Background
Plasma cell myeloma (PCM) is a neoplasm of terminally differentiated B lymphocytes and most often involves the bone marrow. Malignant plasma cells are defined immunophenotypically by diminished or increased expression of at least two antigens not present on non-neoplastic plasma cells. For example, malignant plasma cells show decreased or loss of CD45 and/or CD19 expression and may aberrantly express CD56, CD117, and/or CD20 [ 1 ]. Immunohistochemical stains performed on diagnostic biopsies demonstrate retained expression of non-neoplastic plasma cell antigens (e.g. CD138 and MUM-1) and cytoplasmic light chain restriction. PCM is characterized by molecular heterogeneity, including balanced translocations involving the immunoglobulin heavy chain locus, complex karyotypes, and mutations in the RAS signaling cascade [ 2 – 4 ]. For example, KRAS, NRAS and BRAF mutations are detected in approximately 33% of newly diagnosed PCM patients [ 3 , 4 ].
Disease progression in PCM can be associated with disease at extramedullary sites, high grade plasma cell morphology, acquisition of additional genetic mutations or possibly reactivation of Epstein Barr virus infection [ 3 , 5 – 7 ]. Although plasma cells may resemble blasts and express aberrant myeloid antigens [ 5 , 8 ], malignant plasma cells retain expression of a subset of plasma cell markers and demonstrate light chain restriction, allowing immunohistochemical classification of the tumor as PCM. A subset of patients with PCM develop secondary malignancies following high dose chemotherapy. Therapy-related myeloid neoplasms are the most common secondary malignancy in PCM [ 9 ]. We recently described the rapid onset of therapy-related acute leukemia in patients in complete remission for PCM. In this series, the immunophenotype and karyotype of the leukemic cells was distinctly different than that seen in the original PCM [ 10 ].
Here we report a rare case of multiple soft tissue sarcomas arising in a patient in complete remission for high-risk PCM. Immunohistochemical stains and flow cytometry showed that the tumor cells expressed monocyte-macrophage (CD163, CD68 and lysozyme) and myeloid antigens (myeloperoxidase and CD13) without plasma cell markers. Fluorescence in situ hybridization (FISH) and next generation sequencing (NGS) studies demonstrated a clonal relationship between the diagnostic PCM and transformed tumor cells, including loss of tumor suppressor genes and multiple, clonal/subclonal mutations in the RAS pathway. To our knowledge, this is the first reported case of myeloid transformation in PCM.
Case presentation
A sixty-year-old Caucasian male presented to our institution with chest pain. A complete blood count showed anemia (hemoglobin of 8.0 g/dL; reference range 13–17 g/dL) and thrombocytopenia (platelet count of 69,000/μL; reference range 150,000–450,000/μL). Review of the peripheral blood smear revealed 12% circulating plasma cells. Additional laboratory evaluation demonstrated an elevated total serum protein of 11.3 g/dL (reference range: 6.4–8.3 g/dL) and serum M-component (6.8 g/dL) with increased IgG (9010 mg/dL; reference range: 700–1600 mg/dL) and free lambda light chain (120 mg/dL; reference range 0.57–2.63 mg/dL). The diagnostic bone marrow biopsy demonstrated a hypercellular bone marrow for age extensively involved by lambda light chain-restricted plasma cells (Fig. 1 ). Concurrent flow cytometric analysis showed that the neoplastic plasma cells were positive for CD38, CD138, and CD20 (heterogeneous) and negative for CD45, CD27, CD81, CD56, and CD19. Cytogenetic analysis of the bone marrow aspirate cells revealed a complex karyotype: 43,XY,del(1)(p13p32),+ 3,der(3;6)(q10;p10),del(5)(q15q33),? t(9;15)(p24;q24),-10,add(13)(p11.2),del(14)(q24),-20,-22,inc[3]/46,XY[17]. Myeloma FISH studies were uninformative due to paucity of analyzable plasma cells. Gene array studies were consistent with high-risk c-MAF subgroup [ 2 ]. Foundation One™ NGS studies revealed IGH-MAF gene rearrangement and several genomic alterations, including BRAF G469V and G466A, KRAS A146V, MAP3K6 Q943, CDKN2A/B loss, TRAF3 R505 and PTPRO E379K (Table 1 ). Magnetic-resonance imaging (MRI) and positron-emitted topography (PET) scans highlighted multiple focal lesions in the cervical spine, rib cage, tibia, and fibula, but no extramedullary disease. Fig. 1 Morphologic examination (top) and immunohistochemical stains (bottom) performed on the diagnostic bone marrow core biopsy. The H&E stained sections of the bone marrow biopsy revealed a diffuse infiltrate of plasma cells (× 20) with nuclear pleomorphism; a subset of plasma cells showed prominent nucleoli (× 500). The plasma cells expressed CD138, MUM-1 with lambda light chain restriction (× 200) Table 1 Next-generation sequencing of the diagnostic bone marrow aspirate and left gingival lesion Bone marrow aspirate Soft tissue BRAF1 G466A subclonal, G469 subclonal BRAF G469A KRAS A146V KRAS A146V IGH IGH-MAF rearrangement IGH IGH-MAF rearrangement CDKN2A/B loss CDKN2A/B loss MAP3K6 Q943, truncation exon 22 MAP3K6 Q943, truncation exon 22 TRAF3 R505 NF1 R2450 PTPRO E379K – subclonal CCT6B splice site 615-2A > G TNFAIP3 W85
Table 1
Next-generation sequencing of the diagnostic bone marrow aspirate and left gingival lesion
| Bone marrow aspirate | Soft tissue |
| BRAF1 G466A subclonal, G469 subclonal | BRAF G469A |
| KRAS A146V | KRAS A146V |
| IGH IGH-MAF rearrangement | IGH IGH-MAF rearrangement |
| CDKN2A/B loss | CDKN2A/B loss |
| MAP3K6 Q943, truncation exon 22 | MAP3K6 Q943, truncation exon 22 |
| TRAF3 R505 | NF1 R2450 |
| PTPRO E379K – subclonal | CCT6B splice site 615-2A > G TNFAIP3 W85 |
The patient received induction chemotherapy (Velcade, Dexamethasone, Thalidomide-Cisplatin, Doxorubicin, Cyclophosphamide and Etoposide; VDT-PACE) followed by cytoreduction (Cytoxan, Etoposide, Mesna, Cisplatin, Dexamethasone and Cytarabine; PACMED) and bridging therapy with carfilzomib and daratumumab. An autologous stem cell transplant was performed 10 months after initial diagnosis. Two months after stem cell transplant, bone marrow evaluation was morphologically negative for PCM with no minimal residual disease detected by 8-color flow cytometry; however, PET-CT imaging showed multiple focal lesions in the bilateral femoral shafts, humeri and a 1.8 × 1.2 cm mass in the right perineal region (Fig. 2 ). A PET-CT imaging study showed that the lesion in the perineal region had increased in size to approximately 3.1 × 2.1 cm with new extramedullary lesions noted in the left mandibular soft tissue, lungs/mediastinal lymph nodes and liver (Fig. 2 ). The differential diagnosis included multifocal myelomatous disease progression versus infectious etiology. The patient underwent fine needle aspiration of mediastinal lymph nodes and punch biopsy of the gingival lesion. Fig. 2 PET-CT image (left) showing the lesions in the proximal right tibia, right proximal femur and perineum. PET-CT image (right) demonstrate increased size of the previous lesions and new lesions in the left mandibular soft tissue, liver, lungs and mediastinum three months after first time PET-CT
The Diff-Quik™ stained sections prepared from the mediastinal lymph node FNA showed large atypical cells with abundant cytoplasm with immature chromatin (Fig. 3 ). The H&E stained sections prepared from the cell block demonstrated similar morphologic features including an infiltrate of immature monocytic cells with rare mature granulocytes (Fig. 3 ). Immunohistochemical stains showed that the neoplastic cells expressed myeloperoxidase (MPO; subset), CD163, lysozyme, and were negative for CD138 (Fig. 3 ). Additional immunohistochemical studies revealed positivity for CD68 and lack of MUM-1, PAX-5, CD56, S-100, and P53 expression (not shown). Concurrent flow cytometric analysis revealed atypical cell populations with distinct CD45 expression and forward and side scatter properties comprising 80% of total analyzed events. One population with increased side and forward scatter comprised 40% of total events. These cells expressed CD45 (bright), CD33, HLA-DR, CD14 (bright), CD11b (bright) and CD36 (variable) (Fig. 4 ; red), consistent with monocytic lineage. A second population of cells with decreased forward and side scatter showed a similar immunophenotype with variable expression of CD33 and dimmer expression of CD45, CD11b and CD14 (Fig. 4 ; blue). Both populations were negative for CD34 and CD117. The H&E stained sections of the gingival biopsy showed similar morphologic features, including a dermal infiltrate of large, immature cells with irregular nuclear contours and ample cytoplasm (not shown). Immunohistochemical stains of the gingival biopsy showed an immunophenotype similar to the mediastinal lymph node, including CD68, CD163, lysozyme, MPO (subset) expression and lack of CD138, MUM-1, PAX-5, CD34, and CD56 expression (not shown). FISH studies performed on the mediastinal lymph node and gingival biopsies revealed a translocation between chromosomes 14 and 16 [IGH and MAF genes; t(14;16)(q32;q23)] in approximately 76% and 73% of interphase nuclei examined (Fig. 5 ), respectively. FISH probes for t(11q23) and del(17p13.1) showed normal signal patterns. Cytogenetic studies performed on the mediastinal lymph node were unsuccessful due to no cell growth. The gingival lesion showed a normal karyotype (46,XY[4]/45,Y,-X[1]) with a low mitotic index. NGS studies performed on the gingival lesion demonstrated IGH-MAF rearrangement, BRAF and KRAS mutations, CDKN2A/B loss, TNFAIP3 and NF1 mutations (Table 1 ). Fig. 3 Morphologic examination and immunohistochemical stains performed on the fine needle aspirate of the mediastinal lymph node. The Diff-Quik™ stained slides show large monocytoid cells with ample blue-grey cytoplasm, round to irregular nuclear contours and immature chromatin (× 500, top-left). The H&E stained sections prepared from the cell block shows a diffuse infiltrate of monocytoid cells with ample cytoplasm and round to irregular nuclear contours (× 200 and × 400, top-right). The tumor cells were negative for CD138 and positive for myeloperoxidase (MPO), CD163 and lysozyme (× 200) Fig. 4 Flow cytometric analysis of mediastinal lymph node revealed two cell populations with distinct forward and side scatter and CD45 expression intensity. One population with increased side and forward scatter comprised 40% of total events (red). This population expressed CD33, HLA-DR, CD36 (variable), CD14 (bright) and CD11b (bright) and were negative for CD34 and CD117. A second population of cells with decreased forward and side scatter showed a similar immunophenotype with variable expression of CD33 and dimmer CD11b and CD14 (blue). These cells were also negative for CD34 and CD117 Fig. 5 Fluorescence in-situ hybridization studies demonstrating t(14;16)(q32;q23) in both mediastinal lymph node ( a ) and gingival biopsy ( b ). The abnormal signaling patterns are 2R1G1F ( a ) and 2R1G1F ( b ) by dual color, dual fusion probes
The patient received induction chemotherapy (7 + 3 regimen of cytarabine and idarubicin). At follow up, the patient developed neutropenic fever with persistent pancytopenia despite receiving recombinant granulocytic colony stimulating factor. He was re-admitted one week later for possible sepsis/bacteremia. As the patient’s health continued to deteriorate and the soft tissue masses continued to grow, he decided to stop treatments and medical interventions. The patient went into palliative care approximately two months after the diagnosis of multifocal myeloid sarcoma and died shortly thereafter.
Discussion
We report a case of multiple soft tissue sarcomas in a patient in complete remission for high-risk PCM. The neoplastic cells at the extramedullary sites were large with immature chromatin and expressed the monocyte-macrophage antigen CD163 [ 11 ], CD14 and CD68 as well as myeloid antigens MPO and CD13. The tumor cells were negative for S-100 and CD138, consistent with absence of dendritic cell differentiation [ 12 , 13 ] or relapsed PCM, respectively. The immature nuclear features and expression of the myeloid antigens MPO and CD13 was most consistent with the diagnosis of myeloid sarcoma with monocytic differentiation. Furthermore, FISH studies showed IGH-MAF translocation in the transformed cells and PCR identified an IGH gene rearrangement. NGS- based assays revealed similar genomic alterations suggesting a clonal relationship between the original PCM and secondary myeloid sarcoma.
Hematopoiesis, once viewed as a unidirectional maturation of pluripotent hematopoietic stem cells into specific lineages (such as lymphoid and myeloid), shows considerable plasticity in both normal and malignant hematopoietic cells. Lineage switching has been described in histiocytic sarcoma (HS), Langerhans cell sarcoma or dendritic cell tumor that occur secondary to or synchronous with mediastinal germ cell tumors [ 14 ], lymphoid [ 12 , 13 , 15 – 22 ], and myeloid malignancies [ 23 , 24 ]. Histiocytic sarcoma cells are derived from bone marrow monocyte precursors [ 25 ], expresses monocyte-macrophage antigens (CD163, CD68, and lysozyme) and lack expression of myeloid antigens such as CD33, CD13 and MPO [ 11 , 25 , 26 ]. The identification of clonal associations between HS and antecedent malignancies suggests that HS or myeloid sarcoma can differentiate from other cell lineages or develop from a common progenitor cell [ 12 – 20 , 23 , 27 ].
Several studies indicate that commitment to specific lineage and lineage conversion depends on the activity of lineage-specific transcription factors [ 28 – 30 ]. For example, PAX-5 is required for B cell differentiation and commitment to B cell lineage [ 31 – 33 ]. B cells that lack PAX-5 expression can differentiate into macrophages, dendritic cells, osteoclasts, granulocytes and natural killer cells [ 32 ]. Similarly, the activity of the transcription factors PU.1 and CCAAT/enhancer binding protein alpha (C/EBPα) are important for myeloid progenitor cells to commit to the granulocyte-monocyte lineage [ 34 ]. Xie et al. showed overexpression of C/EBPα and C/EBPβ converted mature murine B cells into macrophages by suppressing PAX-5 expression [ 29 ]. Furthermore, studies using C/EBPα transgenic mice suggest that B cells are directly converted to other lineages through a biphenotypic intermediate cells rather than a two-step process of dedifferentiation and redifferentiation [ 34 ]. In support of a mechanism involving direct transdifferentiation, Feldman et al. showed loss of PAX-5 expression and up regulation of PU.1 and CEBPβ in eight cases of histiocytic-dendritic cell sarcomas derived from antecedent follicular lymphoma [ 12 ]. Since we do not know the expression pattern of PU.1, C/EBPα or C/EBPβ in these soft tissue tumors, their role in lineage transformation is unclear. However, PAX-5 was not expressed in the original PCM, therefore down regulation of PAX-5 cannot explain the development of monocytic-macrophage lineage. MUM-1, a transcription factor required for plasma cell differentiation [ 35 ], was expressed in the original plasma cell tumor but was not detected in the myeloid sarcomas (Figs. 1 and 3 ). Whether down-regulation of MUM-1 contributes to monocyte-macrophage transformation in plasma cell myeloma is unknown.
Limited data exist regarding the molecular genetics of transformed myeloid sarcoma; however several reports evaluating secondary HS suggest molecular complexity and heterogeneity. Similar to our case showing loss of CDKN2A/B, loss of CDKN2A has been reported in HS subsequent to B-lymphoblastic leukemia [ 15 , 36 ]. BRAF V600E mutation has been reported in de novo HS [ 37 ] and HS following splenic marginal zone lymphoma [ 13 ] and hairy cell leukemia [ 38 ]. NGS analysis of the myeloid sarcoma in this case showed a clonal, non V600E activating mutation in BRAF. The BRAF mutation (G469A) is distinct from other variants identified in de novo HS, including BRAF F595 L, BRAF (G466R), BRAF (G464 V) and BRAF (N581S); however, as in this case, these BRAF variants are not mutually exclusive with activating RAS mutations [ 39 , 40 ].
Like other cases of secondary HS [ 23 ], a clonal relationship between the primary PCM and secondary tumor in current case was confirmed by FISH and NGS analyses showing IGH-MAF gene rearrangement, and similar genomic alterations in KRAS, BRAF and MAK3K6. IGH-MAF translocation is present in 3–6% of PCM cases [ 41 ] and this molecular subtype often shows concurrent activating mutations in RAS-RAF and NF-kB signaling pathways [ 42 ]. In human cell lines, c-MAF promotes monocyte-macrophage differentiation through downreguation of CEBPα [ 43 ], suggesting a possible role of c-MAF in PCM phenotypic transformation.
In addition to shared clonal abnormalities, additional aberrancies were detected in the sarcoma tumor cells, including deletion of a subclone of BRAF (G466A), loss of TRAF3 R505 and new clonal mutations in NF1 and TNFAIP3 (Table 1 ). TRAF3 is a critical determinant of B cell survival and loss of function mutations in TRAF3 and TNFAIP3 are associated with B cell malignancies and PCM [ 44 , 45 ]. NF1 mutation, a negative regulator of RAS signaling, has been reported in rare cases of plasma cell myeloma [ 4 ] and approximately 4% of acute myeloid leukemia [ 46 ], but not reported in HS.
It is uncertain whether the molecular switch from PCM to a myeloid lineage tumor involves direct transdifferentiation via transcription factor dysregulation as suggested for B cell lymphomas, or whether the myeloid lineage tumors arose from a distinct, neoplastic clone that expanded following chemotherapy [ 12 , 15 – 18 ]. Regardless of the mechanism, NGS findings suggest a clonal relationship with clonal evolution and a possible role of NF1, TNFAIP3 and TRAF3 in myeloid transformation of plasma cell myeloma.
Conclusion
To our knowledge, this is the first reported case of PCM transformation to a secondary tumor with monocyte-macrophage lineage. As in other reports, the response to chemotherapy and prognosis is poor with patients dying from progressive disease [ 18 , 19 , 23 , 25 , 26 ]. This study highlights the importance of molecular analysis to establish a clonal relationship in metachronous or synchronous tumors, as addressed by other reports [ 47 , 48 ]. The findings of an additional mutation in RAS-BRAF signaling (NF1 mutation) and NF-kB activation (TNFAIP3) suggests multiple mechanisms contribute to lineage transformation.
Abbreviations
Fluorescence in situ hybridization
Histiocytic sarcoma
Myeloperoxidase
Myeloid sarcoma
Next generation sequencing
Plasma cell myeloma
Acknowledgements
We thank the University of Arkansas for Medical Sciences Department of Pathology for providing funds to perform IGH gene rearrangement studies and the molecular laboratory staff who performed this assay (Stacie Delaune and Molly Robbins).
Funding
Not applicable.
Availability of data and materials
All data generated or analyzed during this study are included in this published article.
Authors’ contributions
JG, GRP, FVR and YY collected case information. JG, GRP and YY wrote the manuscript. JG, GRP, FVR and YY edited the manuscript. All authors have read and approve the final manuscript.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent for publication of their clinical details and/or clinical images was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
1. Rawstron AC Orfao A Beksac M Bezdickova L Brooimans RA Bumbea H Dalva K Fuhler G Gratama J Hose D Report of the European myeloma network on multiparametric flow cytometry in multiple myeloma and related disorders Haematologica 2008 93 3 431 438 10.3324/haematol.11080 18268286
2. Zhan F Huang Y Colla S Stewart JP Hanamura I Gupta S Epstein J Yaccoby S Sawyer J Burington B The molecular classification of multiple myeloma Blood 2006 108 6 2020 2028 10.1182/blood-2005-11-013458 16728703 PMC1895543
3. Bolli N Avet-Loiseau H Wedge DC Van Loo P Alexandrov LB Martincorena I Dawson KJ Iorio F Nik-Zainal S Bignell GR Heterogeneity of genomic evolution and mutational profiles in multiple myeloma Nat Commun 2014 5 2997 10.1038/ncomms3997 24429703 PMC3905727
4. Lohr JG Stojanov P Carter SL Cruz-Gordillo P Lawrence MS Auclair D Sougnez C Knoechel B Gould J Saksena G Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy Cancer Cell 2014 25 1 91 101 10.1016/j.ccr.2013.12.015 24434212 PMC4241387
5. Lee CK Ma ES Shek TW Lam CC Au WY Wan TS Chan LC Plasmablastic transformation of multiple myeloma Hum Pathol 2003 34 7 710 714 10.1016/S0046-8177(03)00181-3 12874768
6. Fernandez de Larrea C Jimenez R Rosinol L Gine E Tovar N Cibeira MT Fernandez-Aviles F Martinez C Rovira M Blade J Pattern of relapse and progression after autologous SCT as upfront treatment for multiple myeloma Bone Marrow Transplant 2014 49 2 223 227 10.1038/bmt.2013.150 24076551
7. Ambrosio MR De Falco G Gozzetti A Rocca BJ Amato T Mourmouras V Gazaneo S Mundo L Candi V Piccaluga PP Plasmablastic transformation of a pre-existing plasmacytoma: a possible role for reactivation of Epstein Barr virus infection Haematologica 2014 99 11 e235 e237 10.3324/haematol.2014.111872 25193957 PMC4222476
8. Epstein J Xiao HQ He XY Markers of multiple hematopoietic-cell lineages in multiple myeloma N Engl J Med 1990 322 10 664 668 10.1056/NEJM199003083221005 2137556
9. Mailankody S Pfeiffer RM Kristinsson SY Korde N Bjorkholm M Goldin LR Turesson I Landgren O Risk of acute myeloid leukemia and myelodysplastic syndromes after multiple myeloma and its precursor disease (MGUS) Blood 2011 118 15 4086 4092 10.1182/blood-2011-05-355743 21795746 PMC3204729
10. Singh ZN Jethava Y Post GR Alapat D Sawyer J Waheed S Nair B Usmani SZ Bailey C Petty N Fulminant onset of acute leukemia from normal hematopoiesis within 3 months of follow up for multiple myeloma treated with total therapy protocols Clin Case Rep 2015 3 3 183 192 10.1002/ccr3.180 25838910 PMC4377252
11. Nguyen TT Schwartz EJ West RB Warnke RA Arber DA Natkunam Y Expression of CD163 (hemoglobin scavenger receptor) in normal tissues, lymphomas, carcinomas, and sarcomas is largely restricted to the monocyte/macrophage lineage Am J Surg Pathol 2005 29 5 617 624 10.1097/01.pas.0000157940.80538.ec 15832085
12. Feldman AL Arber DA Pittaluga S Martinez A Burke JS Raffeld M Camos M Warnke R Jaffe ES Clonally related follicular lymphomas and histiocytic/dendritic cell sarcomas: evidence for transdifferentiation of the follicular lymphoma clone Blood 2008 111 12 5433 5439 10.1182/blood-2007-11-124792 18272816 PMC2424145
13. West DS Dogan A Quint PS Tricker-Klar ML Porcher JC Ketterling RP Law ME McPhail ED Viswanatha DS Kurtin PJ Clonally related follicular lymphomas and Langerhans cell neoplasms: expanding the spectrum of transdifferentiation Am J Surg Pathol 2013 37 7 978 986 10.1097/PAS.0b013e318283099f 23759932
14. Nichols CR Roth BJ Heerema N Griep J Tricot G Hematologic neoplasia associated with primary mediastinal germ-cell tumors N Engl J Med 1990 322 20 1425 1429 10.1056/NEJM199005173222004 2158625
15. Alten J Klapper W Leuschner I Eckert C Beier R Vallo E Krause M Claviez A Vieth S Bleckmann K Secondary histiocytic sarcoma may cause apparent persistence or recurrence of minimal residual disease in childhood acute lymphoblastic leukemia Pediatr Blood Cancer 2015 62 9 1656 1660 10.1002/pbc.25523 25833113
16. Feldman AL Minniti C Santi M Downing JR Raffeld M Jaffe ES Histiocytic sarcoma after acute lymphoblastic leukaemia: a common clonal origin Lancet Oncol 2004 5 4 248 250 10.1016/S1470-2045(04)01428-7 15050956
17. Fraser CR Wang W Gomez M Zhang T Mathew S Furman RR Knowles DM Orazi A Tam W Transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma to interdigitating dendritic cell sarcoma: evidence for transdifferentiation of the lymphoma clone Am J Clin Pathol 2009 132 6 928 939 10.1309/AJCPWQ0I0DGXBMHO 19926586
18. Stoecker MM Wang E Histiocytic/dendritic cell transformation of B-cell neoplasms: pathologic evidence of lineage conversion in differentiated hematolymphoid malignancies Arch Pathol Lab Med 2013 137 6 865 870 10.5858/arpa.2012-0104-RS 23721279
19. Thakral B Khoury JD Histiocytic sarcoma: secondary neoplasm or “transdifferentiation” in the setting of B-acute lymphoblastic leukemia Blood 2016 128 20 2475 10.1182/blood-2016-08-735795 27856472
20. Vaughn JL Freitag CE Hemminger JA Jones JA BRAF V600E expression in histiocytic sarcoma associated with splenic marginal zone lymphoma: a case report J Med Case Rep 2017 11 1 92 10.1186/s13256-017-1253-z 28376906 PMC5381012
21. Ambrosio MR De Falco G Rocca BJ Barone A Amato T Bellan C Lazzi S Leoncini L Langerhans cell sarcoma following marginal zone lymphoma: expanding the knowledge on mature B cell plasticity Virchows Arch 2015 467 4 471 480 10.1007/s00428-015-1814-8 26286813
22. Buser L Bihl M Rufle A Mickys U Tavoriene I Griskevicius L Tzankov A Unique composite hematolymphoid tumor consisting of a pro-T lymphoblastic lymphoma and an indeterminate dendritic cell tumor: evidence for divergent common progenitor cell differentiation Pathobiology 2014 81 4 199 205 10.1159/000365396 25228298
23. Ansari J Naqash AR Munker R El-Osta H Master S Cotelingam JD Griffiths E Greer AH Yin H Peddi P Histiocytic sarcoma as a secondary malignancy: pathobiology, diagnosis, and treatment Eur J Haematol 2016 97 1 9 16 10.1111/ejh.12755 26990812
24. Zhao J Niu X Wang Z Lu H Lin X Lu Q Histiocytic sarcoma combined with acute monocytic leukemia: a case report Diagn Pathol 2015 10 110 10.1186/s13000-015-0350-9 26187047 PMC4506588
25. Takahashi E Nakamura S Histiocytic sarcoma : an updated literature review based on the 2008 WHO classification J Clin Exp Hematop 2013 53 1 1 8 10.3960/jslrt.53.1 23801128
26. Grogan TM SHCE S Harris NL Jaffe ES Pileri SA Stein H Thiele J Vardiman JW Histiocytic sarcoma WHO classification of Tumours of Haematopoietic and lymphoid tissues 2008 Lyon International Agency for Research on Cancer (IARC) 356
27. Rocca BJ Ambrosio MR Gozzetti A Bocchia M Leoncini L Lazzi S Myeloid sarcoma and adenocarcinoma of the large bowel as collision tumors: a case report Histol Histopathol 2012 27 7 941 947 22648549 10.14670/HH-27.941
28. Laslo P Spooner CJ Warmflash A Lancki DW Lee HJ Sciammas R Gantner BN Dinner AR Singh H Multilineage transcriptional priming and determination of alternate hematopoietic cell fates Cell 2006 126 4 755 766 10.1016/j.cell.2006.06.052 16923394
29. Xie H Ye M Feng R Graf T Stepwise reprogramming of B cells into macrophages Cell 2004 117 5 663 676 10.1016/S0092-8674(04)00419-2 15163413
30. Nakajima H Role of transcription factors in differentiation and reprogramming of hematopoietic cells Keio J Med 2011 60 2 47 55 10.2302/kjm.60.47 21720200
31. Mikkola I Heavey B Horcher M Busslinger M Reversion of B cell commitment upon loss of Pax5 expression Science 2002 297 5578 110 113 10.1126/science.1067518 12098702
32. Nutt SL Heavey B Rolink AG Busslinger M Commitment to the B-lymphoid lineage depends on the transcription factor Pax5 Nature 1999 401 6753 556 562 10.1038/44076 10524622
33. Schebesta M Heavey B Busslinger M Transcriptional control of B-cell development Curr Opin Immunol 2002 14 2 216 223 10.1016/S0952-7915(02)00324-2 11869895
34. Fukuchi Y Shibata F Ito M Goto-Koshino Y Sotomaru Y Ito M Kitamura T Nakajima H Comprehensive analysis of myeloid lineage conversion using mice expressing an inducible form of C/EBP alpha EMBO J 2006 25 14 3398 3410 10.1038/sj.emboj.7601199 16858416 PMC1523173
35. Shinnakasu R Kurosaki T Regulation of memory B and plasma cell differentiation Curr Opin Immunol 2017 45 126 131 10.1016/j.coi.2017.03.003 28359033
36. Kumar R Khan SP Joshi DD Shaw GR Ketterling RP Feldman AL Pediatric histiocytic sarcoma clonally related to precursor B-cell acute lymphoblastic leukemia with homozygous deletion of CDKN2A encoding p16INK4A Pediatr Blood Cancer 2011 56 2 307 310 10.1002/pbc.22810 20973102
37. Go H Jeon YK Huh J Choi SJ Choi YD Cha HJ Kim HJ Park G Min S Kim JE Frequent detection of BRAF(V600E) mutations in histiocytic and dendritic cell neoplasms Histopathology 2014 65 2 261 272 10.1111/his.12416 24720374
38. Michonneau D Kaltenbach S Derrieux C Trinquand A Brouzes C Gibault L North MO Delarue R Varet B Emile JF BRAF(V600E) mutation in a histiocytic sarcoma arising from hairy cell leukemia J Clin Oncol 2014 32 35 e117 e121 10.1200/JCO.2013.49.0078 24567436
39. Liu Q Tomaszewicz K Hutchinson L Hornick JL Woda B Yu H Somatic mutations in histiocytic sarcoma identified by next generation sequencing Virchows Arch 2016 469 2 233 241 10.1007/s00428-016-1965-2 27259537
40. Kordes M Roring M Heining C Braun S Hutter B Richter D Georg C Scholl C Groschel S Roth W Cooperation of BRAF(F595L) and mutant HRAS in histiocytic sarcoma provides new insights into oncogenic BRAF signaling Leukemia 2016 30 4 937 946 10.1038/leu.2015.319 26582644
41. Avet-Loiseau H, Malard F, Campion L, Magrangeas F, Sebban C, Lioure B, Decaux O, Lamy T, Legros L, Fuzibet JG, et al. Translocation t(14;16) and multiple myeloma: is it really an independent prognostic factor? Blood. 2011;117(6):2009–11. 10.1182/blood-2010-07-295105 20962323
42. Stein CK Pawlyn C Chavan S Rasche L Weinhold N Corken A Buros A Sonneveld P Jackson GH Landgren O The varied distribution and impact of RAS codon and other key DNA alterations across the translocation cyclin D subgroups in multiple myeloma Oncotarget 2017 8 17 27854 27867 10.18632/oncotarget.15718 28427158 PMC5438613
43. Hegde SP Zhao J Ashmun RA Shapiro LH C-Maf induces monocytic differentiation and apoptosis in bipotent myeloid progenitors Blood 1999 94 5 1578 1589 10477683
44. Moore CR Liu Y Shao C Covey LR Morse HC 3rd Xie P Specific deletion of TRAF3 in B lymphocytes leads to B-lymphoma development in mice Leukemia 2012 26 5 1122 1127 10.1038/leu.2011.309 22033491 PMC3433763
45. Troppan K Hofer S Wenzl K Lassnig M Pursche B Steinbauer E Wiltgen M Zulus B Renner W Beham-Schmid C Frequent down regulation of the tumor suppressor gene a20 in multiple myeloma PLoS One 2015 10 4 e0123922 10.1371/journal.pone.0123922 25856582 PMC4391781
46. Boudry-Labis E Roche-Lestienne C Nibourel O Boissel N Terre C Perot C Eclache V Gachard N Tigaud I Plessis G Neurofibromatosis-1 gene deletions and mutations in de novo adult acute myeloid leukemia Am J Hematol 2013 88 4 306 311 10.1002/ajh.23403 23460398
47. Amato T Abate F Piccaluga P Iacono M Fallerini C Renieri A De Falco G Ambrosio MR Mourmouras V Ogwang M Clonality analysis of immunoglobulin gene rearrangement by next-generation sequencing in endemic Burkitt lymphoma suggests antigen drive activation of BCR as opposed to sporadic Burkitt lymphoma Am J Clin Pathol 2016 145 1 116 127 10.1093/ajcp/aqv011 26712879 PMC4778259
48. Ambrosio MR Rocca BJ Ginori A Mourmouras V Amato T Vindigni C Lazzi S Leoncini L A look into the evolution of Epstein-Barr virus-induced lymphoproliferative disorders: a case study Am J Clin Pathol 2015 144 5 817 822 10.1309/AJCP2G0VKTKPNPRR 26486748