The influence of immunodeficiency, disease features, and patient characteristics on survival in plasmablastic lymphoma.

ABSTRACT: Plasmablastic lymphoma (PBL) is a rare and aggressive non-Hodgkin lymphoma associated with immunodeficiency, characterized by uncertain treatment approaches and an unfavorable prognosis. We conducted a multicenter, international, retrospective cohort study, aiming to characterize the clinical features, risk factors, and outcomes of patients with PBL. Data were collected from 22 institutions across 4 countries regarding patients diagnosed with PBL between 1 January 1999 and 31 December 2020. Survival risk factors were analyzed using both univariate and multivariate regression models. Overall survival (OS) was calculated using Kaplan-Meier statistics. First-line treatment regimens were stratified into standard- and higher-intensity regimens, and based on whether they incorporated a proteasome inhibitor (PI). A total of 281 patients (median age, 55 years) were included. Immunodeficiency of any kind was identified in 144 patients (51%), and 99 patients (35%) had HIV-positive results. The 5-year OS for the entire cohort was 36% (95% confidence interval, 30%-42%). In multivariate analysis, inferior OS was associated with Epstein-Barr virus-negative lymphoma, poor performance status, advanced stage, and bone marrow involvement. In an independent univariate analysis, the international prognostic index was associated with OS outcomes. Neither immunosuppression nor HIV infection, specifically, influenced OS. Among patients treated with curative intent (n = 234), the overall response rate was 72%. Neither the intensity of the treatment regimen nor the inclusion of PIs in first-line therapy was associated with OS. In this large retrospective study of patients with PBL, we identified novel risk factors for survival. PBL remains a challenging disease with poor long-term outcomes.

Clinicopathological and genetic landscape of plasmablastic lymphoma in Taiwan.

Plasmablastic lymphoma (PBL) is an aggressive large B-cell lymphoma with a terminal B-cell differentiation phenotype and is frequently associated with immunodeficiency. We aimed to investigate the clinicopathological and immunophenotypic features, genetic alterations, and mutational landscape of PBL in Taiwan. We retrospectively recruited 26 cases. Five (5/18; 28%) patients were HIV-positive and 21 (81%) presented extranodally. There were two morphological groups: one with purely monomorphic large cells (85%) and the other comprising large cells admixed with plasmacytic cells (15%). Phenotypically, the tumors expressed MYC (8/10; 80%), CD138 (20/26; 77%), and MUM1 (20/20; 100%), but not CD20 (n = 26; 0%). Fourteen (54%) cases were positive for EBV by in situ hybridization; the EBV-positive cases were more frequently HIV infected (p = 0.036), with extranodal presentation (p = 0.012) and CD79a expression (p = 0.012), but less frequent light chain restriction (p = 0.029). Using fluorescence in situ hybridization, we identified 13q14 deletion, MYC rearrangement, and CCND1 rearrangement in 74%, 30%, and 5% cases, respectively, without any cases having rearranged BCL6 or IGH::FGFR3 fusion. In the 15 cases with adequate tissue for whole exome sequencing, the most frequent recurrent mutations were STAT3 (40%), NRAS (27%), and KRAS (20%). In conclusion, most PBL cases in Taiwan were HIV-unrelated. Around half of the cases were positive for EBV, with distinct clinicopathological features. Deletion of chromosome 13q14 was frequent. The PBL cases in Taiwan showed recurrent mutations involving JAK-STAT, RAS-MAPK, epigenetic regulation, and NOTCH signaling pathways, findings similar to that from the West.

A challenging diagnosis of plasmablastic lymphoma: importance of integrating morpholgy immunohistochemistry and flow cytometry findings (case report).

Plasmablastic lymphoma (PBL) is a rare clinicopathological entity that still raises many diagnostic and management difficulties, particularly due to the overlap between plasmablastic lymphomas and myeloma features. We report a clinical presentation of PBL affecting bone marrow in a 43-year-old patient who was admitted for B symptoms, hepatosplenomegaly, and bicytopenia investigation. Based on these findings, acute leukemia was suspected. Bone marrow morphology immunohistochemistry and flow cytometry contributed to establishing the diagnosis of medullary PBL. The patient deteriorated and died due to septic shock. This pathology requires collaboration between clinicians, pathologists, and biologists to confirm the diagnosis early. Nevertheless, a delayed diagnosis may contribute to worsening the prognosis particularly due to advanced stage consultation. Our reported case illustrates a rare clinical presentation affecting bone marrow. In our context, a confrontation between flow cytometry and immunohistochemistry was of interest as it helped to detect the immunological features of this neoplasm.

Primary plasmablastic lymphoma of the gastrointestinal tract: A series of 13 HIV-negative cases and a review of literature.

CONTEXT: Primary gastrointestinal plasmablastic lymphoma (GI-PBL) is a rare variant of diffuse B-cell lymphoma with an aggressive clinical course. PBL was initially reported among HIV-positive patients; however, subsequent studies have shown that it also occurs among HIV-negative patients. Its clinical characteristics remain poorly understood. This study aims to retrospectively analyze the clinicopathological findings of primary GI-PBLs in HIV-negative patients. DESIGN: Primary HIV-negative GI-PBL cases from 2008 to 2022 were reviewed. Clinicopathologic features and outcomes were analyzed. RESULTS: The cohort of 13 patients had a male-to-female ratio of 9:1 (3 patients' genders not available), with an average age of 61 (range, 30-92) years. The most involved location was the colon (n = 7 [53.8 %]), followed by the small bowel (n = 3 [23.1 %]), stomach (n = 2 [15.4 %]), rectum (n = 1 [7.7 %]), and anus (n = 1 [7.7 %]). Most patients (n = 10 [77 %]) showed isolated GI tract involvement. Eight patients had chronic inflammatory and/or immunocompromised status, including 4 with inflammatory bowel disease (all of whom underwent treatment), 3 with post-organ transplant status, and 1 with irritable bowel syndrome. All cases exhibited cytokeratin-/CD20-/PAX-5-/CD138+ and/or MUM1+ immunophenotype. Based on available data, 8 of 11 (72.7 %) patients had Epstein-Barr virus reactivation. Among 11 patients with follow-up data, the mean follow-up duration was 13.5 (range, 3-40) months; at the end of follow-up, 45.5 % of patients (5 of 11 patients) showed complete remission after chemotherapy. CONCLUSION: Primary HIV-negative GI-PBL occurs predominantly in the colon of relatively elderly males with immunosuppression. Its clinical course can be heterogenous, presenting a comorbidity with inflammatory bowel disease or post-organ transplantation status.

From the archives of MD Anderson Cancer Center: Plasmablastic lymphoma presenting as a kidney mass in an immunocompetent patient: Case report and literature review.

BACKGROUND: Plasmablastic lymphoma (PBL) is a rare, aggressive large B-cell lymphoma with plasmablastic or immunoblastic morphology and a terminally differentiated B-cell immunophenotype. PBL often presents at extranodal sites, commonly the oral cavity of immunocompromised patients with human immunodeficiency virus (HIV) and/or Epstein-Barr virus (EBV) infection. Cases of PBL arising outside the oral cavity in previously healthy immunocompetent patients are rare. CASE REPORT: We report a 65-year-old HIV- and EBV-negative man who presented with abdominal pain, fatigue, and vomiting. Imaging studies showed a 30 × 18 cm bulky lobulated mass located within the left kidney with surrounding para-aortic lymphadenopathy. Serum and urine protein electrophoresis revealed a monoclonal gammopathy of IgA lambda type. Biopsy of the mass showed PBL. Bone marrow lumbar puncture evaluations also showed evidence of PBL. The patient was treated with chemotherapy and radiation with initial improvement; however, he died 14 months after initial diagnosis. CONCLUSIONS: Based on our literature review, this case of PBL is one of the few reported to present as a kidney mass in immunocompetent, HIV- and EBV-negative patient. Distinguishing PBL from plasma cell myeloma (PCM) can be challenging. Knowledge of clinical features including presence of CRAB (hypercalcemia, renal failure, anemia, bone lesions) or bone marrow infiltration by mature clonal plasma cells is helpful to establish a diagnosis of PCM. Genetic features of PCM (typical translocations or mutations) also can be helpful in distinguishing plasmablastic transformation of PCM and from PBL. The case we report also highlights the need for more studies to identify specific immunohistochemical and molecular markers to improve PBL diagnosis in immunocompetent patients.

Cytological features of oral malignant lymphoma in scraping liquid-based cytology: Cases of plasmablastic lymphoma and anaplastic lymphoma kinase-positive anaplastic large cell lymphoma.

The main purpose of cytological examination in the oral region is to screen for squamous cell carcinoma or intraepithelial neoplasms; thus, the background tends to be considered a deterrent for microscopy. From this perspective, liquid-based cytology (LBC) is favorable for preparing clear samples with few backgrounds. However, background hemocytes are sometimes of critical importance in the diagnosis. We report two cases of oral malignant lymphoma, plasmablastic lymphoma, and anaplastic large cell lymphoma in which careful observation of the background in scraping LBC sample contributed to the early diagnosis. Atypical lymphoid cells were observed only in a very small part of the LBC samples from the presented patients; however, cytological findings, such as large lymphoid cells with outstanding nucleoli, large mitotic cells, or intermediate-to-large lymphoid cells with pleomorphic nuclei were sufficient for obtaining a cytological diagnosis of malignant lymphoma. Although the number and cell size of leukocytes in LBC with Papanicolaou staining were significantly different from those in air-dried conventional smears with Romanovsky staining, which are commonly preferred for the discrimination of hemocytes, the corresponding cytological features could be observed. Therefore, attention should be paid to the background as well as squamous epithelium to prepare for such unexpected cases. The LBC examination with Papanicolaou staining alone can suggest the possibility of malignant lymphoma.

[Plasmablastic lymphoma presenting clinical symptoms similar to plasmablastic myeloma].

A 75-year-old man developed multiple head masses as well as a compression fracture. His blood test revealed elevated immunoglobulin G (IgG) protein levels, and immunofixation electrophoresis revealed the presence of monoclonal IgGκ. Furthermore, positron emission tomography/computed tomography revealed multiple bone lesions, although bone marrow examination revealed only 1.2% of plasma cells. Biopsy of a head mass led to the diagnosis of plasmablastic lymphoma (PBL), an aggressive B-cell lymphoma with plasma cell phenotypes but no B-cell antigen expression. Because the tumor cells have plasmablastic morphologies, it is difficult to distinguish PBL from plasmablastic myeloma, which is a subtype of multiple myeloma. Both diseases have similar immunophenotypes and clinical courses. In this case, PBL was finally diagnosed based on Epstein-Barr virus positivity, and the patient made a complete recovery after treatment with DA-EPOCH.

Plasmablastic lymphoma occurring in ulcerative colitis during treatment with immunosuppressive therapy.

A 53-year-old man who had a history of ulcerative colitis (UC) for 2 years underwent colonoscopy as regular follow-up. The results showed an elevated lesion in the descending colon, which was diagnosed as plasmablastic lymphoma (PBL) based on pathological findings. In situ hybridization for the Epstein-Barr virus-encoded RNA probe was positive. Fluorescence in situ hybridization revealed rearrangement of the MYC gene. He had been taking prednisolone, 5-aminosalicylic acid, azathiopurine, and ustekinumab at the diagnosis of PBL and had multiple prior therapies for UC including infliximab, tacrolimus, and tofacitinib due to steroid dependence. PBL is a rare aggressive B cell lymphoma initially described in the oral cavity of human immunodeficiency virus positive patients and it is suspected to have an association with immunocompromised status of patients. The number of cases of PBL in inflammatory bowel disease (IBD) patients is extremely rare. All these patients were administered immunosuppressive therapy including thiopurines or biologics. IBD patients with immunosuppressive therapy have a higher potential for developing lymphoproliferative disorders. Clinicians should be aware of the risk of lymphoma, including PBL.

Outcomes of patients with limited-stage plasmablastic lymphoma: A multi-institutional retrospective study.

Plasmablastic lymphoma (PBL) is a rare entity, commonly associated with immunosuppressed states such as human immunodeficiency virus (HIV) infection or solid organ transplant. The clinical course is characterized by high relapse rates and a poor prognosis, leading some clinicians to recommend aggressive frontline therapy. However, a specific review of limited stage (LS) PBL patients is not available to evaluate outcomes and justify treatment recommendations. We performed a retrospective review of LS PBL cases to provide insight into this rare disease. Our cohort consisted of 80 stage I or II PBL patients from 13 US academic centers. With a median follow up of 34 months (1-196), the 3-year progression-free survival (PFS) and overall survival (OS) of the entire cohort were 72% (95% CI 62, 83) and 79% (95% CI 70, 89), respectively. The 3-year PFS and OS of patients treated with frontline chemotherapy alone was 65% (95% CI 50, 84) and 71% (95% CI 56, 89), respectively, compared to 85% (95% CI 72, 100) and 96% (95% CI 89, 100), respectively, in patients treated with combined frontline chemotherapy with radiation consolidation. Our data demonstrate favorable outcomes in LS PBL with no improvements in outcome from aggressive frontline treatment including Hyper-CVAD or auto-SCT consolidation. Multivariate regression analysis (MRA) demonstrated improved PFS for patients receiving EPOCH based frontline therapy versus CHOP (HR: 0.23; p = 0.029). Frontline chemotherapy followed by radiation consolidation versus chemotherapy alone appeared to be associated with improved relapse and survival outcomes but did not show statistical significance in MRA.

Human Immunodeficiency Virus Associated Plasmablastic Lymphoma Involving Bones and Peritoneum in a 4-Year-old Child.

In children with underlying Human Immunodeficiency virus infection and AIDS, hematolymphoid cancers, especially non-hodgkin lymphomas are common. Plasmablastic lymphoma is one such non-hodgkin lymphomas arising from the head and neck region (especially sinonasal) but extremely rare. We describe the clinical course in a 4-year-old boy who presented with a solitary bony swelling of the right knee joint, which on diagnostic work-up turned out to be plasmablastic lymphoma. With combination chemotherapy, intrathecal chemotherapy, and early institution ofHighly active anti-retroviral therapy, the child continues to be in remission.

CD138- Plasmablastic Lymphoma: A Multi-institutional Study and Review of the Literature.

CONTEXT.­: Plasmablastic lymphoma (PBL) is a rare aggressive lymphoma, usually positive for CD138 and frequently occurring in the oral cavity of human immunodeficiency virus (HIV) patients. Up to 10% of cases are negative for CD138 and diagnostically very challenging. OBJECTIVE.­: To investigate the appropriate approach to diagnose CD138- plasmablastic lymphoma and avoid misdiagnosis. DESIGN.­: We studied 21 cases of CD138- PBL from multiple large institutes in the United States and 21 cases from the literature. RESULTS.­: CD138- PBLs were positive for different B/plasma cell markers at various percentages: MUM1 (94.4%; 34 of 36), OCT2 (70.6%; 12 of 17), immunoglobulin light chains (68.8%; 22 of 32), CD38 (68.4%; 13 of 19), CD79a (34.2%; 13 of 38), and PAX5 (15.6%; 5 of 32), suggesting that MUM1, OCT2, immunoglobulin light chains, and CD38 are useful markers to help establish the lineage. A total of 83% of cases (30 of 36) were extraoral lesions. Extraoral lesions showed much lower Epstein-Barr virus (EBV) infection rates (16 of 30; 53.3%) and had worse prognosis. MYC was positive in 80% (8 of 10) of EBV+ cases and 40% (2 of 5) EBV- cases, indicating the importance of MYC in pathogenesis, especially in EBV+ cases. CONCLUSIONS.­: Our study emphasizes that CD138- PBLs tend to be extraoral lesions, with much lower EBV infection rates, and diagnostically very challenging. Accurate diagnosis requires a thorough investigation and workup by using appropriate markers.

Clinicopathologic features and abnormal signaling pathways in plasmablastic lymphoma: a multicenter study in China.

BACKGROUND: Plasmablastic lymphoma (PBL) is a rare but aggressive B-cell lymphoma subtype with poor prognosis. Knowledge about the etiology, clinicopathologic and molecular features, and outcomes of PBL is limited. This study aimed to examine the clinicopathologic characteristics, therapeutic approaches, and clinical outcomes of PBL patients in a Chinese population. METHODS: A total of 102 PBL patients were recruited from three cancer centers. The pathologic features and clinical outcomes of 56 patients with available treatment details and follow-up data were reviewed and analyzed. RNA sequencing was performed in 6 PBL and 11 diffuse large B-cell lymphoma (DLBCL) patients. RESULTS: Most patients in our cohort were male (n = 36, 64.3%), and 35 patients presented with Ann Arbor stage I/II disease at diagnosis. All these patients showed negative findings for human immunodeficiency virus, and the vast majority of patients in our cohort were immunocompetent. Lymph nodes (n = 13, 23.2%) and gastrointestinal tract (n = 10, 17.9%) were the most commonly involved site at presentation. Post-treatment complete remission (CR) was the only prognostic factor affecting overall survival (OS) and progression-free survival (PFS) in the multivariate analysis. RNA-seq demonstrated that B-cell receptor (BCR), T-cell receptor (TCR), P53, calcium signaling, and Wnt signaling pathways were significantly downregulated in PBLs compared with GCB (or non-GCB) DLBCLs. CONCLUSIONS: In this multicenter study in the Chinese population, PBL mainly occurred in immunocompetent individuals and most patients present with early-stage disease at diagnosis. Post-treatment CR was an important prognostic factor affecting OS and PFS. RNA-seq showed that the B-cell receptor (BCR), P53, calcium signaling, cell adhesion molecules, and Wnt signaling pathways significantly differed between PBL and GCB (or non-GCB) DLBCL, which provided theoretical basis for its pathogenesis and future treatment.

Bortezomib, Lenalidomide and Dexamethasone Combination Induced Complete Remission in Relapsed/Refractory Plasmablastic Lymphoma: Case Report of a Potential Novel Treatment Approach.

Plasmablastic lymphoma is a rare subtype of large B-cell lymphoma characterised by an aggressive clinical course with frequent relapses and refractoriness to chemotherapy. It is usually associated with HIV, however, it can also be seen in immunocompetent patients. It has distinct pathological characteristics, such as plasmablastic morphology and lack of CD20 expression. These characteristics pose a clinical and pathological challenge. There is no standard of care established in this entity. In this case report, we described a novel bortezomib-based plasma cell targeted regimen in a HIV-negative patient refractory to chemotherapy.

Plasmablastic myeloma in Taiwan frequently presents with extramedullary and extranodal mass mimicking plasmablastic lymphoma.

Plasmablastic myeloma (PBM) is a blastic morphologic variant of plasma cell myeloma with less favorable prognosis than those with non-blastic morphology. PBM is rare, without clear-cut definition and detailed clinicopathologic features in the literature. PBM may mimic plasmablastic lymphoma (PBL) as they share nearly identical morphology and immunophenotype. Using the criteria of ≥ 30% plasmablasts in tissue sections, we retrospectively recruited PBM cases and analyzed their clinical, imaging, and pathologic findings, with emphasis on extramedullary involvement. We performed immunohistochemistry, in situ hybridization for Epstein-Barr virus (EBER), and fluorescence in situ hybridization (FISH) for lymphoma- and myeloma-associated genetic alterations. Of the 25 recruited cases, 15 (60%) had extramedullary involvement, which occurred as initial presentation in nine cases. The most common extramedullary sites were soft tissue and/or skin (10/15, 67%), followed by pleural effusion, the lungs, and lymph nodes. Immunohistochemically, tumor cells expressed MYC (74%; 17/23), CD56 (56%; 14/25), and cyclin D1 (16%; 4/25), while CD117 was all negative (n = 25). Of the 20 cases stained with p53, four (20%) cases were diffusely positive, and the remaining 16 cases showed a heterogeneous pattern. EBER was negative in all 24 cases examined. Of the 13 cases examined with FISH, the genetic aberrations identified included del(13q14)(92%; 12/13), gain of chromosome 1q (90%; 9/10), loss of chromosome 1p (60%; 6/10), IGH-FGFR3 reciprocal translocation (23%; 3/13), rearranged MYC (15%; 2/13), and rearranged CCND1 (8%; 1/13), while there were no cases with TP53 deletion (n = 10) or rearrangement of BCL2 (n = 13) or BCL6 (n = 13). The prognosis was dismal regardless of the presence or absence of extramedullary involvement. In conclusion, PBM in Taiwan frequently presented as extramedullary and extranodal lesions, particularly in soft tissue and/or skin, mimicking PBL. FISH for targeted genetic alterations such as del(13q14), gain of chromosome 1q, loss of chromosome 1p, and IGH-FGFR3 might be helpful for the differential diagnoses. Larger studies are warranted to investigate the genetic alterations between PBM and PBL.

Anal canal lymphoma: Case report and literature review / Linfoma de canal anal, reporte de caso y revisión de la literatura

Abstract Introduction: Primary tumors of the anal canal other than carcinomas are rare entities; among them, anal canal lymphomas are extremely unusual and pose both a diagnostic and therapeutic challenge for the coloproctologist. Case presentation: A male patient with positive human immunodeficiency virus (HIV) with proctalgia and mass sensation at the perianal level. A concentric thickening of the walls of the lower rectum was documented by magnetic resonance imaging, with colonoscopy and biopsies with histopathology compatible with plasmablastic lymphoma. Therefore, a diverting colostomy was performed and, subsequently, the hematology service indicated chemotherapy with the EPOCH scheme. Discussion: Lymphoma of the anus represents 0.2 % of anorectal tumors, most of these are non-Hodgkin's lymphomas; Hodgkin's disease at the anorectal level is even rarer. The population with the highest risk of this entity is HIV-positive patients, such as the patient in this case, although other associated factors are described in the literature.

Resumen Introducción: los tumores primarios del canal anal diferentes a carcinomas son entidades poco frecuentes; dentro de estos, los linfomas del canal anal son extremadamente raros y generan un reto tanto diagnóstico como terapéutico para el coloproctólogo. Presentación de caso: se presenta a continuación un caso clínico de un paciente con virus de inmunodeficiencia humana (VIH) positivo con proctalgia y sensación de masa a nivel perianal, se documentó por resonancia magnética un engrosamiento concéntrico de las paredes del recto inferior, con realización de colonoscopia y biopsias con histopatología compatible con linfoma plasmablástico, por lo que se realizó una colostomía derivativa y, posteriormente, se indicó por el servicio de hematología una quimioterapia con esquema EPOCH. Discusión: el linfoma de ano representa el 0,2 % de los tumores anorrectales, la mayoría de estos corresponde a linfomas no Hodgkin, y es aún más rara la enfermedad de Hodgkin a nivel anorrectal. La población con mayor riesgo de presentar esta entidad es los pacientes con VIH positivo, como el paciente descrito en el caso, aunque existen otros factores asociados descritos en la literatura.

[Endoscopic mucosal resection of localized plasmablastic lymphoma with early rectal cancer:a rare case report and literature review].

A 79-year-old male with a positive fecal occult blood test result underwent total colonoscopy, which revealed a 15-mm-semipedunculated polyp in the rectum. The polyp appeared to be an adenoma using narrow-band imaging observation in magnifying endoscopy, although a 3mm reddish segment with a different surface structure was identified adjacent to the base of the polyp. En-bloc endoscopic mucosal resection (EMR) was performed. From the pathological evaluation using the specimen, the polyp was mainly a tubular adenoma with an adenocarcinoma component within the lesion. Additionally, a tiny plasmablastic lymphoma (PBL) component, which was positive for CD45, CD79a, CD30, CD38, MUM1, and lambda light chain;negative for CD3, CD5, CD20, CD56, CD138, cyclin D1, PAX5, IgG, IgA, IgM, IgE, HHV8, and kappa light chain, coexisted near the stalk. The proliferation index using Ki-67 immunohistochemistry was approximately 80%. Furthermore, Epstein-Barr virus-encoded RNAs were identified in in-situ hybridization, although the human immunodeficiency virus was not detected. The patient received contrast-enhanced computed tomography (CT) and positron emission tomography-CT (PET-CT) follow-ups after treatment without recurrence for two years. This is the first report of gastrointestinal PBL that could be treated using EMR.