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Histologic diagnosis of less well-differentiated cases of canine extramedullary plasmacytomas (CEMPs) may require immunohistochemical confirmation to discriminate these tumors from other round cells tumors including lymphoma, cutaneous histiocytoma, and amelanotic melanomas. CEMPs are characterized by widespread immunoreactivity for multiple myeloma 1 (MUM1) antigen and λ light chains, while the melanocytic marker melan-A has been reported to yield negative results. Here, 33 randomly selected CEMPs, 20 melanocytomas, and 20 malignant melanomas were immunohistochemically tested for MUM1, melan-A, and PNL2. In addition, CEMPs were examined for PAX5, E-cadherin, CD3, CD18, CD20, S100, as well as λ and κ light chain immunoreactivity. All CEMPs were characterized by labeling for MUM1 and λ light chain, as well as variable immunopositivity for the remaining antibodies. Notably, 13 cases of CEMPs (39.4%) exhibited immunolabeling for melan-A. Melanocytic tumors immunolabeled for melan-A (40/40; 100%) and PNL2 (34/40; 85%). An unexpected cytoplasmic immunoreactivity for MUM1 was observed in 2 melanocytic tumors. Summarized, MUM1 or melan-A immunomarkers alone are not sufficient to differentiate between CEMPs and amelanotic melanomas and should be part of a larger immunopanel including λ light chain, CD20, and PNL2. [ABSTRACT FROM AUTHOR]

Diffuse large B-cell lymphoma (DLBCL) accounts for half of non-Hodgkin lymphoma cases in people living with human immunodeficiency syndrome (PLWH). The interplay of viremia, immune dysregulation and co-infection with oncogenic viruses play a role in pathogenesis of DLBCL in PLWH (HIV-DLBCL). This scoping review aimed to describe the molecular landscape of HIV-DLBCL, investigate the impact of biomarker on clinical outcomes and describe technologies used to characterise HIV-DLBCL. Thirty-two papers published between 2001 and 2023 were included in this review. Samples of HIV-DLBCL were relatively small (16-110). Cohort effects influenced frequencies of molecular characteristics hence their impact on survival was not clear. Molecular features were distinct from HIVunrelated DLBCL. The most frequently assessed characteristic was cell of origin (81.3% of studies). Somatic mutations were the least researched (6.3% of studies). Overall, biomarker identification in HIV-DLBCL requires broader richer data from larger or pooled samples using more powerful techniques such as next-generation sequencing. [ABSTRACT FROM AUTHOR]

Background: The diagnosis of multiple myeloma (MM) in dogs may be challenging and complex. The cell blocks are a diagnostic technique that allows the characterization of neoplastic cells and, therefore, might help in the diagnosis of atypical MM. Objective: The objective of the present work is to describe three clinical cases in which the cell blocks and immunohistochemistry contributed to the definitive diagnosis of canine MM. Methods: Three dogs, one female and two males, with different clinical signs, were presented for consultation with anemia, hyperproteinemia with monoclonal gammopathy, and the presence of plasmacytosis in the bone marrow. Cytologic analysis of the spleen was performed in two dogs and was suggestive of the presence of lymphocytes or plasma cells of a neoplastic nature in one of the cases and plasma cell hyperplasia associated with extramedullary hematopoiesis in the other. Given the hypotheses of lymphoid neoplasms with a plasma cell phenotype, cell blocks from aspiration punctures were performed for immunohistochemical analysis with anti‐CD3, CD20, CD79αcy, PAX5, and MUM1 antibodies. Results: The results revealed positive staining for MUM1 in 80% of the cells in the spleen cell block and for CD20 and MUM1 in 70% of the cells in the bone marrow cell blocks, with negative staining for the other antibodies. The immunophenotyping results allowed the diagnosis of MM in the three cases and excluded other lymphoid neoplasms. Conclusions: This work reinforces the importance of using cell blocks in the diagnosis of neoplasms by demonstrating their potential to aid the diagnosis of MM. [ABSTRACT FROM AUTHOR]

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma in the world. It is divided into two important prognostic categories, germinal centre B cell (GCB) and non-germinal centre B cell (non-GCB) subtypes according to the cell of origin. Objectives: In this study, we aimed to determine the frequency of each subtype of DLBCL using a modified Hans algorithm in addition to the association of CD10 and MUM1 immunohistochemical expression with clinicopathological parameters (age, sex, type of specimen (nodal or extranodal) in Ninevah Province (Iraq). Methods: A retrospective and prospective case series study of 61 cases of DLBCL which were collected from histopathological departments of governmental and private labs over 10 months extending from November 2022 to August 2023. DLBCL subtypes (GCB and non-GCB/ABC) were assessed based on immunohistochemical expressions of CD10 and MUM1. Results: A total of 61 patients, (59%) were non-GCB, while (41%) were GCB subtypes. Thirty-four (55.7%) cases were male, whereas twenty-seven (44.3%) were female. The median age was (61 years), 44 (72.1%) cases were nodal and 17 (27.9%) were extranodal primary sites. There is a significant inverse relation between CD10 and MUM1 expression (p-value 0.02). Conclusions: In the Ninevah population, there was a high frequency of unfavourable prognostic markers that included a predominance of non-GCB/ ABC DLBCL. It is necessary to investigate more since it represents high-risk subsets for whom different approaches to diagnosis and treatment should be considered. The significant inverse relation between CD10 and MUM1 supports the Modified Hans algorithm in subtyping DLBCL. [ABSTRACT FROM AUTHOR]

Abstract A 10‐year‐old, entire male, English Springer Spaniel was referred for evaluation of weight loss, polyuria, polydipsia and gastrointestinal tract signs including melena/haematochezia for the previous six months. Results of serum protein electrophoresis, urine analysis, computed tomography of the thorax/abdomen, bone marrow aspiration and core biopsy, and splenic and mesenteric lymph node cytology were consistent with multiple myeloma. Endoscopically obtained gastrointestinal tract biopsies identified marked plasma cell infiltration within the duodenum, ileum and colon; immunohistochemistry showed positive labelling to MUM1 and Lambda confirming clonal plasma cell involvement. The dog entered complete clinical remission seven weeks after starting a melphalan/prednisolone protocol. The dog was euthanised 475 days after starting treatment due to cervical pain and collapse. At the time of euthanasia, blood work was not supportive of a relapse of multiple myeloma. To the authors’ knowledge, this is the first report of multiple myeloma involving the gastrointestinal tract in a dog.

Cosphiadi Irawan,1 Martha Iskandar,1 Agnes Stephanie Harahap,2 Cleopas Martin Rumende,3 Maria Francisca Ham2 1Hematology and Medical Oncology Division, Internal Medicine Department, Dr. Cipto Mangunkusumo Hospital, Faculty of Medicine, Universitas Indonesia, Jakarta, 10430, Indonesia; 2Anatomical Pathology Department, Dr. Cipto Mangunkusumo Hospital, Faculty of Medicine, Universitas Indonesia, Jakarta, 10430, Indonesia; 3Internal Medicine Department, Dr. Cipto Mangunkusumo Hospital, Faculty of Medicine, Universitas Indonesia, Jakarta, 10430, IndonesiaCorrespondence: Martha Iskandar, Tel +628161924095, Email marthaiskandar@gmail.comBackground: Treatment response in diffuse large B-cell lymphoma (DLBCL) is heterogenous. The Hans algorithm (using 30% cut-offs for CD10, BCL6, and MUM1 protein expression) has been the most favored method to categorize DLBCL into germinal center B-cell (GCB) and non-GCB subtypes in order to predict prognosis. However, the algorithm’s ability to prognosticate is not always consistent.Methods: This retrospective cohort study was conducted on DLBCL patients receiving R-CHOP therapy at Dr. Cipto Mangunkusumo Hospital, Jakarta from 2014 to 2017. We aimed to compare the prognostic value of Hans algorithm as well as the protein levels of CD10, BCL6, MUM1, and Ki67 at different cut-offs. Ninety-two patients were classified based on Hans algorithm and various proteins at different cut-off values were analyzed with regard to event-free survival at 24 months using survival analysis. The cut-off values were then compared using receiver operating characteristic curves.Results: A significant survival difference was observed with MUM1 expression cut-off of 50% or more (log rank p = 0.035). CD10, BCL6, Ki67, and Hans algorithm showed AUCs below or near 0.5 (0.405, 0.436, 0.498, and 0.413, respectively), whereas MUM1 showed an AUC of 0.835, in predicting events within 24 months. MUM-1 cut-off of 70.5% yielded an optimal trade-off for sensitivity and specificity.Conclusion: MUM1 expression of 50% or more can help predict prognosis in DLBCL patients receiving R-CHOP therapy and can be considered as for use as a single marker to predict prognosis.Keywords: DLBCL, RCHOP, MUM1, Hans algorithm, prognosisMeSH Terms: lymphoma, large B-cell, dIffuse, MUM1 nucleosome-binding protein, human, antineoplastic combined chemotherapy protocols/adverse effects, rituximab/therapeutic use, retrospective studies, prognosis

Primary cutaneous large B cell lymphoma, leg type is a rare and aggressive variant of cutaneous B cell lymphoma. It predominantly affects elderly women, with the lower limb being the most common site of presentation. The overall prognosis is poor, compared to other cutaneous B cell lymphomas. A 47-year-old man presented with a progressively enlarging nodule over the medial aspect of the left foot since 2 months. Clinical examination revealed a nodular plaque-like lesion with central ulceration that measured 7 × 7 cm, firm in consistency, and with ill-defined margins. The initial clinical diagnosis was lupus vulgaris. An incision biopsy was done, which on histopathology and immunohistochemistry revealed a rare diagnosis of primary cutaneous B cell lymphoma, leg type. The patient was started on chemotherapy; however, he succumbed to his illness about 1 year after the initial presentation. It is a rare type of cutaneous lymphoma, which may masquerade infectious disorders such as lupus vulgaris. A detailed histopathological and immunohistochemical analysis is essential for its correct diagnosis and management. Only a handful of cases of this rare condition are reported to date. This case has been reported in view of its rarity and unusual clinical presentation. [ABSTRACT FROM AUTHOR]

A 10‐year‐old, entire male, English Springer Spaniel was referred for evaluation of weight loss, polyuria, polydipsia and gastrointestinal tract signs including melena/haematochezia for the previous six months. Results of serum protein electrophoresis, urine analysis, computed tomography of the thorax/abdomen, bone marrow aspiration and core biopsy, and splenic and mesenteric lymph node cytology were consistent with multiple myeloma. Endoscopically obtained gastrointestinal tract biopsies identified marked plasma cell infiltration within the duodenum, ileum and colon; immunohistochemistry showed positive labelling to MUM1 and Lambda confirming clonal plasma cell involvement. The dog entered complete clinical remission seven weeks after starting a melphalan/prednisolone protocol. The dog was euthanised 475 days after starting treatment due to cervical pain and collapse. At the time of euthanasia, blood work was not supportive of a relapse of multiple myeloma. To the authors' knowledge, this is the first report of multiple myeloma involving the gastrointestinal tract in a dog. [ABSTRACT FROM AUTHOR]

The aim of this study is to analyze the clinical and pathological features of germinal center (GC)- derived diffuse large B-cell lymphomas (DLBCL) with aberrant co-expression of MUM1 and to further analyze the differences between adults and pediatric populations. Clinical and pathological data of 32 cases of GC-derived DLBCL with aberrant co-expression of MUM1 were reviewed and analyzed. Thirty-two cases were categorized into pediatric (n=12) and adult (n=20) groups. GC-derived DLBCL with aberrant co-expression of MUM1 was found to manifest a wide age range, extensive involvement sites, different histopathological distribution, and complex clinical presentations. Compared to adults, pediatric patients showed a significantly higher frequency of Waldeyer's ring (WR) involvement (P=0.008), higher frequency of stage II (P=0.035), and lower incidence of fatality (P=0.014). Among the 32 cases, lymphomas were frequently involved in WR, followed by the gastrointestinal tract, lymph nodes, and bone marrow. Pediatric patients showed a significantly higher frequency of WR involvement than adult patients (P=0.008). Lymphomas involving WR in adults showed similar localized clinical stages, excellent outcomes, and pathological features compared to the disease in the pediatric population. Lymphomas involving the gastrointestinal tract in adults shared clinical features with the disease in children but with high P53 positive expression. GC-derived DLBCL with aberrant co-expression of MUM1 in adults is clinically more heterogeneous than children. Tumors involving WR in adults share many similarities to their pediatric counterparts. [ABSTRACT FROM AUTHOR]

Three dogs under 12 months old were diagnosed with atypical multiple myeloma (MM), having an aggressive multifocal anaplastic round cell sarcoma in bone marrow, viscera, and/or peripheral blood, which were confirmed by cytology and immunohistochemistry to be of plasma cell origin. The intramedullary sarcomas caused myelophthisis, osteolysis, and hypercalcemia. Complete or free light chain monoclonal gammopathy in the serum and/or urine was demonstrated by protein electrophoresis and immunofixation. The polymerase chain reaction for antigen receptor rearrangement assay performed on 2 cases identified a clonally rearranged immunoglobulin gene. Neoplastic cells lacked expression of CD45, CD3, CD18, CD21, CD34, and MHCII by flow cytometry. Immunohistochemistry revealed MUM1 immunoreactivity of the neoplastic cells. Combining all data, the diagnosis was MM. An aggressive form of MM in young dogs should be a differential diagnosis for patients with an immunoglobulin-productive, B cell-clonal, CD45-negative, MUM1-positive discrete cell neoplasm arising from the bone marrow. [ABSTRACT FROM AUTHOR]

Background: Diffuse large B-cell lymphoma (DLBCL) is considered the commonest subtype of non-Hodgkin lymphoma (NHL) in the world. It is a refractory disease with a high mortality rate due to frequent relapses. Several prognostic parameters are now widely studied for risk stratification and achieving a better outcome. Objectives: In this study, we aim to assess the prognostic value of immunohistochemical expression of CD10, BCL6, and MUM1 independently as surrogate markers for cell of origin (COO) classification of DLBCL and their correlation with clinicopathological characters and survival. Patients and methods: This is a retrospective study conducted on 63 cases of DLBCL, NOS. Full-faced sections were constructed and immunostained for CD10, BCL6, and MUM1. Results: CD10 expression was associated with early-stage (P=0.003), normal serum LDH level (P=0.022), absence of B symptoms (P=0.019), low international prognostic index (IPI) and age-adjusted-IPI (P=0.001) and also associated with longer progression free survival (PFS) (P=0.006). BCL6 expression was associated with centroblastic variant (P=0.005), good ECOG performance status (P=0.038) and low IPI (P=0.004) and also associated with better overall survival (OS) (P=0.028) and PFS (P=0.018). MUM1 expression was associated with advanced-stage (P=0.002) while no significant association was detected with other clinicopathological parameters or survival. Conclusion CD10, BCL6, and MUM1 can be used independently as prognostic immunohistochemical markers for DLBCL that may denote the clinical behavior of the disease and further patients' outcomes.

Follicular lymphoma (FL) of B cell type is a common mature B cell neoplasm of germinal center origin that effaces the nodal architecture usually by back to back follicles. These are usually composed of an admixed population of small centrocytes with cleaved and angulated nuclei and centroblasts which are larger cells with dispersed chromatin and variably prominent peripheral nucleoli. While the proliferation index using Ki-67 (MIB1) is not used to grade follicular lymphomas, studies have shown that FL with a higher proliferation index may behave differently and more aggressively than FL with lower proliferation index. In addition, it has been repeatedly recognized that additional chromosomal aberrations affect the biologic and clinical behavior of FL. In this manuscript, we report four different cases of FL diagnosed from small core needle biopsies and discuss the challenges faced interpreting limited biopsies, significance of incorporating the proliferation fraction, and additional chromosomal or gene aberrations from concurrent cytogenetic studies.

Background: CD10, BCL6, and MUM1 are commonly used immunohistochemical stains for classifying diffuse large B-cell lymphoma (DLBCL), which is useful in predicting outcome. Conflicting reports of the prognostic value of other markers such as BCL2, CD23, and Ki67 proliferation index have been reported. Our objective was to correlate these immunostains and Hans classification with response to therapy and overall survival. Materials and Methods: A retrospective study of patients diagnosed with DLBCL from 2008–2014 at a tertiary-care cancer hospital. The slides with the IHC stains were reviewed by two independent pathologists. The clinical outcomes––assessed independently––were response to therapy and overall survival. The treatment response evaluation was based on the new Lugano classification. Statistical analyses were conducted using the Fisher’s exact test and Kaplan–Meier survival curves. Significance was set at P < 0.05. Results: Forty-one patients were included in the study with a known Hans classification, available clinical data, and at least 5-year follow-up. CD10 immunostain was reported in all patients, whereas CD23 was the least reported in only four patients. No significant association was observed between CD10, BCL6, MUM1, BCL2, and both Response to therapy and overall survival. Owing to few cases reported CD23 immunostain, further analysis of association is not reported. High Ki67 proliferative index of >80% was statistically significantly associated with shorter overall survival and not statistically significant associated with no response to therapy. Hans classification subtypes were not predictive in regard to therapy response. Conclusion: High Ki67 expression (>80%) was associated with shorter overall survival in DLBCL. Hans classification subtypes were not predictive.

We described four patients with diffuse large B-cell lymphoma (DLBCL) carrying t(9;14)(p13;q32) that places the PAX5 adjacent to the immunoglobulin heavy chain (IGH) gene. Ages ranged between 63 and 80, and three were female. One developed a nodal disease, and the other three involved extranodal organs. The lymphoma cells were CD10- /BCL6- /MUM1+ in three and CD10+ /BCL6+ /MUM1+ in one. BCL2 was weak or negative. All had t(9;14)(p13;q32), and three had additional 14q32/IGH translocations or +der(14)t(9;14)(p13;q32). Fluorescence in situ hybridization using the PAX5 break-apart probe showed that the locus was disrupted between the 5' and 3' probes or within the 5' probe. Immunohistochemistry (IHC) using a monoclonal antibody against PAX5 showed strong nuclear positivity in all four patients. Cell block IHC of a CD30+ DLBCL cell line, KIS-1, which carried the t(9;14)(p13;q32) and PAX5-IGH fusion gene, reproduced the CD10- /BCL6- /MUM1+ immunophenotype, low-level BCL2, and strong nuclear PAX5. Uniform nuclear positivity of MUM1 in all four cases and KIS-1 cells suggest that these lymphomas arose at a late stage of B-cell differentiation, where expression of PAX5 physiologically becomes downregulated. It is therefore possible that high-level PAX5 resulting from t(9;14)(p13;q32) at this stage of differentiation perturbs the plasma cell differentiation program initiated by PAX5 repression, thereby contributing to the development of a fraction of DLBCL. [ABSTRACT FROM AUTHOR]

Chronic endometritis is characterized by plasma cell (PC) infiltration of endometrial stroma. Identification of PCs can be challenging by routine hematoxylin and eosin (H&E) stain due to the low numbers of PCs or to their being obscured by other cells in the stroma. CD138 is widely used as an ancillary immunohistochemistry stain to identify PCs; however, it has a high background reaction. In this study, multiple myeloma 1 (MUM1) transcription factor is introduced as an alternative PC marker in endometrial tissues. In this study, 311 endometrial biopsies, submitted to rule out chronic endometritis, were selected. They were divided into Group I (n = 87) and Group II (n = 224). Both had MUM1 and H&E while Group I also had accompanying CD138 stains. In both groups combined, MUM1 detected plasma cells in 48% of the cases, while CD138 and H&E identified the cells in 23% and 15% of the biopsies, respectively. In addition to having a clean background, MUM1 is a more sensitive stain than CD138 for detection of PCs in endometrium. [ABSTRACT FROM AUTHOR]

Lenalidomide is an active agent for the treatment of MALT lymphoma. Recently, high expression levels of cereblon (CRBN) and MUM1 have been associated with better response rates in multiple myeloma treated with lenalidomide. However, there are no data on CRBN and MUM1 expression in MALT lymphoma. In the current study, we have systematically investigated a potential correlation of CRBN/MUM1 immunohistochemical expression and response to lenalidomide-based therapy in a series of 46 patients with MALT lymphoma treated at the Medical University Vienna 2009 to 2014. In total, 28% (13/46) of biopsy specimens derived from gastric tissues, while 72% (33/46) originated from extragastric MALT lymphoma. In terms of CRBN, 54% showed high expression (CRBN+, ≥50% positive cells); the remaining 46% were classified as low expression (CRBN-). In contrast to other reports, there was a non-significant trend towards worse response rates in CRBN+ (68% versus 86%, P = 0.161). Relapse rates (P = 0.592) and PFS (P = 0.306) did not differ between CRBN+/CRBN-, but all 3 patients progressing on lenalidomide were CRBN+ and both patients completely lacking CRBN expression responded to treatment. Concerning MUM1, 62% were MUM1-negative (MUM1-) and 38% positive (MUM1+). There was no difference in response to lenalidomide by MUM1-status (MUM1+ 71% versus MUM1- 79%, P = 0.546) and also relapse rates (P = 0.828) and PFS (P = 0.681) did not differ. Interestingly, a subgroup analysis of gastric lymphoma revealed a significantly better PFS for CRBN- and MUM1- patients, respectively (both P < 0.05). To conclude, there was no significant difference in response to lenalidomide between patients with low or high expression of CRBN/MUM1 in a general population of MALT lymphoma, and immunohistochemical CRBN/MUM1 assessment cannot be recommended in the clinical routine. [ABSTRACT FROM AUTHOR]

Introduction: Primary central nervous system diffuse large B-cell lymphoma (PCNSL DLBCL) in the immunocompetent is an uncommon tumor that has an activated B-cell immunophenotype resembling germinal center exit B cells. They also differ from primary central nervous diffuse large B-cell lymphomas in the immunocompromised as they show no association with the Epstein-Barr virus. Objective: To determine if immunophenotypic subtyping of PCNS DLBCL from Asian subcontinent are also different similar to its systemic counterpart is unclear, as there are only limited studies from Asia, and none from India. Material and Methods: The immunohistochemical profile of 24 South Indian patients with primary central nervous system diffuse large B-cell lymphoma was studied using germinal center markers - CD10 and Bcl-6, and activation markers - MUM1 and CD138, which are markers for late/post germinal centre B cells. Insitu hybridization for EBV genome and LMP1 by immunohistochemistry was carried out in all cases to determine association with EBV. Results: Centroblastic morphology and uniform activated B-cell phenotype with positivity for MUM1 was seen in 91.6% of tumors. Co-expression of Bcl-6 and MUM1 was evident in 50%, which is more frequent than in systemic diffuse large B-cell lymphomas. All cases were negative for Epstein-Barr virus using EBER in-situ hybridization and LMP1 immunohistochemistry. Conclusion: Primary diffuse large B-cell lymphoma in the immunocompetent is a distinct clinicopathological entity with centroblastic morphology, a uniform activated B-cell immunophenotype that is not associated with the Epstein-Barr virus regardless of geographic origin. [ABSTRACT FROM AUTHOR]

Background: The revised 2008 World Health Organization classification maintains a histological grading system (grades 1–3) for follicular lymphoma (FL). The value of grading FL has been debated. This study will yield deeper insights into the morphologic, immunophenotypic characterization and t(14;18) translocation in FL and explore their significance of diagnosis of Chinese FL subgroups. Methods: We retrospectively reviewed the FL diagnoses according to the 2008 WHO classification in all diagnostic specimens from a multicentric cohort of 122 Chinese patients. Upon review, 115 cases proved to be truly FL. CD10, BCL6, MUM1, BCL2 and t(14;18) (q32;q21) translocation were detected by Envision immunostaining technique and fluorescence in situ hybridization. Results: FL1 has larger proportion of follicular pattern (93.0%) than that of FL2 (73.7%, P = 0.036), FL3B (63.6%, P = 0.003) and FL3A (77.4%, P = 0.053), although the last P value was more than 0.05 (Pearson’s chi-squared test). Areas of DLBCL were present in 25.8% (8/31) of FL3A and more frequent in FL3B (59.1%, 13/22; P = 0.015). The positivity of CD10 and BCL2 in FL1-2 were significantly higher than those in FL3 (P < 0.001, P = 0.043, respectively). The positivity of MUM1 in FL1-2 was significantly lower than that in FL3 (10.2% vs. 51.0%; P < 0.001). Furthermore the positivity of MUM1 in FL3A was significantly lower than that in FL3B (37.9% vs. 68.2%; P = 0.032). The positivity of t(14;18) was higher in FL1-2 than in FL3 (73.5% vs. 35.6%, P < 0.001), and was higher in FL3A than in FL3B (51.9% vs. 11.1%, P = 0.005). t(14;18) was significantly correlated with CD10+ (R = 0.453, P < 0.001) and MUM1+ (R = -0.482, P < 0.001). Conclusions: FL1 and FL2 were immunophenotypically and genomically similar, while FL3A and FL3B were partly immunophenotypically similar but morphologically, genomically distinct. FL3A was genomically closer to FL1-2, whereas FL3A was genomically closer DLBCL. Thus we hypothesize that FL may in fact be a heterogeneous indolent lymphoma encompassing entities with distinct molecular pathogenesis and genetic characteristics. Immunohistochemical and genetic characterization helps to distinguish subgroups of FLs. [ABSTRACT FROM AUTHOR]

Abstract: Current laboratory technics, clinicopathologic findings cannot always reliably distinguish primary cutaneous CD30(+) lymphoproliferative disorders (LPD), such as lymphomatoid papulosis (LyP), primary cutaneous CD30(+) anaplastic large cell lymphoma (PCALCL), transformed mycosis fungoides (T-MF) and systemic ALK(−) anaplastic large cell lymphoma (ALCL) with skin involvement. We investigated the presence of IRF4 translocation with break apart DNA-FISH method of these entities according to the recent studies of Feldman et al. In our study group with 53 cases, the detection of IRF4 translocation had a specificity and positive predictive value for PCALCL of 100%. In contrast MUM1/IRF4 protein expression was distributed widely without any predictive value. [Copyright &y& Elsevier]

We report a case of primary esophageal CD30/ALK/MUM1 anaplastic large cell lymphoma (ALCL) and discuss its diagnosis and treatment, specifically in regard to the unusual expression of the B cell marker, MUM1. A 29-year-old Mexican male presented with an esophageal mass with stenosis and dysphagia. Endoscopic samples were sent for hematoxylin-eosin staining and immunohistochemical analysis. Pathologic and immunohistochemical examination resulted in a diagnosis of primary ALCL of the esophagus with CD30/ALK/MUM1 phenotype. This diagnosis was confirmed by molecular analysis [fluorescence in situ hybridization (FISH)]. Initially, two cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy were given, but the patient exhibited progressive disease. Subsequent treatment consisted of four cycles of ifosfamide, carboplatin, and etoposide (ICE). As of the 12-month follow-up examination, the patient is in complete remission. This case suggests that ALCL of the esophagus should be considered in the differential diagnosis of esophageal neoplasms. Biopsy through esophagoscopy or surgical exploration is recommended, and treatment with chemotherapy or radiotherapy can achieve long-term survival. [ABSTRACT FROM AUTHOR]

Firstly, increased Ki67 and MUM-1 staining has been associated with worse prognosis in marginal zone B cell lymphomas (MZL). However, ours is the first study to assess the impact of proliferative indices on chemotherapy response. Secondly, loss of p53 and p16 tumor suppressor genes (TSG) has traditionally been associated with cancer progression. The significance of these markers in MZL was investigated. Thirdly, we explored the role of proliferative indices and tumor suppressor genes in identifying MZLs with significant plasmacytic differentiation (PD). Consecutive MZL cases (2006-2008) were identified. Slides were reviewed to confirm the diagnosis; immunohistochemical stains for Ki67, MUM-1, WT-1, p53, and p16 were subsequently performed and graded for percentage staining. Wilcoxon two-sample test and Pearson correlation coefficient were performed. Twenty-nine cases were analyzed. None of the assayed markers were correlated with treatment response. Ki67 and MUM1 expression, however, were correlated with PD ( p = 0.0136 and p = 0.0042). A correlation between MUM1 and p16 staining was also seen ( p = 0.0006). IHC assay for TSGs, p53 and p16, and proliferative indices (Ki67, MUM1, WT1) is unlikely to predict treatment response in low-grade MZL. Ki67 and MUM1 staining, however, may serve as a useful adjunct in ascribing PD. [ABSTRACT FROM AUTHOR]

Lawrie C H, Ballabio E, Soilleux E, Sington J, Hatton C S R, Dirnhofer S & Tzankov A (2012) Histopathology 61, 18-25 Inter- and intra-observational variability in immunohistochemistry: a multicentre analysis of diffuse large B-cell lymphoma staining Aims: Although many immunohistochemical (IHC) cancer biomarkers have been identified, very few have translated into routine clinical practice, primarily because of technical and observational inconsistencies between studies. However, despite the obvious need to address such variability, very few studies have done so. Methods and results: Using bcl-6, CD10, MUM1, GCET1 and FOXP1 antibody staining on diffuse large B-cell lymphoma cases ( n = 138) as a model, we employed Cronbach α analysis to quantify interobserver and intraobserver variability between four independent observers (two per institution), scoring two tissue microarrays (TMAs) stained at both institutions using differing staining procedures. The overall concordance between all observations irrespective of staining procedure or TMA source was high (average α = 0.951), with the highest level being reached for CD10 staining (average α = 0.967) and the lowest for bcl-6 (average α = 0.924). Interslide and interinstitutional reproducibility were similarly high (average α = 0.952 and average α = 0.934, respectively). Interobserver/intrainstitutional and interobserver/interinstitutional comparisons showed lower levels of concordance (average α = 0.870 and average α = 0.877, respectively), and intraobserver/interinstitutional comparisons showed the lowest levels of concordance (average α = 0.810), particularly for bcl-6 staining ( α = 0.658). Conclusions: This study suggests that most variability in IHC studies between centres results from inherent limitations of the biomarkers investigated rather than procedural or observational differences. [ABSTRACT FROM AUTHOR]

PEComas are mesenchymal neoplasms composed of perivascular epithelioid cells (PEC) and include a spectrum of tumors. PEComas and malignant melanoma share common morphological, immunohistochemical, and ultrastructural features, such as epithelioid cell morphology and melanocytic immunophenotype. Melanocytic markers commonly expressed in PEC tumors include HMB-45, Melan-A/MART-1, tyrosinase, microphthalmia transcription factor (MITF), and occasionally, S100. Given this morphological and immunophenotypical overlap, the differential diagnosis between a PEComa and malignant melanoma can represent a challenge. Additional diagnostic difficulty is the differentiation of melanoma and PEComa from clear cell sarcoma that is indistinguishable from melanoma based on the immunohistochemical profile. Recent studies have shown that MUM-1, a known lymphocyte marker shows positive immunostaining in nevi and melanomas, its expression in PEComas and clear cell sarcoma, however, has not been previously addressed. In this study, the authors analyzed MUM-1 expression using immunohistochemistry in PEComas (n = 8), the PEComa family members, angiomyolipomas (n = 13), and clear cell sarcomas (n = 11) and compared the staining pattern with malignant melanomas (n = 25), both primary (n = 14) and metastatic (n = 11). It was found that 92.3% of primary melanomas and 81.3% of metastatic melanomas were MUM-1 positive. In contrast, MUM-1 was only weakly positive in only 25% of PEComas and negative in all angiomyolipomas. MUM-1 expression was noted in 72.7% of clear cell sarcomas. The study demonstrated differential MUM-1 expression between PEComas and other true melanocytic tumors and suggested that the addition of MUM-1 to the usual panel of melanocyte markers could be a helpful adjunctive study to aid in the differential diagnosis between these entities. [ABSTRACT FROM PUBLISHER]

Oncogenes involved in recurrent chromosomal translocations serve as diagnostic markers and therapeutic targets in hematopoietic tumors. In contrast to myeloid and B-cell neoplasms, translocations in peripheral T-cell lymphomas (PTCLs) are poorly understood. Here, we identified recurrent translocations involving the multiple myeloma oncogene-1/interferon regulatory factor-4 (IRF4) locus in PTCLs. IRF4 translocations exist in myeloma and some B-cell lymphomas, but have not been reported earlier in PTCLs. We studied 169 PTCLs using fluorescence in situ hybridization and identified 12 cases with IRF4 translocations. Two cases with t(6;14)(p25;q11.2) had translocations between IRF4 and the T-cell receptor-alpha (TCRA) locus. Both were cytotoxic PTCLs, unspecified (PTCL-Us) involving bone marrow and skin. In total, 8 of the remaining 10 cases were cutaneous anaplastic large-cell lymphomas (ALCLs) without TCRA rearrangements (57% of cutaneous ALCLs tested). These findings identified IRF4 translocations as a novel recurrent genetic abnormality in PTCLs. Cytotoxic PTCL-Us involving bone marrow and skin and containing IRF4/TCRA translocations might represent a distinct clinicopathologic entity. Translocations involving IRF4 but not TCRA appear to occur predominantly in cutaneous ALCLs. Detecting these translocations may be useful in lymphoma diagnosis. Further, due to its involvement in translocations, MUM1/IRF4 protein may play an important biologic role in some PTCLs, and might represent a possible therapeutic target. [ABSTRACT FROM AUTHOR]

Summary: Diffuse large B-cell lymphomas can be considered primary bone tumors if they are monostotic or polyostotic, affecting multiple skeletal sites without visceral or lymph node involvement. They are rarely considered as extranodal lymphomas or as bone tumors, respectively. To elucidate the prognostic relevance of clinicopathologic characteristics in such disease, we collected a cohort of primary diffuse large B-cell lymphomas of the bone and retrospectively investigated 33 patients. The cohort encompassed the years 1975 to 2004. Protein expression patterns were identified by immunohistochemistry applied to a tissue microarray. The patients included 23 males (mean age, 37 years) and 10 females (mean age, 54 years). Disease stage was I and II in 30 and IV in 3 patients. Within the mean follow-up of 28 months, 6 patients died. Median overall survival was reached after 78 months. Clinical factors favoring a good prognosis were age younger than 53 and administration of chemotherapy. Of the phenotypic markers analyzed (CD10, CD44s, CD138, Bcl-2, Bcl-6, MUM1, and Ki-67), MUM1 expression in more than 10% of the tumor cells and CD10 expression in less than 55% as well as a nongerminal center signature substantiated adverse outcome in a univariate model. In summary, poor survival in PB-DLBCL was clearly predicted in patients older than 53, who had not received chemotherapy, and who demonstrated MUM1 expression and nongerminal center phenotype. [Copyright &y& Elsevier]

Background Primary cutaneous CD30+ lymphoproliferative disorders include lymphomatoid papulosis (LyP) and primary cutaneous CD30+ anaplastic large T-cell lymphoma (ALCL). Because of overlapping histological features, it is impossible to distinguish ALCL from LyP on histological grounds. MUM1 ( Multiple Myeloma oncogene 1) is expressed in systemic ALCL and classical Hodgkin lymphoma. MUM1 expression has not been studied in detail in CD30+ lymphoproliferative disorders. Objectives To examine the expression of MUM1 in CD30+ lymphoproliferative disorders and to assess its value as a diagnostic marker. Methods Thirty-one formalin-fixed paraffin-embedded specimens of LyP ( n = 15), primary cutaneous ALCL ( n = 10), secondary cutaneous infiltrates of systemic ALCL ( n = 4) and secondary cutaneous Hodgkin lymphoma ( n = 2) were analysed by immunohistochemistry with a monoclonal antibody against MUM1. Results Positive staining for MUM1 was observed in 13 cases of LyP (87%), two cases of primary cutaneous ALCL (20%), four cases of secondary cutaneous ALCL (100%) and two cases of secondary cutaneous Hodgkin lymphoma (100%). In 11 of 13 LyP cases (85%), MUM1 was displayed by the majority, i.e. 50–90%, of the tumour cells. In contrast to LyP and secondary cutaneous ALCL, only two cases of primary cutaneous ALCL (20%) harboured MUM1-positive tumour cells. There was a statistically significant difference in the expression of MUM1 between LyP and primary cutaneous ALCL ( P = 0·002) and between primary cutaneous ALCL and secondary cutaneous ALCL ( P = 0·015). Conclusions MUM1 expression is a valuable tool for the distinction of LyP and ALCL and thus represents a novel adjunctive diagnostic marker in CD30+ lymphoproliferative disorders. [ABSTRACT FROM AUTHOR]

Summary: MUM1 is a member of the interferon regulatory factor family of transcription factors. It is normally expressed in plasma cells, late B cells, and activated T cells, and has been described in several B-cell malignancies. Although its expression has been reported in some T-cell neoplasms, the full range and character of expression have not been explored. We studied 58 cases of T-cell lymphoproliferative lesions, including systemic and cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis (LyP), mycosis fungoides (MF), MF with large cell transformation, and Sézary syndrome (SS). Nearly all cutaneous (5/5) and systemic anaplastic large cell lymphomas (4/5) were positive for MUM1, mainly in the large cell population. Similarly, 12 of 16 types A and C LyP showed MUM1 reactivity in greater than 50% of the large cells. Focal MUM1 staining was seen in 3 type B LyP, mostly in reactive lymphoid cells. All 9 MF with large cell transformation expressed MUM1 in large cells, where it paralleled CD30 expression. In comparison, most MF (11/12) were MUM1 negative. Interestingly, all SS cases (8/8) were MUM1 positive, 3 of which demonstrated diffuse staining. There was a significant difference in MUM1 expression between MF and SS groups as well as between MF and large cell transformation of MF groups (P < .001 for both). In summary, MUM1 is not helpful in separating different types of CD30-positive lymphoproliferative disorders. Potentially, MUM1 could serve as an adjunct marker for SS and/or large cell transformation of MF. [Copyright &y& Elsevier]

MUM1/IRF4 is normally expressed in late germinal center/post germinal center B-cells. Previous studies of chronic lymphocytic leukemia in bone marrow and lymph node have demonstrated variable expression of MUM1/IRF4 and conflicting prognostic significance. In this study we evaluated MUM1/IRF4 expression in peripheral blood CLL cells utilizing Histogel™ cell blocks. MUM1/IRF4 was absent in 4/36 (11%) specimens. The remaining cases demonstrated variable intensity and proportion of positive cells: <20% positive 16/36 (44%), 20 - 50% positive 12/36 (33%), >50% 4/36 (11%). No correlation was identified between MUM1/IRF4 and percent of CD38 positive cells, CD38 status (+/-), ZAP-70 status (+/-), and IgVH mutational status. The variability in MUM1/IRF4 staining suggests a level of biologic complexity that is not adequately reflected in the current binary models of CLL pathobiology. This heterogeneity may reflect the role of MUM1/IRF4 as an effector and integrator of several lymphocyte activation pathways including antigenic and environmental stimuli. [ABSTRACT FROM AUTHOR]

The bcl6/CD10/MUM1/CD138 B-cell differentiation immunophenotypes were analysed in 101 cases of classical Hodgkin lymphomas (cHL) aiming to elucidate their histogenesis. Three major bcl6/CD10/MUM1/CD138 immunophenotypes were distinguished on the basis of the immunohistochemical positivity of Hodgkin and Reed-Sternberg (H/RS) cells: (a) the late germinal center (GC)/early post-GC B-cell-like immunophenotype (bcl6-/CD10-/MUM1+/CD138-); 59/101 cases (59%), (b) the post-GC B-cell-like immunophenotype (bcl6-/CD10-/MUM1+/CD138+); 24/101 cases (24%) and (c) the indeterminate immunophenotype (bcl6+/CD10-/MUM1+/CD138-: 14 cases and bcl6+/CD10-/MUM1+/CD138+: four cases); 18/101 cases (18%). The above findings indicate that H/RS cells in most cHL display bcl6/CD10/MUM1/CD138 immunophenotypes consistent with late GC/early post-GC or post-GC B-cell differentiation. In addition, H/RS cells in a small fraction of cHL display indeterminate bcl6/CD10/MUM1/CD138 immunophenotypic profiles which are characterized by simultaneous expression of GC, late GC/early post-GC and post-GC B-cell differentiation proteins. These immunophenotypic profiles do not correspond to the differentiation immunophenotypes of normal B-cells and their identification in a part of cHL suggests that the differentiation process of H/RS cells is not complete in a fraction of these cells and/or is still ongoing at the time of observation. [ABSTRACT FROM AUTHOR]

Summary. Biological and clinical studies have shown that Hodgkin's disease (HD) can be divided into two major categories, termed nodular lymphocyte predominance HD (NLP HD) and classic HD (CHD). Within CHD four subtypes have been distinguished: nodular sclerosis, mixed cellularity, lymphocyte rich and lymphocyte depletion. To refine the histogenesis of the pathological spectrum of HD, 75 CHD and 13 NLP HD were analysed for the expression pattern of MUM1/IRF4 (Mu ltiple M yeloma-1/I nterferon R egulatory F actor-4), a lymphocyte-specific member of the IRF family, that is expressed by late centrocytes and post-germinal centre (GC) B cells. MUM1 reacted with Hodgkin's and Reed–Sternberg (HRS) cells of all CHD cases (75/75 cases), with a moderate to strong staining intensity. Conversely, lymphocyte and histiocyte (L & H) cells, the putative tumour cells of NLP HD, were negative for MUM-1 expression (9/13 cases) or displayed a weak reactivity for the antigen in < 10% neoplastic cells (4/13 cases). With respect to HD microenvironment, NLP HD displayed numerous MUM1-positive T lymphocytes located in close proximity to L & H cells whereas, in CHD, MUM1-positive T lymphocytes appeared to be distributed randomly with no specific relationship with HRS cells. Overall, this study shows that MUM1 expression differs in L & H cells versus HRS cells, corroborating the notion that NLP HD and CHD represent different stages of B-cell differentiation. As MUM1-positive T lymphocytes form rosettes around tumour cells of NLP HD, but not of CHD, these data point also to differences in the microenvironment of NLP HD and CHD, and postulate an interactive role of MUM1-positive T lymphocytes with L & H cells. [ABSTRACT FROM AUTHOR]

Simple Summary: Uveal melanoma (UM) is a rare aggressive eye cancer. Although treatment of the eye tumour is successful, about 50% of UM patients develop a relapse of their cancer in the liver. At present, such advanced disease is not curable. A better understanding of the metastatic UM (mUM) in the liver is essential to improve patient survival. This study examines both the response of immune cells within the liver to the UM secondaries (metastases), as well as the expression of various proteins by the UM cells. Our study demonstrates that there is a limited immune response to the mUM, but reveals that a certain type of reactive immune cell: a protumourigenic subset of macrophage is dominant within the mUM. Our research also reveals novel proteins within the mUM, which are specific to these cells and therefore may be targetable in future therapies. Metastatic uveal melanoma (mUM) to the liver is incurable. Transcriptome profiling of 40 formalin-fixed paraffin-embedded mUM liver resections and 6 control liver specimens was undertaken. mUMs were assessed for morphology, nuclear BAP1 (nBAP1) expression, and their tumour microenvironments (TME) using an "immunoscore" (absent/altered/high) for tumour-infiltrating lymphocytes (TILs) and macrophages (TAMs). Transcriptomes were compared between mUM and control liver; intersegmental and intratumoural analyses were also undertaken. Most mUM were epithelioid cell-type (75%), amelanotic (55%), and nBAP1-ve (70%). They had intermediate (68%) or absent (15%) immunoscores for TILs and intermediate (53%) or high (45%) immunoscores for TAMs. M2-TAMs were dominant in the mUM-TME, with upregulated expression of ANXA1, CD74, CXCR4, MIF, STAT3, PLA2G6, and TGFB1. Compared to control liver, mUM showed significant (p < 0.01) upregulation of 10 genes: DUSP4, PRAME, CD44, IRF4/MUM1, BCL2, CD146/MCAM/MUC18, IGF1R, PNMA1, MFGE8/lactadherin, and LGALS3/Galectin-3. Protein expression of DUSP4, CD44, IRF4, BCL-2, CD146, and IGF1R was validated in all mUMs, whereas protein expression of PRAME was validated in 10% cases; LGALS3 stained TAMs, and MFGEF8 highlighted bile ducts only. Intersegmental mUMs show differing transcriptomes, whereas those within a single mUM were similar. Our results show that M2-TAMs dominate mUM-TME with upregulation of genes contributing to immunosuppression. mUM significantly overexpress genes with targetable signalling pathways, and yet these may differ between intersegmental lesions. [ABSTRACT FROM AUTHOR]

Introduction Diffuse large B-cell lymphoma (DLBCL) is an aggressive B-cell lymphoma and is the most common type of non-Hodgkin's lymphoma (NHL) worldwide. The World Health Organization (WHO) classification of hematopoietic tumors has recognized three morphological variants of DLBCL: centroblastic, immunoblastic, and anaplastic. Some studies have shown that the anaplastic variant of DLBCL is associated with aggressive clinicopathological features. Anaplastic DLBCL is rare, and the clinicopathological characteristics of this subtype of DLBCL are not widely studied in our population. Therefore, in this study, we evaluated the frequency of the anaplastic variant of DLBCL and its association with other clinicopathological parameters. Methods A retrospective study was conducted in the Department of Histopathology at the Liaquat National Hospital and Medical College over a period of six years, from January 2015 to December 2020. All cases diagnosed as DLBCL based on morphology and immunohistochemical (IHC) profile were included in the study. The diagnosis of anaplastic DLBCL was rendered based on morphology (large bizarre pleomorphic cells in a cohesive or sheet-like growth pattern), combined with CD30 IHC expression. Results The mean age of the patients was 52.90 ±16.42 years, and the mean Ki67 index was 73.18 ±16.52%. Of the 220 cases of DLBCL, 47.3% cases were germinal center B-cell (GCB) subtype, and 59.1% cases were nodal. BCL-2, BCL-6, MUM1, c-MYC, and CD10 positivity were noted in 60%, 45.5%, 40.9%, 44.1, and 38.6% cases, respectively. Only 14 cases (6.4%) were recognized as anaplastic variants of DLBCL according to the previously defined criterion. The only significant association of anaplastic-variant DLBCL was noted with a lack of BCL-2 expression. No significant association of anaplastic-variant DLBCL was noted with age, gender, Ki67 index, DLBCL subtype, or any other IHC marker expression. Conclusion We found a low frequency of the anaplastic variant of DLBCL in our study. No significant association of this DLBCL variant was noted with any of the clinicopathological parameters, except for the lack of BCL-2 expression. Alternatively, from a pathological perspective, it is important to recognize this variant of DLBCL as it often mimics other CD30-positive lymphoma and undifferentiated carcinoma., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Hashmi et al.)

Background: CD10, BCL6, and MUM1 are commonly used immunohistochemical stains for classifying diffuse large B-cell lymphoma (DLBCL), which is useful in predicting outcome. Conflicting reports of the prognostic value of other markers such as BCL2, CD23, and Ki67 proliferation index have been reported. Our objective was to correlate these immunostains and Hans classification with response to therapy and overall survival., Materials and Methods: A retrospective study of patients diagnosed with DLBCL from 2008-2014 at a tertiary-care cancer hospital. The slides with the IHC stains were reviewed by two independent pathologists. The clinical outcomes--assessed independently--were response to therapy and overall survival. The treatment response evaluation was based on the new Lugano classification. Statistical analyses were conducted using the Fisher's exact test and Kaplan-Meier survival curves. Significance was set at P < 0.05., Results: Forty-one patients were included in the study with a known Hans classification, available clinical data, and at least 5-year follow-up. CD10 immunostain was reported in all patients, whereas CD23 was the least reported in only four patients. No significant association was observed between CD10, BCL6, MUM1, BCL2, and both Response to therapy and overall survival. Owing to few cases reported CD23 immunostain, further analysis of association is not reported. High Ki67 proliferative index of >80% was statistically significantly associated with shorter overall survival and not statistically significant associated with no response to therapy. Hans classification subtypes were not predictive in regard to therapy response., Conclusion: High Ki67 expression (>80%) was associated with shorter overall survival in DLBCL. Hans classification subtypes were not predictive., Competing Interests: There are no conflicts of interest., (Copyright: © 2020 Avicenna Journal of Medicine.)