Small B-cell neoplasms, such as follicular lymphoma (FL)

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1 Resident Short Review Histiocytic/Dendritic Cell Transformation of B-Cell Neoplasms Pathologic Evidence of Lineage Conversion in Differentiated Hematolymphoid Malignancies Maggie M. Stoecker, MD; Endi Wang, MD, PhD B-cell lymphomas, such as low-grade follicular lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma, can transform to histiocytic/dendritic cell sarcoma (H/DS) in rare cases. The diagnosis of this unconventional neoplastic evolution relies on a combination of immunophenotypic analysis and genotypic studies. A genotype identical to that of the primary B-cell neoplasm in a secondary neoplasm with H/DS immunophenotype supports the lineage conversion to H/DS. Putative mechanisms for this unusual phenomenon include dedifferentiation, common immature progenitor, and transdifferentiation models, the latter of which is suggested by clinical laboratory data at the present time. Elucidation of the molecular mechanisms governing this lineage conversion may facilitate the understanding of carcinogenesis of not only hematopoietic but also nonhematolymphoid neoplasms. The clinical outcome of secondary H/DS is dismal, as observed in sporadic cases, and the optimal treatment remains to be determined. (Arch Pathol Lab Med. 2013;137: ; doi: / arpa rs) Accepted for publication June 21, From the Department of Pathology, Duke University Medical Center, Durham, North Carolina. The authors have no relevant financial interest in the products or companies described in this article. Reprints: Maggie M. Stoecker, MD, Department of Pathology, Duke University Medical Center, 1 Trent Dr, Box 3712, Durham, NC ( Maggie.Stoecker@duke.edu). Small B-cell neoplasms, such as follicular lymphoma (FL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), are derived presumably from their benign counterparts and commonly demonstrate mature features in morphology and immunophenotype. They often have a prolonged clinical course and sometimes transform into more aggressive neoplasms of the same clonal origin, such as diffuse large B-cell lymphoma (DLBCL). 1,2 The clonal relationship between primary indolent small B-cell neoplasms and secondary DLBCL has been documented by molecular/genetic studies. 2 Theoretically, neoplastic cells of small B-cell lymphoma/leukemia are fully differentiated and should be committed to B-cell lineage during the course of transformation; however, some in vitro assays suggest the possibility of transdifferentiation/dedifferentiation across fully differentiated cell lines under manipulated biological conditions. 3,4 While rare cases of small B-cell malignancies have been described either preceding or concurring with histiocytic/dendritic cell sarcoma (H/DS), 5 7 the clonal relationship between these 2 morphologically and immunophenotypically distinct neoplasms in the same individual has not been completely characterized until recently Here, we provide a brief review of this unusual clinicopathologic phenomenon with emphasis on clinical laboratory evaluation of the clonal relationship between primary B-cell neoplasms and secondary or concurrent H/DS. CLINICAL FEATURES Small B-cell neoplasms comprise approximately 60% of B- cell leukemias/lymphomas with an annual incidence of 16 per in the United States, 16 whereas H/DSs are extremely infrequent, constituting much less than 1% of hematolymphoid malignancies in the Western world. 17 The true incidence of H/DSs remains to be determined because of poor diagnostic recognition of this entity in the past. Although rare cases of H/DS have been periodically reported in association with indolent B-cell lymphomas, 5 7 this literature review includes only 22 cases reported recently with genotypic analysis for the clonal relationship between the B-cell neoplasm and H/DS (Table) 8 15 and excludes those cases reported before the era of sophisticated molecular/ genetic tests. Of these 22 cases, 17 (77%) are male patients and 5 (23%) are female. Age ranges from 30 to 85 years, with a median age of 61.5 years, at the time when the primary diagnosis of a B-cell neoplasm was made. At the diagnosis of H/DS, the median age is 63 years with a range of 42 to 93 years, in contrast to the median age of 46 to 52 years in the patient population with de novo H/DS. 17,18 The types of primary B-cell malignancy include FL 8 13 in 12 cases, CLL/ SLL 14,15 in 8 cases, DLBCL 9 in 1 case, and splenic marginal zone lymphoma 12 in the remaining 1 case. Secondary neoplasms include histiocytic sarcoma (HS) 8 13,15 in 15 cases, interdigitating dendritic cell sarcoma (IDCS) 8,14,15 in 6 cases, and Langerhans cell sarcoma 15 in the remaining 1 case. Of note, 3 cases demonstrated a biphasic presentation of Arch Pathol Lab Med Vol 137, June 2013 Histiocytic Transformation of B-Cell Neoplasms Stoecker & Wang 865

2 neoplasms secondary to FL, or a divergent clonal evolution, with concurrent HS and DLBCL in 2 cases (cases 9 and 11 in the Table) and sequential development of HS and DLBCL in 1 case (case 13). Histiocytic/dendritic cell sarcoma involved lymph nodes in 13 cases, spleen in 1 case, and extranodal sites in 8 cases. Seventeen cases had H/DS occurring after the primary B-cell neoplasm (cases 1 3 and 8 21 in the Table) with a median interval of 36 months (range, months), while 5 cases had H/DS diagnosed simultaneously with the B-cell neoplasm (cases 4, 6, 7, 11, and 22 in the Table). When cases are pooled together, the median interval is 12 months with a range of 0 to 156 months. HISTOLOGIC AND IMMUNOPHENOTYPIC FINDINGS Primary B-cell neoplasms can involve lymph nodes, bone marrow, and/or extranodal or extramedullary sites. Follicular lymphoma commonly involves lymph nodes. Chronic lymphocytic leukemia/small lymphocytic lymphoma often presents in the bone marrow, and neoplastic lymphoid cells tend to circulate in the peripheral blood. On histologic sections, they usually show effacement of normal tissue architecture with a nodular (seen in FL; Figure 1, A) or diffuse (seen in CLL/SLL) pattern of neoplastic growth. The growth pattern is often highlighted by immunohistochemical analysis, particularly B-cell antigen markers (Figure 1, A, inset). Because of the infrequency, H/DS, either subsequent to or concurrent with B-cell lymphoma, is often initially suspected to be large cell transformation (DLBCL), which is commonly seen in indolent B-cell lymphomas, such as FL and CLL/SLL. Of 22 cases reported in the literature, 8 15 all the cases with large cells noted on the sections, either subsequent to or concurrent with B-cell malignancies, were thought to be DLBCL related to the primary B-cell neoplasms at initial evaluation. Only after extensive immunohistochemical analysis was a histiocytic/dendritic cell phenotype identified and diagnosis of H/DS established. While H/DS usually shows some morphologic features distinct from large B-cell lymphoma, they can be overlapping, and distinction is difficult by morphology alone. For instance, HS tends to have round, oval, or pleomorphic nuclei and abundant eosinophilic cytoplasm (Figure 1, B), and DS usually shows a whorled growth pattern with spindled cells. These features, including spindled morphology, have been described in large B-cell lymphoma. 19,20 Therefore, the diagnosis of H/DS is based largely upon the immunophenotypic profile of neoplastic cells, per the 2008 World Health Organization classification. 17 The characteristic antigens expressed in HS include CD163, CD68 (Figure 1, B, inset), and lysozyme. The neoplastic histiocytes are also positive for HLA-DR, CD45, and CD45RO, but these antigen markers are considered to be nonlineage specific among hematolymphoid neoplasms. Staining with S100 could be positive, but is usually focal and weak. In contrast, dendritic cell sarcoma, particularly IDCS, constantly expresses S100 protein with stronger staining in the cytoplasm, while staining with CD45, CD68, and lysozyme is either negative or focal and weak. Both HS and IDCS are usually negative for follicular dendritic cell antigen markers CD21, CD23, and CD35. Tumors derived from Langerhans cells, such as Langerhans cell sarcoma, typically stain for CD1a and S100. Although positive for CD45, H/DS is negative for B-cell specific antigens, including CD19, CD20, CD22, CD79a, and PAX5. This latter feature can be used to exclude large B-cell transformation in those cases with a history of a primary indolent B-cell neoplasm; however, rare cases could show loss of some of their B-cell specific antigens during aggressive transformation without acquisition of specific antigen markers for other lineages, particularly after immune-directed therapy. 21 GENOTYPIC STUDIES FOR CLONAL IDENTITY When H/DS is associated with an indolent B-cell leukemia/lymphoma, either metachronous or concurrent, the issue of its clonal relationship with the primary B-cell neoplasm is raised. In this circumstance, the clonal relationship between the 2 distinct hematolymphoid neoplasms cannot be determined simply by immunophenotyping of the 2 neoplasms because of the possibility of lineage conversion in the transformed neoplasm. It has been documented that terminally differentiated hematolymphoid cells can have their morphology and immunophenotype altered after an aggressive transformation, but their basic genotypes are persistent and typically remain the same. 1,2 Therefore, the clonal relationship between 2 distinct hematolymphoid neoplasms, such as a B-cell neoplasm and H/DS, in the same individual has been defined by detecting the following genotypic signatures: (1) identical products of immunoglobulin gene rearrangement; 8,10 15 or (2) identical cytogenetic abnormalities or identical stem line karyotypic changes in cases of primary B-cell malignancies harboring a specific cytogenetic abnormality In the former scenario, clonal rearrangement products of either heavy-chain or j light-chain gene are usually detected by polymerase chain reaction (PCR) based assays, and the base-pair length of amplicons from primary B-cell malignancies and secondary H/DS are compared. The same sizes of clonal amplicons from primary and secondary neoplasms are considered to have possibly identical configuration of the immunoglobulin gene rearrangement, and thus, to share a presumably common clonal origin (Figure 1, C and D), whereas different sizes of clonal amplicons or absence of a clonal amplicon in the secondary histiocytic/dendritic neoplasm are essentially thought to be clonally unrelated. Ultimately, clonal amplicons from primary and secondary hematolymphoid neoplasms can be eluted from an electrophoresis gel and sequenced to further confirm the identical breakpoint or segmental use of the gene rearrangement products. 8,12 15 In many cases of transformation, the secondary hematolymphoid neoplasm, such as H/DS, often contains admixed primary indolent B-cell neoplasms on histologic sections. Therefore, identical amplicons between primary and secondary neoplasms have to be interpreted with caution because the clonal amplicon may be amplified from the residual primary B-cell clone rather than from H/ DS on the section with the predominant latter neoplasm. To avoid this issue, immunohistochemical stains targeted against the B-cell neoplasm are carefully evaluated to ensure the absence of the primary B-cell neoplasm on the tissue section tested for immunoglobulin gene rearrangement in the neoplastic cells of H/DS. 8,12 15 In addition, the immune-directed laser-capture microdissection technique has been applied to collect the cells of isolated B-cell leukemia/lymphomas or H/DSs before extraction of DNA for gene rearrangement analysis. 8,15 Ideally, immune-guided cell sorting can provide a more targeted cell population for the analysis, but owing to the nature of clinical diagnosis and the rarity of the events, fresh tissue is usually unavailable for such a procedure. 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3 Figure 1. Pathologic and genetic evaluation of histiocytic transformation of follicular lymphoma (FL). The left side of the panel (A, C, and E) shows the evaluation of primary FL, and the right side of the panel (B, D, and F) represents the evaluation of secondary histiocytic sarcoma (HS). A, Follicular lymphoma. B, Histiocytic sarcoma. C and D, Polymerase chain reaction based immunoglobulin heavy chain gene (IGH) rearrangement study on FL (C) and HS (D). Note the amplicons from the 2 neoplasms with identical base-pair size (317 bp). E and F, IGH/BCL2 fusion gene in FL (E) and HS (F) detected by dual-color dual-fusion interphase fluorescence in situ hybridization (FISH) analysis. Note multiple interphase nuclei with 2 fusions of red and green fluorescent signals (yellow color) and separated red (BCL2) and/or green (IGH) signal representing cells harboring fusion of IGH and BCL2 genes (arrows). The nuclei with single fusion and separated red and/or green signals likely represent truncated nuclei with IGH/BCL2 fusion, or less likely, random colocalization of 2 fluorescent probes. The nuclei with negative IGH/BCL2 findings contain 2 separate red signals and 2 separate green signals, but a negative nucleus could contain less than 2 of each color signal because of truncation of the individual nucleus during tissue block sectioning (hematoxylin-eosin, original magnifications 320 [A] and 3400 [B]; CD79a, original magnification 320 [inset A]; CD68, original magnification 3400 [inset B]; FISH, original magnifications [E and F]). scenario, the cytogenetic abnormalities can be detected by conventional karyotyping and fluorescence in situ hybridization (FISH). In most medical institutions in the United States, conventional karyotyping is often not performed on an extramedullary tissue specimen for diagnostic purposes, and thus, fresh tissue is usually not collected for this purpose, unless there is a special indication. If a specific cytogenetic abnormality is identified or suggested in the Arch Pathol Lab Med Vol 137, June 2013 Histiocytic Transformation of B-Cell Neoplasms Stoecker & Wang 867

4 primary B-cell neoplasm, IGH/BCL2 is seen in 90% of lowgrade FLs (Figure 1, E); for instance, FISH with the probe for the fusion gene or other changes can be used on the secondary H/DS to determine its clonal identity (Figure 1, F) FISH analysis can now be performed not only on metaphase cells but also on fresh interphase cells as well as on formalin-fixed, paraffin-embedded tissue sections. Other cytogenetic abnormalities identified in primary B-cell neoplasms, such as trisomy 12, deletion 13q, deletion 11q, and deletion 17p in CLL/SLL, can be tested on H/DS to confirm the clonal identity, if they are present (cases 15, 18, and 22 in the Table). Unlike a PCR-based assay, interphase FISH analysis does not often have the issue of contamination by the primary B-cell neoplasm because the sections containing pathologically isolated neoplasms can be selected for the assay. For example, a high percentage of IGH/ BCL2 fusions on the section with H/DS but with no immunohistochemical evidence of B-cell lymphoma would confirm that H/DS harbors the cytogenetic abnormality. 12,13 Nonetheless, targeted FISH has been used by some investigators to avoid the issue when B cells are focally present on the sections with H/DS. 22 Polymerase chain reaction for the major breakpoint of IGH/BCL2 fusion gene has been performed to compare the amplicons from FL to those from H/DS in the same individuals (Table), 8,12 but conclusions should be drawn with caution because of the issue of amplification from residual FL in H/DS. Although IGH/BCL2 has been detected with ultrasensitive PCR techniques in peripheral blood or other tissues of some individuals without lymphoma, particularly in the elderly, its frequency has been demonstrated to be extremely low 23 and beyond the detection limit by FISH. IGH/BCL2 has not been identified in all but one of the reported sporadic H/DS cases according to the literature, 22 making it an optimal marker for evaluation of the clonal relationship between FL and H/DS. Figure 2. Schematic representation of clonal evolution of B-cell lymphoma. B-cell progenitors acquire t(14;18) in the bone marrow before migrating to the germinal centers of a lymph node, where the differentiated B-cells with IGH/BCL2 (indicated by asterisks) transform into follicular lymphoma (FL), presumably under the effect of other genetic alterations. Clonal evolution follows the cis-pathway in most cases, resulting in large B-cell lymphoma (LBL; solid line), presumably due to additional changes in MYC, TP53, or other genes, while transevolution may occur in rare cases resulting in histiocytic/ dendritic cell sarcoma (H/DS; dotted blue line) or other hematolymphoid neoplasms with an unclear molecular mechanism. The broken blue line represents a hypothetical dedifferentiation pathway in lineage conversion. Asterisks in nuclei of H/DS and LBL indicate clonally rearranged immunoglobulin heavy- or light-chain genes with hypermutated variable regions (IGVH) and IGH/BCL2 fusion inherited from FL clones. Abbreviations: CBP, committed B-cell progenitor; CMP, committed myeloid progenitor; HSC, hematopoietic stem cell; MMP, myelomonocytic precursor; PCP, pluripotent common progenitor. PATHOGENESIS A mature B cell, such as a neoplastic cell in FL, is more advanced in differentiation and has presumably lost its lineage plasticity. How does it circumvent this restriction and convert to a neoplasm of different lineage? A few possible pathways have been proposed to explain this extraordinary phenotypic conversion, including dedifferentiation, common progenitor, and transdifferentiation mechanisms (Figure 2). 8,24,25 Both dedifferentiation and common progenitor models postulate that neoplastic mature B cells lack lineage plasticity, and thus, may not undergo clonal evolution to different lineages directly from a mature neoplastic clone. In the dedifferentiation model, 25,26 this barrier is hypothetically bypassed by regressing to the pluripotent progenitor stage and then regaining the capability of differentiation along a different route, such as toward histiocytic or other hematolymphoid lineages. Similarly, in the common progenitor model, 24 a premalignant progenitor, particularly a pluripotent progenitor, is shared by neoplastic B cells and histiocytic/dendritic cells. In transdifferentiation, 8,25 a process bypassing the progenitor stage, mature neoplastic B cells differentiate directly into phenotypically different hematolymphoid lineages presumably via genetic or epigenetic changes, which are poorly understood at the present time. If conversion of the B-cell neoplasm to H/DS occurs via dedifferentiation, then arrest of maturation would be expected in the secondary neoplasm, but instead, immature hematolymphoid neoplasms were not identified in any of the cases tested. 8,12,13,15 Therefore, absence of detectable neoplastic progenitor cells in the reported cases with lineage conversion undermines the dedifferentiation model for the lineage switch. On the other hand, if a common immature progenitor explains the lineage conversion, then the transformed neoplasm should keep a genuine genotype or genotypic signature genealogically linked to the progenitor cell, rather than harboring a genotype indicative of continued B-cell development. For instance, a common immature progenitor shared by FL and H/DS in the same individual contains presumably rearranged immunoglobulin gene without hypermutation on its variable regions, a prefollicle center B-cell genotype, and the transformed H/DS should retain the same immunoglobulin gene configuration without additional landmark genetic alterations seen in a differentiated B cell. Of 22 cases reported, 2 cases had mutation analysis of immunoglobulin gene heavy-chain variable regions (IGVH) performed on secondary HS, and both showed hypermutation of the IGVH locus (cases 13 and 14 in the Table). It has been documented that random somatic mutation occurs within the IGVH locus 868 Arch Pathol Lab Med Vol 137, June 2013 Histiocytic Transformation of B-Cell Neoplasms Stoecker & Wang

5 Case No. Summary of Reported Cases of Lineage Conversion From B-Cell Neoplasm to Histiocytic/Dendritic Cell Sarcoma Age, y/sex 1st Dx Interval, mo 2nd Dx IG PCR IGH/BCL2 PCR IGVH Mutation Cytogenetic Identity a Treatment FU, mo Outcome Source, y 1 62/M FL 24 HS þ þ ND IGH/BCL2 ND ND ND Feldman et al, 8 (2008) 2 30/F FL 144 HS þ þ ND IGH/BCL2 ND ND ND Feldman et al, 8 (2008) 3 60/M FL 36 HS þ þ ND IGH/BCL2 ND ND ND Feldman et al, 8 (2008) 4 55/F FL 0 IDCS þ þ ND IGH/BCL2 ND ND ND Feldman et al, 8 (2008) 5 48/F FL 2 HS þ þ ND IGH/BCL2 ND ND ND Feldman et al, 8 (2008) 6 62/M FL 0 HS þ þ ND - ND ND ND Feldman et al, 8 (2008) 7 58/M FL 0 HS - ND ND IGH/BCL2 ND ND ND Feldman et al, 8 (2008) 8 67/M FL 7 HS - þ ND - ND ND ND Feldman et al, 8 (2008) 9 53/M FL 156 HS/LB þ ND ND IGH/BCL2 DHAP 3 Died Bassarova et al, 9 (2009) 10 62/M DLBL 12 HS þ ND ND IGH/BCL2 MIME/R 4 Died Bassarova et al, 9 (2009) 11 50/M FL 0 HS/LB ND ND ND IGH/BCL2 ND ND ND Zhang et al, 10 (2009) 12 39/M FL 48 HS þ þ ND IGH/BCL2 2nd PI 9 Died Zeng et al, 11 (2011) 13 44/F FL 142 HS/LB þ ND þ IGH/BCL2 R 19.5 Died Wang et al, 12 (2010); Wang et al, 13 (2011) 14 61/F SMZL 12 HS þ ND þ ND ND ND ND Wang et al, 12 (2010) 15 77/M CLL 36 IDCS þ ND ND þ12 ND ND ND Fraser et al, 14 (2009) 16 55/M CLL 10 IDCS þ ND ND - ND ND ND Shao et al, 15 (2011) 17 62/M CLL.100 LCS þ ND ND - ND ND ND Shao et al, 15 (2011) 18 65/M CLL 36 IDCS þ ND ND 17p ND ND ND Shao et al, 15 (2011) 19 71/M CLL 12 HS þ ND ND - ND ND ND Shao et al, 15 (2011) 20 77/M CLL 36 IDCS þ ND ND ND ND ND ND Shao et al, 15 (2011) 21 82/M CLL 132 IDCS þ ND ND - ND ND ND Shao et al, 15 (2011) 22 85/M CLL 0 HS þ ND ND 17p ND ND ND Shao et al, 15 (2011) Abbreviations: CLL, chronic lymphocytic leukemia/small lymphocytic lymphoma; DHAP, cytarabine, cisplatin, and dexamethasone; DLBL, diffuse large B-cell lymphoma; FISH, fluorescence in situ hybridization; FL, follicular lymphoma; FU, follow-up; HS, histiocytic sarcoma; HS/LB, biphasic HS and DLBL; IDCS, interdigitating dendritic cell sarcoma; IG PCR, PCR-based immunoglobulin gene rearrangement analysis; IGH/BCL2 PCR, PCRbased detection of IGH/BCL2 fusion gene; IGVH Mutation, immunoglobulin gene variable region hypermutation analysis; LCS, Langerhans cell sarcoma; MIME, Methylglyoxal-bis (guanylhydrazone), ifosfamide, methotrexate, and etoposide; ND, not done; PCR, polymerase chain reaction; R, radiotherapy; SMZL, splenic marginal zone B-cell lymphoma; 1st Dx, primary diagnosis; 2nd Dx, secondary diagnosis; 2nd PI, second-generation protease inhibitor; þ, positive result supporting a related clone; -, unsatisfactory result. a All cytogenetic abnormalities were identified by FISH analysis except for case 9, in which IGH/BCL2 was detected by karyotyping in addition to FISH. when a B cell migrates through the follicle center, and thus, mutation status is considered to be a genetic landmark indicating the developmental stage of the B cell. Therefore, a hypermutated IGVH locus in the secondary HS suggests they harbor a follicle center or postfollicle center B-cell genotype, arguing against the common immature progenitor model for lineage conversion. 12,13 Interestingly, Chen et al 22 and Vos et al 27 reported clonal rearrangement of IGH and/or IGK genes in more than 40% of the biopsy specimens with sporadic H/DS, raising the possibility of a shared progenitor between a B-cell neoplasm and H/DS. The mutation status of clonal IGVH/K genes was not analyzed in either study. Alternatively, the common precursor might be a differentiated B-cell clone that is in a quiescent stage and responsible for aggressive transformation into DLBCL in most cases and into H/DS on rare occasions. 13 Nonetheless, the latter putative pathway would fulfill the definition of transdifferentiation or transevolution, since the common precursor is a differentiated neoplastic or preneoplastic B cell instead of an immature cell with endogenous pluripotent potential. If a B-cell neoplasm converts to H/DS via transdifferentiation or an alternative mechanism, then what determines the direction of this unconventional clonal evolution? While altered expression of PAX5 has been suggested to play a pivotal role in this process, 8 recent investigations suggest that genes other than PAX5 may be involved in the process. 9 Fraser et al, 14 in a study of a case of CLL/SLL transformed to IDCS, demonstrated altered expression of transcription factors, including PU.1 and C/EBPa, in IDCS, suggesting their possible role in this lineage conversion. Expression of p53 protein has been previously reported in sporadic cases of HS, 28 but its role in lineage conversion from B-cell lymphoma to H/DS is currently unknown. Future studies may focus on genetic changes and gene expression profiles in secondary H/DS in comparison with primary B-cell neoplasms and secondary DLBCL as well as de novo H/DS in order to elucidate the molecular mechanism of this unusual clinicopathologic phenomenon. DIFFERENTIAL DIAGNOSIS Given the difference in treatment and prognosis, the differential diagnosis usually focuses on excluding DLBCL as the secondary hematolymphoid neoplasm because large B- cell transformation is more common in indolent B-cell lymphoma. 1,2 This can be achieved by applying flow cytometric analysis and immunohistochemical studies on the secondary neoplasms The absence of a monoclonal B-cell population by flow cytometric analysis and the negative staining of B-cell specific antigen markers on large atypical cells on sections raise the possibility of lineage conversion or a de novo neoplasm of non B-cell lineage. Positive staining with histiocytic and/or dendritic cell antigen markers on the large cells of secondary neoplasms confirms the diagnosis of H/DS, either arising from the original B-cell clone (lineage conversion) or de novo. The latter issue, histiocytic/dendritic transformation versus de novo H/DS, can be distinguished by genotypic analysis of both the primary B-cell neoplasm and secondary H/DS, as discussed in the section Genotypic Studies for Clonal Identity. Arch Pathol Lab Med Vol 137, June 2013 Histiocytic Transformation of B-Cell Neoplasms Stoecker & Wang 869

6 TREATMENT AND PROGNOSIS Sporadic H/DS is usually an aggressive disease with poor response to therapy. 17,18 Most patients die of disease progression within the first year of diagnosis. 18 Currently, standard therapy for H/DS has not been established. In the past, surgical resection and/or chemotherapy have been used with limited success. The efficacy of autologous hematopoietic stem cell transplant with or without thalidomide has been reported, but the data are limited to rare case reports with relatively short follow-up. 29,30 For these reasons, the optimal treatment for H/DS secondary to an indolent B-cell neoplasm is unknown. Of 22 cases reported, only 4 cases (cases 9, 10, 12, and 13 in the Table) had treatment and clinical outcome described. Each of these 4 patients were treated with different agents/protocols, and all died of disease progression, with a median survival of 6.5 months (range, months). 9,11 13 We hope that along with elucidation of the molecular mechanism for lineage conversion of B-cell neoplasms, the dynamic process of this unconventional neoplastic transformation will be better understood and therapeutic interventions will be better targeted. CONCLUSIONS B-cell lymphomas can transform to H/DS in extremely rare cases. The diagnosis of this lineage conversion relies on a combination of immunophenotypic analysis and genotypic studies. Putative mechanisms include dedifferentiation, common immature progenitor, and transdifferentiation models, the latter of which is suggested by clinical laboratory data at the present time, although additional scientific studies are necessary for further elucidation of this process. In sporadic cases, the prognosis for secondary H/ DS has been dismal, and the optimal treatment for these patients requires further investigation. We thank Steven R. Conlon, AAS, for his technical assistance with the line art and pathology images. References 1. Yano T, Jaffe ES, Longo DL, Raffeld M. MYC rearrangements in histologically progressed follicular lymphomas. Blood. 1992;80(3): Mao Z, Quintanilla-Martinez L, Raffeld M, et al. IgVH mutational status and clonality analysis of Richter s transformation: diffuse large B-cell lymphoma and Hodgkin lymphoma in association with B-cell chronic lymphocytic leukemia (B-CLL) represent 2 different pathways of disease evolution. Am J Surg Pathol. 2007;31(10): Xie H, Ye M, Feng R, Graf T. Stepwise reprogramming of B cells into macrophages. Cell. 2004;117(5): Laiosa CV, Stadtfeld M, Xie H, de Andres-Aguayo L, Graf T. 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