Prognostic value of POD18 combined with improved IELSG in primary central nervous system lymphoma

Purpose The International Extranodal Lymphoma Study Group (IELSG) score is widely used in clinical practice to stratify the risk of primary central nervous system lymphoma (PCNSL) patients. Our study aims to confirm and improve the IELSG score in PCNSL patients based on Chinese populations. Materials and methods A total of 79 PCNSL patients were retrospectively analyzed. All patients treated with high-dose methotrexate (HD-MTX)-based therapy collected clinical data. The receiver-operating characteristic (ROC) curve was used to determine the optimal cut-off values for the factors in IELSG score. Progression of disease (POD) at the most landmark time point was determine by Epanechnikov kernel and the area under the ROC curve (AUROC). Kaplan–Meier and multivariable regression methods were used to analyze survival data. Nomogram was generated for calculating the weight of each selected factor. Results The traditional IELSG score had no significant difference on OS and PFS except ECOG ≥ 2 and could not stratify the risk groups in PCNSL. The improved IELSG scoring system was established, which incorporated age ≥ 54 years, ECOG ≥ 2, deep brain structure, elevated CSF protein, and LDH/ULN > 0.75. On the other hand, POD18 was identified as a new powerful prognostic factor for PCNSL. In multivariate analysis, POD18 and the improved IELSG scoring system were independent prognostic factors for OS. Nomogram including the two significant variables showed the best performance (C-index = 0.828). Conclusions In this study, the IELSG score was improved and a new prognostic indicator POD18 was incorporated to construct a nomogram prognostic model, thereby further improving the predictive ability of the model (AU)

An Atypical relapsing follicular lymphoma to composite Hodgkin's lymphoma.

Composite lymphoma is defined as two or more lymphomas with distinct morphological and immunophenotypical characteristics synchronously diagnosed at the same anatomical site. Composite lymphoma is rare, and the most common combination is follicular lymphoma (FL) associated with diffuse large B cell lymphoma, followed by FL associated with classic Hodgkin's lymphoma (HL). Histologically, composite lymphomas display a mixed pattern or distinct zonal distribution of each lymphoma component. Composite lymphoma poses a diagnostic challenge, especially when two lymphoma components are mixed in the same lymph node. Here, we report a case of composite HL and FL 11 years after initial and repeat biopsies consistent with FL in a man in his 70s emphasising the importance of repeat biopsy in lymphoma diagnosis.

Case report: Chronic lymphocytic leukemia/small lymphocytic lymphoma and monomorphic epitheliotropic intestinal T-cell lymphoma: A composite lymphoma.

Background: Composite lymphomas involving B-cell and T-cell lymphomas is very rare. Case presentation: We reported a 63-year-old gentleman with composite chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL). The patient was admitted to our hospital due to abdominal pain, and was diagnosed with CLL/SLL after bone marrow (BM) biopsy, BM aspiration, and flow cytometry. Two weeks later, he was diagnosed with MEITL based on pathological analysis after intestine excision. Next gene sequencing (NGS) findings identified two hotspot mutation sites (STAT5B and DNMT3A) closely related with the pathogenesis of CLL/SLL and MEILT. Additionally, BCOR mutation was only detected in the CLL/SLL area. The likely pathogenic mutations of CLL were SETD2, NOTCH1, SF3B1, and PTPN11, while the likely pathogenic mutations related with the MEILT were TET2 and ZRSR2. Mutations of GATA3, PLCG2, and FAT1 were identified in both CLL/SLL and MEITL areas, but the clinical significance was unknown. Finally, the patient died in the 12-month follow-up after surgery. Conclusion: We report a rare case of composite CLL/SLL and MEITL that highlights the importance of careful inspection of hematologic neoplasms. We also present the results of NGS of different gene mutations in CLL and MEITL tissues.

[Composite lymphoma: Case report of a coexisting follicular and mantle cell lymphoma in situ in a cervical node]. / Lymphome composite : Case report d'un ganglion cervical siège d'un lymphome folliculaire et d'un lymphome à cellules du manteau in situ.

Composite lymphoma represents 1-4% of lymphomas. Only 8 case reports concerned coexisting follicular lymphoma and mantle cell lymphoma. Here, we report the case of an 81 years old man who has been diagnosed with a composite follicular and in situ mantle cell lymphoma. The use of a large panel of immunohistochemical stains associated with the flow cytometry results have allowed us to make this particular diagnosis. We highlight here a common clonal origin of the composite lymphoma's two entities, as described in previous publications.

Incidence Patterns of Sequential or Composite Lymphoma: A Population-Based Cancer Registry Study.

The development of multiple histologic types of lymphoma in a single patient has been sporadically reported as sequential or composite lymphoma. However, the incidence pattern of such patients has been rarely evaluated in a large population-based setting. We investigated the incidence of sequential or composite lymphoma based on 11,174 lymphoma records from a population-based cancer registry between 1985-2012 in Nagasaki Prefecture, Japan. We identified 99 lymphoma records were of 49 independent patients other than relapse. The prevalence of the sequential or composite lymphomas in a single patient was 0.44% (95% confidence interval [95% CI], 0.32-0.56%) without sex difference. Among the 49 patients, five (10.2%) were composite/discordant lymphoma. The most frequent "composite lymphoma" was a combination of diffuse large B-cell lymphomas (DLBCL) and adult T-cell leukemia (n = 3). A case of "discordant lymphoma" was a combination of follicular lymphoma on spleen and Waldenström macroglobulinemia on bone marrow. The rest of the patients (n = 44, 89.8% of all composite lymphoma) were "sequential lymphoma" with various combination of lymphoma subtypes on different dates. The major combination of the sequential lymphoma was DLBCL after marginal zone lymphomas (n = 4). In the era of improved survival of lymphoma patients, hematologists should be aware of the development of additional lymphomas.

Composite lymphoma of T-cell rich, histiocyte-rich diffuse large B-cell lymphoma and nodular lymphocyte predominant Hodgkin lymphoma: a case report.

BACKGROUND: Composite lymphoma is a rare entity where two or more distinct subtypes of lymphoma coexist within a single organ or tissue. CASE PRESENTATION: We report a new case of a 67-year-old Caucasian male patient, who presented with fatigue, weakness, weight loss, and polyuria. He also had epigastric and left lumbar pain, enlarged spleen, and enlarged left axillary lymph node on examination, with no relevant medical or familial history. A biopsy from the node showed an appearance of T-cell rich, histiocyte-rich diffuse large B-cell lymphoma and nodular lymphocyte predominant Hodgkin lymphoma. The patient was initially treated with adriamycin (doxorubicin), bleomycin, vinblastine, dacarbazine chemotherapy regimen, then switched to rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone regimen. During the therapy, some regression was noticed, especially in the size of the splenic enlargement; however, the patient died 2 months after completing the regimen. CONCLUSION: Composite lymphomas should continue to be studied. Also, treatment is still debatable in type, efficacy, and outcomes.

Angioimmunoblastic T-Cell Lymphoma and Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: A Novel Form of Composite Lymphoma Potentially Mimicking Richter Syndrome.

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is an indolent small B-cell neoplasm that may transform into a clinically aggressive disease, namely Richter syndrome, usually as diffuse large B-cell lymphoma. Besides, CLL/SLL encompasses an increased risk of developing other secondary cancers, including a variety of T-cell lymphomas, often of the anaplastic large-cell type or with a cytotoxic phenotype. Here, we report a small series of patients with composite lymphomas consisting of CLL/SLL and angioimmunoblastic T-cell lymphoma (AITL), a hitherto unrecognized association. The 3 patients (1 male/2 females, 68 to 83 y) presented with high-grade-type symptoms. One patient was clinically suspicious for Richter syndrome, in the others CLL/SLL and AITL were concomitant de novo diagnoses. CLL/SLL and AITL were admixed in the same lymph nodes (3/3 cases) and in the bone marrow (1/2 cases). In all cases, the AITL comprised prominent clear cells with a strong T follicular helper immunophenotype and similar mutations consisting of TET2 or DNMT3A alterations, IDH2 R172K/M, and RHOA G17V. The 3 patients received chemotherapy. One died of early AITL relapse. The other 2 remained in complete remission of AITL, 1 died with recurrent CLL, and 1 of acute myeloid leukemia. These observations expand the spectrum of T-cell lymphoma entities that occur in association with CLL/SLL, adding AITL to the rare variants of aggressive neoplasms manifesting as Richter syndrome. Given that disturbances of T-cell homeostasis in CLL/SLL affect not only cytotoxic but also helper T-cell subsets, these may contribute to the emergence of neoplasms of T follicular helper derivation.

Pathological and molecular analysis of a composite lymphoma of mantle cell lymphoma and Epstein-Barr virus-positive follicular lymphoma.

Composite lymphoma (CL) is a very rare clinical entity defined by the presence of two or more different subtypes of lymphoma in the same lymph node. We report a case of CL in a 78-year-old male presenting with leukocytosis and swelling of multiple lymph nodes. A left axillary node biopsy showed atypical lymphocytes in both the interfollicular and follicular areas. Immunohistochemistry revealed that mantle cell lymphoma (MCL) was mainly present in the interfollicular area and follicular lymphoma (FL) was present in the follicular area. Polymerase chain reaction analysis of immunoglobulin heavy chain gene rearrangements confirmed that they were clonally related neoplasms. However, Epstein-Barr virus (EBV) DNA was detected in only FL cells, suggesting that MCL and FL had split into two clones in the early steps of pathogenesis. This is the first reported case of CL with EBV-negative B-cell non-Hodgkin lymphoma (NHL) and EBV-positive B-cell NHL with a clonal relationship. We discuss the developmental processes of these two lymphomas.

Composite lymphoma of cervical lymph nodes with classical Hodgkin lymphoma and diffuse large B cell lymphoma: a case report and literature review.

Composite lymphoma (CL) is a clinically rare entity, with unknown pathogenic mechanisms. Its diagnosis is quite difficult, and there is currently no proven treatment. In this article, we report a 64-year-old male patient presenting with swelling and mild pain in the bilateral cervical lymph nodes. Radiology revealed lesions only involved the neck. Histological examination showed that the tumor tissue had two components: mixed cellularity classical Hodgkin lymphoma (CHL-MC) and diffuse large B cell lymphoma (DLBCL). The final diagnosis was CL in the bilateral cervical lymph nodes composed of CHL-MC and DLBCL stage IA. The patient received six cycles of rituximab plus cyclophosphamide, pirubicin, vincristine, and prednisone (R-CHOP) and two cycles of rituximab maintenance therapy, and complete response (CR) was achieved. No progression was found during the 9 months of follow-up. We conducted a literature review of 28 cases of CL with CHL and DLBCL. The demography of the disease, the location of the disease involved, the subtype of CHL, the Epstein-Barr virus infection, treatment and survival were described in detail. In the discussion section, we analyzed the definition, pathogenesis, diagnosis, treatment and prognosis of CL. We hope that through case reports and literature review, we can improve the understanding of CL and optimize its treatment.

Composite follicular lymphoma and "early" (in situ and mantle zone growth pattern) mantle cell neoplasia: A rare entity with peculiar cytogenetic and clinical features.

Composite follicular lymphoma (FL) and mantle cell lymphoma (MCL) is rare and not fully characterized from a genetic and clinicopathological point of view. We report a composite lymphoma (CL) in which a G1-2 FL was associated with an in situ mantle cell neoplasia (ISMCN) and a mantle zone growth pattern (MZGP) MCL, followed-up for six years after the first diagnosis, until the exitus of the patient. We performed a comprehensive immunohistochemical study and a detailed cytogenetic analysis, including conventional karyotyping, SKY FISH, FISH on metaphases and interphasic separated nuclei, and FISH on histological sections. The study was completed by the review of the 13 published composite FL and MCL. Our results show that this entity generally behaves like an indolent lymphoma, with the outcome of patients driven by the progression of the FL component. The MCL component generally does not evolve in an aggressive disease. Indeed, half of the cases present exclusively ISMCN. In our case, mantle cell neoplasia at diagnosis was represented by ISMCN and MZGP MCL and it was characterized by a simple karyotype, with t(11;14) as the sole cytogenetic abnormality. This cytogenetic aspect well correlates with the indolent behavior of the mantle cell component. Conversely, the complex karyotype of the FL component was associated with disseminated disease that influenced patient's outcome. Finally, we suggest that not only ISMCN, but also isolated MZGP MCL, may be considered as lesions with low potential of transformation in an aggressive MCL.

Transformation of a low-grade follicular lymphoma into a composite lymphoma combining a high-grade B-cell lymphoma and a lymphoblastic neoplasm expressing Terminal deoxynucleotidyl Transferase: a case report.

BACKGROUND: High-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6 is an aggressive mature B-cell neoplasm, whereas B-lymphoblastic lymphoma is immature cell proliferation, with a frequent positivity for terminal deoxynucleotidyl transferase. The transformation of a low-grade follicular lymphoma into a lymphoblastic neoplasm expressing terminal deoxynucleotidyl transferase is a very rare event. CASE PRESENTATION: A 55-year-old Caucasian man was followed for a grade 1-2 follicular lymphoma carrying a t(14;18) IGH/BCL2+ and was initially treated with R-CHOP. The follicular lymphoma presented two relapses. In the third relapse, the patient had multiple lymphadenopathy and ascites, which motivated a retroperitoneal biopsy and an ascitic tap. These samples were analyzed by histological, cytological, flow cytometric, cytogenetic, and molecular assessments. The patient died of a multiple organ dysfunction syndrome 2 weeks after his third relapse. The biopsy revealed a diffuse proliferation made up of two types of tumor cells: centroblasts (Bcl-6-positive) and immature cells (terminal deoxynucleotidyl transferase-positive). Flow cytometric analysis confirmed the immature phenotype, with an expression of terminal deoxynucleotidyl transferase, combined with a loss of membrane immunoglobulins. The cytogenetic analysis performed on the ascites revealed a clonal evolution characterized by a t(8;22)(q24;q11) MYC+ translocation not previously detected in follicular lymphoma. Fluorescence in situ hybridization confirmed the double rearrangement of the BCL2 and MYC genes. Polymerase chain reactions and sequencing were used to study the clonal relationship between follicular lymphoma and the secondary tumors. The IGVH gene rearrangement revealed a unique clonal rearrangement involving an IGVH4-59 subset in all three specimens. CONCLUSION: These findings suggest a clonal relationship between the two types of lymphoma cells. Furthermore, they support the transformation of an acute follicular lymphoma into a composite lymphoma combining a high-grade B-cell lymphoma and a lymphoblastic neoplasm expressing terminal deoxynucleotidyl transferase. This case report highlights the possible transformation of follicular lymphoma into a highly aggressive and immature proliferation.

Cutaneous composite lymphoma of mycosis fungoides and Hodgkin lymphoma: Response to sequential therapy.

Composite lymphoma is defined as two or more morphologically and immunophenotypically distinct lymphoma clones that occur in the same tissue site. The occurrence of cutaneous composite lymphoma (CCL) is extremely rare. Here we report a unique case of CCL consisting of Hodgkin lymphoma (HL) and mycosis fungoides (MF). Our patient presented with longstanding erythematous plaques on the skin and later developed axillary lymph node enlargement. Histopathologically, the skin lesions were characterized by a dense dermal lymphocytic infiltrate with prominent epidermotropism of pleomorphic T-cells, consistent with typical MF. Nonetheless, scattered large atypical cells resembling Reed-Sternberg (R-S) cells were interspersed among these atypical T-cells in the deep dermis. Immunophenotyping suggested a HL origin of these R-S cells. Monoclonality of T-cell receptor beta gene was detected in the skin, monoclonal immunoglobulin heavy chain gene rearrangement was identified in these R-S cells microdissected from the deep dermis, confirming the origin from HL. The lymph node biopsy showed nodular sclerosis classic Hodgkin lymphoma. Therefore, CCL of HL and MF, with lymph node HL was diagnosed. The lesions of this patient responded to a sequential treatment to HL and MF. Being aware of this rare CCL facilitates correct diagnosis and proper clinical management.

Methotrexate-associated lymphoproliferative disorder demonstrating composite lymphoma of EBV-negative diffuse large B-cell lymphoma and EBV-positive mucocutaneous ulcer.

Other iatrogenic immunodeficiency-associated lymphoproliferative disorders induced by immunosuppressive drugs, such as methotrexate (MTX-LPD), exhibit numerous pathological findings. We report the case of an 81-year-old Japanese woman diagnosed with MTX-LPD exhibiting two distinct pathological features from two different sites. Excisional biopsy of the left cervical lymph node revealed EBV-negative diffuse large B-cell lymphoma and biopsy of a pharyngeal ulcer revealed EBV-positive mucocutaneous ulcer. She was treated using an R-CHOP regimen and maintained complete remission for years. This case demonstrates the heterogeneous pathology of MTX-LPD and suggests the necessity of multiple biopsy.

Composite Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma and Mantle Cell Lymphoma; Small Cell Variant: A Real Diagnostic Challenge. Case Presentation and Review of Literature.

BACKGROUND Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and mantle cell lymphoma (MCL) both have a common origin arising from mature CD5+ B-lymphocytes. Their distinction is crucial since MCL is a considerably more aggressive disease. Composite lymphoma consisting of CLL/SLL and MCL has been rarely reported. This type of composite lymphoma may be under-diagnosed as the 2 neoplasms have many features in common, both morphologically and immunophenotypically. CASE REPORT We report the case of a 57-year-old male patient who presented with a 4-month history of recurrent abdominal pain and distention with hepatosplenomegaly. Peripheral blood showed a high leukocytes count (46.7×10³/uL) with marked lymphocytosis of 35.0×10³/uL, mostly small mature-looking, with some showing nuclear irregularities, with approximately 3% prolymphocytes. Immunophenotyping by flow cytometry and immunohistochemistry revealed 2 immunophenotypically distinct abnormal CD5+monotypic B-cell populations. Fluorescence in situ hybridization (FISH) on peripheral blood demonstrated IGH/CCND1 rearrangement consistent with t(11;14) in 65% of cells analyzed. Accordingly, based on compilation of findings from morphology, flow cytometry, immunohistochemistry, and FISH, A diagnosis of composite lymphoma consisting of MCL; small cell variant and CLL/SLL was concluded. CONCLUSIONS We describe a case of composite lymphoma of MCL (small cell variant) and CLL/SLL that emphasizes the crucial role of the multiparametric approach, including vigilant cyto-histopathologic examination, immunophenotyping by flow cytometry and immunohistochemistry, as well as genetic testing, to achieve the correct diagnosis.

Orbital soft tissue composite lymphoma presenting as recurrence of a nodal lymphoma with mantle and follicular cell components: A case report, literature review and guideline for the treatment of patients.

Composite lymphoma with mantle and follicular cell components is a challenging diagnosis. Flow cytometry, immunohistochemistry and molecular genetics are required to distinguish the two components, as often the more aggressive one is predominant and masks the other. A 58-year-old man with history of nodal composite lymphoma presented with right exophthalmos and diplopia. A head CT scan showed an orbital tumor. A biopsy of the tumor revealed a mantle cell lymphoma predominating over a follicular lymphoma. Immunoglobulin heavy chain and light chain rearrangements analysis by PCR proved that both components of the orbital tumor were recurrences of the same nodal composite lymphoma diagnosed two years earlier. The nodal lymphoma was composed of a follicular lymphoma and an in situ mantle cell neoplasia. Consensus view is that dominant lymphoma should be treated when needed but taking into account if the mantle cell lymphoma is an in situ neoplasia and if it expresses CD5 and SOX11.

Composite Epstein-Barr virus-positive mucosa-associated lymphoid tissue lymphoma and Epstein-Barr virus-negative diffuse large B-cell lymphoma in the parotid salivary gland of a patient with Sjögren's syndrome and rheumatoid arthritis: a case report.

BACKGROUND: Epstein-Barr virus is associated with many human hematopoietic neoplasms; however, Epstein-Barr virus-positive mucosa-associated lymphoid tissue lymphoma is extremely rare. In routine clinical practice, detection of mucosa-associated lymphoid tissue lymphoma and diffuse large B-cell lymphoma in a tissue sample presumes a clonal relation between these neoplasms and that diffuse large B-cell lymphoma developed by transformation of the mucosa-associated lymphoid tissue lymphoma. However, evidence to support this presumption is sparse and controversial. Assessment of the clonal relationship of the lymphoid components of a composite lymphoma is important for understanding its pathogenesis and correct diagnosis. CASE PRESENTATION: We present an unusual case of composite lymphoma (Epstein-Barr virus-positive mucosa-associated lymphoid tissue lymphoma/Epstein-Barr virus-negative diffuse large B-cell lymphoma) in the parotid salivary gland of a 62-year-old Caucasian woman with Sjögren's syndrome and rheumatoid arthritis. Simultaneous occurrence of mucosa-associated lymphoid tissue lymphoma and diffuse large B-cell lymphoma in the parotid salivary gland led us to initially assume a clonal relationship between diffuse large B-cell lymphoma and mucosa-associated lymphoid tissue lymphoma. Epstein-Barr virus was detected by in situ hybridization and polymerase chain reaction in the mucosa-associated lymphoid tissue lymphoma, but not in diffuse large B-cell lymphoma, suggesting that these lymphomas were not clonally related. Fragment analysis of frame region 3 polymerase chain reaction products from microdissected mucosa-associated lymphoid tissue lymphoma and diffuse large B-cell lymphoma components revealed different clonal pattern rearrangements of the immunoglobulin heavy chain gene. CONCLUSIONS: Our patient's case highlights the importance of assessing the clonal relationships of the lymphoid components of a composite lymphoma and Epstein-Barr virus screening in mucosa-associated lymphoid tissue lymphoma in patients with autoimmune disease.

Diagnostic utility of programmed cell death ligand 1 (clone SP142) in mediastinal composite lymphoma: A report of two cases.

Composite lymphoma is a well-known diagnostic entity exhibiting the synchronous occurrence of two or more distinct types of lymphomas in the same specimen. Here we report two patients, a 14-year-old female (Case 1) and a 45-year-old male (Case 2), with mediastinal composite lymphoma, comprising nodular sclerosis classic Hodgkin lymphoma (NSCHL) and primary mediastinal large B-cell lymphoma (PMBL). Both patients had a mediastinal mass, and manifested two different histologic components in the same biopsy, one characteristic of NSCHL and the other PMBL. The NSCHL areas included Hodgkin and Reed-Sternberg (HRS) cells with typical immunophenotypic features (CD30-positive and CD20-negative), whereas the sheets of large tumor cells characteristic of PMBL were strongly and uniformly CD20-positive. Interestingly, although both cases showed neoplastic PD-L1 (nPD-L1) positivity on the HRS cells of NSCHL, they differed regarding nPD-L1 expression on the PMBL tumor cells. In Case 1, the nPD-L1-negative PMBL component was anatomically situated outside the NSCHL lesion. On the other hand, in Case 2, the nPD-L1-positive PMBL component was characterized by transitional or continuous areas with the NSCHL component. These findings suggested that nPD-L1 expression may define two subtypes of PMBL that are more similar to or distinct from classic Hodgkin lymphoma.

Composite Lymphoma Containing Mantle Cell and Peripheral T-cell Lymphoma, Not Otherwise Specified: A Report of 2 Cases Treated With Up-front Autologous Stem Cell Transplantation.

We report 2 cases of composite lymphoma comprising mantle cell lymphoma and peripheral T-cell lymphoma, not otherwise specified, a rare association that has only been reported twice in the literature. In case 1, a 64-year-old woman presented with massive splenomegaly and lymphadenopathy. Immunohistochemical studies of the lymph node biopsy suggested the presence of 2 lymphomas, a predominant component of a peripheral T-cell lymphoma, not otherwise specified and an in situ mantle cell neoplasia. These suspicions were confirmed with polymerase chain reaction and fluorescence in situ hybridization studies. In case 2, a 45-year-old man presented with an enlarged right tonsil. Contrary to case 1, the biopsy suggested a predominant infiltration of a classical mantle cell lymphoma and an atypical proliferation of T cells. Biclonality was also confirmed with fluorescence in situ hybridization and molecular techniques. Both cases were treated with an up-front autologous stem cell transplantation after achieving first complete remission, and they remained free of disease for a long period of time.