T-cell/histiocyte-rich Large B-cell Lymphoma Research Articles

Nodular Lymphocyte Predominant Hodgkin Lymphoma and T cell/Histiocyte Rich Large B Cell Lymphoma Endpoints of a Spectrum of one Disease?

Question: In contrast to the commonly indolent clinical behavior of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), T cell/histiocyte rich large B cell lymphoma (THRLBCL) is frequently diagnosed in advanced clinical stages and has a poor prognosis. Besides the different clinical presentations of these lymphoma entities, there are variants of NLPHL with considerable histopathologic overlap compared to THRLBCL. Especially THRLBCL-like NLPHL, a diffuse form of NLPHL, often presents a histopathologic pattern similar to THRLBCL. The present study therefore aimed to find markers, which can be applied in the differential diagnosis between NLPHL and THRLBCL.

Variant Histological Patterns of Nodular Lymphocyte Predominant Hodgkin Lymphoma in Children Treated in Trials of the GPOH-HD

Question: Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) predominantly affects middle aged men and generally shows a favourable clinical course. However, also children can be affected by this rare subtype of Hodgkin lymphoma. NLPHL can show a typical nodular or variant histopathologic growth pattern. Some of the histological variants mimic T-cell/histiocyte-rich-large B-cell Lymphoma (THRLBCL). Recently, we showed that histopathologic variants of NLPHL more frequently present in advanced clinical stages and have an increased risk of relapse in adults.

Grey-Zone lymphomas: the fear of all lymphoma pathologists

Grey-zone lymphomas (GZLs) are operationally defined as lymphomas that show morphologic, immunophenotypic and frequently genetic overlap between two well-defined and accepted lymphoid entities. In 2008, the WHO defined two provisional categories, including mediastinal grey-zone lymphomas (MGZL) [biopsies showing overlapping features between primary mediastinal large cell lymphoma (PMBCL) and nodular sclerosis Hodgkin lymphoma (NSHL)] and cases that lie between diffuse large B cell lymphoma (DLBCL) and Burkitt lymphoma (BL). A third grey-zone also exists between cases of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and so-called T cell/ histiocyte-rich large B cell lymphoma (TCHRBCL). MGZLs are typically of two major types: one that resembles NSHL but shows a B cell phenotype, and cases that are PMBCL-like but reveal overlapping phenotypic features with Hodgkin lymphoma. Both clinical features and survival distinguish these cases from both PMBCL and NSHL. The GZLs between DLBCL and BL are more frequent and pose a diagnostic challenge. They are less well defined, but show an enrichment of cases harbouring MYC translocations with BCL2 and/or BCL6 rearrangements. Distinguishing these cases from de novo DLBCL has clinical relevance. Lastly, the GZ between TCHRBCL and NLPHL will be discussed using illustrative cases.

Nodular Lymphocyte Predominant Hodgkin Lymphoma versus T-Cell/Histiocyte-Rich Large B-Cell Lymphoma: A Diagnostic Challenge.

Lymphomas with overlapping histological features of two distinct entities cause difficulty in classification. Their classification is of particular significance when the two alternatives require different treatment modalities. We present a diagnostically challenging case of a nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) with features of T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL). Our patient is a 39-year-old woman who presented with painless subclavicular and axillary lymphadenopathy. The biopsied lymph node showed diffuse architectural effacement and scattered large neoplastic cells with large irregular nuclei and prominent nucleoli. These cells were positive for CD20 and Bcl-6 and negative for CD15, CD30, IgD, and Bcl-2. The background cells were predominantly T lymphocytes, whereas B cells were markedly depleted. The lymph node was interpreted as NLPHL, consistent with THRLBCL-like variant. NLPHL, especially THRLBC-like variant, and de novo THRLBCL are characterized by significant morphologic and immunophenotypic overlap. Our case demonstrates a rare predominance of background T-cells in NLPHL and emphasizes the importance of thorough evaluation of multiple morphologic and immunophenotypic features as an essential approach for arriving at the correct diagnosis.

Nodular Lymphocyte Predominant Hodgkin Lymphoma and T Cell/Histiocyte Rich Large B Cell Lymphoma - Endpoints of a Spectrum of One Disease?

In contrast to the commonly indolent clinical behavior of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), T cell/histiocyte rich large B cell lymphoma (THRLBCL) is frequently diagnosed in advanced clinical stages and has a poor prognosis. Besides the different clinical presentations of these lymphoma entities, there are variants of NLPHL with considerable histopathologic overlap compared to THRLBCL. Especially THRLBCL-like NLPHL, a diffuse form of NLPHL, often presents a histopathologic pattern similar to THRLBCL, suggesting a close relationship between both lymphoma entities. To corroborate this hypothesis, we performed gene expression profiling of microdissected tumor cells of NLPHL, THRLBCL-like NLPHL and THRLBCL. In unsupervised analyses, the lymphomas did not cluster according to their entity. Moreover, even in supervised analyses, very few consistently differentially expressed transcripts were found, and for these genes the extent of differential expression was only moderate. Hence, there are no clear and consistent differences in the gene expression of the tumor cells of NLPHL, THRLBCL-like NLPHL and THRLBCL. Based on the gene expression studies, we identified BAT3/BAG6, HIGD1A, and FAT10/UBD as immunohistochemical markers expressed in the tumor cells of all three lymphomas. Characterization of the tumor microenvironment for infiltrating T cells and histiocytes revealed significant differences in the cellular composition between typical NLPHL and THRLBCL cases. However, THRLBCL-like NLPHL presented a histopathologic pattern more related to THRLBCL than NLPHL. In conclusion, NLPHL and THRLBCL may represent a spectrum of the same disease. The different clinical behavior of these lymphomas may be strongly influenced by differences in the lymphoma microenvironment, possibly related to the immune status of the patient at the timepoint of diagnosis.

Matched-Pair Analysis Comparing the Outcomes of T Cell/Histiocyte-Rich Large B Cell Lymphoma and Diffuse Large B Cell Lymphoma in Patients Treated with Rituximab-CHOP

Background: T cell/histiocyte-rich large B cell lymphoma (THRLBCL) is a rare morphological variant of diffuse large B cell lymphoma (DLBCL), accounting for 1-3% of all DLBCLs. However, its impact on treatment outcome and prognosis is still not clearly defined. Methods: We compared the clinical outcomes between THRLBCL and DLBCL, not otherwise specified (NOS), in patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). Results: Data from 11 patients with THRLBCL were matched to 33 patients with DLBCL-NOS. Patients were matched by five established prognostic factors of the International Prognostic Index, including age, Ann Arbor stage, Eastern Cooperative Oncology Group performance status, serum lactate dehydrogenase level and the number of extranodal involvement. There was no significant difference in the complete response rate to R-CHOP between THRLBCL (91%, 10/11) and DLBCL-NOS (97%, 32/33; p = 0.442). The 3-year event-free survival rate was 81% for both THRLBCL and DLBCL-NOS (p = 0.813). The 3-year overall survival rates were 75 and 81%, respectively (p = 0.719). Conclusions: The treatment outcomes of THRLBCL are similar to those of DLBCL-NOS. The addition of rituximab to CHOP seems to be helpful for the management of THRLBCL, as it is for DLBCL-NOS.

Does Functional Imaging Distinguish Nodular Lymphocyte-Predominant Hodgkin Lymphoma From T-Cell/Histiocyte-Rich Large B-Cell Lymphoma?

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is often associated with concurrent or subsequent development of T-cell/histiocyte-rich large B-cell lymphoma (THR-LBCL). Distinguishing the two is important because their therapies are different. Functional imaging with PET/CT is used to stage both Hodgkin and non-Hodgkin lymphomas. Aggressive lymphomas are usually more PET avid than the indolent subtypes. Therefore, it is possible that PET/CT may help distinguish NLPHL from THR-LBCL. Herein, we retrospectively describe the clinical and PET/CT findings of 12 patients with NLPHL or THR-LBCL seen from 2004-2010. Six patients each were identified and the average SUVmax was 6.9 (range, 5.7-7.3) in NLPHL and 16.6 (range, 4-29) in THR-LBCL (p= 0.055). Bone and extranodal involvement was found in one patient with NLPHL compared to four patients with THR-LBCL. This patient failed to respond to ABVD and was subsequently found to have THR-LBCL. We suggest that patients with NLPHL and THR-LBCL have different clinical and PET/CT characteristics. NLPHL patients had lower SUVmax on PET/CT compared to those with THR-LBCL. The presence of bone or extranodal involvement is more common in patients with THR-LBCL. Patients with NLPHL and an uncharacteristically higher SUVmax on PET/CT, or those with bone or extranodal involvement, should alert the clinician to consider the presence of THR-LBCL.

Macrophages in T cell/histiocyte rich large B cell lymphoma strongly express metal-binding proteins and show a bi-activated phenotype

Abundant macrophage infiltration in tumors often correlates with a poor prognosis. T cell/histiocyte rich large B cell lymphoma (THRLBCL) is a distinct aggressive B cell lymphoma entity showing a high macrophage content. To further elucidate the role of tumor-associated macrophages in THRLBCL, we performed gene expression profiling of microdissected histiocyte subsets of THRLBCL, nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), Piringer lymphadenitis, sarcoidosis, nonspecific lymphadenitis and monocytes from peripheral blood. In a supervised principal component analysis, histiocytes from THRLBCL were most closely related to epithelioid cells from NLPHL, with both types of cells expressing genes related to proinflammatory and regulatory macrophage activity. Moreover, histiocytes from THRLBCL strongly expressed metal-binding proteins like MT2A, by which histiocytes of THRLBCL can be distinguished from the other histiocyte subsets investigated. Interestingly, the validation at the protein level showed a strong expression of TXN, CXCL9, MT2A and SOD2 not only in macrophages of THRLBCL but also in the tumor cells of NLPHL and classical Hodgkin lymphoma (cHL). Overall, the present findings indicate that macrophages in the microenvironment of THRLBCL have acquired a distinct gene expression pattern that is characterized by a mixed M1/M2 phenotype and a strong expression of several metal binding proteins. The microenvironments in NLPHL and THRLBCL appear to have a similar influence on the macrophage phenotype. The high expression of metal binding proteins in histiocytes of THRLBCL may be diagnostically useful, but a potential pathophysiological role remains to be identified.

T-Cell/Histiocyte-Rich Large B-Cell Lymphoma of the Thyroid

T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a rare subtype of diffuse large B-cell lymphoma, and has been reported to mainly affect lymph nodes with advanced Ann Arbor stage. We present a 69-year-old woman with a past history of chronic thyroiditis, who had suffered from rapidly-growing thyroid tumor. No other lymph nodes swelling or extranodal lesions were detected. She promptly underwent surgery with resection of the thyroid tumor, and the diagnosis of THRLBCL was established pathologically. She was successfully treated by standard rituximab-containing chemotherapy. To our knowledge, this is the first case report of THRLBCL exclusively arising in the thyroid.

T cell/histiocyte-rich large B-cell lymphoma: an update on its biology and classification

T cell/histiocyte-rich large B-cell lymphoma (THRLBCL), originally considered an uncommon variant of Diffuse Large B-Cell Lymphoma (DLBCL), is recognized by the World Health Organisation as a separate clinicopathological entity since 2008. It predominantly affects middle aged men often presenting with advanced stage disease frequently involving spleen, liver and bone marrow at time of diagnosis. According to the WHO, this lymphoma is morphologically characterized by less than 10% of large neoplastic B cells in a background of abundant T cells and frequently histiocytes. Differentiating THRLBCL from other lymphoproliferative disorders such as Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL) and Lymphocyte-Rich classical Hodgkin lymphoma (LRcHL) is important from a clinical point of view and can be achieved in most cases, given adequate biopsy specimens, by careful morphological and immunohistochemical evaluation of both the neoplastic cells as well as the nonneoplastic stromal component. According to this WHO definition, THRLBCL is still considered a clinically heterogeneous entity, though it is noted that especially the cases containing numerous histiocytes behave aggressively and show resistance to current therapies for DLBCL. Gene expression profiling studies of THRLBCL provided evidence for a prominent role for this histiocytic component that is important for a tolerogenic host immune response in which they may assist neoplastic cells in escaping the T cell-mediated immune surveillance. Therefore, reserving the diagnosis of THRLBCL to cases containing a large proportion of histiocytes might be relevant, as modulating their activity could provide new therapeutic options.

Primary T Cell/Histiocyte-Rich Large B-Cell Lymphoma of the Orbit

T cell/histiocyte-rich large B-cell lymphoma (THRBCL) is an uncommon morphologic variant of diffuse large B-cell lymphoma characterized by a minor population of neoplastic B cells existing in a background of predominant reactive T lymphocytes. Diagnosis of this entity is occasionally difficult and would require careful immunohistochemical analysis of the tumor cells, as it may appear similar to other lymphoid diseases, such as nodular lymphocyte-predominant Hodgkin lymphoma, classical Hodgkin lymphoma, and peripheral T-cell lymphoma. The authors report a case of 37-year-old man who presented with a slowly growing, painless proptosis of the right eye with a well-defined mass in the posterosuperior aspect of globe. An incisional biopsy of the mass was performed. Histopathologic examination and immunohistochemical analysis revealed the diagnosis of THRBCL. To the best of the authors' knowledge, this is the first case of primary THRBCL occurring in the orbit.

T-Cell-Rich Diffuse Large B-cell Lymphoma Presenting as an Intraosseous Maxillary Neoplasm

ABSTRACT Non-Hodgkin lymphomas are a group of highly diverse malignancies with great tendency to affect organs and tissues that do not ordinarily contain lymphoid cells. T-cell/histiocyte-rich large B-cell lymphoma (TCRBCL) is an uncommon histological variant of large B-cell non- Hodgkin lymphoma, morphologically characterized by a minor population of clonal B-cells distributed in a background of prominent reactive T lymphocytes. This is an interesting case of extranodal isolated TCRBCL in jaw bone and to our knowledge this is the first report of its kind in a nonimmune compromised 40-year-old female. An increase in the number of case reports of non-Hodgkin lymphoma in head and neck region definitely makes it to be included as differential diagnosis. The patient has completed 5 years of therapy with no evidence of recurrence.

Small intestinal presentation of nodular lymphocyte-predominant Hodgkin lymphoma with T cell/histiocyte-rich B cell lymphoma-like areas—with review of literature on extranodal presentation of this disease

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), accounts for ∼5% of all cases of Hodgkin lymphoma and is characterized by involvement of the peripheral lymph nodes. NLPHL occurs in young adults and is associated with frequent relapses. In 3% to 7% of cases, NLPHL progresses to a diffuse large B cell lymphoma. Furthermore, a proportion of NLPHL also have areas with features of T cell/histiocyte-rich large B cell lymphoma (THRLBCL), either at presentation or on follow-up. Here, we describe a 32-year-old man who presented to the emergency department with small bowel perforation. The resected small bowel showed full-thickness mural ulceration and involvement by a lymphoma with features of NLPHL that also had areas resembling THRLBCL. The patient had axillary lymphadenopathy, biopsy of which showed NLPHL with focal THRLBCL-like areas. Such a lymphoma presenting as small intestinal lesion/perforation has not been reported in the literature before. We take this opportunity to review the literature on extranodal presentations of NLPHL and discuss the natural history of this disease.

T-cell/histiocyte-rich large B-cell lymphoma

T-cell/histiocyte-rich large B-cell lymphoma (THRLB-CL) can be used as a paradigm to highlight the difficulties in defining specific subtypes of diffuse large B-cell lymphoma. Since the first recognition of certain large B-cell lymphomas in which the tumor cell content was dramatically outnumbered

Morphologic, immunphenotypic and clinical discriminators between T-cell/histiocyterich large B-cell lymphoma and lymphocyte-predominant Hodgkin lymphoma

Features of T-cell/histiocyte rich large B-cell lymphoma (THRLBCL) overlap with those of lymphocyte predominant Hodgkin lymphoma (LPHL). The two lymphomas may represent a spectrum of the same disease, and differentiation between the two can sometimes be difficult. We looked at histomorphologic, immunophenotypic and clinical information that may help differentiate the two entities. Cases of THRLBCL and LPHL were blindly reviewed and studied for histological pattern (nodular vs. diffuse), nuclear features and pattern of expression of CD20, CD30, CD57, epithelial membrane antigen (EMA) and Epstein-Barr virus (EBV). A score encompassing diffuse histology, high nuclear grade, CD20 single-cell pattern, CD30+, CD57-, EMA-, and EBV+ was estimated for the diagnosis of TCHRLBCL. There were 58 cases, including 30 cases of TCHRLBL and 28 cases of LPHL. The median age was 36 years for TCHRLBCL and 21 years for LPHL (P = 0.0001). Three types of nuclei were identified (lymphocytic/histocytic, Reed-Sternberg and centroblast-like). The latter two high-grade nuclei were suggestive of TCHRLBCL. TCHRLBCL and LPHL, respectively, showed diffuse histology, 90% vs. 4% (P = 0.001), single CD20+ cells, 93% vs. 3.5% (P = 0.00004), CD30+ cells, 30% vs. 0% (P = 0.01), CD57+ cells, 41% vs. 93% (P = 0.008), EMA+ cells, 27% vs. 60% (P = 0.113), EBV+ cells, 24% vs. 0% (P = 0.117), high nuclear grade, 70% vs. 0% (P = 0.001), total score 2-7 (mean 4.68) vs. 0-2 (mean 0.72) (P = 0.001), high stage, 86% vs. 7% (P = 0.0001). Our findings indicate that a combination of multiple parameters can help differentiate between the two diseases. Two cases originally diagnosed as LPHL were re-assigned the diagnosis of THRLBCL.

T‐cell/histiocyte‐rich large B‐cell lymphoma associated with a near‐tetraploid karyotype and complex genetic abnormalities

Cytogenetic data for T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) are scarcely available. We report here a case of THRLBCL with a near-tetraploid karyotype and complex chromosomal aberrations, without rearrangement of BCL2 or BCL6, and characterized pathologically by a variegated morphologic appearance with areas resembling nodular lymphocyte-predominant Hodgkin's lymphoma (NLPHL).

Anti-CD20 Monoclonal Antibody (Rituximab) for Therapy of T-Cell/Histiocyte-Rich Large B-Cell Non-Hodgkin Lymphoma.

T-cell/histiocyte-rich large B cell lymphoma (THR-BCL) is morphologic variants and subtypes of diffuse large B cell lymphoma (DLBCL). Four immunomorphologic criteria were applied to distinguish THR-BCL from DLBCL.a diffuse or vaguely nodular pattern of neoplastic infiltrate,the presence of scattered large atypical lymphoid cells that are of B-cell phenotype,predominance of a reactive background infiltrate, composed of both T-cell and non-epithelioid histiocytes,minimal presence of small B-cells in neoplastic areas.Bcl-6 protein expression, which was generally accepted markers of germinal center differentiation, was noted more than half of the THR-BCL cases. THR-BCL predominantly affected middle-aged men who present with advanced disease and an unusually high percentage of bone marrow (BM) involvement. Here we report a pediatric case of THR-BCL. 14-year-old boy was presented with both cervical mass which was observed 1 month ago. He complained generalized weakness and chest discomfort had fever. Cervical lymph node and BM biopsy were taken. Laboratory finding was as follows; Hemoglobin 10.4 mg/dL, hematocrit 31 %, leukocyte 6,730/μL, platelet 219,000/μL. Na 128 mmol/L, K 4.6 mmol/L, Cl 95.4 mmol/L, BUN 10 mg/dL, Cr 1.2 mg/dL, LDH 2,108 U/L. Lymph node specimen showed diffuse large B cell lymphoma and numerous histiocytes. Immnuohistochemical staining; CD 20(+), CD 10(−), CD 3(+), CD 68(+). Ann Arbor stage is IVB, international prognostic index is high-intermediate risk. He received induction chemotherapy with prednisolone, vincristine, cyclophosphamide, doxorubicin, rituximab and achieved remission and now he have continued chemotherapy for 7 months in state of complete remission. THR-BCL is a distinct clinicopathologic entity within DLBCL that is characterized by an aggressive behavior and high risk of treatment of failure. That is the reason why delineate this subgroup. Experimental therapeutic strategy was indicated in patients who relapsed after having obtained a complete remission or had partial response after initial chemotherapy.

Gray zone lymphomas

1. Gray zone between Classical Hodgkin lymphoma (CHL) and diffuse large B-cell lymphoma (DLBCL), in particular primary mediastinal large B-cell lymphoma (MLBCL). 2. Gray Zone between CHL and ALK negative anaplastic large cell lymphoma (ALCL) and/or peripheral T-cell lymphoma (PTCL). 3. Gray zone between CHL or nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and T-cell/histiocyte-rich large B-cell lymphoma (TRLBCL)

T-Cell/Histiocyte-Rich Large B-Cell Lymphoma Displays a Heterogeneity Similar to Diffuse Large B-Cell Lymphoma

T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL), a proliferating peripheral B-cell neoplasm, is a morphologic variant of diffuse large B-cell lymphoma (DLBCL), which may be confused with Hodgkin's lymphoma, non-Hodgkin's lymphoma, and reactive lymphadenopathies. Though more recent studies suggested that it might be a distinct clinicopathologic entity and/or a heterogeneous entity with derivation from germinal center B cells, its histogenetic derivation remains controversial. The authors analyzed 30 cases of THRLBCL to further characterize the origin of the neoplastic cells using immunohistochemical and molecular studies for expression of Bcl-6, CD10, and CD138, as well as rearrangements of IgH/bcl-2 genes on paraffin-embedded tissue. Half of the cases (15/30) showed Bcl-6 expression and five cases (19%) showed CD10 expression, but none had CD138 expression (0/20). Only three cases showed coexpression of both Bcl-6 and CD10. Molecular studies performed in 21 cases detected rearrangement of immunoglobulin heavy gene in 18 cases, with none having detectable Bcl-2 gene rearrangement. These data indicate that similar to DLBCL, the cell origin of neoplastic cells in THRLBCL is composed of a heterogeneous group of proliferating peripheral B cells, with only some cases originating from germinal center B cells and others derived from heterogeneous origins. Lack of Bcl-2 gene rearrangements seems to argue against a possible progression from preexisting follicular lymphoma. Thus, the normal counterpart of the neoplastic cells cannot at this time be the sole basis for the subclassification of THRLBCL.

Pediatric EBV-positive T-cell/histiocyte-rich large B-cell lymphoma with clonal cells in the bone marrow without overt involvement

T-cell/histiocyte-rich large B-cell lymphoma (TCHRLBCL) is a variant of large B-cell lymphoma only rarely encountered in children. Here we report the case of an 8-year-old African American boy with Epstein-Barr virus (EBV)-positive TCHRLBCL who initially presented with right submandibular, anterior cervical and supraclavicular lymphadenopathy. Cytogenetic analysis of the lymph node revealed a near-triploid karyotype with complex chromosomal aberrations. Although morphologically the bone marrow was normal, the same cytogenetically abnormal clone was detected. The patient responded to chemotherapy with CHOP (doxorubicin, cyclophosphamide, vincristine and prednisone) therapy, with disappearance of the abnormal clone from the bone marrow. The patient remains in remission 26 months after the initial diagnosis.