland, June 12 to 15, 2002. J Clin Oncol 21:2407-2414, 2003 7. Valsamis MP, Levine PH, Rapin I, et al: Primary intracranial Burkitt’s lymphoma in an infant. Cancer 37:1500-1507, 1976 8. Giromini D, Peiffer J, Tzonos T: Occurrence of a primary Burkitt-type lymphoma of the central nervous system in an astrocytoma patient: A case report. Acta Neuropathol 54:165-167, 1981 9. Kobayashi H, Sano T, Ii K, et al: Primary Burkitt-type lymphoma of the central nervous system. Acta Neuropathol 64:12-14, 1984
10. Tekko¨k IH, Tahta K, Erbengi A, et al: Primary intracranial extradural Burkitt-type lymphoma: A unique presentation with unilateral loss of vision in a child. Childs Nerv Syst 7:172-174, 1991 11. Toren A, Mandel M, Shahar E, et al: Primary central nervous system Burkitt’s lymphoma presenting as Guillain-Barre´ syndrome. Med Pediatr Oncol 23:372-375, 1994 12. Spa¨th-Schwalbe E, Genvresse I, Stein H, et al: Primary cerebral highlymalignant B-cell lymphoma of the Burkitt type[in German]. Dtsch Med Wochenschr 124:451-455, 1999 13. Silfen ME, Garvin JH Jr, Hays AP, et al: Primary central nervous system lymphoma in childhood presenting as progressive panhypopituitarism. J Pediatr Hematol Oncol 23:130-133, 2001 14. Monabati A, Rakei SM, Kumar P, et al: Primary Burkitt lymphoma of the brain in an immunocompetent patient: Case report. J Neurosurg 96:1127-1129, 2002 15. Shehu BB: Primary central nervous system Burkitt’s lymphoma presenting with proptosis. Ann Trop Paediatr 23:319-320, 2003 16. Gobbato PL, Pereira Filho Ade A, de David G, et al: Primary meningeal Burkitt-type lymphoma presenting as the first clinical manifestation of acquired immunodeficiency syndrome. Arq Neuropsiquiatr 64:511-515, 2006 17. Abel TW, Thompson MA, Kim J, et al: Primary central nervous system Burkitt lymphoma: Report of a case confirmed with identification of t(8;14)by FISH. Brain Pathol 16:97-97, 2006 (suppl 1) 18. Koza´kova´ D, Macha´lekova´ K, Brtko P, et al: Primary B-cell pituitary lymphoma of the Burkitt type: Case report of the rare clinic entity with typical clinical presentation. Cas Lek Cesk 147:569-573, 2008 19. Gu Y, Hou YY, Zhang XB, et al: Primary central nervous system Burkitt lymphoma as concomitant lesions in the third and the left ventricles: A case study and literature review. J Neurooncol 99:277-281, 2010 20. Jiang M, Zhu J, Guan YS, et al: Primary central nervous system Burkitt lymphoma with non-immunoglobulin heavy chain translocation in right ventricle: Case report. Pediatr Hematol Oncol 28:454-458, 2011 21. Jiang L, Li Z, Finn LE, et al: Primary central nervous system B cell lymphoma with features intermediate between diffuse large B cell lymphoma and Burkitt lymphoma. Int J Clin Exp Pathol 5:72-76, 2012
DOI: 10.1200/JCO.2013.49.1316; published online ahead of print at www.jco.org on March 31, 2014
■ ■ ■
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33
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NUMBER
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JOURNAL OF CLINICAL ONCOLOGY
D I A G N O S I S
O N C O L O G Y
sis of the left upper extremity as well as a bilateral defect of ocular abduction. Laboratory tests at the time of admission yielded the following results. Hematologic tests revealed a slightly elevated WBC count (10,400/L), with no abnormalities in the differential leukocyte count and no atypical cells. The soluble interleukin-2 receptor serum level was 362 U/mL, and the serum LDH level was 252 IU/L; serologic tests for HIV antibodies were negative. Bone marrow infiltration was absent. Tumor cells (82 cells/L) were found in the CSF. A brain magnetic resonance imaging examination (T1-weighted image) revealed a tumorous lesion (30 ⫻ 30 mm) showing a homogeneous and intense gadolinium enhancement in the right frontal to parietal lobe, surrounded by edema. Bleeding inside the tumor was also noted (Fig 1A, axial; Fig 1B, sagittal; Fig 1C, coronal). Contrast-enhanced computed tomography of the neck through pelvis revealed no tumorous lesions in any organs other than the CNS, suggesting that the tumor originated from the intracranial cavity. The patient was rated as low risk according to the IPI for primary CNS lymphoma (PCNSL). Flow cytometry of the brain tumor cells of this patient revealed expression of the chain, CD20, and CD19 on the cell membrane (Fig 2; FSC-H, forward scatter height values; IgM, immunoglobulin M; SSC-H, side scatter height values). Hematoxylin and eosin staining of the biopsy specimens from the brain tumor revealed tingible body macrophages (phagocytosing apoptotic tumor cells) at low magnification, whereas examination at higher magnification revealed that the tumor was primarily composed of medium- to large-sized lymphocytes (Fig 3A, ⫻100 magnification; Fig 3B, ⫻600 magnification). Immunostaining revealed that the brain tumor cells were medium sized, CD20⫹, CD3⫺, weakly CD5⫹, and CD10⫹, consistent with the findings of flow cytometry (Figs 3C to 3K, ⫻600 magnification; Fig 3C, CD20; Fig 3D, CD3; Fig 3E, CD5; Fig 3F, CD10; Fig 3G, cyclin D1; Fig 3H, Ki-67; Fig 3I, BCL2; Fig 3J, CD79a; Fig 3K, TdT, terminal deoxynucleotidyl transferase). Cyclin D1⫹ and BCL2⫹ are characteristic of MCL, whereas CD10⫹ is characteristic of Burkitt’s lymphoma (BL). The tumor cells were CD5⫹, CD10⫹, cyclin D1⫹, and BCL2⫹, with a high Ki-67 index; thus, they possessed the surface marker characteristics of both BL and MCL. Because a pooled biopsy
Primary CNS CCND1/MYC-Positive Double-Hit B-Cell Lymphoma: A Case Report and Review of the Literature Introduction Double-hit (DH) B-cell lymphomas are B-cell lymphomas that concurrently carry a chromosomal translocation involving MYC/ 8q24 as well as another chromosomal translocation, typically BCL2/ 18q21 (62%).1 The median age of patients with DH lymphomas is 51 to 65 years. This disease is often characterized by an abnormal elevation in the serum lactate dehydrogenase (LDH) level and tumor invasion of the bone marrow and CNS. According to the International Prognostic Index (IPI), this disease is often rated as having a poor prognosis. Doxorubicin-based chemotherapy, high-dose chemotherapy, and hematopoietic stem-cell transplantation have been used to treat this condition; however, the prognosis is quite poor, with a reported mean survival of 0.2 to 1.5 years. CCND1/MYC-positive DH lymphomas carrying chromosomal translocations involving CCND1/11q13 and MYC/8q24 are seen in approximately 5% to 10% of all patients with mantle-cell lymphoma (MCL). Many of these patients are leukemic and have a blastoid, pleomorphic, or even Burkitt’s-like morphology.2 We report a patient with CCND1/MYC-positive DH B-cell lymphoma of CNS origin who was recently treated at our facility. Case Report A 55-year-old man first became aware of paralysis of the left upper extremity and numbness of the left half of his body in midSeptember 2010 and visited the Department of Neurosurgery at our hospital (Juntendo University Urayasu Hospital). His past medical history and family history were not noteworthy. A brain tumor was suspected, and a craniotomy for a tumor biopsy was performed in October of the same year. At the time of admission, the patient’s mental acuity was normal. Superficial lymph nodes were not palpable. No skin lesions were noted. A neurologic examination revealed motor and sensory paraly-
A
I N
B
C
Fig 1. Journal of Clinical Oncology, Vol 33, No 19 (July 1), 2015: pp e79-e83
© 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on November 14, 2015. For personal use only. No other uses without permission. Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
e79
Sakurai et al
0.7
89.5
CD 19
1.2
λ-ch
FSC-H
98.6
0.0
κ-ch
SSC-H
Ig M
0.8
70.5
CD 5 0.4
CD 3
85.7
0.7
CD 10
0.7
CD 8
15.0
9.3
27.3
CD 20
0.0
CD 34
Fig 2.
specimen was not available, paraffin sections were used for paraffinembedded tissue section–fluorescent in situ hybridization. If we had used fusion probes for the biopsy, the separated red and green signals might have been mistaken as one yellow fusion signal if they overlapped because of the thickness (4 m) of the specimen. To avoid such false-positive results, a break-apart probe was selected for the biopsy
specimen. In this patient, the MYC split-signal positive rate was 75.0% (Fig 4A, MYC centromere [red arrows] and telomere [green arrows] probes). An analysis revealed negative results for both the CCND1 split signal and the BCL2 split signal (Fig 4B, CCND1 centromere [green arrows] and telomere [red arrows] probe; Fig 4C, BCL2 centromere [green arrows] and telomere [red arrows] probe), but the
A
B
C
D
E
F
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I
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K
Fig 3. e80
© 2014 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
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Diagnosis in Oncology
A
B
D
E
C
Fig 4.
percentage of cells showing an excess on the telomere side of the CCND1/11q13 was 62%. These results mean that some reciprocal translocations with other unknown genes are likely to exist. Because tumor cell infiltration of the CSF was noted in this patient, a more specific fluorescent in situ hybridization using fusion probes was performed on a thin specimen (⬍ 1 m) in the CSF, revealing an MYCIgH fusion signal positive rate of 100% and a CCND1-IgH fusion signal positive rate of 99% (Fig 4D, MYC [red] and IgH [green] probes; Fig 4E, CCND1 [red] and IgH [green] probes, fusion signal [white arrows]). On the basis of these results, the tumor was diagnosed as a CCND1/MYC-positive DH lymphoma originating from the CNS. Chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone was begun in October 2010. Later, on the 20th hospital day, high-dose methotrexate plus high-dose cytarabine therapy was begun because of an elevated serum LDH level. However, the tumor did not diminish in size, and the patient began to develop seizures. From the 37th hospital day, chemotherapy with rituximab, cyclophosphamide, vincristine, doxorubicin, and dexamethasone was administered. A brain computed tomography scan obtained on the 73rd hospital day after two courses of this therapy revealed a tempo-
rary response to the treatment. However, in January 2011, bleeding inside the tumor recurred, and the tumor continued to increase in size, with the seizures becoming uncontrollable. The patient died in February 2011 (116th hospital day). No postmortem examination was performed. Discussion Imai et al3 reported 40 patients with PCNSL in their series; 12 patients (30%) were CD5⫹, whereas all of the patients were cyclin D1 negative. To our knowledge, only three patients with primary CNS MCL (including the patient presented here) have been reported to date, reflecting the extremely rare occurrence of this condition (Table 1).4,5 In all three reported patients, tumor infiltration of the CSF was noted, suggesting a poor prognosis for this disease. All three patients were rated as having a low to low-intermediate risk, according to the IPI. Only the first patient was rated as having a high risk according to the PCNSL IPI criteria.6 The first patient had a primary CNS MCL that was CD10⫺, suggesting that the tumor was unlikely to be a CCND1/ MYC-positive DH lymphoma.4 The second patient reported was 29 years old, which is relatively young for the onset of MCL. The second
Table 1. Summary of Primary CNS Mantle-Cell Lymphomas in the Literature Patient
Age (years)
Sex
Location
Markers
IPI
PCNSL IPI
Treatment
Outcome
Reference
1 2 3
74 29 55
F M M
Frontoparietal region/CSF CSF Frontal lobe/CSF
CD5⫹ CD20⫹ CD10⫺ CD23⫺ CD5⫹ CD20⫹ IgG⫹ CD5⫹ CD20⫹ CD10⫹ CCND1⫹
ⴱ
High Lowⴱ Low
MTX ASCT MTX, Ara-C
Dead, 1 month CR Dead, 4 months
4 5 Current article
LI Lowⴱ Low
Abbreviations: Ara-C, cytarabine; ASCT, autologous stem-cell transplantation; CCND1, cyclin D1; CR, complete remission; IgG, immunoglobulin G; IPI, International Prognostic Index; LI, low intermediate; MTX, methotrexate; PCNSL, primary CNS lymphoma. ⴱ Concerning.
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Sakurai et al
Table 2. Summary of Primary Cerebral Burkitt’s Lymphomas in the Literature Age Patient (years) Sex
HIV IPI
PCNSL IPI
ND
ND ND
ND
ND ND ND
ND ND ND ND ND ND
ND ND ND
Location
1
⬍1
M
2 3 4
11 55 5
M F M
Both temporal tips and partial temporal region Left temporo-occipital region Right temporoparietal region Frontal base dura and adjacent bone
5
6
F
CSF
6
40
M
7 8
15 49
9
Markers
ND
ND
Cerebellum and pons
CD19⫹ CD20⫹ CD10⫹ IgM⫹ ND
ND ND
ND
M F
Pituitary stalk Left parietal region
ND LCA⫹ CD19⫹
ND ND ⫺ ND
ND ND
8
M
ND
10
38
M
11
50
M
12 13
60 75
F F
Right lateral orbit and left temporal region Right front-temporoparietal subdural spade Central thalamus, right thalamus, and periventricular white matter Sellar region Intraventricular lesions
14
14
M
⫺
Adjuvant Treatment Chemotherapy ⫹ radiotherapy None None Chemotherapy ⫹ radiotherapy Chemotherapy
Outcome
Reference
Died, 20 months
7
Alive, 1 year Died, 1 month Better vision
8 9 10
CR, 2 years
11
ND
ND
Chemotherapy ⫹ radiotherapy Chemotherapy CHOP ⫹ craniospinal radiotherapy Chemotherapy
CD20⫹ CD79a⫹ CD10⫹ ⫹ ND BCL6⫹ CD20⫹ CD10⫹ ND ND
ND
None
Died, 11 days
16
ND
ND
ND
17
⫺
CD45⫹ CD79⫹ BCL 2⫺ LCA⫹ CD10⫹ CD20⫹ CD79a⫹ Right anterior horn and body of lateral CD20⫹ CD10⫹ CD79a⫹ BCL6⫹ ventricle
CR, 1 year
12
CR, 17 months DF, 6 months
13 14
Died, 11 months
15
⫺ ⫺
ND L
ND ND
ND Radiotherapy
ND Alive, 9 months
18 19
⫺
L
ND
Gamma knife ⫹ HDMTX ⫹ VP
CR, 18 months
20
Abbreviations: CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CR, complete remission; DF, disease free; HDMTX, high-dose methotrexate; IgM, immunoglobulin M; IPI, International Prognostic Index; L, low risk; LCA, leukocyte common antigen; ND, not described; PCNSL, primary CNS lymphoma; VP, vincristine plus prednisolone.
patient’s tumor was CD5⫹, CD19⫹, and CD20⫹; however, the diagnosis was questionable because of the lack of description regarding CD23 and histologic findings.5 On the basis of these findings and reports, the present is, to our knowledge, the first reported case of CCND1/MYC-positive DH lymphoma of CNS origin. Considering that primary CNS MCL follows a rapid clinical course and is likely to have a poor prognosis, as seen in the first patient case to be reported in the literature,4 the prognosis of CCND1/MYC-positive DH lymphoma of CNS origin is expected to be extremely poor. In fact, our patient died about 4 months after disease onset despite undergoing massive chemotherapy. To date, 14 cases of primary intracranial BL have been reported, and this disease is rare (Table 2).7-20 The age at onset of this disease shows two peaks (childhood and middle/advanced age). It is seen slightly more frequently in men. Although no prognostic factors for PCNSL have been identified, the responses of this disease to treatment can be divided in a rather clear-cut manner into a favorable group and an unfavorable group (Table 2). Information on CD5 expression was not available for any of the reported cases. Jiang et al21 published the first report on primary CNS B-cell lymphoma with features intermediate between those of diffuse large B-cell lymphoma and BL, stating that the patient showed excessive BCL2 expression but no t(14;18). Their report did not refer to cyclin D1, and additional details of this case remain obscure. In the present case, the disease was found to be therapy resistant on the 81st hospital day. Although high-dose chemotherapy was begun subsequently, the tumor tended to grow week after week, and the growth of the tumor, accompanied by bleeding inside the tumor, e82
© 2014 by American Society of Clinical Oncology
began to be visible 2 weeks after the start of this therapy. The growth of this tumor seemed to be difficult to suppress using the chemotherapy regimens that are conventionally used for PCNSL. In conclusion, the patient presented here had CCND1/MYCpositive DH lymphoma, which was morphologically akin to MCL (blastoid variant) originating from the CNS. To our knowledge, no previous report of a DH lymphoma of CNS origin has been published; the present patient case seems to be the first such case. The prognosis of this patient was predicted to be extremely poor, and in fact, the patient followed a rapid clinical course and died 4 months after the diagnosis. When dealing with such patients, chemotherapy that is conventionally used for PCNSL is unlikely to be sufficiently effective, and some modified treatment approaches are needed.
Hiroko Sakurai Juntendo University Urayasu Hospital, Chiba; Juntendo University, Tokyo, Japan
Kei-Ji Sugimoto Juntendo University Urayasu Hospital, Chiba, Japan
Asami Shimada Juntendo University Urayasu Hospital, Chiba; Juntendo University, Tokyo, Japan
Hidenori Imai, Mutsumi Wakabayashi, and Yasunobu Sekiguchi Juntendo University Urayasu Hospital, Chiba, Japan
Yasunori Ota and Koji Izutsu Toranomon Hospital, Tokyo, Japan JOURNAL OF CLINICAL ONCOLOGY
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Diagnosis in Oncology
Kengo Takeuchi The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
Norio Komatsu Juntendo University, Tokyo, Japan
Masaaki Noguchi Juntendo University Urayasu Hospital, Chiba, Japan
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest. REFERENCES 1. Aukema SM, Siebert R, Schuuring E, et al: Double-hit B-cell lymphomas. Blood 117:2319-2331, 2011 2. Hao S, Sanger W, Onciu M, et al: Mantle cell lymphoma with 8q24 chromosomal abnormalities: A report of 5 cases with blastoid features. Mod Pathol 15:1266-1272, 2002 3. Imai H, Shimada K, Shimada S, et al: Comparative clinicopathological study of primary CNS diffuse large B-cell lymphoma and intravascular large B-cell lymphoma. Pathol Int 59:431-437, 2009 4. Finsterer J, Lubec D, Jellinger K, et al: Recovery from coma caused by primary CNS mantle cell lymphoma presenting as encephalitis. Neurology 46:824-826, 1996 5. Trip SA, Wroe SJ, Davies G, et al: Primary CNS mantle cell lymphoma associated with an isolated CSF monoclonal IgG band. Eur Neurol 49:187-188, 2003 6. Ferreri AJ, Abrey LE, Blay JY, et al: Summary statement on primary central nervous system lymphomas from the Eighth International Conference on Malignant Lymphoma, Lugano, Switzerland, June 12 to 15, 2002. J Clin Oncol 21:2407-2414, 2003 7. Valsamis MP, Levine PH, Rapin I, et al: Primary intracranial Burkitt’s lymphoma in an infant. Cancer 37:1500-1507, 1976 8. Giromini D, Peiffer J, Tzonos T: Occurrence of a primary Burkitt-type lymphoma of the central nervous system in an astrocytoma patient: A case report. Acta Neuropathol 54:165-167, 1981 9. Kobayashi H, Sano T, Ii K, et al: Primary Burkitt-type lymphoma of the central nervous system. Acta Neuropathol 64:12-14, 1984
10. Tekko¨k IH, Tahta K, Erbengi A, et al: Primary intracranial extradural Burkitt-type lymphoma: A unique presentation with unilateral loss of vision in a child. Childs Nerv Syst 7:172-174, 1991 11. Toren A, Mandel M, Shahar E, et al: Primary central nervous system Burkitt’s lymphoma presenting as Guillain-Barre´ syndrome. Med Pediatr Oncol 23:372-375, 1994 12. Spa¨th-Schwalbe E, Genvresse I, Stein H, et al: Primary cerebral highlymalignant B-cell lymphoma of the Burkitt type[in German]. Dtsch Med Wochenschr 124:451-455, 1999 13. Silfen ME, Garvin JH Jr, Hays AP, et al: Primary central nervous system lymphoma in childhood presenting as progressive panhypopituitarism. J Pediatr Hematol Oncol 23:130-133, 2001 14. Monabati A, Rakei SM, Kumar P, et al: Primary Burkitt lymphoma of the brain in an immunocompetent patient: Case report. J Neurosurg 96:1127-1129, 2002 15. Shehu BB: Primary central nervous system Burkitt’s lymphoma presenting with proptosis. Ann Trop Paediatr 23:319-320, 2003 16. Gobbato PL, Pereira Filho Ade A, de David G, et al: Primary meningeal Burkitt-type lymphoma presenting as the first clinical manifestation of acquired immunodeficiency syndrome. Arq Neuropsiquiatr 64:511-515, 2006 17. Abel TW, Thompson MA, Kim J, et al: Primary central nervous system Burkitt lymphoma: Report of a case confirmed with identification of t(8;14)by FISH. Brain Pathol 16:97-97, 2006 (suppl 1) 18. Koza´kova´ D, Macha´lekova´ K, Brtko P, et al: Primary B-cell pituitary lymphoma of the Burkitt type: Case report of the rare clinic entity with typical clinical presentation. Cas Lek Cesk 147:569-573, 2008 19. Gu Y, Hou YY, Zhang XB, et al: Primary central nervous system Burkitt lymphoma as concomitant lesions in the third and the left ventricles: A case study and literature review. J Neurooncol 99:277-281, 2010 20. Jiang M, Zhu J, Guan YS, et al: Primary central nervous system Burkitt lymphoma with non-immunoglobulin heavy chain translocation in right ventricle: Case report. Pediatr Hematol Oncol 28:454-458, 2011 21. Jiang L, Li Z, Finn LE, et al: Primary central nervous system B cell lymphoma with features intermediate between diffuse large B cell lymphoma and Burkitt lymphoma. Int J Clin Exp Pathol 5:72-76, 2012
DOI: 10.1200/JCO.2013.49.1316; published online ahead of print at www.jco.org on March 31, 2014
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