Plasmablastic Differentiation Research Articles

Plasmablastic Lymphoma of the Nasopharynx in an HIV-Negative Patient

Plasmablastic lymphoma (PBL) is a rare and aggressive subtype of non-Hodgkin's lymphoma. It was originally described to occur predominantly in oral cavity of human immunodeficiency virus (HIV)-positive patients. However, some are known to be associated with other forms of immunosuppression or immunocompetent patients. We report an unusual case of PBL presenting in nasopharynx of an 85-year-old woman without HIV infection. Histopathologic examinations demonstrated a large cell lymphoma with plasmablastic differentiation. Considering morphology, positivity for CD138 and leukocyte common antigen, and focal high ki67 index, PBL was most consistent although Epstein-Barr virus encoded RNA was not detected. Positron emission tomography scan revealed hypermetabolic lesions in the nasopharynx and the right cervical lymph nodes. Marrow involvement was confirmed by biopsy of the iliac crest. According to the Ann Arbor staging system, she was diagnosed as stage IV. After endoscopic removal of the tumor, she completed six cycles of chemotherapy, but expired due to the disease progression.

Spatial transcriptome of a germinal center plasmablastic burst hints at MYD88/CD79B mutants-enriched diffuse large B-cell lymphomas.

The GC reaction results in the selection of B cells acquiring effector Ig secreting ability by progressing toward plasmablastic differentiation. This transition is associated with exclusion from the GC microenvironment. The aberrant expansion of plasmablastic elements within the GC fringes configures an atypical condition, the biological characteristics of which have not been defined yet. We investigated the in situ immunophenotypical and transcriptional characteristics of a nonclonal germinotropic expansion of plasmablastic elements (GEx) occurring in the tonsil of a young patient. Compared to neighboring GC and perifollicular regions, the GEx showed a distinctive signature featuring key regulators of plasmacytic differentiation, cytokine signaling, and cell metabolism. The GEx signature was tested in the setting of diffuse large B‐cell lymphoma (DLBCL) as a prototypical model of lymphomagenesis encompassing transformation at different stages of GC and post‐GC functional differentiation. The signature outlined DLBCL clusters with different immune microenvironment composition and enrichment in genetic subtypes. This report represents the first insight into the transcriptional features of a germinotropic plasmablastic burst, shedding light into the molecular hallmarks of B cells undergoing plasmablastic differentiation and aberrant expansion within the noncanonical setting of the GC microenvironment.

ALK-positive large B-cell lymphomas: A clinicopathologic study.

Anaplastic lymphoma kinase (ALK)-positive large B-cell lymphomas (ALK+-LBCLs) are aggressive CD20-negative lymphomas, accounting for <1% of diffuse LBCLs. Being rare and with peculiar immunophenotypic characteristics, these can be easily misdiagnosed. We present 11 cases of ALK+-LBCLs diagnosed over a period of 11 years at a tertiary care hospital in South India to analyze the clinical, morphological, and immunophenotypic profile of these tumors. ALK+-LBCL cases diagnosed from September 2009 to August 2020 were included. Clinical details were obtained from stored electronic records and summarized. Available hematoxylin and eosin (H and E) stained slides and immunohistochemistry slides were reviewed and observations tabulated. Eleven patients (nine males and two females) were diagnosed with ALK+-LBCLs in the study period with seven presenting primarily with extranodal disease manifestations. Tumors in the lymph nodes showed diffuse architecture effacement and variable sinusoidal invasion. All tumors showed immunoblastic and plasmablastic-type large lymphoid cells with scattered anaplastic/multinucleate large cells, including rare Reed-Sternberg-like cells. Cytoplasmic granular ALK-1 staining, CD20 negativity, and immunohistochemical features of plasmablastic differentiation were noted in all. Of eight patients treated, only one achieved remission with multi-agent chemotherapy but relapsed after 6 months. Two patients died of disease and five others had progressive/persistent disease and were lost to follow-up. Although rare, these tumors should always be in the differential diagnoses of tumors with plasmablastic and immunoblastic morphology, especially in extranodal sites to avoid diagnostic delay/misdiagnosis.

Prognostic value of plasmablastic morphology and p21, p53 and Cyclin D1 expression in myeloma cells: retrospective study of 122 patients with newly diagnosed multiple myeloma

Multiple myeloma (MM) is the most common bone marrow malignancy which is defined with bone marrow infiltration of more than 10% of terminally differentiated plasma cells sive myeloma cells. The aim of this study was to find correlations between the expression of some immunohistochemical markers (Cyclin D1, p53, p21), plasmablastic differentiation and prognosis of MM. Immunohistochemistry was used to detect expression of cell cycle proteins. Bone marrow trephine biopsies of 122 MM patients were analyzed to determine the plasmablastic morphology of myeloma cells and myeloma cells expression of immunohistochemical markers (p21, p53, Cyclin D1). The following clinical data of MM patients were obtained: β2-microglobulin, albumin, haemoglobin, platelet count, glomerular filtration rate (GFR), creatinine, calcium level, M-gradient and presence of osteolytic lesions. These data were compared with the bone marrow histological findings. Plasmablastic differentiation correlated with decreased level of haemoglobin, albumin and GFR. Cyclin D1 expression correlated with significantly higher serum calcium level, more common osteolytic lesions in bones. Patients with p21 expression in myeloma cells had lower albumin levels, higher M-gradient levels and more advanced stage by Salmon–Durie. These results suggest that there are correlations between plasmablastic differentiation, expression of p53, CyclinD1 and p21 and poor prognosis in cases of MM.

A Diagnostically Challinging Case of Primary Thyroid Kappa-restricted Plasma Cell- Rich Hematolymphoid Neoplasm with Focal Plasmablastic Differentiation

Abstract Introduction/Objective Most low-grade B-cell lymphomas of the thyroid are extranodal marginal cell lymphomas (MZL) and may exhibit focal plasma cell differentiation (PCD). PCD could occasionally be extensive, mimicking a true plasma cell neoplasm (PCN). PCN of the thyroid are extremely rare, representing either a component of plasma cell myeloma (PCM), or a primary thyroid extraosseous plasmacytoma (EOPC). We present a case of primary thyroid plasma cell (PC)-rich neoplasm with considerable diagnostic challenge. Methods A 46-year-old male underwent total thyroidectomy for hypothyroidism and compressive symptoms. Microscopically, sheets and nodules of PC with focal plasmablastic features were demonstrated in a background of fibrosing chronic thyroiditis. One benign perithyroidal lymph node was seen. The differential diagnosis included B-cell neoplasm with extensive PCD (ie, MZL or lymphoplasmacytic lymphoma) and PCN. Results Immunohistochemically, the PCs were positive for CD79a, MUM1, BCL2 and IgM with Kappa light-chain restriction and partial CD138 expression, and negative for CD20, PAX5, HHV8, Cyclin-D1, SOX11, CD117 and IgG. EBER was negative. Rare reactive-appearing B-cell aggregates with associated T-cells were noted. FISH for API/MALT1-fusion t(11;18) and PCR for MYD-88 mutation were negative. However, polysomy 18 (seen in 15–33% of B-cell lymphomas, including MZL) was detected. Serum proteins and PCM workup were negative. The findings were consistent with primary thyroid Kappa-restricted PC-rich neoplasm. While the absence of detectable B-cell neoplastic component was suggestive of EOPC, the diagnosis of MZL with extensive PCD was favored due to the thyroid involvement in a background of thyroiditis, absence of lymph node involvement, detection of polysomy 18, and absence of MYD-88. Follow-up of the patient was thought to be most reasonable. Conclusion Plasma cell-rich hematolymphoid neoplasms of the thyroid may cause a considerable diagnostic challenge. Differentiating between B-cell lymphomas with extensive PCD and PCN may be difficult or even impossible by morphology alone. Additional ancillary tests may be necessary.

MULTIPLE MYELOMA: PRIMARY PALATAL MANIFESTATION

Multiple myeloma (MM) is a neoplastic disorder originating from clonal proliferation of malignant plasma cells in the bone marrow microenvironment. MM is identified by the accumulation of differentiated B cells. The aim of this study is to report a case of a 65-year-old man presenting with a sessile swelling on the left palate measuring 8 cm in its largest diameter and covered by a necrotic membrane on the central surface area. Provisional clinical diagnosis included mucoepidermoid carcinoma and squamous cell carcinoma and an incisional biopsy was performed. Histologic analysis showed a diffuse proliferation of malignant cells with plasmablastic differentiation. Immunoreactions, bone marrow biopsy and systemic evaluation of the patient confirmed the diagnosis of MM. The patient was classified as stage 0 of the disease, underwent chemotherapy and use of thalidomide, and is under clinical control for 6 months. Multiple myeloma (MM) is a neoplastic disorder originating from clonal proliferation of malignant plasma cells in the bone marrow microenvironment. MM is identified by the accumulation of differentiated B cells. The aim of this study is to report a case of a 65-year-old man presenting with a sessile swelling on the left palate measuring 8 cm in its largest diameter and covered by a necrotic membrane on the central surface area. Provisional clinical diagnosis included mucoepidermoid carcinoma and squamous cell carcinoma and an incisional biopsy was performed. Histologic analysis showed a diffuse proliferation of malignant cells with plasmablastic differentiation. Immunoreactions, bone marrow biopsy and systemic evaluation of the patient confirmed the diagnosis of MM. The patient was classified as stage 0 of the disease, underwent chemotherapy and use of thalidomide, and is under clinical control for 6 months.

Lymphoid Neoplasms With Plasmablastic Differentiation: A Comprehensive Review and Diagnostic Approaches.

Plasmablastic neoplasms encompass several entities including plasmablastic lymphoma, plasmablastic plasmacytoma/multiple myeloma, primary effusion lymphoma and its extracavitary variant, anaplastic lymphoma kinase-positive large B-cell lymphoma, and Kaposi sarcoma-associated herpesvirus/human herpesvirus 8 (HHV8)-positive diffuse large B-cell lymphoma, not otherwise specified. Morphologically, the tumor cells are large with eccentrically located nuclei, prominent nucleoli, and basophilic/amphophilic cytoplasm. Immunophenotypically, the tumor cells express plasma cell-related antigens including CD38, CD138, interferon regulatory factor-4 (IRF4)/MUM1, PR domain zinc finger protein-1 (PRDM1), and/or X-box binding protein-1 (XBP1), with frequent loss of CD20. These tumors are diagnostically challenging for general pathologists due to their overlapping morphology and immunophenotype, and due to their rarity, and particularly so when clinical and radiologic information is insufficient. We also discuss HHV8-negative effusion-based lymphoma due to its overlapping features with primary effusion lymphoma. In this review, we focus on the useful diagnostic markers and pertinent molecular findings in these distinct entities and propose a practical diagnostic algorithm using anaplastic lymphoma kinase, HHV8, in situ hybridization for Epstein-Barr virus-encoded small RNA, immunoglobulin M, light chain stains, and clinicoradiologic criteria to avoid misdiagnosis. At the molecular level, MYC protein overexpression with or without MYC rearrangement and PRDM1-inactivating mutations or deletions are noted in a subset of such tumors, especially in plasmablastic lymphoma. Prognosis in these entities is dismal with conventional CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy. Therefore, novel target therapies, such as anti-CD30 agents, and/or immune blockade therapy, are potential treatment options in the future.

Oral Diffuse Large B-Cell Lymphoma with Plasmablastic Differentiation in an HIV-Negative Patient

A 52-year-old man was admitted to the oral diagnoses department for evaluation of a painless facial swelling for 4 months. A physical examination revealed dysphagia and facial asymmetry in the left jaw. In an intraoral exam, an expansive and necrotic lesion limiting stomatognathic function was observed. The radiographic aspect confirmed a primary soft tissue lesion with osteolytic capacity. Incisional biopsy and the microscopy showed diffuse small cell proliferation, with nuclear hyperchromatism, high mitotic activity, and clear perinuclear space, associated with large cells, with clear cytoplasm resembling macrophages, in a connective tissue stroma, resembling a “starry sky”. Immunohistochemical analysis revealed positivity for CD38, CD138, weak for CD20, and negative for CD79, CD19, CD10, CD3, CAM5.2, CK (LMH), PAX, TDT, and AE1AE3. With diagnosis of diffuse large B-cell lymphoma with plasmablastic differentiation, the patient was evaluated for human immunodeficiency virus, with negative results. The patient died after the first chemotherapy cycle.

Plasmablastic Lymphoma of the Oral Cavity: Report of Two Cases

Plasmablastic lymphoma (PBL) is an aggressive, diffuse, large B-cell lymphoma frequently observed in the oral cavity of individuals with human immunodeficiency virus (HIV) infection. We present 2 new cases of oral PBL. The first patient was a 35-year-old man with uncontrolled HIV infection, presenting with an extensive mass measuring 8 cm in the hard palate and upper gingiva. The second patient was a 32-year-old man with HIV infection, presenting with an extensive maxillary ulcerated mass that caused facial asymmetry and destruction of nasal cavity corticals. Microscopically, both cases showed round cells with plasmablastic differentiation, eccentric nuclei, and abundant cytoplasm. Tumor cells were strongly positive for CD138 and MUM1 and negative for CD20. Ki-67 was 90%. Both patients were treated with antiretrovirals and chemotherapy. The first patient is well without recurrence, and the second is under treatment. PBL may affect the hard palate as an extensive ulcerated swelling in young adults with HIV infection.

CD3-positive plasmablastic B-cell neoplasms: a diagnostic pitfall

AbstractRare B-cell neoplasms with plasmablastic differentiation may aberrantly express CD3 by immunohistochemical staining, which places a great challenge for diagnosis. We here studied 17 cases of CD3+ plasmablastic B-cell neoplasms, including 12 plasmablastic lymphomas and 5 plasmablastic plasma cell myelomas. All 17 cases occurred in the extranodal sites with a male predominance (13/17). Four cases were initially misinterpreted by outside institutions, among which three were diagnosed as ‘peripheral T-cell lymphoma, not otherwise specified' and one was classified as ‘poorly differentiated neuroendocrine carcinoma'. The plasmablastic cells were present in all 17 cases diffusely or in a subset of tumor cells. CD3 expression was mostly diffuse (12/17) and moderate to strong (11/16) with a cytoplasmic staining pattern (14/16). Other T-cell markers were nearly absent, including CD2 (0/10), CD4 (1/13), CD5 (0/14), CD7 (0/11), and CD8 (0/13). CD138 was positive in all 17 cases and CD79a was variably positive in 8 of 14 cases. Only one case had immunoreactivity to CD20 (1/17) and PAX5 (1/12). CD56 expression and EBV infection were detected in 8/15 and 6/17, respectively. No HHV8 infection was noted in all 11 cases tested. Most cases (11/13) revealed either kappa or lambda light chain restriction. Of the nine cases studied, six had clonal IGH rearrangements but no clonal TRG rearrangements. Our study further emphasizes that the accurate classification of CD3+ plasmablastic neoplasms requires thorough morphologic examination, incorporation of more B-cell and T-cell markers in addition to CD3 and CD20, frequent addition of CD138 staining, and utilization of necessary molecular and genetic studies.

Molecular genetics of aggressive B-cell lymphoma.

Molecular genetics of aggressive B-cell lymphoma.

Plasmablastic lymphoma presenting as a large intracardiac mass and bilateral pleural effusions

Plasmablastic lymphoma (PBL) is a rare aggressive lymphoma arising most frequently in the oral cavity of HIV-infected patients. Rare cases of PBL have been reported in extra-oral sites, as well as in HIV-negative patients. Cardiac involvement by lymphoma is very rare. The most common primary cardiac lymphoma is diffuse large B-cell lymphoma. We report an unusual case of PBL in a 49-year-old, HIV-positive man presenting with a large intracardiac mass and bilateral pleural effusions. Histological examination of the cardiac mass biopsy and cytological evaluation of the pleural fluid demonstrated large lymphoma cells with plasmablastic differentiation. By immunohistochemistry, the large lymphoma cells expressed CD30, CD45, CD138, MUM1, and kappa light chain, were weakly positive for EMA, and were negative for T-cell and B-cell markers, lambda light chain, and human herpes virus 8 (HHV8). In situ hybridization for Epstein Barr Virus-encoded RNA (EBER) was negative in large lymphoma cells. To our knowledge, in the English literature, this is the second reported case of PBL with cardiac origin and the first reported case of PBL that presents as a combination of intracardiac mass and pleural effusions.

What is a plasmablast? A commentary to: “Plasmablastic lymphoma versus diffuse large B-cell lymphoma with plasmablastic differentiation: proposal for a novel diagnostic scoring system” by Sonja Catharina Boy et al., J. Hematopathol 2015

Plasmablastic lymphoma is an aggressive neoplasm occurring in a sharply defined clinical setting, although other B cell lymphomas may show plasmacytic/plasmablastic differentiation. Here, we discuss the controversies in definition and nomenclature of these entities.

Plasmablastic lymphoma versus diffuse large B cell lymphoma with plasmablastic differentiation: proposal for a novel diagnostic scoring system

High-grade non-Hodgkin’s lymphomas with plasmablastic differentiation are frequently encountered in HIV-positive patients. Differentiating between diffuse large B cell lymphoma (DLBCL) with plasmablastic differentiation and true cases of plasmablastic lymphoma (PBL) is sometimes challenging, particularly as a substantial overlap in immunphenotype exists between late-stage B cell neoplasms and PBL. This study sought to develop an immunohistochemical panel to more reliably distinguishing between PBL and DLBCL with plasmablastic differentiation. Thirty-nine CD20-negative, ALK-negative, HHV8-negative non-Hodgkin’s lymphomas with plasmablastic differentiation defined by their morphological features, high proliferation index and positivity for MUM1/IRF4 and PRDM/Blimp1 protein expression were compared regarding their protein expression profiles, viral status and c-MYC-gene aberrations. These lymphomas were subsequently divided in two groups utilising CD10 and Pax5. Tumours without reactivity for either of these markers exhibited higher expression of CD138 and CD117 frequently used as the plasma cell (PC) markers, whilst tumours with reactivity for one or both markers showed a significantly higher expression of CD38 and MYC-gene aberrations. A novel diagnostic scoring system which includes the immunohistochemical expression of CD10 and Pax5 is proposed to differentiate between DLBCL with plasmablastic differentiation and true cases of PBL.

Extracavitary primary effusion lymphoma: A case report from India

We present a case of extracavitary primary effusion lymphoma presenting, as jejunal polyps in a 38-year-old man. This is the first report of this entity from India. Although rare in our country, the diagnosis should be suspected in cases of CD20 negative large cell lymphoma with plasmablastic or immunoblastic differentiation in seropositive patients. Immunostaining for latency-associated nuclear antigen-1 and in situ hybridization for Epstein-Barr virus-associated RNA will confirm the diagnosis.

ALK-positive diffuse large B-cell lymphoma of the duodenum: A case report and review of the literature.

Anaplastic lymphoma kinase (ALK)-positive diffuse large B-cell lymphoma (ALK+ DLBCL) is characterized by the presence of immunoblastic or plasmablastic cells with a strong ALK protein expression that is frequently associated with t(2;17)(p23;q23). The present study reports a case of ALK+ DLBCL in a 26-year-old male with a duodenal mass. Histologically, the neoplastic cells demonstrated prominent plasmablastic differentiation with abundant amphophilic cytoplasma and central nucleoli. Paraffin immunohistochemistry revealed: an exclusively cytoplasmic granular expression of ALK; CD138, immunoglobulin A (IgA) and CD79α positivity; and focal expression of multiple myeloma oncogene 1 (Mum-1), CD30 and epithelial membrane antigen (EMA). However, the immunohistochemical staining was negative for CD3, CD38 and CD20. Fluorescence in situ hybridization (FISH) analysis using an ALK break-apart probe revealed the presence of ALK gene rearrangements in the patient. To the best of our knowledge, the current case represents the first example of primary extranodal ALK+ DLBCL presenting as a duodenal mass.

BRAF V600E Mutation and Clonal Evolution in a Patient With Relapsed Refractory Myeloma With Plasmablastic Differentiation

BRAF V600E Mutation and Clonal Evolution in a Patient With Relapsed Refractory Myeloma With Plasmablastic Differentiation

ALK-positive large B-cell lymphomas express a terminal B-cell differentiation program and activated STAT3 but lack MYC rearrangements

ALK-positive large B-cell lymphoma is an aggressive lymphoid neoplasm characterized by a monomorphic proliferation of immunoblast-like cells expressing a plasmablastic phenotype and carrying ALK rearrangements. MYC rearrangements are frequent in plasmablastic lymphomas, advanced plasma cell myelomas and a subgroup of diffuse large B-cell lymphomas, but their presence in ALK-positive large B-cell lymphomas is unknown. MYC expression is downregulated by BLIMP1, a master modulator of plasma cell differentiation. BLIMP1 and MYC are upregulated by STAT3, a signal transducer activated by ALK. To determine the role of BLIMP1, MYC and STAT3 in the pathogenesis of ALK-positive large B-cell lymphomas, we investigated MYC rearrangement and the expression of MYC, phosphorylated STAT3, BLIMP1, PAX5 and XBP1 in 12 ALK-positive large B-cell lymphomas. All cases expressed ALK with a granular cytoplasmic pattern. Nine cases had a split signal consistent with an ALK rearrangement. Three additional cases showed a deletion of the 5′ or 3′ end of the ALK probe consistent with cryptic translocation. PAX5 was virtually negative in all cases tested, whereas BLIMP1 was expressed in all tumors and XBP1 in 11 of 12. Phosphorylated STAT3 was observed in all cases with a strong and diffuse nuclear pattern. MYC rearrangements were not identified in any tumor, but MYC gains and amplification were detected in six cases and one case, respectively. MYC protein was expressed in all tumors independently of MYC gene alterations. These results indicate that ALK-positive large B-cell lymphomas express a complete plasmablastic differentiation program but, contrary to plasmablastic lymphomas, do not have MYC rearrangements. STAT3 is constantly activated and may be an alternative mechanism to promote MYC expression in these tumors. The relevance of the ALK/STAT3 pathway in the pathogenesis of ALK-positive large B-cell lymphomas may offer an attractive target for new therapies.

I. Pathological and clinical diversity in diffuse large B‐cell lymphoma

I. Pathological and clinical diversity in diffuse large B‐cell lymphoma

B-Zell-Neoplasien mit plasmazellulärer und plasmablastischer Differenzierung

Plasma cell malignancies are tumors of terminally differentiated B-cells in which the neoplastic plasma cells are the dominant and proliferating tumor cell component. Plasma cell myeloma (PCM) is one of the most common hematological neoplasms and typically does not cause diagnostic problems. A morphologically and immunophenotypically detectable plasmacellular orplasmablastic differentiation is, however, commonly observed in a wide range of mature B-cell lymphomas. A confident separation of the distinct entities requires the integration of clinical and morphological findings as well as an adequate phenotyping of both the plasma cell and the B-cell component if present. Detection of lymphotropic viruses, specific translocations and novel molecular markers, such as the MYD88 L265P mutation occurring in the vast majority of lymphoplasmacytic lymphomas complement our diagnostic repertoire. In this review we describe the most commonly observed diagnostic problems in separating small B-cell lymphomas from PCM and high-grade B-cell non-Hodgkin lymphoma (B-NHL) with plasmablastic differentiation from extramedullary spread of aggressive PCM and provide helpful criteria for routine diagnostics.