536223
research-article2014
IJSXXX10.1177/1066896914536223International Journal of Surgical PathologyZanelli et al
Case Report
Anaplastic Lymphoma Kinase–Positive Large B-Cell Lymphoma: Description of a Case With an Unexpected Clinical Outcome
International Journal of Surgical Pathology 2015, Vol. 23(1) 78–83 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1066896914536223 ijs.sagepub.com
Magda Zanelli, MD1, Riccardo Valli, MD1, Isabella Capodanno, MD1, Moira Ragazzi, MD1, and Stefano Ascani, MD2
Abstract Anaplastic lymphoma kinase–positive (ALK-positive) large B-cell lymphoma is a rare and aggressive variant of large B-cell lymphoma (LBCL), first reported by Delsol et al in 1997, showing distinctive morphologic, immunophenotypic and cytogenetic features. The latest 2008 World Health Organization Classification of Tumours of Haematopoietic and Lymphoid tissues recognizes ALK-positive LBCL as a separate entity. Here, we report a case of ALK-positive large B-cell lymphoma in a 53-year-old man with diffuse abdominal and mediastinal lymph-nodes involvement. According to the Ann Arbor staging system, the patient had a stage IIIB lymphoma. The age-adjusted International Prognostic Index was 2 (stage III and elevated lactate dehydrogenase), so the disease was considered high risk. The patient underwent chemotherapy, radiotherapy, and an autologous stem cell transplantation. The patient is alive and free of disease 35 months after diagnosis. Keywords large B-cell lymphoma, anaplastic lymphoma kinase (ALK), ALK-positive large B-cell lymphoma, ALK positivity, immunohistochemistry, t(2; 17).
Introduction Anaplastic lymphoma kinase–positive (ALK-positive) large B-cell lymphoma is a rare variant of large B-cell lymphoma (LBCL) with ALK expression. Since the original description by Delsol et al1 in 1997, more than 50 cases have been reported.2-11 It occurs most frequently in male adults, spanning all age-groups with a median age of 36 years. It commonly presents with high-stage nodal disease, although extranodal sites can be involved, and it is not associated with immunosuppression. All reported cases are negative for Epstein–Barr virus (EBV) and human herpes virus-8 (HHV8). Most patients follow an aggressive clinical course with advanced stage and poor outcome. Histologically, the tumor cells have a plasmablastic or immunoblastic appearance, with a sinusoidal pattern of infiltration, and a unique immunophenotypic profile characterized mostly by lack of expression of CD20, and positivity for plasma cell markers, such as CD138, EMA, and MUM1. By definition, this lymphoma expresses ALK, with its staining frequently confined to the cytoplasm and usually in a granular pattern. The most commonly reported cytogenetic abnormality3,4 is the chromosomal translocation t(2;17)(p23;q23), which leads to fusion of the CLTC
(clathrin) gene with the ALK gene. There are also a few reported cases associated with the translocation t(2;5) (p23;q35) or nucleophosmin (NPM)/ALK as described in ALK-positive T/null anaplastic large cell lymphoma (ALCL)8; other rare cytogenetic abnormalities have also been described.12 In reporting this case we would like to focus on the difficulty of identifying this type of lymphoma in routine pathology. Some morphological features such as the sinusoidal growth pattern, the plasmablastic appearance, and the CD20-negativity make this entity a diagnostic challenge with broad differential diagnoses, including metastatic carcinoma, ALK-positive anaplastic large cell 1
Anatomic Pathology Unit, IRCSS Santa Maria Nuova Hospital, Reggio Emilia, Italy 2 Hematology Unit, IRCSS Santa Maria Nuova Hospital, Reggio Emilia, Italy 3 Institute of Pathology, Ospedale di Terni, University of Perugia, Perugia, Italy Corresponding Author: Moira Ragazzi, Anatomic Pathology Unit, IRCSS Santa Maria Nuova Hospital, Viale Risorgimento, 80, 42123 Reggio Emilia, Italy. Email: [email protected]
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Zanelli et al lymphoma (with T/null-cell phenotype), and plasmablastic lymphoma. Moreover the case herein reported is unexpectedly characterized by a positive clinical course that leads us to compare it with a few cases with favourable outcome reported in the literature.
Case Report On March 2011, a 53-year-old man, HIV negative, with no remarkable past medical history, presented to the Emergency Department of Arcispedale Santa Maria Nuova Hospital (Reggio Emilia, Italy) with severe abdominal pain; the ultrasound scan showed the presence of multiple enlarged abdominal lymph nodes. The total body computed tomography scan confirmed the presence of lymphadenopathies, both in retroperitoneum (4.2 cm in maximum diameter), and in posterior mediastinum (2 cm in maximum diameter). Furthermore, a bilateral massive pulmonary embolism was detected, in absence of respiratory symptoms. An excisional biopsy of a large abdominal lymph node was performed, and routine haematoxylin and eosin–stained sections were prepared from formalin-fixed, paraffin-embedded (FFPE) blocks. Immunohistochemical analyses included a broad panel of antibodies against CD20, CD79α, PAX5, OCT2, CD30, MUM1/IRF4, EMA, CD138, ALK, BCL6, CD10, CD3, CD2, CD7, CD4, CD8, CD57, TIA1, c-MYC, HHV8, pancytokeratin, and Ki67. All antibodies were prediluted, provided by Ventana Benchmark, and were tested using an automated immunostainer (Benchmark, Ventana Inc, Tucson, AZ). EBV study using Epstein–Barr virus–encoded RNA (EBER) chromogenic in situ hybridization (CISH) was performed (EBER Histosonda Cenbimo, Spain, CE). A molecular analysis to detect Ig gene rearrangement was done. DNA was extracted from FFPE tissue using Biostic FFPE Tissue DNA isolation kit. Subsequently, gene rearrangement studies for IgH and IgK were performed using Beckman Coulter fluorescence detection clonality assay as required by BIOMED2 protocol (In vivo Scribe Technologies, San Diego, CA). Histologically, the lymph node was diffusely involved by malignant cells with a prominent sinusoidal pattern of infiltration (Figure 1). The cells looked quite monomorphic and large with an immunoblastic-like morphology. The nuclei were round with evident single central nucleoli. The cytoplasm was amphophylic and, sometimes, with a paranuclear hof, suggesting plasmablastic differentiation. Immunohistochemical and molecular results are listed in Table 1. The neoplastic cells were positive for CD138 (Figure 2A), EMA, MUM1/IRF4 (Figure 2B), OCT2 and CD4 and showed restricted cytoplasmic granular staining for ALK (Figure 2C). The neoplastic cells were otherwise negative for B cell markers such as CD20 (Figure 2D), CD79α, PAX5, T-cell markers (CD3, CD2, CD7, CD8),
Figure 1. Architectural features. The neoplastic cells show a predominant sinusoidal pattern of lymph node infiltration (hematoxylin and eosin, ×20).
Table 1. Immunohistochemical and Molecular Results. Clone/Dilution Immunohistochemistry CD138 EMA MUM1 OCT2 CD4 ALK CD30 CD20 CD79α PAX5 CD3 CD2 CD7 CD8 BCL6 CD10 CD57 TIA1 c-MYC CK HHV8 Molecular studies IgH gene rearrangement EBER CISH
B-A38/PD E29/PD MRQ-43/PD Policlonale/1:25a SP35/PD ALK-01/PD Ber-H2/PD L26/PD SP18/PD SP34/PD 2GV6/PD LFA-2/1:50b CD7-272/1:50b SP57/PD GI191E/A8/PD SP67/PD NK-1/1:100c 2G9A10F5/1:100d Y69/PD AE1/AE3/PCK26/PD 13B10/PD
Results + + + + + + −/+ − − − − − − − − − − − − − − + −
Abbreviations: PD, prediluted Ventana benchmark; EBER, Epstein–Barr virus–encoded RNAs; CISH, chromogenic in situ hybridization. a Aczone. b Novocastra. c BioGenex. d Beckman Coulter.
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Figure 2. Immunohistochemical results. (A) CD138: The neoplastic cells strongly express CD138 (×20). (B) MUM1: Neoplastic cells show MUM1 positivity (×20). (C) ALK: The lymphoma cells show a restricted cytoplasmic granular staining for ALK (×40). (D) CD20: The neoplastic cells do not express CD20 (×20)
BCL6, CD10, CD57, TIA1, c-MYC, pancytokeratin, and HHV8. Occasional CD30-positive cells were noted. In situ hybridization for EBV-encoded RNA was negative. The proliferative index, evaluated using Ki67 staining, was about 80%. A clonal IgH gene rearrangement was found. A staging bone marrow biopsy was negative for lymphoma. According to the Ann Arbor staging system, the patient had a stage IIIB lymphoma. The age-adjusted International Prognostic Index was 2 (because of stage III and elevated LDH), so the disease was considered high risk.13 The patient was treated with a high-dose chemotherapy regimen, consisting of 2 cycles of CODOX-M (cyclophosphamide–vincristine–doxorubicin–cytarabine–methotrexate) alternated with 2 cycles IVAC (ifosfamide–etoposide–cytarabine– methotrexate) every 3 to 4 weeks, followed by high-dose BEAM chemotherapy (BCNU, cytarabine, VP-16, melphalan) and autologous stem cell transplantation. Because of the high risk of progression in the central nervous system, prophylactic intrathecal chemotherapy with methotrexate and cytarabine was also administered.
During treatment, the patient developed a new deep vein thrombosis at the left tibioperoneal vein. At the end of chemotherapy, the patient received consolidation radiotherapy on abdominal lymph nodes present at diagnosis. A total body positron emission tomography performed after the first cycle of chemotherapy showed a very good partial response. At the end of treatment the patient was in complete remission. Despite the advanced clinical stage, the development of major thrombotic complications, both at diagnosis and during treatment, and the histological subtype of lymphoma, the patient achieved a complete remission after first line treatment; he shows no sign of relapse and is in good clinical condition 35 months after diagnosis.
Discussion Since the initial description of Delsol et al1 in 1997, more than 50 cases of ALK-positive LBCL have been reported1-11 and ALK-positive LBCL is listed as a distinct entity in 2008 WHO Classification of Tumours of
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Zanelli et al Table 2. Main Differential Diagnoses. IHC/ISH
Metastatic Carcinoma
Metastatic Melanoma
ALK+ ALCL
PBL
DLBCL
ALK+ LBCL
CK CD20 CD138 EMA MUM1 CD30 ALK EBV
+ − +/− + − − −/+ −
− − − − + − − −
− − − + − + + −
−/+ − + +/− + +/− − +
− + − − +/− −/+ − −
−/+ − + + + −/+ + −
Abbreviations: IHC, immunohistochemistry; ISH, in situ hybridization; ALK+ ALCL, anaplastic lymphoma kinase–positive anaplastic large cell lymphoma; PBL, plasmablastic lymphoma; DLBCL, diffuse large B-cell lymphoma; ALK+ LBCL, anaplastic lymphoma kinase–positive large B-cell lymphoma; +, positive; −, negative; +/−, frequently positive; −/+, occasionally positive.
Haematopoietic and Lymphoid Tissues.14 It frequently presents with advanced clinical stage and, despite aggressive chemotherapy, the prognosis is often dismal especially in high stage disease,2,5,9 with a reported median survival of 11 months.14 Histologically, ALK-positive LBCL shows an immunoblastic/plasmablastic morphology, often an intrasinusoidal growth pattern and an unique immunophenotypic profile characterized by lack of B cell (CD20, CD79α) and T-cell (CD3) markers, expression of plasma cell markers (CD138, EMA, MUM1/IRF4), variable expression of CD4, and cytoplasmic granular ALK reactivity. CD20 negativity, together with the expression of EMA and CD138, is indicative of terminal B-cell differentiation phenotype of this type of lymphoma. In presenting this case, our aim is to focus on a potential pitfall in pathology practice. Nowadays, despite the full knowledge of this entity, diagnosis of ALK-positive LBCL in routine pathology remains challenging. ALK-positive LBCL is considered to be underrecognized because of its morphologic and immunophenotypic profile overlapping with other hematologic and nonhematologic neoplasms.15 The main differential diagnoses are described in Table 2. First of all, the typical cohesive and prominent sinusoidal growth pattern of nodal infiltration morphologically mimics a metastatic, poorly differentiated, carcinoma. Immunohistochemistry can be misleading: occasional immunoreactivity of cytokeratin together with EMA positivity and the negativity for CD45 and B- and T-cell markers, may lead to the mistaken diagnosis of carcinoma.9 This misdiagnosis may be further supported by the fact that CD138 is immunoreactive in the majority of carcinomas.16 It is also worth mentioning that about 2% to 7% of non–small cell lung carcinomas show a cytoplasmic granular staining for ALK, due to rearrangement of ALK with echinoderm microtubule-associated protein like 4 (EML4).17 On the other hand, it has been reported that MUM1/IRF4 expression was detected in hematolymphoid neoplasms and malignant melanoma, but not
in carcinomas.18,19 Given that ALK-positive LBCL are generally positive for both CD138 and MUM1/IRF4, the combination of these markers, together with ALK positivity, is useful to differentiate ALK-positive LBCL from carcinoma. Because of the sinusoidal pattern of nodal infiltration, the possibility of a metastatic melanoma, which can be MUM1/IRF4 positive as already mentioned, should be prudently ruled out by negative staining for S100 and HMB45.19 Another important differential diagnosis is anaplastic large cell lymphoma (ALCL) with T or null phenotype. Although ALK-positive LBCL and ALCL share some common immunophenotypic features such as EMA positivity, distinction between these 2 entities strongly relies on the marked expression of CD30 in ALCL and CD138 in ALK-positive LBCL. Because of its plasmablastic morphology, ALK-positive LBCL has to be distinguished from plasmablastic lymphoma (PBL).14,20 Clinically, PBL was originally described in the oral cavity of immunocompromised patients, but it can occur in immunocompetent patients, in other extranodal sites and, even if rarely, can have a nodal presentation; ALK-positive LBCL occurs in nonimmunocompromised patients and has a predominant nodal distribution, although it can involve extranodal sites.14 Important pathologic features distinguishing these entities are mainly represented by the fact that PBL is mostly EBV positive, whereas ALK-positive LBCL is EBV negative and it shows ALK protein expression. CLTC-ALK is the most common molecular alteration described in ALK-positive LBCL.3,4 The ALK staining pattern in ALK-positive LBCL is reported to correlate well with the type of underlying gene rearrangement.5 Cases with CLTC-ALK/ t(2;17) rearrangement show a distinct granular cytoplasmic ALK staining pattern, whereas those with an NPM-ALK/ t(2;5) gene rearrangement show cytoplasmic and nuclear staining.3,4,8 As Laurent et al5 reported
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International Journal of Surgical Pathology 23(1)
Table 3. Clinical Features of High-Stage ALK+ Large B-Cell Lymphoma With Good Prognosis Reported in Literature. Reference
Gender/Age (Years)
Delsol et al (1997)1 Gascoyne et al (2003)4
Male/51 Male/46
Beltran et al (2009)2
Male/70
Laurent et al (2009)5
Female/32
Male/27
Present study
Male/53
Clinical Presentation NA Supraclavicular and abdominal LA Cervical axillary and inguinal LA Ovaries, spleen, and retroperitoneal LA Systemic LA and bone marrow Abdominal and mediastinal LA
Follow-up (Months)
Stage
IPI
Therapy
III/IV III
NA NA
AWD (14) AWD (27)
IIIB
3
ACVBP CT + CT and RT after relapse CHOP
IV
NA
CHOP-derived
AWD (45)
IV
NA
CHOP-derived
AWD (19)
IIIB
2
CODOX-M/IVAC – BEAM – ASCT + ICC + RT
AWD (35)
AWD (72)
Abbreviations: IPI, International Prognostic Index; NA, not available; AWD, alive without disease; LA, lymph adenopathy; ACVBP, doxorubicin– cyclophosphamide–vindesine–bleomycin–prednisone; CT, chemotherapy; RT, radiation therapy; CHOP, cyclophosphamide doxorubicin vincristine prednisone; CODOX-M, cyclophosphamide vincristine doxorubicin cytarabine methotrexate; IVAC, ifosfamide etoposide cytarabine methotrexate; BEAM, BCNU, cytarabine VP-16 melphalane; ASCT, autologous stem cell transplantation; ICC, intrathecal chemotherapy.
in 2009, the characteristic granular cytoplasmic restricted ALK positivity may represent a single surrogate marker of the t(2;17). In our case, molecular cytogenetic studies were not performed, and, based on the exclusive cytoplasmic granular staining pattern of ALK, we considered a t(2;17) involving ALK and CLTC to be the most likely cytogenetic abnormality. Therefore, although fluorescence in situ hybridization and reverse transcriptase–polymerase chain reaction are needed for definitive demonstration of such t(2;17) translocation, immunohistochemistry can be a more simple and less expensive alternative to the more sophisticated molecular techniques which are not always available in pathology laboratories. Irrespective of the type of translocation, ALK-positive LBCL is an aggressive disease, often with a poor response to conventional therapies especially in high-stage disease.2,5,9 The case we report had an unexpected positive clinical outcome. Despite the advanced clinical stage, our patient achieved a complete remission after first line treatment and he shows no sign of relapse 35 months after diagnosis. To the best of our knowledge, only 5 cases of ALK-positive LBCL in advanced stages have been reported in the literature to have pursued a prolonged survival (Table 3). Compared with the other described cases, our patient underwent a more intensive multiagent chemotherapy. Two alternating intensive regimens (CODOX-M and IVAC) were utilized, involving the use of seven drugs. Magrath et al21 from the National Cancer Institute developed this chemotherapy cycle in 1996 for patients with high-risk aggressive non–Hodgkin’s lymphoma, including Burkitt’s lymphoma. Notably, a standardized therapy does not exist for patients with ALK-positive LBCL, probably because of the rarity of this entity. The therapeutic
regimens described in the literature are several, and clinical outcomes seem to not be influenced by them. Nowadays, in the targeted therapy era, the potential use of ALK inhibitors is an attractive option for oncologists.15,22,23 Recent experimental evidence has suggested that ALK inhibitors may be efficacious in the treatment of ALK-positive LBCL.22 However, to the best of our knowledge, only 1 patient affected by ALK-positive LBCL and treated with crizotinib has been described in the literature, but with discouraging results.23 Further clinical studies are needed to evaluate if ALK inhibitors may actually provide a new therapeutic option for patients with this disease. In conclusion, here we have described a case of ALKpositive LBCL with a surprisingly favorable clinical outcome after intensive chemotherapy treatment and autologous stem cell transplantation. In fact, despite the advanced clinical stage, which is known to be the strongest predictor of survival,2,5 our patient is alive and without disease. On the other hand, from the histopathologic point of view, the case of ALK-positive LBCL described here is very typical, but gives us the chance to stress the diagnostic challenge represented by this rare entity, which can be confused with other hematologic and nonhematologic neoplasms. Acknowledgments The authors wish to thank Monica Pessino at University of California, Santa Barbara, and Veronica Pessino, PhD candidate in Biophysics, at University of California, San Francisco, for the linguistic revisions of the article.
Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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Zanelli et al Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Delsol G, Lamant L, Mariame B, et al. A new subtype of large B-cell lymphoma expressing the ALK kinase and lacking the 2; 5 translocation. Blood. 1997;89:1483-1490. 2. Beltran B, Castillo J, Salas R, et al. ALK-positive diffuse large B-cell lymphoma: report of four cases and review of the literature. J Hematol Oncol. 2009;2:11. 3. De Paepe P, Baens M, van Krieken H, et al. ALK activation by the CLTC-ALK fusion is a recurrent event in large B-cell lymphoma. Blood. 2003;102:2638-2641. 4. Gascoyne RD, Lamant L, Martin-Subero JI, et al. ALKpositive diffuse large B-cell lymphoma is associated with Clathrin-ALK rearrangements: report of 6 cases. Blood. 2003;102:2568-2573. 5. Laurent C, Do C, Gascoyne RD, et al. Anaplastic lymphoma kinase-positive diffuse large B-cell lymphoma: a rare clinicopathologic entity with poor prognosis. J Clin Oncol. 2009;27:4211-4216. 6. Li K, Tipps AM, Wang HY. Anaplastic lymphoma kinasepositive diffuse large B-cell lymphoma presenting as an isolated nasopharyngeal mass: a case report and review of literature. Int J Clin Exp Pathol. 2011;4:190-196. 7. Li S. Anaplastic lymphoma kinase-positive large B-cell lymphoma: a distinct clinicopathological entity. Int J Clin Exp Pathol. 2009;2:508-518. 8. Onciu M, Behm FG, Downing JR, et al. ALK-positive plasmablastic B-cell lymphoma with expression of the NPM-ALK fusion transcript: report of 2 cases. Blood. 2003;102:2642-2644. 9. Reichard KK, McKenna RW, Kroft SH. ALK-positive diffuse large B-cell lymphoma: report of four cases and review of the literature. Mod Pathol. 2007;20:310-319. 10. Sellami-Dhouib R, Nasfi A, Mejri NT, et al. Ovarian ALK+ diffuse large B-cell lymphoma: a case report and a review of the literature. Int J Gynecol Pathol. 2013;32:471-475. 11. Zhang D, Denley RC, Filippa DA, Teruya-Feldstein J. ALK-positive diffuse large B-cell lymphoma with the t(2;17)(p23;q23). Appl Immunohistochem Mol Morphol. 2009;17:172-177. 12. Stachurski D, Miron PM, Al-Homsi S, et al. Anaplastic lymphoma kinase-positive diffuse large B-cell lymphoma with a complex karyotype and cryptic 3′ ALK gene insertion to chromosome 4 q22-24. Hum Pathol. 2007;38:940-945.
13. A predictive model for aggressive non-Hodgkin’s lym phoma. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. N Engl J Med. 1993;329:987994. 14. Swerdlow SH, Jaffe ES, International Agency for Research on Cancer, World Health Organization, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008. 15. Morgan EA Nascimento AF. Anaplastic lymphoma kinasepositive large B-cell lymphoma: an underrecognized aggressive lymphoma. Adv Hematol. 2012;2012:529572. 16. O’Connell FP, Pinkus JL, Pinkus GS. CD138 (syndecan-1), a plasma cell marker immunohistochemical profile in hematopoietic and nonhematopoietic neoplasms. Am J Clin Pathol. 2004;121:254-263. 17. Lindeman NI, Cagle PT, Beasley MB, et al; College of American Pathologists International Association for the Study of Lung Cancer and Association for Molecular Pathology. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Mol Diagn. 2013;15:415-453. 18. Natkunam Y, Warnke RA, Montgomery K, Falini B, van De Rijn M. Analysis of MUM1/IRF4 protein expression using tissue microarrays and immunohistochemistry. Mod Pathol. 2001;14:686-694. 19. Sundram U, Harvell JD, Rouse RV, Natkunam Y. Expression of the B-cell proliferation marker MUM1 by melanocytic lesions and comparison with S100, gp100 (HMB45), and MelanA. Mod Pathol. 2003;16:802-810. 20. Colomo L, Loong F, Rives S, et al. Diffuse large B-cell lymphomas with plasmablastic differentiation represent a heterogeneous group of disease entities. Am J Surg Pathol. 2004;28:736-747. 21. Magrath I, Adde M, Shad A, et al. Adults and children with small non-cleaved-cell lymphoma have a similar excellent outcome when treated with the same chemotherapy regimen. J Clin Oncol. 1996;14:925-934. 22. Cerchietti L, Damm-Welk C, Vater I, et al. Inhibition of anaplastic lymphoma kinase (ALK) activity provides a therapeutic approach for CLTC-ALK-positive human diffuse large B cell lymphomas. PLoS One. 2011;6:e18436. 23. Wass M, Behlendorf T, Schädlich B, et al. Crizotinib in refractory ALK-positive diffuse large B-cell lymphoma: a case report with a short-term response. Eur J Haematol. 2014;92:268-270.
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research-article2014
IJSXXX10.1177/1066896914536223International Journal of Surgical PathologyZanelli et al
Case Report
Anaplastic Lymphoma Kinase–Positive Large B-Cell Lymphoma: Description of a Case With an Unexpected Clinical Outcome
International Journal of Surgical Pathology 2015, Vol. 23(1) 78–83 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1066896914536223 ijs.sagepub.com
Magda Zanelli, MD1, Riccardo Valli, MD1, Isabella Capodanno, MD1, Moira Ragazzi, MD1, and Stefano Ascani, MD2
Abstract Anaplastic lymphoma kinase–positive (ALK-positive) large B-cell lymphoma is a rare and aggressive variant of large B-cell lymphoma (LBCL), first reported by Delsol et al in 1997, showing distinctive morphologic, immunophenotypic and cytogenetic features. The latest 2008 World Health Organization Classification of Tumours of Haematopoietic and Lymphoid tissues recognizes ALK-positive LBCL as a separate entity. Here, we report a case of ALK-positive large B-cell lymphoma in a 53-year-old man with diffuse abdominal and mediastinal lymph-nodes involvement. According to the Ann Arbor staging system, the patient had a stage IIIB lymphoma. The age-adjusted International Prognostic Index was 2 (stage III and elevated lactate dehydrogenase), so the disease was considered high risk. The patient underwent chemotherapy, radiotherapy, and an autologous stem cell transplantation. The patient is alive and free of disease 35 months after diagnosis. Keywords large B-cell lymphoma, anaplastic lymphoma kinase (ALK), ALK-positive large B-cell lymphoma, ALK positivity, immunohistochemistry, t(2; 17).
Introduction Anaplastic lymphoma kinase–positive (ALK-positive) large B-cell lymphoma is a rare variant of large B-cell lymphoma (LBCL) with ALK expression. Since the original description by Delsol et al1 in 1997, more than 50 cases have been reported.2-11 It occurs most frequently in male adults, spanning all age-groups with a median age of 36 years. It commonly presents with high-stage nodal disease, although extranodal sites can be involved, and it is not associated with immunosuppression. All reported cases are negative for Epstein–Barr virus (EBV) and human herpes virus-8 (HHV8). Most patients follow an aggressive clinical course with advanced stage and poor outcome. Histologically, the tumor cells have a plasmablastic or immunoblastic appearance, with a sinusoidal pattern of infiltration, and a unique immunophenotypic profile characterized mostly by lack of expression of CD20, and positivity for plasma cell markers, such as CD138, EMA, and MUM1. By definition, this lymphoma expresses ALK, with its staining frequently confined to the cytoplasm and usually in a granular pattern. The most commonly reported cytogenetic abnormality3,4 is the chromosomal translocation t(2;17)(p23;q23), which leads to fusion of the CLTC
(clathrin) gene with the ALK gene. There are also a few reported cases associated with the translocation t(2;5) (p23;q35) or nucleophosmin (NPM)/ALK as described in ALK-positive T/null anaplastic large cell lymphoma (ALCL)8; other rare cytogenetic abnormalities have also been described.12 In reporting this case we would like to focus on the difficulty of identifying this type of lymphoma in routine pathology. Some morphological features such as the sinusoidal growth pattern, the plasmablastic appearance, and the CD20-negativity make this entity a diagnostic challenge with broad differential diagnoses, including metastatic carcinoma, ALK-positive anaplastic large cell 1
Anatomic Pathology Unit, IRCSS Santa Maria Nuova Hospital, Reggio Emilia, Italy 2 Hematology Unit, IRCSS Santa Maria Nuova Hospital, Reggio Emilia, Italy 3 Institute of Pathology, Ospedale di Terni, University of Perugia, Perugia, Italy Corresponding Author: Moira Ragazzi, Anatomic Pathology Unit, IRCSS Santa Maria Nuova Hospital, Viale Risorgimento, 80, 42123 Reggio Emilia, Italy. Email: [email protected]
Downloaded from ijs.sagepub.com at The University of Iowa Libraries on March 16, 2015
79
Zanelli et al lymphoma (with T/null-cell phenotype), and plasmablastic lymphoma. Moreover the case herein reported is unexpectedly characterized by a positive clinical course that leads us to compare it with a few cases with favourable outcome reported in the literature.
Case Report On March 2011, a 53-year-old man, HIV negative, with no remarkable past medical history, presented to the Emergency Department of Arcispedale Santa Maria Nuova Hospital (Reggio Emilia, Italy) with severe abdominal pain; the ultrasound scan showed the presence of multiple enlarged abdominal lymph nodes. The total body computed tomography scan confirmed the presence of lymphadenopathies, both in retroperitoneum (4.2 cm in maximum diameter), and in posterior mediastinum (2 cm in maximum diameter). Furthermore, a bilateral massive pulmonary embolism was detected, in absence of respiratory symptoms. An excisional biopsy of a large abdominal lymph node was performed, and routine haematoxylin and eosin–stained sections were prepared from formalin-fixed, paraffin-embedded (FFPE) blocks. Immunohistochemical analyses included a broad panel of antibodies against CD20, CD79α, PAX5, OCT2, CD30, MUM1/IRF4, EMA, CD138, ALK, BCL6, CD10, CD3, CD2, CD7, CD4, CD8, CD57, TIA1, c-MYC, HHV8, pancytokeratin, and Ki67. All antibodies were prediluted, provided by Ventana Benchmark, and were tested using an automated immunostainer (Benchmark, Ventana Inc, Tucson, AZ). EBV study using Epstein–Barr virus–encoded RNA (EBER) chromogenic in situ hybridization (CISH) was performed (EBER Histosonda Cenbimo, Spain, CE). A molecular analysis to detect Ig gene rearrangement was done. DNA was extracted from FFPE tissue using Biostic FFPE Tissue DNA isolation kit. Subsequently, gene rearrangement studies for IgH and IgK were performed using Beckman Coulter fluorescence detection clonality assay as required by BIOMED2 protocol (In vivo Scribe Technologies, San Diego, CA). Histologically, the lymph node was diffusely involved by malignant cells with a prominent sinusoidal pattern of infiltration (Figure 1). The cells looked quite monomorphic and large with an immunoblastic-like morphology. The nuclei were round with evident single central nucleoli. The cytoplasm was amphophylic and, sometimes, with a paranuclear hof, suggesting plasmablastic differentiation. Immunohistochemical and molecular results are listed in Table 1. The neoplastic cells were positive for CD138 (Figure 2A), EMA, MUM1/IRF4 (Figure 2B), OCT2 and CD4 and showed restricted cytoplasmic granular staining for ALK (Figure 2C). The neoplastic cells were otherwise negative for B cell markers such as CD20 (Figure 2D), CD79α, PAX5, T-cell markers (CD3, CD2, CD7, CD8),
Figure 1. Architectural features. The neoplastic cells show a predominant sinusoidal pattern of lymph node infiltration (hematoxylin and eosin, ×20).
Table 1. Immunohistochemical and Molecular Results. Clone/Dilution Immunohistochemistry CD138 EMA MUM1 OCT2 CD4 ALK CD30 CD20 CD79α PAX5 CD3 CD2 CD7 CD8 BCL6 CD10 CD57 TIA1 c-MYC CK HHV8 Molecular studies IgH gene rearrangement EBER CISH
B-A38/PD E29/PD MRQ-43/PD Policlonale/1:25a SP35/PD ALK-01/PD Ber-H2/PD L26/PD SP18/PD SP34/PD 2GV6/PD LFA-2/1:50b CD7-272/1:50b SP57/PD GI191E/A8/PD SP67/PD NK-1/1:100c 2G9A10F5/1:100d Y69/PD AE1/AE3/PCK26/PD 13B10/PD
Results + + + + + + −/+ − − − − − − − − − − − − − − + −
Abbreviations: PD, prediluted Ventana benchmark; EBER, Epstein–Barr virus–encoded RNAs; CISH, chromogenic in situ hybridization. a Aczone. b Novocastra. c BioGenex. d Beckman Coulter.
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Figure 2. Immunohistochemical results. (A) CD138: The neoplastic cells strongly express CD138 (×20). (B) MUM1: Neoplastic cells show MUM1 positivity (×20). (C) ALK: The lymphoma cells show a restricted cytoplasmic granular staining for ALK (×40). (D) CD20: The neoplastic cells do not express CD20 (×20)
BCL6, CD10, CD57, TIA1, c-MYC, pancytokeratin, and HHV8. Occasional CD30-positive cells were noted. In situ hybridization for EBV-encoded RNA was negative. The proliferative index, evaluated using Ki67 staining, was about 80%. A clonal IgH gene rearrangement was found. A staging bone marrow biopsy was negative for lymphoma. According to the Ann Arbor staging system, the patient had a stage IIIB lymphoma. The age-adjusted International Prognostic Index was 2 (because of stage III and elevated LDH), so the disease was considered high risk.13 The patient was treated with a high-dose chemotherapy regimen, consisting of 2 cycles of CODOX-M (cyclophosphamide–vincristine–doxorubicin–cytarabine–methotrexate) alternated with 2 cycles IVAC (ifosfamide–etoposide–cytarabine– methotrexate) every 3 to 4 weeks, followed by high-dose BEAM chemotherapy (BCNU, cytarabine, VP-16, melphalan) and autologous stem cell transplantation. Because of the high risk of progression in the central nervous system, prophylactic intrathecal chemotherapy with methotrexate and cytarabine was also administered.
During treatment, the patient developed a new deep vein thrombosis at the left tibioperoneal vein. At the end of chemotherapy, the patient received consolidation radiotherapy on abdominal lymph nodes present at diagnosis. A total body positron emission tomography performed after the first cycle of chemotherapy showed a very good partial response. At the end of treatment the patient was in complete remission. Despite the advanced clinical stage, the development of major thrombotic complications, both at diagnosis and during treatment, and the histological subtype of lymphoma, the patient achieved a complete remission after first line treatment; he shows no sign of relapse and is in good clinical condition 35 months after diagnosis.
Discussion Since the initial description of Delsol et al1 in 1997, more than 50 cases of ALK-positive LBCL have been reported1-11 and ALK-positive LBCL is listed as a distinct entity in 2008 WHO Classification of Tumours of
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Zanelli et al Table 2. Main Differential Diagnoses. IHC/ISH
Metastatic Carcinoma
Metastatic Melanoma
ALK+ ALCL
PBL
DLBCL
ALK+ LBCL
CK CD20 CD138 EMA MUM1 CD30 ALK EBV
+ − +/− + − − −/+ −
− − − − + − − −
− − − + − + + −
−/+ − + +/− + +/− − +
− + − − +/− −/+ − −
−/+ − + + + −/+ + −
Abbreviations: IHC, immunohistochemistry; ISH, in situ hybridization; ALK+ ALCL, anaplastic lymphoma kinase–positive anaplastic large cell lymphoma; PBL, plasmablastic lymphoma; DLBCL, diffuse large B-cell lymphoma; ALK+ LBCL, anaplastic lymphoma kinase–positive large B-cell lymphoma; +, positive; −, negative; +/−, frequently positive; −/+, occasionally positive.
Haematopoietic and Lymphoid Tissues.14 It frequently presents with advanced clinical stage and, despite aggressive chemotherapy, the prognosis is often dismal especially in high stage disease,2,5,9 with a reported median survival of 11 months.14 Histologically, ALK-positive LBCL shows an immunoblastic/plasmablastic morphology, often an intrasinusoidal growth pattern and an unique immunophenotypic profile characterized by lack of B cell (CD20, CD79α) and T-cell (CD3) markers, expression of plasma cell markers (CD138, EMA, MUM1/IRF4), variable expression of CD4, and cytoplasmic granular ALK reactivity. CD20 negativity, together with the expression of EMA and CD138, is indicative of terminal B-cell differentiation phenotype of this type of lymphoma. In presenting this case, our aim is to focus on a potential pitfall in pathology practice. Nowadays, despite the full knowledge of this entity, diagnosis of ALK-positive LBCL in routine pathology remains challenging. ALK-positive LBCL is considered to be underrecognized because of its morphologic and immunophenotypic profile overlapping with other hematologic and nonhematologic neoplasms.15 The main differential diagnoses are described in Table 2. First of all, the typical cohesive and prominent sinusoidal growth pattern of nodal infiltration morphologically mimics a metastatic, poorly differentiated, carcinoma. Immunohistochemistry can be misleading: occasional immunoreactivity of cytokeratin together with EMA positivity and the negativity for CD45 and B- and T-cell markers, may lead to the mistaken diagnosis of carcinoma.9 This misdiagnosis may be further supported by the fact that CD138 is immunoreactive in the majority of carcinomas.16 It is also worth mentioning that about 2% to 7% of non–small cell lung carcinomas show a cytoplasmic granular staining for ALK, due to rearrangement of ALK with echinoderm microtubule-associated protein like 4 (EML4).17 On the other hand, it has been reported that MUM1/IRF4 expression was detected in hematolymphoid neoplasms and malignant melanoma, but not
in carcinomas.18,19 Given that ALK-positive LBCL are generally positive for both CD138 and MUM1/IRF4, the combination of these markers, together with ALK positivity, is useful to differentiate ALK-positive LBCL from carcinoma. Because of the sinusoidal pattern of nodal infiltration, the possibility of a metastatic melanoma, which can be MUM1/IRF4 positive as already mentioned, should be prudently ruled out by negative staining for S100 and HMB45.19 Another important differential diagnosis is anaplastic large cell lymphoma (ALCL) with T or null phenotype. Although ALK-positive LBCL and ALCL share some common immunophenotypic features such as EMA positivity, distinction between these 2 entities strongly relies on the marked expression of CD30 in ALCL and CD138 in ALK-positive LBCL. Because of its plasmablastic morphology, ALK-positive LBCL has to be distinguished from plasmablastic lymphoma (PBL).14,20 Clinically, PBL was originally described in the oral cavity of immunocompromised patients, but it can occur in immunocompetent patients, in other extranodal sites and, even if rarely, can have a nodal presentation; ALK-positive LBCL occurs in nonimmunocompromised patients and has a predominant nodal distribution, although it can involve extranodal sites.14 Important pathologic features distinguishing these entities are mainly represented by the fact that PBL is mostly EBV positive, whereas ALK-positive LBCL is EBV negative and it shows ALK protein expression. CLTC-ALK is the most common molecular alteration described in ALK-positive LBCL.3,4 The ALK staining pattern in ALK-positive LBCL is reported to correlate well with the type of underlying gene rearrangement.5 Cases with CLTC-ALK/ t(2;17) rearrangement show a distinct granular cytoplasmic ALK staining pattern, whereas those with an NPM-ALK/ t(2;5) gene rearrangement show cytoplasmic and nuclear staining.3,4,8 As Laurent et al5 reported
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Table 3. Clinical Features of High-Stage ALK+ Large B-Cell Lymphoma With Good Prognosis Reported in Literature. Reference
Gender/Age (Years)
Delsol et al (1997)1 Gascoyne et al (2003)4
Male/51 Male/46
Beltran et al (2009)2
Male/70
Laurent et al (2009)5
Female/32
Male/27
Present study
Male/53
Clinical Presentation NA Supraclavicular and abdominal LA Cervical axillary and inguinal LA Ovaries, spleen, and retroperitoneal LA Systemic LA and bone marrow Abdominal and mediastinal LA
Follow-up (Months)
Stage
IPI
Therapy
III/IV III
NA NA
AWD (14) AWD (27)
IIIB
3
ACVBP CT + CT and RT after relapse CHOP
IV
NA
CHOP-derived
AWD (45)
IV
NA
CHOP-derived
AWD (19)
IIIB
2
CODOX-M/IVAC – BEAM – ASCT + ICC + RT
AWD (35)
AWD (72)
Abbreviations: IPI, International Prognostic Index; NA, not available; AWD, alive without disease; LA, lymph adenopathy; ACVBP, doxorubicin– cyclophosphamide–vindesine–bleomycin–prednisone; CT, chemotherapy; RT, radiation therapy; CHOP, cyclophosphamide doxorubicin vincristine prednisone; CODOX-M, cyclophosphamide vincristine doxorubicin cytarabine methotrexate; IVAC, ifosfamide etoposide cytarabine methotrexate; BEAM, BCNU, cytarabine VP-16 melphalane; ASCT, autologous stem cell transplantation; ICC, intrathecal chemotherapy.
in 2009, the characteristic granular cytoplasmic restricted ALK positivity may represent a single surrogate marker of the t(2;17). In our case, molecular cytogenetic studies were not performed, and, based on the exclusive cytoplasmic granular staining pattern of ALK, we considered a t(2;17) involving ALK and CLTC to be the most likely cytogenetic abnormality. Therefore, although fluorescence in situ hybridization and reverse transcriptase–polymerase chain reaction are needed for definitive demonstration of such t(2;17) translocation, immunohistochemistry can be a more simple and less expensive alternative to the more sophisticated molecular techniques which are not always available in pathology laboratories. Irrespective of the type of translocation, ALK-positive LBCL is an aggressive disease, often with a poor response to conventional therapies especially in high-stage disease.2,5,9 The case we report had an unexpected positive clinical outcome. Despite the advanced clinical stage, our patient achieved a complete remission after first line treatment and he shows no sign of relapse 35 months after diagnosis. To the best of our knowledge, only 5 cases of ALK-positive LBCL in advanced stages have been reported in the literature to have pursued a prolonged survival (Table 3). Compared with the other described cases, our patient underwent a more intensive multiagent chemotherapy. Two alternating intensive regimens (CODOX-M and IVAC) were utilized, involving the use of seven drugs. Magrath et al21 from the National Cancer Institute developed this chemotherapy cycle in 1996 for patients with high-risk aggressive non–Hodgkin’s lymphoma, including Burkitt’s lymphoma. Notably, a standardized therapy does not exist for patients with ALK-positive LBCL, probably because of the rarity of this entity. The therapeutic
regimens described in the literature are several, and clinical outcomes seem to not be influenced by them. Nowadays, in the targeted therapy era, the potential use of ALK inhibitors is an attractive option for oncologists.15,22,23 Recent experimental evidence has suggested that ALK inhibitors may be efficacious in the treatment of ALK-positive LBCL.22 However, to the best of our knowledge, only 1 patient affected by ALK-positive LBCL and treated with crizotinib has been described in the literature, but with discouraging results.23 Further clinical studies are needed to evaluate if ALK inhibitors may actually provide a new therapeutic option for patients with this disease. In conclusion, here we have described a case of ALKpositive LBCL with a surprisingly favorable clinical outcome after intensive chemotherapy treatment and autologous stem cell transplantation. In fact, despite the advanced clinical stage, which is known to be the strongest predictor of survival,2,5 our patient is alive and without disease. On the other hand, from the histopathologic point of view, the case of ALK-positive LBCL described here is very typical, but gives us the chance to stress the diagnostic challenge represented by this rare entity, which can be confused with other hematologic and nonhematologic neoplasms. Acknowledgments The authors wish to thank Monica Pessino at University of California, Santa Barbara, and Veronica Pessino, PhD candidate in Biophysics, at University of California, San Francisco, for the linguistic revisions of the article.
Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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Zanelli et al Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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