Primary Cutaneous Diffuse Large B-cell Lymphoma Research Articles

Primary cutaneous diffuse large B-cell lymphoma NOS with short-term relapse

Primary cutaneous B-cell lymphomas are a unique, heterogeneous group of lymphoproliferative dis¬orders without evidence of extra-cutaneous manifestations. Primary cutaneous diffuse large B-cell lymphomas (PCDLBCLs) are aggressive neoplasms with poor prognosis. The infiltrate in some cases could involve the underlying subcutaneous tissues, but rarely reported. Accurate diagnosis is man¬datory as these patients respond well to systemic anthracycline-based chemotherapy (R-CHOP). In this article, we report a case of PCDLBCL/NOS that presented with skin manifestations and was diagnosed based on clinical features, pathology, and immunohistochemical staining. The patients were treated with systemic chemotherapy, CHOP-R, and responded well and the PET scan showed no evidence of residual disease after the 5th cycle. After 3 months of follow-up, the patient succumbed to his disease involving almost all his skin.

Clinicopathological, cytogenetic, and molecular profiles of primary cutaneous diffuse large B-cell lymphomas

We analyzed the clinicopathological, cytogenetic, and molecular features of 18 primary cutaneous diffuse large B-cell lymphomas (PCDLBCLs)and 15 DLBCLs secondarily localized to the skin (SCDLBCLs), highlighting biological similarities and differences between the 2 groups. PCDLBCLs were subclassified after histopathological review as PCDLBCL-leg type (PCDLBCL-LT, 10 cases) and the PCDLBCL-not otherwise specified (PCDLBCL-NOS, 8 cases). Immunohistochemistry for Hans' algorithm markers, BCL2, and MYC was performed. The molecular study included the determination of the cell of origin (COO) by Lymph2Cx assay on NanoString platform, FISH analysis of IgH, BCL2, BCL6, and MYC genes, as well as the mutation analysis of MYD88 gene. In immunohistochemistry analysis, BCL2 and MYC hyperexpression was more frequent in LT than in NOS cases and, according to Hans' algorithm, PCDLBCL-LTs were mostly of the non-GC type (8/10), whereas in PCDLBCL-NOS, the GC type prevailed (6/8). The determination of COO using Lymph2Cx supported and further confirmed these results. In FISH analysis, all but one LT cases versus 5 of 8 PCDLBCL-NOS showed at least one gene rearrangement among IgH, BCL2, MYC, or BCL6. In addition, MYD88 mutations were more frequently present in LT than in NOS subtypes. Interestingly, MYD88-mutated patients were older, with a non-GC phenotype and had worse OS, compared to MYD88 WT cases. Overall, SCDLBCL did not show, at the genetic and expression level, different profiles than PCDLBCL, even if they bear a significantly worse prognosis. At survival analysis, the most important prognostic factors in patients with PCDLBCL were age and MYD88 mutation, whereas relapse and high Ki-67 expression were relevant in patients with SCDLBCL. Our study comprehensively analyzed the clinicopathological and molecular features of PCDLBCL-LT, PCDLBCL-NOS, and SCDLBCL, underlining the differences among them and the importance of properly identifying these entities at the time of diagnosis.

Cases of CHOP Chemotherapy - Unresponsive Primary Cutaneous Diffuse of Large B-Cell Lymphoma in Abdul Wahab Sjahranie Regional Public Hospital: A Case Presentation and Brief Review of Literature

Introduction: Primary cutaneous diffuse large B-cell lymphoma (PCDLBCL) is a variety of B-cell neoplasms that are present in the skin with no evidence of extra-cutaneous disease at the time of diagnosis or even after 6 months of the diagnosis. Cutaneous B-cell Lymphoma (CBCL) comprises 25 to 35% of all primary cutaneous lymphomas. Due to the relative rarity of PCDLBCL, there are no completed randomized trials to clarify the optimal treatment. Reported therapy options include radiotherapy, multiagent chemotherapy, chemotherapy, polychemotherapy with rituximab, and rituximab as a single agent.Case Presentation: Several red nodular lesions on the back developed over 10 months are found in a 40-year-old woman. The first Incision biopsy revealed these lesions were malignant roundcell tumors. After being treated with 10 cycles of chemotherapy regimens comprising cyclophosphamide, doxorubicin, vincristine, dan prednisone (CHOP), there was a progressive response as several red nodular lesions are getting larger and turned into an ulcerated wound. Wide excisions and skin flaps were done. Anatomical pathology examination showed diffuse non-Hodgkin lymphoma, a large B cell that belongs to intermediate malignancy, as immunohistochemistry was positive for CD20 and CD45. The patient was then diagnosed with primary cutaneous diffuse large B-cell lymphoma and given rituximab, a CD20-targeted therapy. The patient was allowed to be discharged on the second day after surgery.Conclusions: This case report presents cases of CHOP chemotherapy-unresponsive PCDLBCL in Abdul Wahab Sjahranie Regional Public Hospital of Samarinda, East Kalimantan.

Molecular Diagnostics for TP53 Is Recommended in B-Cell Lymphomas

Introduction Multiple studies in patients with B-cell lymphomas (BCL) have shown that TP53 is associated with inferior therapeutic efficacy and survival outcomes. Current treatment algorithms for chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) are tailored for patients harboring a TP53 mutation using a different therapeutic strategy. Regardless, targeted next generation sequencing (tNGS) is not standard practice in the diagnostic workup of lymphomas. In solid malignancies, e.g., ovarian cancer (PMID: 35752743), our institute has shown that p53 immunohistochemistry (IHC) is a good and widely used marker to assess TP53 mutations. In lymphomas however, this correlation is not yet as clearly established. Here we evaluate the accuracy of p53 IHC as a surrogate marker for TP53 mutational analysis in a large cohort of BCL. Method For this retrospective study 278 consecutive patients diagnosed with BCL between 2014-2022 were selected. The cases were diagnosed according to the revised 4th edition WHO classification (2016), and included diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS, n=145), primary cutaneous DLBCL leg type (PCDLBCL LT, n=13), high grade B-cell lymphoma (HGBCL, n=8), primary central nervous system lymphoma (PCNSL, n=11), primary mediastinal B-cell lymphoma (PMBCL, n=3), Burkitt lymphoma (n=4), mantle cell lymphoma (MCL, n=18) and a diverse group of indolent mature B-cell neoplasms (MBCN, n=76, specified in figure 1). P53 IHC staining was performed using the Dako Autostainer Link 48 (Dako Omnis, Glostrup, Denmark), according to standard procedures. For each case, p53 IHC was blindly and independently assigned by one junior (LMH) and one senior (PMJ) hematopathologist to one of the following categories: abnormal (complete absence OR staining > 50% of tumor cells) or wild type (WT) (staining 1-50% of tumor cells). All discordant cases were discussed at a consensus meeting attending both pathologists and assigned a definitive category. The inter-rater reliability was measured with Cohen's kappa coefficient. Pathogenic variants of TP53 for all cases were identified with an in-house developed tNGS panel (LYMFv1), including 52 B-cell lymphoma-relevant genes and covering all exons of TP53, as described before (PMID: 34478526). Results IHC showed 213 p53 WT and 65 abnormal. Kappa correlation of the p53 IHC assessment between the two pathologists was 0,82, indicating a strong level of agreement. tNGS identified a TP53 mutation in 75 patients (26,9%), of which DLBCL NOS was the largest subgroup (n=43), followed by MBCN (n=14) and MCL (n=7). Overall, most TP53 mutations were non-synonymous (80,5%) and localized in exon 7 (36%), as shown in the Oncoprintplot (figure 1). In MBCN the most frequent location was exon 5 (33%), while in DLBCL as the largest subgroup, mainly exon 7 (38%) was affected. The overall accuracy of p53 IHC was 85,6% (95% CI 80,9-89,5%) for the presence of TP53 mutation. The corresponding sensitivity and specificity were 66,7% (95% CI 56,0-77,4%) and 92,2% (95% CI 88,5-95,9%), respectively. 25 BCLs showed a false-negative (FN) p53 WT IHC, despite detection of TP53 mutation. MBCN was the least accurate performing group (8/14 FN), followed by DLBCL NOS (13/43 FN). On the other hand, there were 15 BCLs with a false-positive (FP) abnormal IHC staining without identification of a TP53 mutation (figure 2). Again, MBCN was the lowest performing group (7/62 FP), but the overall specificity was high. Conclusion Our data indicate that the performance of p53 IHC is not sufficient as a surrogate marker for TP53 mutations in the diagnostic workup of lymphoma patients. Although the specificity is high with a low amount of FP, the sensitivity is relatively low with a high number of FN. It seems that misinterpretation of the p53 IHC is not an adequate explanation for the low sensitivity, considering the strong inter-rater reliability and the re-assessment of all discordant cases. By utilizing only p53 IHC there is a significant chance a TP53 mutation is missed, resulting in misevaluation of a high-risk patient. Therefore, molecular analysis is recommended in all patients with BCL, especially for further development of risk-directed therapies based on TP53 mutation status. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Neurolymphomatosis as a manifestation of relapsed diffuse large B-cell lymphoma.

A 49-year-old woman presented with right drop foot and desensitization in the peroneal region. She had been diagnosed with stage IE primary cutaneous diffuse large B-cell lymphoma (PCLBCL), leg type, 13 months ago. Five months ago, she had achieved complete remission after receiving six cycles of R-CHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone), as determined using 18-F fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT). She consulted an orthopedic physician and was diagnosed with unidentified right peroneal neuropathy. Her symptom neither aggravation nor improved. However, 8 months after onset, she presented with cutaneous nodules on the right foot. Nodule biopsy led to a diagnosis of PCLBCL relapse. 18F-FDG-PET/CT imaging showed increased metabolism in the right inguinal lymph node, right sural nerve, right tibial nerve, right fibula nerve, and right sciatic nerve (Figure 1, left image and upper right image). Contrast-enhanced magnetic resonance imaging (MRI) showed diffuse enlargement with an enhancement of the right sciatic nerve and right tibial nerve on T1-weighted images (Figure 1, bottom right image). Owing to the risk of irreversible neurological deficits, we did not perform a nerve biopsy. Neurolymphomatosis with relapsed PCLBCL appeared highly probable. There was no lymphomatous infiltration of the meninges on cerebrospinal fluid (CSF) cytopathologic evaluation or central neuraxis on MRI. The patient was treated with conventional chemotherapy, CHASER (rituximab, cyclophosphamide, cytarabine, etoposide, and dexamethasone). After two cycles of CHASER, 18F-FDG-PET/CT showed no abnormal uptake; however, there was no clinical improvement with regard to deficits of right peroneal neuropathy because of the prolonged neural damage. Complete remission was achieved with conventional chemotherapy; therefore, the patient planned to receive myeloablative chemotherapy with autologous stem cell transplantation. Neurolymphomatosis is defined as direct endoneurial invasion by lymphoma cells, such as that of the cranial nerves, peripheral nerve roots, plexus, or peripheral nerves [1]. It occurs in approximately 5% of patients with lymphomas, with a strong preponderance of diffuse large B-cell lymphomas [1]. Four clinical patterns have been recognized. Most commonly, neurolymphomatosis presents as painful polyneuropathy or polyradiculopathy, followed by cranial neuropathy, painless polyneuropathy, and peripheral mononeuropathy [2]. Its diagnosis requires the integration of clinical information; imaging findings (MRI and 18F-FDG-PET/CT); and morphologic data obtained from neural tissue, nonneural tissue, and CSF. Especially in the absence of systemic lymphoma, the diagnosis is often delayed, as in our case. As the index manifestation of recurrent lymphoma, neurolymphomatosis should always be considered. Its successful treatment is contingent upon recognition of the condition and its exact neuroanatomic localization without delay. The authors declare no conflict of interest. The authors received no funding for this study. TI monitored the patient. KS performed radiological investigations. IS and TI wrote the report. Written consent to publish this case was obtained from the patient. Data sharing is not applicable to this report as no datasets were generated or analyzed during the current study.

Primary Cutaneous B-Cell Lymphoma: An Update on Pathologic and Molecular Features

Primary cutaneous B-cell lymphomas (PCBCLs) account for 25% of all primary cutaneous lymphomas. Three major types are currently recognized by the WHO classification: primary cutaneous marginal zone B-cell lymphoma (PCMZL), primary cutaneous follicle centre lymphoma (PCFCL) (both considered indolent lymphomas) and primary cutaneous diffuse large B-cell lymphoma, leg-type (PCDLBCL-LT), which is, instead, a very aggressive disease. Nowadays, the PCBCL’s category also includes some rare entities such as intravascular B-cell lymphoma (IVBL) and the EBV+ mucocutaneous ulcer (EBVMCU). Furthermore, controversies still exist concerning the category of primary cutaneous diffuse large B-cell lymphoma (PCDLBCL), because some cases may present with clinical and histological features between PCFCL and PCDLBCL-LT. Therefore, some authors proposed introducing another category called PCDLBCL, not otherwise specified (NOS). Regardless, PCBCLs exhibit distinct features and differ in prognosis and treatment from their nodal/systemic counterparts. Therefore, clinicopathologic analysis is a key diagnostic element in the work-up of these lymphomas.

Cutaneous Epstein-Barr virus–positive diffuse large B-cell lymphoma, not otherwise specified: A systematic review and comparative analysis with Epstein-Barr virus–negative, leg type

To the Editor: Epstein-Barr virus (EBV)–positive diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) is an EBV-associated B-cell lymphoma often presenting in elderly patients without any known immunodeficiencies.1,2 For a systematic review to characterize cutaneous EBV-positive DLBCL-NOS, we searched 5 databases (Supplemental Fig 1; available via Mendeley at https://doi.org/10.17632/dby7kdtzk8.1).3 We also searched the Asan Medical Center database for cases of cutaneous EBV-positive DLBCL-NOS and primary cutaneous EBV-negative DLBCL–leg type for comparative analysis.

Primary cutaneous diffuse large B-cell lymphoma after total knee arthroplasty: a case study and a systematic review of its cutaneous manifestations and treatment options.

IntroductionPrimary cutaneous diffuse large B-cell lymphoma (PCDLBCL) after total knee arthroplasty (TKA) is rare.AimThe literature that analyses the cutaneous manifestations of PCDLBCL and assesses the effect and the outcome of treatment is scarce.Material and methodsWe described a case of PCDLBCL after TKA, whose cutaneous mass develops around surgical sites, mimicking a prosthetic joint infection. In addition, we conducted a systematic review of 29 reported cases with PCDLBCL. Primary endpoint for the review was main cutaneous manifestations of PCDLBCL. Secondary endpoint included treatment options of PCDLBCL and optimal therapeutic method.ResultsWe found that the main cutaneous manifestations include infiltrative cutaneous lesions such as macules, papules or nodules, some of them presented as ulcerations or formation of vesicles, subcutaneous nodules or both. The treatment options include excision, radiotherapy, chemotherapy, and even “watchful waiting” as spontaneous regression was noted in some cases. Systemic chemotherapy is the most frequent initial treatment approach chosen, of which rituximab is often combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy and patients who received systemic rituximab tend to have a better overall survival (OS) time than those who did not.ConclusionsPCDLBCL is a rare disease after TKA, however, an early recognition and distinguishing from infection is still needed. Patients with PCDLBCL may profit from rituximab-based chemotherapy, increasing the survival rate, despite the high relapse rate and limited OS time in some cases.

Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type: A Narrative Review

Primary cutaneous lymphomas are rare manifestations of extranodal lymphomas. Comprising the majority of cutaneous lymphoma cases with neoplastic B-cell origins, three main subtypes exist. In general, grossly and microscopically these subtypes are similar. However, these are three distinct variants with diverse clinicopathologic, cytogenetic, molecular, and prognostic features. Primary cutaneous diffuse large B-cell lymphoma, leg type is an exceedingly rare and aggressive variant of primary cutaneous B-cell lymphomas. Thus, increased clinical awareness is needed to differentiate between the three subtypes because earlier identification not only leads to the appropriate treatment, but also improved survival. Here, characteristic features of the three predominant variants of primary cutaneous B-cell lymphomas are presented while remaining focused on the most aggressive subtype- primary cutaneous diffuse large B-cell lymphoma, leg type.

Primary Cutaneous DLBCL Non-GCB Type: Challenges of a Rare Case.

Several types of B-cell lymphomas, including both primary cutaneous lymphomas and systemic lymphomas, may affect the skin, with partially overlapping clinical, morphological and immunohistochemical features. Currently, the World Health Organization (WHO) classification of primary cutaneous B-cell lymphomas does not include diffuse large B-cell lymphomas (DLBCL) and considers leg-type DLBCL the only primary cutaneous DLBCL. Here we report the case of a 72-year-old white woman with a primary cutaneous neoplasm comprised of large cells with round nuclei, irregularly clumped chromatin and one or more inconspicuous nucleoli. The immunohistochemistry demonstrated positivity for CD20 and MUM1, with no significant genetic translocations detected by fluorescence in-situ hybridization. After staging, we considered this neoplasm a primary cutaneous DLBCL with a non-germinal center phenotype, not otherwise specified, inconsistent with a leg-type DLBCL. Because of this view, we underscore the need for greater knowledge of the molecular landscape of B-cell lymphomas in order to reconsider the classification of such neoplasms in the skin.

Extranodal Diffuse Large B Cell Lymphoma: Molecular Features, Prognosis, and Risk of Central Nervous System Recurrence.

Diffuse large B cell lymphoma (DLBCL) arises from extranodal organs in about 30% of cases. Its prognosis and risk of recurrence in the central nervous system (CNS) vary according to the primary site of origin. Recent studies begin to clarify these differences using molecular classification. Testicular, breast, and uterine DLBCL (as well as possibly primary cutaneous DLBCL, leg-type) share a high prevalence of the non-germinal center B cell (non-GCB) phenotype and the MYD88/CD79B-mutated (MCD) genotype. These biologic features, which resemble primary CNS lymphoma, may underlie their stage-independent propensity for CNS involvement. Management of these lymphomas should involve CNS prophylaxis, preferably using systemic high-dose methotrexate to prevent intraparenchymal recurrence. Involvement of the kidneys, adrenal glands, ovary, bone marrow, lung, or pleura usually indicates disseminated disease, conferring worse prognosis. Involvement of these sites is often associated with high CNS-International Prognostic Index (IPI), concurrent MYC and BCL2 or BCL6 rearrangements, or intravascular lymphoma-risk factors warranting CNS prophylaxis. In contrast, craniofacial, thyroid, localized bone, or gastric lymphomas have a variable prevalence of the non-GCB phenotype and lack MYD88 mutations. Their outcomes with standard immunochemotherapy are excellent, and the risk of CNS recurrence is low. We recommend individualized consideration of CNS prophylaxis based on the CNS-IPI score and anatomical proximity in cases of epidural, orbital, or skull involvement. Rituximab-containing immunochemotherapy is a standard approach for all extranodal DLBCLs. Surgery is no longer required for any primary site, but routine consolidative radiation therapy is recommended for testicular lymphoma. Radiation therapy also appears to be associated with better progression-free survival in primary bone DLBCL. Future studies should better distinguish primary from secondary sites of extranodal involvement, and investigate the association of newly identified genotypes with the risk of CNS or systemic recurrence.

Tumor Microenvironment and Checkpoint Molecules in Primary Cutaneous Diffuse Large B-Cell Lymphoma-New Therapeutic Targets.

Programmed death ligand 1 (PD-L1) is expressed by 20% to 57% of systemic diffuse large B cell lymphomas (DLBCLs). PD-L1 expression in primary cutaneous DLBCL (pcDLBCL) has not been studied so far. Sixteen paraffin-embedded tissue samples of pcDLBCL (13 leg type [LT], 3 others [OT]) were investigated for PD-1, PD-L1, and CD33 expression and the cellular composition of the tumor microenvironment, focusing on myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages. Membrane-bound PD-L1 expression by the tumor cells was observed in all samples, albeit to a variable extent (19.9%). As expected, most DLBCL-LT (10 cases) were classified as activated B cell like type, with a higher PD-L1 score (21.9%) compared with that of the germinal center B cell like type (7.7%). The surrounding infiltrate consisted predominately of CD163(+) M2 rather than CD68(+) macrophages (CD68:CD163=1:4 to 6). Moreover, a considerable proportion of CD33(+) MDSCs with PD-L1 coexpression was admixed. Tumor cells expressed CD33 to variable degrees (2% to 60%). The number of MDSCs or M2 macrophages did not correlate with pcDLBCL subtypes LT or OT. T cells were only a minor component of the tumor microenvironment. We propose that PD-L1(+) tumor cells and PD-L1(+) MDSCs shield the tumor against PD-1(+) tumor-infiltrating lymphocytes, consequently leading to inhibition and diminution of tumor-infiltrating lymphocytes. Moreover, we found a polarization to M2 macrophages, which may contribute to the poor prognosis of DLBCL patients. Thus, targeting of tumor cells and MDSCs using anti-PD-1/anti-PD-L1 or anti-CD33 antibodies might be a worthwhile new approach to treat this aggressive form of cutaneous B-cell lymphoma.

Primary cutaneous B-cell lymphoma and chronic leg ulcers in a patient with type 2 diabetes.

The incidences of type 2 diabetes mellitus and many cancers are rapidly increasing worldwide. Diabetes is a strong risk factor for some cancers (including lymphomas) and is also associated with adverse cancer outcomes. After gastrointestinal tract, the skin is the second most frequent extranodal site involved by non-Hodgkin lymphomas and the cutaneous B-cell lymphomas (CBCLs) range from 25% to 30% of all primary cutaneous lymphomas. The primary cutaneous diffuse large B-cell lymphoma (PCDLBCL) is an aggressive lymphoma with a poor prognosis, representing roughly 20% of all primary CBCLs. Classically, the cutaneous manifestation of this lymphoma is a red or violaceous tumors arising on a leg. To date, despite the large body of evidence suggesting that diabetes is strongly associated with an increased risk of some cancers, very little information is available regarding a possible association between type 2 diabetes and primary cutaneous diffuse large B-cell lymphoma. In this report, we will present the case of a white adult patient with type 2 diabetes with chronic leg ulcers complicated by a primary cutaneous diffuse large B-cell lymphoma.Learning points:Diabetes mellitus is increasing worldwide as well as the incidence of many cancers.Diabetes mellitus is a powerful risk factor for some cancers (including lymphomas) and is strongly associated with adverse cancer outcomes.Seen that diabetes is strongly associated with an increased risk of cancers (including cutaneous lymphomas), clinicians should always keep in mind this complication in elderly patients with type 2 diabetes, even in a chronic leg ulcer with hypertrophy of the wound edge, which is hard to heal and does not have the typical characteristics of a diabetic or vascular ulcer. In these cases, a biopsy should be performed to rule out a neoplasm.Early diagnosis and correct management of cancer in a patient with type 2 diabetes are crucial to improve clinical outcomes.

Age as a potential new prognostic indicator in primary cutaneous B-cell lymphoma (PCBCL).

e19034 Background: PCBCL is a group of rare lymphoproliferative disorders, with an estimated annual incidence of 2.5 per 1,000,000 persons. Indolent subtypes include Primary Cutaneous Marginal Zone Lymphoma (PCMZL) and Primary Cutaneous Follicular Center Lymphoma (PCFCL). Primary Cutaneous Diffuse Large B-cell Lymphoma (PCDLBCL) is an aggressive subtype with a fatality rate of 50%. The Cutaneous Lymphoma International Prognostic Index (CLIPI) can risk-stratify indolent subtypes, but age is not considered. Here we present our single-institutional analysis of clinicopathologic features and outcomes of patients with PCBCL. Methods: This is a retrospective study of patients evaluated at Moffitt Cancer Center between 01/1990 and 12/2016. Patients were identified using our PCBCL database and diagnosis was verified by independent hematopathologists and dermatopathologists. Staging was determined by ISCL/EORTC criteria. Demographics, subtype, stage, disease course, and CLIPI scores were collected. Continuous and categorical values were tested using Kruskal-Wallis ANOVA method and Fisher’s Exact Test, respectively. Kaplan-Meier curves were produced to determine PFS. Results: We identified 37 patients who met diagnostic criteria for PCBCL (35% PCFCL, 40.5% PCMZL, 13.5% PCDLBCL, and 11% indolent, unspecified). Male:female ratio was 2.4:1. 51% of patients were ≥ 60 years old (yo), and 49% were < 60 yo. 54% had stage T1 disease, 27% T2, and 19% T3. Median PFS for patients <60 was 1.1 years, but was not reached for those ≥60. Mean follow-up time was 2.6 years for all patients. Log-rank test showed a statistically significant difference in PFS between the two age groups (p=0.01). PFS for stage of indolent subtypes showed marginal significance (p <0.06). CLIPI for indolent subtypes did not show a significant difference in PFS. Conclusions: We found that age is a highly statistically significant prognostic parameter in PCBCL, as patients ≥ 60 yo had a longer PFS compared to younger patients, even after adjusting for stage and CLIPI. These results are promising for age as a possible prognostic indicator for PCBCL, but validation is needed with a larger sample size.

Primary Cutaneous B-cell Lymphomas: Case Report of Two Cases.

Primary cutaneous lymphomas are a unique, heterogeneous group of lymphoproliferative disorders which have a primary cutaneous manifestation in the absence of systemic involvement of lymph nodes, bone marrow, or visceral organs at the time of diagnosis. Among the primary cutaneous lymphomas, B-cell lymphoma is much less common and accounts for 20%–25% of cases. Primary cutaneous diffuse large B-cell lymphomas (PCDLBCLs) are aggressive neoplasms with poor prognosis. Early and accurate diagnosis is required as these patients respond well to systemic anthracycline-based chemotherapy (R-CHOP). In this article, we report two cases of PCDLBCL, other which presented with rapidly enlarging skin nodules and were diagnosed based on clinical features, histomorphology, and characteristic immunohistochemical expression. Both the patients were treated with systemic chemotherapy and responded well. During the 6 months’ follow-up period, the lesions regressed. The patients are symptom free with no evidence of disease relapse or dissemination to extracutaneous sites.

The Role of HIV in Race-Based Differences in Diffuse Large B-Cell Lymphoma(DLBCL) Treatment and Outcomes

Introduction: African American (AA) race is associated with inferior survival in DLBCL compared to white (W) race (Shenoy, Cancer, 2011). This has been attributed to a disparity in administration of chemo-immunotherapy (Flowers, Cancer Epidemiol Biomarkers Prev 2012). Prevalence of human immunodeficiency virus (HIV) in AA with DLBCL is 8-fold higher than in W with DLBCL (Centers for Disease Control, 2014). We hypothesized that HIV infection is associated with a reduction in both administration of chemo-immunotherapy (rituximab) and overall survival (OS) in patients with DLBLC. We examined the relationship between race, HIV status, treatment with rituximab, and overall survival (OS) in a large cohort of United States Veterans with DLBCL with equal insurance access..Methods We identified 3,227 DLBCL pts between 1998 and 2008 in the Veterans Health Administration Central Cancer Registry. We excluded pts with primary cutaneous or central nervous system DLBCL and pts treated with unknown agents outside the VHA, 2,163 met this inclusion criterion. Given Rituximab did not become standard of care in aggressive lymphomas until approximately 2002; we did a planned sub-analysis of the 1,672 patients diagnosed and treated after January 1, 2002. Data on stage, lactate dehydrogenase (LDH), medical co-morbidities (Charlson Comorbidity Index), date of death, treatment and supportive care medications were obtained for each patient. OS was defined as time from DLBCL diagnosis to date of death. Univariate comparisons were performed to identify differences in treatment and other prognostic variables between race groups, where appropriate. Multivariable analyses were performed using logistic regression and Cox proportional hazards modeling, producing odds-ratios (OR) or hazard ratios (HR), respectively.Results: Of the 2,163 pts that met inclusion criteria, 88% were W and 12% AA. There was a higher prevalence of HIV in AA patients versus W patients (21% v. 4%, p <0.0001). Consistent with previous reports, African American race was associated with a higher frequency of elevated LDH (64% vs. 54%, p = 0.003) and younger age at diagnosis (57.6 years vs. 66 years, p=0.0001). There was no significant difference between AA race and use of rituximab compared to W race (70.4% vs. 73.7%, P= 0.271). Patients who were HIV positive were significantly less likely to receive rituximab (OR = 0.1, 95% CI 0.06 - 0.18). Patients who were HIV positive had an increased risk of death (HR = 1.67, 95% CI 1.27 - 2.2) compared to those who were HIV negative. After adjusting for HIV status in a multivariable Cox analysis, there was no racial disparity in overall survival (HR = 1.02, 95% CI 0.83 - 1.25). Kaplan-Meier analysis of age-adjusted overall survival stratified by race and HIV status is presented in Figure 1.Conclusions: Prior studies have shown detrimental survival outcomes in patient with HIV receiving Rituximab. Previously, it was also common practice to exclude Rituximab in treatment plans in HIV positive DLBCL patients (Kaplan, Blood, 2005).In this population of veterans with health insurance coverage, the observed racial disparity in survival after DLBCL diagnosis is largely explained by differences in the prevalence of HIV in the AA and W patient population. Thus, in order to reduce the racial outcome disparity among patients with DLBCL, public health efforts should focus on decreasing HIV transmission and enhancing HIV treatment in the AA community. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Antigen-Independent, Autonomous B-Cell Receptor Signaling As a Dominant Candidate Oncogenic Mechanism in ABC DLBCL

BackgroundThe activated B-cell (ABC) type of diffuse large B-cell lymphoma (DLBCL) is clinically more aggressive than the germinal center (GCB) type. The gene expression profile of ABC DLBCL resembles that of mature B cells upon stimulation via their B-cell receptor (BCR). In app. 10% of ABC DLBCL cases, this signature can be explained by gain-of-function mutations in CARD11. Recent evidence suggests that autoantigen recognition by the BCR sustains the viability of ABC DLBCL in vitro (Young, PNAS 2015), although the functional relationship to CARD11 mutations remains unresolved. Antigen-independent, constitutively active BCR signaling is a fundamental oncogenic mechanism of CLL (Dühren-von Minden, Nature 2012). We therefore explored the hypothesis that autonomous BCR signaling akin to CLL could be operative in ABC DLBCL and would represent an alternative but functionally complementary oncogenic mechanism to activating CARD11 mutations in ABC DLBCL lymphomagenesis.MethodsBCR transcripts were identified from archived fresh-frozen biopsies of 14 histologically confirmed, CD10-negative, IgM-expressing DLBCL by ARTISAN PCR, a novel anchored RT-PCR for unbiased isolation of full-length BCR transcripts facilitated by template switching (Koning, BJH 2016). Clonal full-length BCR were identified by single molecule sequencing on the PacBio platform. All biopsies were screened for mutations in CARD11 and CD79 by Sanger sequencing. To test for autonomous BCR signaling activity, murine triple KO (TKO) cells were transduced with functional DLBCL BCR (Dühren-von Minden, Nature 2012). TKO cells lack the rag2 and lambda5 genes and are therefore developmentally arrested at the pre-B-cell stage. In addition, TKO cells have their wild-type SLP65 adaptor replaced with a tamoxifen-dependent SLP65 variant. When transduced with a functional BCR, autonomous or antigen-induced BCR signaling can be measured upon restoring functionality of the BCR signalling cascade with tamoxifen as calcium flux by flow cytometry and robust cellular proliferation.ResultsRe-examination by immunohistochemistry for CD10, PAX5, MUM1, and Bcl-6 was possible in 12 cases and identified three cases as GCB-type DLBCL. Nine cases were classified as non-GCB DLBCL, including one primary CNS DLBCL and three leg-type primary cutaneous DLBCL (LT DLBCL). One non-GCB DLBCL was found to carry a potentially activating CARD11 M212K mutation (Table).BCR of the three GCB DLBCL served as controls and lacked an autonomous BCR signal. In contrast, TKO cells transduced with five of the seven remaining DLBCL BCR (71%) showed robust calcium flux and proliferation upon activation of SLP65 by tamoxifen without additional BCR crosslinking. In accordance with our hypotheses, the CARD11-mutated non-GCB DLBCL case lacked autonomous BCR signaling. This case and the second, non-GCB DLBCL case lacking autonomous BR activity that carried wild-type CARD11 both expressed a BCR with the IGHV4-34 allele. Unexpectedly, the three LT DLBCL also did not exhibit autonomous BCR signaling.ConclusionOur data demonstrate autonomous BCR activity in a dominant fraction of non-GCB DLBCL. In striking similarity to CLL, these results point to an oncogenic role of a structurally normal BCR in non-GCB DLBCL that does not require binding of external autoantigens. Consistent with our hypotheses, antigen-independent signaling of a structurally normal BCR signaling cascade is a compelling candidate alternative mechanism to activating mutations in signal-transducing components of the BCR pathway. Both mechanisms may therefore induce the characteristic gene expression signature of ABC DLBCL. In addition, this finding readily explains the higher likelihood of ABC DLBCL with wild-type CD79 and CARD11 to respond to BCR signaling inhibition by BTK inhibitors (Wilson, Nat Med 2015). In contrast, LT DLBCL, which otherwise resembles ABC DLBCL, does not exhibit autonomous BCR signaling, suggesting yet another oncogenic mechanism that may explain its dismal prognosis. Finally, the non-GCB DLBCL lacking both autonomous BCR signaling and a potentially activating CARD11 mutation expressed the inherently autoreactive IGHV4-34 allele, opening the possibility that strong autoantigen stimulation might substitute for autonomous BCR signaling activity, thereby offering an alternative explanation for the BCR signaling pathway addiction in IGHV4-34-expressing cases. [Display omitted] DisclosuresVermeer:Innate Pharma: Other: Investigator in a clinical trial.

Primary cutaneous marginal-zone lymphoma

Primary cutaneous B cell lymphomas (PCBCL) are thesecond most common type of primary cutaneouslymphoma. The three main types of PCBCL areprimary cutaneous marginal-zone lymphoma(PCMZL), primary cutaneous follicle-centerlymphoma, and primary cutaneous diffuse largeB-cell lymphoma, leg type. PCMZL has an indolentcourse with a five-year survival rate approaching99%. Lesions most often present on the trunk or armas erythematous-to-violaceous papules, plaques, ornodules. Approximately one-half of patients havesolitary skin lesions. Treatment options includesurgery, radiation, and topical, intralesional orsystemic therapy. We present the case of a 33-yearoldHispanic woman with firm, pruritic, pink papuleson the forehead and cheeks, who was diagnosedwith PCMZL.

Akt activation confers an inferior survival in patients with activated B-cell subtype of diffuse large B-cell lymphoma: a report from The International DLBCL Rituximab-CHOP Consortium Program

Context Akt plays an essential role in diverse cellular processes such as cell proliferation, cell growth and apoptosis. Dysregulation of Akt signaling has been shown to correlate with an inferior survival in patients with a number of solid tumors and some hematologic malignances. The prognostic significance of Akt expression and the gene expression profile of Akt activation in diffuse large B-cell lymphoma (DLBCL) have not been thoroughly assessed. Objective In this study, we investigated Akt activation and analyzed its prognostic importance in a large cohort of patients with de novo DLBCL treated with R-CHOP immunochemotherapy. We also characterized the gene expression profile of DLBCL with activated Akt. Patients The study group consisted of 493 DLBCL patients treated with R-CHOP. These cases were organized as a part of the International DLBCL R-CHOP Consortium Program Study, and diagnosed according to the WHO criteria. Patients with primary mediastinal large B-cell lymphoma, primary cutaneous DLBCL, primary central nervous system DLBCL, and DLBCLs transformed from a low-grade B-cell lymphoma or associated with HIV infection were excluded. Methods Immunohistochemical studies (IHC) were performed in formalin-fixed paraffin-embedded sections of tissue microarrays to evaluate the expression of phosphorylated (activated) Akt and other relevant markers. Genetic alterations were examined by FISH for MYC , BCL-2 , and BCL-6 translocations and sequencing for TP53 mutation. Gene expression profiling (GEP) was performed to characterize the gene expression profile in Akt-activated DLBCL. The cell-of-origin (COO) subtypes were determined by GEP (gold standard) and IHC. Results Phosphorylated (activated) Akt (pAkt) expression was detected in 98 of 493 (20%) DLBCL tumors including 49 of 253 (19%) GCB DLBCL and 49 of 240 (20%) ABC DLBCL. In the GCB subtype, MYC, BCL-2 and MYC/BCL-2 translocations were more frequently found in pAkt+ DLBCL compared with pAkt- DLBCL ( P =0.04, 0.007 and 0.03, respectively). In contrast, translocations of these genes were rare and detected equally in pAkt+ and pAkt- subgroups within the ABC subtype ( P =0.7, 0.9 and 0.9, respectively). In the GCB group, TP53 mutation frequency was similar between pAkt+ and pAkt- DLBCL ( P =0.45). In contrast, TP53 mutations were significantly less frequent in ABC group (5% versus 22%; P = 0.01). Akt activation predicted a poorer survival, but the negative prognostic impact of Akt activation was significant in the ABC (5-year survival rate: 44% in pAkt+ versus 65% in pAkt-; P =0.01; 5-year PFS: 40% in pAkt+ versus 59% in pAkt-; P =0.01), but not GCB subtype (5-year survival rate: 67% in pAkt+ versus 74% in pAkt-, P =0.31; 5-year PFS rate: 61% in pAkt+ versus 69% in pAkt-, P =0.27). The negative impact of Akt activation appeared to be independent of Myc/Bcl-2 expression and TP53 mutation. In multivariate analysis, pAkt expression was an independent predictor of poorer OS (HR=2.72, 95% CI, 1.50-4.98, P =0.001) and PFS (HR=2.16, 95% CI, 1.22-3.82, P =0.008) in patients with ABC wild type- TP53 . In addition, AKT1 mRNA expression conferred significantly poor survival in DLBCL. Gene expression profiling revealed a distinct high-risk signature characterized by increased expression of multiple pro-survival genes (6 of 16 up-regulated genes; 40%) and decreased expression of genes encoding tumor suppressors (5 of 20 down-regulated genes; 25%) in pAkt+ ABC DLBCL. Conclusions Akt is activated in DLBCL, is equally distributed in COO subtypes, and has prognostic significance in patients with ABC DLBCL. Given the promising anti-lymphoma activity of Akt inhibitors in clinical trials, these findings may have clinical implications for DLBCL patients. Akt activation may be useful for prognostic stratification and could serve as a biomarker to guide patient selection and predict response to targeted anti-Akt therapy. Disclosures No relevant conflicts of interest to declare.

IX. Is it only about MYC? How to approach the diagnosis of diffuse large B-cell lymphomas.

Keywords: diffuse large B-cell lymphoma; cell of origin; genetic alterations; double hit; double expresser; MYC; BCL2; BCLU