- Email: [email protected]
Concurrent immunoglobulin G-lambda type multiple myeloma and mixed cellularity classical Hodgkin lymphoma: A case report
J Infect Chemother xxx (xxxx) xxx
Contents lists available at ScienceDirect
Journal of Infection and Chemotherapy journal homepage: http://www.elsevier.com/locate/jic
Case Report
Concurrent immunoglobulin G-lambda type multiple myeloma and mixed cellularity classical Hodgkin lymphoma: A case report* Kazuhito Suzuki a, b, *, 1, Takeshi Saito a, Yasuhiro Arakawa a, Takehiro Mitsuishi c, Takaki Shimada a, Hiroki Yokoyama a, Yutora Kamiyama a, Atsushi Katsube a, Masahiro Ikegami c, Shingo Yano a a b c
Division of Clinical Oncology/Hematology, Department of Internal Medicine, The Jikei University School of Medicine, Japan Division of Clinical Oncology/Hematology, Department of Internal Medicine, The Jikei University Kashiwa Hospital, Japan Division of Human Pathology and Morphology, The Jikei University School of Medicine, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 13 May 2019 Received in revised form 30 May 2019 Accepted 6 June 2019 Available online xxx
A 66-year-old man with a swollen right inguinal lymph node (LN) had pain on the lower side of the back. Computed tomography revealed bone disease in the back and swollen right inguinal LNs. Laboratory studies showed anemia and serum immunoglobulin G-lambda (IgG-l) type monoclonal protein. The bone marrow contained 39.6% plasma cells. He was diagnosed with IgG-l type multiple myeloma (MM). However, the pathological findings of the right inguinal LN were mixed cellular classical Hodgkin lymphoma (HL). The administration of melphalan, prednisone, and bortezomib (MPB) was started for MM; however, swelling in the right inguinal LN increased. After three cycles of MPB, the administration of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) was started for HL. However, HL was refractory to ABVD. Pancytopenia subsequently progressed and rapid swelling occurred in his LNs. He died 7 months after diagnosis. Multiple myeloma was diagnosed, based on the typical symptoms, although the pathological findings of the LN indicated a diagnosis of HL. We analyzed the molecular relationship between MM and HL cells using a direct sequencing method. The sequencing results demonstrated that the variable-diversity-joining (VDJ) region of the IgH gene was identified with 94.4% of IGLV3-32*01 in the bone marrow sample at diagnosis. Furthermore, clonotypic IgH sequence was identified in CD30positive cells from the LN. These results suggested that the clonal HL cells were derived from the same source as the clonal MM cells and demonstrated that MM and HL in this patient may have originated from the same B cell progenitor. © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Keywords: Multiple myeloma Hodgkin lymphoma Direct sequencing method
1. Introduction Multiple myeloma (MM) is a clonal plasma cell neoplasm that develops primarily in the bone marrow (BM). In most MM cases, immunoglobulin heavy chain (IgH) genes are rearranged clonally, primarily via somatic hypermutation. A clonotypic sequence is
* All authors meet the ICMJE authorship criteria. * Corresponding author. The Jikei University School of Medicine, Division of Clinical Oncology/Hematology, Department of Internal Medicine, 3-25-8 NishiShinbashi, Minato-ku, Tokyo, 105-8461, Japan. E-mail address: [email protected] (K. Suzuki). 1 Present Address: The Jikei University Kashiwa Hospital, Division of Clinical Oncology/Hematology, Department of Internal Medicine, 163-1 Kashiwa-shita, Kashiwa-shi, Chiba 277-8567, Japan.
frequently isolated in the IgH gene of MM cells by using reverse transcriptase polymerase chain reaction (PCR) and direct sequencing methods [1]. Classical Hodgkin lymphoma (HL) is also a B cell lymphocyte neoplasm. The origin of classical HL is germinal center B cells with rearrangement of immunoglobulin genes [2]. Several reports have demonstrated that HL and B cell non-HL can occur in the same patient [3e5]. However, limited cases of concurrent MM and classical HL have been reported [6e9]. We report a 66-year-old man with concurrent MM and mixed cellularity classical HL (MCCHL). In addition, we used a direct sequencing method to investigate the relationship between rearrangements of the immunoglobulin genes in myeloma cells and classical HL cells.
https://doi.org/10.1016/j.jiac.2019.06.002 1341-321X/© 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Please cite this article as: Suzuki K et al., Concurrent immunoglobulin G-lambda type multiple myeloma and mixed cellularity classical Hodgkin lymphoma: A case report, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.06.002
2
K. Suzuki et al. / J Infect Chemother xxx (xxxx) xxx
2. Case presentation A 66-year-old man with a swollen right inguinal lymph node (LN), pain in lower right side of the back, and pain in the left thigh visited in our institute in August 200X. Osteolytic lesions in the upper cervical, lower thoracic, lumber, and sacral vertebrae was identified using CT scan. High density area of the medulla of left femur was detected although osteolytic lesion was not pointed out. Using magnetic resonance imaging (MRI), abnormal intensity area was pointed out in left femur; low intensity by T1-weighted MRI, high intensity by STIR images. Laboratory studies showed a hemoglobin concentration of 8.7 g/dL, serum immunoglobulin (Ig) G level of 8261 mg/dL, IgA level of 41 mg/dL, serum IgM level of 31 mg/dL, serum albumin level of 2.6 g/dL, serum beta-2 microglobulin level of 8.3 mg/L, and serum lactase dehydrogenase level of 182 U/L. IgG-lambda (IgG-l) type monoclonal protein was detected using serum immunoelectrophoresis tests. The BM contained 39.6% of large plasma cells with clear nucleoli (Fig. 1a). His karyotype was 46XY using the Q banding method. He was diagnosed with IgG-l type MM (international staging system 3, Durie and Salmon stage 3A). Right inguinal and iliac LNs swelling were pointed out using CT scan which revealed bone disease due to MM. The pathological findings from the right inguinal LN showed HodgkineReedeSternberg cells such as eosinophils and neutrophils in an inflammatory background without nodular sclerosing fibrosis. Immunohistochemistry findings showed the cells were positive for CD15 and CD30, and negative for CD20, CD79a, CD3, CD5, and Epstein-Barr encoding region (EBER) (Fig. 1bed). Thus, the pathological findings of the right inguinal LN were diagnosed as MCCHL. BM biopsy did not identify as HL. B symptom was not pointed out. Finally, we diagnosed him with concurrent IgG-l type MM and MCCHL (clinical stage IIA). Therapy with MPB (melphalan, 9 mg/m2, days 1e4; prednisolone, 40 mg/m2, days 1e4; bortezomib, 1.3 mg/m2, days 1, 8, 15, and 22) was started for MM in December because he experienced bone
pain in the left thigh. A partial response was achieved after two cycles of MPB. In February of the following year, his bone pain became severe to the extent that he could not walk. Therefore, radiation therapy (30 Gy/10 Fr) was applied to his left thigh, upper cervical, lower thoracic, and lumber vertebrae. The MPB regimen was restarted after radiation therapy in March. However, a 15-mm diameter skin mass appeared in the right lateral thorax after 3 cycles of MPB. The pathological findings of the skin mass showed large plasma cells with large nucleoli proliferating diffusely. Immunohistochemistry findings showed the cells were positive for the l chain, cyclin D1, and CD30 (weakly positive), and negative for the kappa (k) chain, CD20, CD79a, CD15, CD3, CD5, CD56, EBER, and PAX5 (Fig. 2aed). The skin mass was diagnosed as a new plasmacytoma. Thus, his myeloma progressed. The swelling in the right inguinal LN had increased rapidly and gotten more painful although plasmacytoma progressed slowly and was not painful after 3 cycles of MPB and radiation therapies. Therapy with ABVD (doxorubicin, 25 mg/m2, days 1 and 15; bleomycin, 10 mg/m2, days 1 and 15; vinblastine, 6 mg/m2, days 1 and 15; dacarbazine, 375 mg/m2, days 1 and 15) was started in April. After two cycles of ABVD, we observed the progression of pancytopenia and rapid swelling in inguinal LNs. BM aspiration revealed low cellularity and hemophagocytosis. The proportion of plasma cells was 1.8%. The MCCHL cells were not histologically detected in the BM. The patient died from sepsis caused by hemophagocytosis from the progression of MCCHL in June 200Xþ1. We analyzed the molecular relationship between the myeloma and HL cells. We harvested three samples: myeloma cells from the BM at diagnosis, MCCHL cells from the right inguinal LN, and plasma cells from the skin mass. We analyzed the rearranged the IgH sequences in the three samples as a tumor specific marker by using a direct sequencing method. The sequencing results demonstrated that the variablediversity-joining (VDJ) region of IgH gene was identified with 94.4% of IGLV3-32*01 in the BM sample at diagnosis. The clonotypic
Fig. 1. Morphological findings in bone marrow and right inguinal lymph-node. (a) bone marrow by May-Giemsa staining (x400), (b) right inguinal lymph-node by HE staining (x400), (c) CD15 staining (x400), and (d) CD30 staining (x400).
Please cite this article as: Suzuki K et al., Concurrent immunoglobulin G-lambda type multiple myeloma and mixed cellularity classical Hodgkin lymphoma: A case report, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.06.002
K. Suzuki et al. / J Infect Chemother xxx (xxxx) xxx
3
Fig. 2. Morphological findings in skin lesion. (a) skin lesion by Hematoxylin-Eosin staining (x400), (b) by l chain staining (x400), (c) k chain staining (x400), and (d) CD30 staining (x400).
IgH sequence in the BM at diagnosis was similar to that of the skin mass (identity ratio, 96%) and was identified in that of the CD30positive cells from the right inguinal LN (identity ratio, 100%). These results suggested that the clonal MCCHL cells were derived from the same source as the clonal MM cells. 3. Discussion We reported our experience with a 66-year-old man diagnosed with concurrent IgG-l type MM and MCCHL. The number of patients with concurrent MM and classical HL in the absence of prior radiation or chemotherapy is low [6e9, Table 1]. This is the first case report of MM and HL cells that were derived from same origin, as proven using direct sequencing methods. Most previously reported cases of concurrent MM and classical HL occurred in people older than 50 years, which is the elderly peak in the incidence of classical HL. The prognosis is usually poor, although only one patient lived for 3 years. The patient with long survival was initially treated with bortezomib and dexamethasone, but HL progressed; therefore, ABVD started and was active for both HL and MM [9]. Adriamycin may have an important role for patients with concurrent MM and HL. We analyzed whether the MM and MCCHL originated from the same B lineage cells or not. Rearrangement of IgH genes has been detected in some cases of classical HL by using PCR with BIOMED-2
primers [1,10,11]. These reports demonstrated that monoclonal rearrangement of IgH genes were detected in 23.8% of cases of classical HL. Rearrangements of IgH genes were detected in patients with MCCHL more frequently than in patients with nodular sclerosing HL, and was detected in EBER-positive cases more frequently than in EBER-negative cases. Our patient was diagnosed with MCCHL but EBER status was negative. Marafioti et al. [5] reported a patient who had been diagnosed with nodular sclerosing classical HL and follicular lymphoma. They concluded that the origin of the ReedeSternberg cells and those of follicular lymphoma cells were the same germinal center B cell because both types of lymphoma cells shared the same CDR3 and VH3 sequences of IgH genes using a direct sequencing method. In our patient, the MM and MCCHL cells shared the same CDR2 and VH3 sequences. We analyzed the cells in the CD30-positive area of right inguinal LN by using PCR methods. Zheng et al. [12] reported that CD30positive myeloma cells were infrequent but present, based on flow cytometry. CD30 is expressed in limited subpopulations of activated B and T cells in healthy people [13]. CD30 is often weak in normal plasma cells and more infrequently expressed in neoplastic plasma cells than in normal plasma cells [14]. In our patient, the CD30positive area of LN was stained by paired box 5 (PAX5). PAX5 is a B cell specific transcription factor that is expressed subsequently in all stages of B cell development until the plasma cell stage, and the
Table 1 Previous cases with myeloma and Hodgkin lymphoma concurrently. reference
age
sex
M protein-type
subtype of cHL
chemotherapy
OS
outcome
Ibbotson RM et al., 1977 [6] Lalayanni C et al., 2000 [7] Huppmann AR et al., 2010 [8] Chandran R et al., 2013 [9] Our case
60 52 82 72 66
male male male male male
IgG-lammda IgG-kappa IgG-kappa IgG-kappa IgG-lammda
NSCHL MCCHL HL NCSHL MCCHL
non COPP/ABVD
shortly
dead dead dead alive dead
BD, ABVD BD, ABVD
14 days 3 years 7 months
cause of death
MCCHL
MCCHL
molecular analysis no no no no yes
NSCHL, nodular sclerosis classical Hodgkin lymphoma; MCCHL, mixed cellular classical Hodgkin lymphoma; HL, Hodgkin lymphoma; COPP/ABVD, cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, and dacarbazine; BD, bortezomib and dexamethasone.
Please cite this article as: Suzuki K et al., Concurrent immunoglobulin G-lambda type multiple myeloma and mixed cellularity classical Hodgkin lymphoma: A case report, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.06.002
4
K. Suzuki et al. / J Infect Chemother xxx (xxxx) xxx
expression of PAX5 is downregulated during maturating from B cell to plasma cells [15]. Thus, CD30-and PAX-5-positive cells were generally identified, not with myeloma cells, but with HL cells. This study had two limitations. First, reactivation of the EpsteineBarr virus may cause MCCHL in patients with an immunesuppressed condition caused by MM. The serum deoxyribonucleic acid (DNA) level of the EpsteineBarr virus was not evaluated in our patient. Second, we did not perform an autopsy to analyze the multiple bone lesions and swollen LNs that were visible on a CT scan just before he died. Thus, his true cause of death was not clear. In conclusion, we reported a rare case of a patient who was concurrently diagnosed with MM and HL. The origin of MM and MCCHL in the same patient might have been a single clonal progenitor B cell because the MM and MCCHL cells shared the same sequences in the IgH genes as observed using direct sequencing methods. Conflicts of interests All the authors indicated no potential conflicts of interest. References [1] van Dongen JJ, Langerak AW, Brüggemann M, Evans PA, Hummel M, Lavender FL, et al. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia 2003;17:2257e317. https:// doi.org/10.1038/sj.leu.2403202. [2] Kupper R, Rajewsky K. The origin of Hodgkin and Reed/Sternbarg cells in Hodgkin's disease. Annu Rev Immunol 1998;16:471e93. https://doi.org/10. 1146/annurev.immunol.16.1.471. [3] Harris NL. The relationship between Hodgkin's disease and non-Hodgkin's Lymphoma. Semin Diagn Pathol 1992;9:304e10. PMID:1480853.
[4] Jaffe ES, Zarate-Osorno A, Medeiros LJ. The interrelationship of Hodgkin lymphoma and B-cell non-Hodgkin lymphoma: lessons learned from composite and sequential malignancies. Semin Diagn Pathol 1992;9:297e303. PMID:1480852. [5] Marafioti T, Hummel M, Anagnostopoulos I, Foss HD, Huhn D, Stein H. Classical hodgkin lymphoma and follicular lymphoma originating from the same germinal center B cell. J Clin Oncol 1999;17:3804e9. https://doi.org/10.1200/ JCO.1999.17.12.3804. [6] Ibbotson RM, Revell PA, Molland EA, Minton MJ. The simultaneous presentation of Hodgkin's disease of myeloma. Postgrad Med 1977;53:52e3. https:// doi.org/10.1136/pgmj.53.615.52. [7] Lalayanni C, Theodoridou S, Athanasiadou A, Saloum R, Tsatalas C. Simultaneous occurrence of multiple myeloma and Hodgkin's disease. A case report. Haematologica 2000;85:772e3. PMID:10897138. [8] Huppmann AR, Liu ML, Nava VE. Concurrent diagnoses of Hodgkin lymphoma and biclonal myeloma in the bone marrow. Ann Diagn Pathol 2010;14: 268e72. https://doi.org/10.1016/j.anndiagpath.2009.09.006. [9] Chandran R, Simon M, Spurgeon SE. Concurrent presentation of hodgkin lymphoma and multiple myeloma. Case Rep Hematol 2013;2013:398769. https://doi.org/10.1155/2013/398769. [10] Taylor BJ, Kriangkum J, Strachan ER, Wizniak J, Pilarski LM. Identification of clonotypic IgH VDJ sequences in multiple myeloma. Methods Mol Med 2005;113:121e44. https://doi.org/10.1385/1-59259-916-8:121. [11] Chute DJ, Cousar JB, Mahadevan MS, Siegrist KA, Silverman LM, Stoler MH. Detection of immunoglobulin heavy chain gene rearrangements in classical Hodgkin lymphoma using commercially available BIOMED-2 primers. Diagn Mol Pathol 2008;17:65e72. https://doi.org/10.1097/ PDM.0b013e318150d695. [12] Zheng W, Liu D, Fan X, Powers L, Goswami M, Hu Y, et al. Potential therapeutic biomarkers in plasma cell myeloma: a flow cytometry study. Cytometry B Clin Cytom 2013;84:222e8. https://doi.org/10.1002/cyto.b.21083. [13] Horie R, Watanabe T. CD30: expression and function in health and disease. Semin Immunol 1998;10:457e70. https://doi.org/10.1006/smim.1998.0156. [14] Beschorner R, Horny HP, Petruch UR, Kaiserling E. Frequent expression of haemopoietic and non-haemopoietic antigens by reactive plasma cells: an immunohistochemical study using formalin-fixed, paraffin-embedded tissue. Histol Histopathol 1999;14:805e12. https://doi.org/10.14670/HH-14.805. [15] Nutt SL, Taubenheim N, Hasbold J, Corcoran LM, Hodgkin PD. The genetic network controlling plasma cell differentiation. Semin Immunol 2011;23: 341e9. https://doi.org/10.1016/j.smim.2011.08.010.
Please cite this article as: Suzuki K et al., Concurrent immunoglobulin G-lambda type multiple myeloma and mixed cellularity classical Hodgkin lymphoma: A case report, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.06.002
Contents lists available at ScienceDirect
Journal of Infection and Chemotherapy journal homepage: http://www.elsevier.com/locate/jic
Case Report
Concurrent immunoglobulin G-lambda type multiple myeloma and mixed cellularity classical Hodgkin lymphoma: A case report* Kazuhito Suzuki a, b, *, 1, Takeshi Saito a, Yasuhiro Arakawa a, Takehiro Mitsuishi c, Takaki Shimada a, Hiroki Yokoyama a, Yutora Kamiyama a, Atsushi Katsube a, Masahiro Ikegami c, Shingo Yano a a b c
Division of Clinical Oncology/Hematology, Department of Internal Medicine, The Jikei University School of Medicine, Japan Division of Clinical Oncology/Hematology, Department of Internal Medicine, The Jikei University Kashiwa Hospital, Japan Division of Human Pathology and Morphology, The Jikei University School of Medicine, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 13 May 2019 Received in revised form 30 May 2019 Accepted 6 June 2019 Available online xxx
A 66-year-old man with a swollen right inguinal lymph node (LN) had pain on the lower side of the back. Computed tomography revealed bone disease in the back and swollen right inguinal LNs. Laboratory studies showed anemia and serum immunoglobulin G-lambda (IgG-l) type monoclonal protein. The bone marrow contained 39.6% plasma cells. He was diagnosed with IgG-l type multiple myeloma (MM). However, the pathological findings of the right inguinal LN were mixed cellular classical Hodgkin lymphoma (HL). The administration of melphalan, prednisone, and bortezomib (MPB) was started for MM; however, swelling in the right inguinal LN increased. After three cycles of MPB, the administration of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) was started for HL. However, HL was refractory to ABVD. Pancytopenia subsequently progressed and rapid swelling occurred in his LNs. He died 7 months after diagnosis. Multiple myeloma was diagnosed, based on the typical symptoms, although the pathological findings of the LN indicated a diagnosis of HL. We analyzed the molecular relationship between MM and HL cells using a direct sequencing method. The sequencing results demonstrated that the variable-diversity-joining (VDJ) region of the IgH gene was identified with 94.4% of IGLV3-32*01 in the bone marrow sample at diagnosis. Furthermore, clonotypic IgH sequence was identified in CD30positive cells from the LN. These results suggested that the clonal HL cells were derived from the same source as the clonal MM cells and demonstrated that MM and HL in this patient may have originated from the same B cell progenitor. © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Keywords: Multiple myeloma Hodgkin lymphoma Direct sequencing method
1. Introduction Multiple myeloma (MM) is a clonal plasma cell neoplasm that develops primarily in the bone marrow (BM). In most MM cases, immunoglobulin heavy chain (IgH) genes are rearranged clonally, primarily via somatic hypermutation. A clonotypic sequence is
* All authors meet the ICMJE authorship criteria. * Corresponding author. The Jikei University School of Medicine, Division of Clinical Oncology/Hematology, Department of Internal Medicine, 3-25-8 NishiShinbashi, Minato-ku, Tokyo, 105-8461, Japan. E-mail address: [email protected] (K. Suzuki). 1 Present Address: The Jikei University Kashiwa Hospital, Division of Clinical Oncology/Hematology, Department of Internal Medicine, 163-1 Kashiwa-shita, Kashiwa-shi, Chiba 277-8567, Japan.
frequently isolated in the IgH gene of MM cells by using reverse transcriptase polymerase chain reaction (PCR) and direct sequencing methods [1]. Classical Hodgkin lymphoma (HL) is also a B cell lymphocyte neoplasm. The origin of classical HL is germinal center B cells with rearrangement of immunoglobulin genes [2]. Several reports have demonstrated that HL and B cell non-HL can occur in the same patient [3e5]. However, limited cases of concurrent MM and classical HL have been reported [6e9]. We report a 66-year-old man with concurrent MM and mixed cellularity classical HL (MCCHL). In addition, we used a direct sequencing method to investigate the relationship between rearrangements of the immunoglobulin genes in myeloma cells and classical HL cells.
https://doi.org/10.1016/j.jiac.2019.06.002 1341-321X/© 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Please cite this article as: Suzuki K et al., Concurrent immunoglobulin G-lambda type multiple myeloma and mixed cellularity classical Hodgkin lymphoma: A case report, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.06.002
2
K. Suzuki et al. / J Infect Chemother xxx (xxxx) xxx
2. Case presentation A 66-year-old man with a swollen right inguinal lymph node (LN), pain in lower right side of the back, and pain in the left thigh visited in our institute in August 200X. Osteolytic lesions in the upper cervical, lower thoracic, lumber, and sacral vertebrae was identified using CT scan. High density area of the medulla of left femur was detected although osteolytic lesion was not pointed out. Using magnetic resonance imaging (MRI), abnormal intensity area was pointed out in left femur; low intensity by T1-weighted MRI, high intensity by STIR images. Laboratory studies showed a hemoglobin concentration of 8.7 g/dL, serum immunoglobulin (Ig) G level of 8261 mg/dL, IgA level of 41 mg/dL, serum IgM level of 31 mg/dL, serum albumin level of 2.6 g/dL, serum beta-2 microglobulin level of 8.3 mg/L, and serum lactase dehydrogenase level of 182 U/L. IgG-lambda (IgG-l) type monoclonal protein was detected using serum immunoelectrophoresis tests. The BM contained 39.6% of large plasma cells with clear nucleoli (Fig. 1a). His karyotype was 46XY using the Q banding method. He was diagnosed with IgG-l type MM (international staging system 3, Durie and Salmon stage 3A). Right inguinal and iliac LNs swelling were pointed out using CT scan which revealed bone disease due to MM. The pathological findings from the right inguinal LN showed HodgkineReedeSternberg cells such as eosinophils and neutrophils in an inflammatory background without nodular sclerosing fibrosis. Immunohistochemistry findings showed the cells were positive for CD15 and CD30, and negative for CD20, CD79a, CD3, CD5, and Epstein-Barr encoding region (EBER) (Fig. 1bed). Thus, the pathological findings of the right inguinal LN were diagnosed as MCCHL. BM biopsy did not identify as HL. B symptom was not pointed out. Finally, we diagnosed him with concurrent IgG-l type MM and MCCHL (clinical stage IIA). Therapy with MPB (melphalan, 9 mg/m2, days 1e4; prednisolone, 40 mg/m2, days 1e4; bortezomib, 1.3 mg/m2, days 1, 8, 15, and 22) was started for MM in December because he experienced bone
pain in the left thigh. A partial response was achieved after two cycles of MPB. In February of the following year, his bone pain became severe to the extent that he could not walk. Therefore, radiation therapy (30 Gy/10 Fr) was applied to his left thigh, upper cervical, lower thoracic, and lumber vertebrae. The MPB regimen was restarted after radiation therapy in March. However, a 15-mm diameter skin mass appeared in the right lateral thorax after 3 cycles of MPB. The pathological findings of the skin mass showed large plasma cells with large nucleoli proliferating diffusely. Immunohistochemistry findings showed the cells were positive for the l chain, cyclin D1, and CD30 (weakly positive), and negative for the kappa (k) chain, CD20, CD79a, CD15, CD3, CD5, CD56, EBER, and PAX5 (Fig. 2aed). The skin mass was diagnosed as a new plasmacytoma. Thus, his myeloma progressed. The swelling in the right inguinal LN had increased rapidly and gotten more painful although plasmacytoma progressed slowly and was not painful after 3 cycles of MPB and radiation therapies. Therapy with ABVD (doxorubicin, 25 mg/m2, days 1 and 15; bleomycin, 10 mg/m2, days 1 and 15; vinblastine, 6 mg/m2, days 1 and 15; dacarbazine, 375 mg/m2, days 1 and 15) was started in April. After two cycles of ABVD, we observed the progression of pancytopenia and rapid swelling in inguinal LNs. BM aspiration revealed low cellularity and hemophagocytosis. The proportion of plasma cells was 1.8%. The MCCHL cells were not histologically detected in the BM. The patient died from sepsis caused by hemophagocytosis from the progression of MCCHL in June 200Xþ1. We analyzed the molecular relationship between the myeloma and HL cells. We harvested three samples: myeloma cells from the BM at diagnosis, MCCHL cells from the right inguinal LN, and plasma cells from the skin mass. We analyzed the rearranged the IgH sequences in the three samples as a tumor specific marker by using a direct sequencing method. The sequencing results demonstrated that the variablediversity-joining (VDJ) region of IgH gene was identified with 94.4% of IGLV3-32*01 in the BM sample at diagnosis. The clonotypic
Fig. 1. Morphological findings in bone marrow and right inguinal lymph-node. (a) bone marrow by May-Giemsa staining (x400), (b) right inguinal lymph-node by HE staining (x400), (c) CD15 staining (x400), and (d) CD30 staining (x400).
Please cite this article as: Suzuki K et al., Concurrent immunoglobulin G-lambda type multiple myeloma and mixed cellularity classical Hodgkin lymphoma: A case report, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.06.002
K. Suzuki et al. / J Infect Chemother xxx (xxxx) xxx
3
Fig. 2. Morphological findings in skin lesion. (a) skin lesion by Hematoxylin-Eosin staining (x400), (b) by l chain staining (x400), (c) k chain staining (x400), and (d) CD30 staining (x400).
IgH sequence in the BM at diagnosis was similar to that of the skin mass (identity ratio, 96%) and was identified in that of the CD30positive cells from the right inguinal LN (identity ratio, 100%). These results suggested that the clonal MCCHL cells were derived from the same source as the clonal MM cells. 3. Discussion We reported our experience with a 66-year-old man diagnosed with concurrent IgG-l type MM and MCCHL. The number of patients with concurrent MM and classical HL in the absence of prior radiation or chemotherapy is low [6e9, Table 1]. This is the first case report of MM and HL cells that were derived from same origin, as proven using direct sequencing methods. Most previously reported cases of concurrent MM and classical HL occurred in people older than 50 years, which is the elderly peak in the incidence of classical HL. The prognosis is usually poor, although only one patient lived for 3 years. The patient with long survival was initially treated with bortezomib and dexamethasone, but HL progressed; therefore, ABVD started and was active for both HL and MM [9]. Adriamycin may have an important role for patients with concurrent MM and HL. We analyzed whether the MM and MCCHL originated from the same B lineage cells or not. Rearrangement of IgH genes has been detected in some cases of classical HL by using PCR with BIOMED-2
primers [1,10,11]. These reports demonstrated that monoclonal rearrangement of IgH genes were detected in 23.8% of cases of classical HL. Rearrangements of IgH genes were detected in patients with MCCHL more frequently than in patients with nodular sclerosing HL, and was detected in EBER-positive cases more frequently than in EBER-negative cases. Our patient was diagnosed with MCCHL but EBER status was negative. Marafioti et al. [5] reported a patient who had been diagnosed with nodular sclerosing classical HL and follicular lymphoma. They concluded that the origin of the ReedeSternberg cells and those of follicular lymphoma cells were the same germinal center B cell because both types of lymphoma cells shared the same CDR3 and VH3 sequences of IgH genes using a direct sequencing method. In our patient, the MM and MCCHL cells shared the same CDR2 and VH3 sequences. We analyzed the cells in the CD30-positive area of right inguinal LN by using PCR methods. Zheng et al. [12] reported that CD30positive myeloma cells were infrequent but present, based on flow cytometry. CD30 is expressed in limited subpopulations of activated B and T cells in healthy people [13]. CD30 is often weak in normal plasma cells and more infrequently expressed in neoplastic plasma cells than in normal plasma cells [14]. In our patient, the CD30positive area of LN was stained by paired box 5 (PAX5). PAX5 is a B cell specific transcription factor that is expressed subsequently in all stages of B cell development until the plasma cell stage, and the
Table 1 Previous cases with myeloma and Hodgkin lymphoma concurrently. reference
age
sex
M protein-type
subtype of cHL
chemotherapy
OS
outcome
Ibbotson RM et al., 1977 [6] Lalayanni C et al., 2000 [7] Huppmann AR et al., 2010 [8] Chandran R et al., 2013 [9] Our case
60 52 82 72 66
male male male male male
IgG-lammda IgG-kappa IgG-kappa IgG-kappa IgG-lammda
NSCHL MCCHL HL NCSHL MCCHL
non COPP/ABVD
shortly
dead dead dead alive dead
BD, ABVD BD, ABVD
14 days 3 years 7 months
cause of death
MCCHL
MCCHL
molecular analysis no no no no yes
NSCHL, nodular sclerosis classical Hodgkin lymphoma; MCCHL, mixed cellular classical Hodgkin lymphoma; HL, Hodgkin lymphoma; COPP/ABVD, cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, and dacarbazine; BD, bortezomib and dexamethasone.
Please cite this article as: Suzuki K et al., Concurrent immunoglobulin G-lambda type multiple myeloma and mixed cellularity classical Hodgkin lymphoma: A case report, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.06.002
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expression of PAX5 is downregulated during maturating from B cell to plasma cells [15]. Thus, CD30-and PAX-5-positive cells were generally identified, not with myeloma cells, but with HL cells. This study had two limitations. First, reactivation of the EpsteineBarr virus may cause MCCHL in patients with an immunesuppressed condition caused by MM. The serum deoxyribonucleic acid (DNA) level of the EpsteineBarr virus was not evaluated in our patient. Second, we did not perform an autopsy to analyze the multiple bone lesions and swollen LNs that were visible on a CT scan just before he died. Thus, his true cause of death was not clear. In conclusion, we reported a rare case of a patient who was concurrently diagnosed with MM and HL. The origin of MM and MCCHL in the same patient might have been a single clonal progenitor B cell because the MM and MCCHL cells shared the same sequences in the IgH genes as observed using direct sequencing methods. Conflicts of interests All the authors indicated no potential conflicts of interest. References [1] van Dongen JJ, Langerak AW, Brüggemann M, Evans PA, Hummel M, Lavender FL, et al. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia 2003;17:2257e317. https:// doi.org/10.1038/sj.leu.2403202. [2] Kupper R, Rajewsky K. The origin of Hodgkin and Reed/Sternbarg cells in Hodgkin's disease. Annu Rev Immunol 1998;16:471e93. https://doi.org/10. 1146/annurev.immunol.16.1.471. [3] Harris NL. The relationship between Hodgkin's disease and non-Hodgkin's Lymphoma. Semin Diagn Pathol 1992;9:304e10. PMID:1480853.
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Please cite this article as: Suzuki K et al., Concurrent immunoglobulin G-lambda type multiple myeloma and mixed cellularity classical Hodgkin lymphoma: A case report, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.06.002