Primary Cutaneous Diffuse Large B-cell Lymphoma, Leg Type Research Articles

Abstract 3833: Primary cutaneous diffuse large B-cell lymphoma-leg type and clinicopathologic determinants of survival: Analysis of a pooled database

Abstract Background: Primary Cutaneous Diffuse Large B-cell Lymphoma-Leg Type (PCDLBCL-LT) is a rare but non-indolent subtype of B-cell lymphoma. While most PCDLBCL-LT starts over the lower extremities, some cases may present at other cutaneous sites. The determinants of survival outcomes in this disease are not very well defined. Therefore, we conducted this pooled database analysis to identify the prognostic factors, clinicopathological characteristics, and therapeutic strategies that influence survival in this disease. Methods: To study the demographic characteristics, molecular and immunohistochemical signatures, therapeutic interventions, survival, and prognostic factors, we compiled a pooled database of 122 cases that fit the diagnostic criteria for PCDLBCL-LT. Kaplan-Meier survival curves were constructed. Cox proportional hazards model and Log-rank tests were used to assess the influence of demographic and clinicopathologic factors on overall survival (OS) and disease-free survival (DFS). Results: A total of 122 patients with confirmed PCDLBCL-LT were identified. The median age was 76. There was a male preponderance with M:F of 2.4. Seventy-three percent involved the extremities. The median duration of symptoms before diagnosis was 3.5 months. Involvement of lymph nodes, bone marrow, bone, and CNS occurred in 11%, 3%, 4%, and 3%, respectively. Constitutional symptoms were reported in 5%. The median OS and DFS of the whole group were 39 and 32 months, respectively. Patients younger than 70 had better median DFS (NR vs. 24 months, p=0.02) with a non-significant better median OS. Lymphadenopathy (45 vs. 18 months, p=0.006) and stage T3 compared to T1/T2 (16 vs 41 months, p=0.006) were associated with worse OS. Sex, constitutional symptoms, IHC phenotype, extra-lymphatic/extra-cutaneous organ involvement, and histologic cutaneous patterns did not impact OS. Compared to no treatment, chemotherapy, XRT+/-surgery, and stem cell transplant had numerically better OS without reaching statistical significance (5 vs. 39 vs. 41 vs. NR months, p=0.15). Patients who attained CR as their best response also had a superior median OS compared to responses less than CR and none (61 vs. 23 vs. 11 months, p<0.0001). Conclusion: This study presents updated clinicopathologic data from a large, pooled cohort of patients with PCDLBCL-LT. It identifies age, lymph node involvement, T stage, type of therapy, and quality of response to treatment as critical determinants of OS. Citation Format: Philip A. Haddad, Millicent Amankwah. Primary cutaneous diffuse large B-cell lymphoma-leg type and clinicopathologic determinants of survival: Analysis of a pooled database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3833.

A Descriptive Study of 103 Primary Cutaneous B-Cell Lymphomas: Clinical and Pathological Characteristics and Treatment from the Spanish Lymphoma Oncology Group (GOTEL).

Primary cutaneous B-cell lymphomas (PCBCLs) are B-cell lymphomas that can occur in the skin without evidence of extracutaneous involvement. The 2005 WHO/EORTC classification of cutaneous lymphomas and its 2018 update have distinguished three main categories based on clinicopathological, immunohistochemical, and genetic characteristics: primary cutaneous marginal zone lymphoma (PCMZL), primary cutaneous follicle centre lymphoma (PCFCL), and primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT). PCMZL and PCFCL are clinically indolent, while PCDLBCL-LT is an aggressive lymphoma. Due to its low incidence and lack of prospective studies, it is difficult to establish a standard treatment for each subgroup. The objective of our study was to describe the clinical and pathological characteristics of 103 patients with cutaneous B-cell lymphoma from 12 centres belonging to the Spanish Lymphoma Oncology Group. The median age was 53 years (40-65). According to skin extension, 62% had single-site lymphoma, 17% had regional lymphoma, and 20% had multifocal lymphoma. Histology: 66% had PCMZL, 26% had PCFCL, and 8% had PCDLBCL-LT. Twenty-three percent of the patients were treated exclusively with surgery, 26% with radiotherapy only, 21% with surgery plus radiotherapy, 10% with polychemotherapy, and 5% with rituximab monotherapy. Overall, 96% of patients achieved a complete response, and 44% subsequently relapsed, most of them relapsing either locally or regionally. The 10-year OS was 94.5% for the entire cohort, 98% for the PCMZL cohort, 95% for the PCFCL cohort, and 85.7% for the PCDLBCL-LT cohort. Our data are comparable to those of other published series, except for the high frequency of PCMZL. The expected heterogeneity in therapeutic management has been observed.

F-18 FDG PET/CT in staging and response assessment of primary cutaneous diffuse large B-cell lymphoma (leg type)

Primary cutaneous Diffuse Large B-Cell Lymphoma-leg type (PCDLBCL-LT) is a rare subtype of cutaneous lymphomas, with high frequency of extra-cutaneous relapse and poor prognosis. We report a case of 70-year-old lady who was diagnosed with PCDLBCL-LT on biopsy and underwent a baseline F-18 FDG PET/CT, followed by interim and post-treatment PET/CTs. With this case report, we highlight the findings of F-18 FDG PET/CT in the staging of this cutaneous lymphoma, and also emphasize on its role in the response assessment.

CD30 expression in cutaneous B-cell lymphomas.

CD30 expression has been infrequently described in cutaneous B-cell lymphomas (CBCLs). We examined CD30 expression in reactive lymphoid hyperplasia (RLH) and CBCL and correlated expression with clinicopathologic features. CD30 was examined in 82 CBCL patients and 10 RLH patients that had been evaluated in our cutaneous lymphoma clinics. The CBCL patients included: primary cutaneous follicle center lymphoma (PCFCL), Grade 1/2 systemic/nodal follicular lymphoma (SFL); primary cutaneous marginal zone lymphoma/lymphoproliferative disorder (PCMZL/LPD); systemic marginal zone lymphoma (SMZL); primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT); and extracutaneous/systemic diffuse large B-cell lymphoma (eDLBCL). We scored CD30 expression for intensity and extent and related CD30 expression to age at first diagnosis, sex, site of biopsy, clinical appearance, extracutaneous involvement, multiple cutaneous lesions, B-symptoms, lymphadenopathy, positive positron emission tomography/computed tomography (PET/CT), elevated lactate dehydrogenase (LDH), and positive bone marrow biopsy. CD30 expression was identified in 35% of CBCL, ranging from few, weak, scattered cells to strong and diffuse expression. It was most common in PCFCL and was not expressed in PCDLBCL-LT. Rare PCFCL expressed strong, diffuse CD30. Some cases of PCMZL/LPD, SMZL, FL, and RLH showed scattered, strongly positive cells. CD30 expression in CBCL was associated with favorable clinical features: younger age, negative PET/CT, and an LDH within normal limits. CD30 may be expressed in CBCL, possibly causing diagnostic confusion. CD30 expression was most commonly identified in PCFCL and is associated with favorable clinical features. In cases with strong and diffuse expression, CD30 could be a therapeutic target.

Unilateral lower extremity lymphedema as a first symptom of primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT)

Unilateral lower extremity lymphedema as a first symptom of primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT)

Images in haematology: Primary cutaneous diffuse large B cell lymphoma, leg type with an unusual presentation: A diagnostic challenge.

An 83-year-old woman with a history of arterial hypertension treated with amlodipine, and a well-differentiated cutaneous squamous cell carcinoma completely excised during the past year, was referred to dermatology consultations for the progressive appearance of indurated nodular skin lesions over the last two months, which began on the right lower extremity and progressed to the upper extremities, trunk and buttocks, with no other symptoms associated. With the differential between cutaneous lymphoma versus subcutaneous metastases, a punch biopsy of one of the lesions was performed. Histopathological examination demonstrated a dense hypodermal infiltrate composed of atypical large lymphocytes showing a round-shaped nucleus with vesicular chromatin and prominent single or multiple nucleoli. The immunohistochemical study showed positivity in neoplastic cells for CD79a, CD20, Bcl-2, MUM-1, c-myc and IgM, along with a high expression of Ki-67; and negativity for CD3, CD10, Bcl-6, CD30, p53, PD-L1 and Epstein-Barr Virus Encoded RNA. Molecular analyses were then performed without detecting BCL-2, BCL-6 or c-MYC rearrangements by fluorescence in situ hybridization, as well as the absence of p.L265P mutation in MYD88 through a quantitative polymerase chain reaction. Taking into account both histopathological and clinical findings, a primary cutaneous diffuse large B cell lymphoma, leg type (PCDLBCL-LT) and skin involvement in the course of a systemic DLBCL were considered, so blood tests and a positron emission tomography (18-FDG PET/CT) were then solicited. Blood tests showed a haemoglobin value of 12.5 g/dl with a normal white blood cell count and a slight β-2-microglobulin elevation (3.33 mg/L) in the context of a decreased renal function (54.38 ml/min/1.73m2). 18-FDG PET/CT revealed 23 hypermetabolic subcutaneous nodules distributed predominantly in the right arm and lower extremities, with no sign of disease in other locations (Figure 1), confirming the primary cutaneous origin of the disease and the final diagnosis of a PCDLBCL-LT. The patient underwent treatment with 6 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone, with progressive improvement of the skin lesions and complete resolution of them, and is currently being followed up by haematology and dermatology departments. Although the majority of PCDLBCL-LT, arise in the lower limbs (80%–85%), some patients can develop the disease in other areas, but in those cases, the lesions are usually individual or few in number, contrary to our case. PET imaging tests have a major role in the initial staging of the disease and treatment response evaluation, and they could even avoid bone marrow biopsy in selected patients. The double expression of bcl-2 and c-myc is frequent in PCDLBC-LT, although the prognostic value of this dual expression is yet unclear, whereas the absence of the MYD88 mutation could be associated with both better response to lenalidomide as well as better prognosis. For these reasons, immunohistochemical and molecular techniques can be helpful in defining prognosis and deciding therapeutic options in patients with PCDLBCL-LT and should be performed in routine practice. In conclusion, we present an extremely rare 18-FDG PET/CT image of a PCDLBCL-LT with 23 subcutaneous nodules, underlying the importance of this test for the study of these patients. Lucía Prieto-Torres – Attending the case and performing clinical research and manuscript revision. Pablo Villagrasa-Boli – Attending the case, revising existing literature and manuscript writing. Luis Ignacio Sancho-Val – Attending the case and manuscript revision. Pedro Paul – Attending the case and manuscript revision. Ana Leticia Tardin-Cardoso – Performing the imaging tests and their clinical interpretation. Mar García-García – Pathology diagnosis, taking microscopic images and manuscript revision. Mariano Ara-Martín – Proof checking. The authors have nothing to report. The authors declare that they have no conflict of interest. No funding has been received for this article.

Assessment of Liquid Biopsy in Primary Cutaneous Diffuse Large B-Cell Lymphoma–Leg Type

Liquid biopsy assessment has been first established in solid tumors, allowing the detection of either circulating tumor cells, cell-free vesicles and/or circulating tumor cell-free DNA (ctDNA), in the plasma or other biological fluids. In systemic diffuse large B-cell lymphomas (DLBCL), ctDNA is detectable, reflecting tumor mutational status, and may predict clinical outcome ( Bohers et al., 2018 Bohers E, Viailly P-J, Becker S, Marchand V, Ruminy P, Maingonnat C, et al. Non-Invasive Monitoring of Diffuse Large B-Cell Lymphoma by Cell-Free DNA High-Throughput Targeted Sequencing: Analysis of a Prospective Cohort. Blood Cancer J. 2018;1;8(8):74. Google Scholar ). In addition, dynamics of ctDNA correlates with clinical response ( Kurtz et al., 2019 Kurtz D.M. Esfahani M.S. Scherer F. Soo J. Jin M.C. Liu C.L. et al. Dynamic risk profiling using serial tumor biomarkers for personalized outcome Prediction. Cell. 2019; 178: 699-713.e19 Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar ; Deng et al., 2020 Deng Q, G Han, N Puebla-Osorio, M Chun John Ma, P Strati, B Chasen, et al. Characteristics of Anti-CD19 CAR T Cell Infusion Products Associated with Efficacy and Toxicity in Patients with Large B Cell Lymphomas. Nat Med. 2020;26 (12): 1878-1887. Google Scholar ; Kurtz et al. 2018). Primary cutaneous diffuse large B-cell lymphoma-leg type (PCDLBCL-LT) is an aggressive cutaneous lymphoma, presenting as rapid progressive tumor(s) in elderly ( Willemze et al., 2019 Willemze R. Cerroni L. Kempf W. Berti E. Facchetti F. Swerdlow S.H. Jaffe E.S. The 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas. Blood. 2019; 133: 1703-1714 Crossref PubMed Scopus (535) Google Scholar ). Mutational landscape of PCDLBCL-LT showed Activated B-cell-like DLBCL canonical mutations, ( Mareschal et al., 2017 Mareschal S. Pham-Ledard A. Viailly P.J. Dubois S. Bertrand P. Maingonnat C. et al. Identification of Somatic Mutations in Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type by Massive Parallel Sequencing. J Invest Dermatol. 2017; 137: 1984-1994 Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar ; Zhou et al. 2018) especially with high prevalence of MYD88L265P (70%) and CD79B (40%) mutations that allows its classification in MCD or C5 subgroup among DLBCL ( Schmitz et al., 2018 Schmitz R. Wright G.W. Huang D.W. Johnson C.A. Phelan J.D. Wang J.Q. et al. Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma. N Eng J Med. 2018; 378: 1396-1407 Crossref PubMed Scopus (936) Google Scholar ) ( Chapuy et al., 2018 Chapuy B, Stewart C, Dunford AJ, Kim J, Kamburov A, Redd RA, et al. 2018. Molecular Subtypes of Diffuse Large B-cell Lymphoma are Associated with Distinct Pathogenic Mechanisms and Outcomes ». Nat Med. 2018;24(5):679-690. Google Scholar ). Genetic analysis on primary tumors may be limited by tumor site, sample size but also by spatial and temporal mutational heterogeneity (Condoluci et Rossi 2019; Phallen et al., 2017 Phallen J, Sausen M, Adleff V, Leal A, Hruban C, White J, et alDirect detection of early-stage cancers using circulating tumor DNA. Sci Transl Med. 2017;16;9(403):eaan2415. Google Scholar ). Droplet digital PCR (ddPCR) and its increased sensitivity of 0.01% (Diaz et Bardelli 2014) may detect infraclinical systemic involvement and appears appropriate for single hot-spot mutations detection such as MYD88L265P. Next Generation Sequencing (NGS) may be more appropriate to capture the mutational landscape of ctDNA ( Galimberti et al., 2019 Galimberti S. Genuardi E. Mazziotta F. Iovino L. Morabito F. Grassi S. et al. The Minimal Residual Disease in Non-Hodgkin’s Lymphomas: From the Laboratory to the Clinical Practice. Front Oncol. 2019; 26: 528 Crossref Scopus (14) Google Scholar ).

Lymphome cutané primitif diffus à grandes cellules B-type jambe- de localisation faciale: image en médecine

Primary cutaneous diffuse large B-cell lymphoma, leg-type (PCDLBCL-LT) is a very rare, aggressive variant of extranodal lymphomas (accounting for 4% of all cutaneous lymphomas). It mainly affects women, with a median age of 76 years. As its name suggests, PCDLBCL-LT mainly occurs on the lower limbs. We here report the case of a 63-year-old male African patient presenting with multifocal nodules on his face that had been evolving for 3 months and whose appearance was primarily suggestive of cutaneous carcinoma, localized cutaneous granulomatosis or cutaneous metastasis. The diagnosis of PCDLBCL-LT was confirmed after skin biopsy with immunohistochemistry, showing positive B markers (CD20 and CD79a) associated with BCL2, BCL6 and Mum1 positivity and CD10 CD3 and CD5 negativity. The Ki67 proliferation index was estimated at 71% and Pet-scan did not show any other disease location. The patient received immunochemotherapy combining rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone, with good clinical improvement.

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

Genetic Stability of Driver Alterations in Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type and Their Relapses: A Rationale for the Use of Molecular-Based Methods for More Effective Disease Monitoring.

Simple SummaryPrimary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is an aggressive cutaneous lymphoma with high response rates to initial immune-polychemotherapy but with frequent relapses and disease-related death. To study the genetic profile during the disease course, 73 samples of primary/pre-treatment and relapsed/refractory disease of 57 patients with PCDLBCL-LT were molecularly characterized, including paired analysis in 16 patients. Targeted next-generation sequencing demonstrated genetic stability of the main oncogenic driver alterations of PCDLBCL-LT, especially (hotspot) mutations in MYD88/CD79B and loss of CDKN2A. As nearly all patients (95%) harboured one or more of these drivers, patients could benefit from targeted therapies addressing these alterations. Additionally, genetic stability serves as a rationale for the use of molecular-based methods for disease monitoring during follow-up, improving response evaluation and early identification and intervention of disease relapses in PCDLBCL-LT patients.Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is a rare, aggressive cutaneous lymphoma with a 5-year disease-specific survival of only ~55%. Despite high response rates to initial immune-polychemotherapy, most patients experience a disease relapse. The genetic evolution of primary and relapsed/refractory disease has only scarcely been studied in PCDLBCL-LT patients. Therefore, in this retrospective cohort study, 73 primary/pre-treatment and relapsed/refractory biopsies of 57 patients with PCDLBCL-LT were molecularly characterized with triple FISH and targeted next-generation sequencing for 52 B-cell-lymphoma-relevant genes, including paired analysis in 16 patients. In this cohort, 95% of patients harboured at least one of the three main driver alterations (mutations in MYD88/CD79B and/or CDKN2A-loss). In relapsed/refractory PCDLBCL-LT, these oncogenic aberrations were persistently present, demonstrating genetic stability over time. Novel alterations in relapsed disease affected mostly CDKN2A, MYC, and PIM1. Regarding survival, only MYC rearrangements and HIST1H1E mutations were statistically significantly associated with an inferior outcome. The stable presence of one or more of the three main driver alterations (mutated MYD88/CD79B and/or CDKN2A-loss) is promising for targeted therapies addressing these alterations and serves as a rationale for molecular-based disease monitoring, improving response evaluation and early identification and intervention of disease relapses in these poor-prognostic PCDLBCL-LT patients.

Histopathological Features of Primary Cutaneous Diffuse Large B-Cell Lymphoma Leg Type: A Case Report

Background: Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT), is a rare and aggressive lymphoma with poor prognostic. It is difficult to diagnose PCDLBCL-LT at an early stage due to its nonspecific manifestations that overlap with other lymphomas. A histopathological examination can be performed to establish the diagnosis.
 Case Presentation: A 74-year-old female presented with itchy red, swollen patches accompanied by a burning sensation on both her legs. Clinical examination revealed a hard ping pong ball-sized lump palpable on her left inner thigh. Haematoxylin eosin staining demonstrated the proliferation of diffused neoplastic cells, homogenous cells with atypical nuclei, and mitoses. Immunohistochemical examination revealed positive for CD 45 as well as CD 20 and negative for CD3. These findings were consistent with a diagnosis of PCDLBCL-LT.
 Conclusion: The presented case demonstrates that skin lesions in patients with diagnosed PCDLBCL-LT may have a variable clinical presentation. Histologically is characterized by a diffuse dermal infiltrate mostly consisting of activated B-cell (centroblast) and activated lymphocyte (immunoblast), with high mitotic activity and a minimal T-reactive component. Immunohistochemical analysis is necessary for establishing the diagnosis of PCDLBCL-LT which shows positive markers for CD 45, CD 20, CD79a, Bcl-2, MUM-1, FOX-P1, CD10, IgM, CD 138, Ki-67, CD 30 and MYC.

Patient-Derived Xenograft and Cell Line Models of Human Primary Cutaneous Diffuse Large B-Cell Lymphoma-Leg Type

Primary cutaneous diffuse large B-cell lymphoma, leg-type (PCDLBCL-LT) is a rare and aggressive malignancy, mostly occurring on the leg of elderly women (Willemze et al., 2019). PCDLBCL-LT harbors an activated B-cell‒like diffuse large B-cell lymphoma (ABC-DLBCL) signature and is enriched for mutations involving the toll-like receptor, B-cell receptor, and NF-κB pathways (Pham-Ledard et al., 2012; Zhou et al., 2018). The high frequency of MYD88L265P mutation in combination with those of CD79B and PIM1 relates these lymphomas to the MCD/C5 subset of diffuse large B-cell lymphomas, which includes ABC-DLBCL occurring in extranodal sites (Danilov et al., 2022).

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.

Immunohistochemical algorithms and gene expression profiling in primary cutaneous B-cell lymphoma

Objectiveto assess whether immunohistochemical (IHC) algorithms used to classify the cell of origin (COO) of nodal Diffuse Large B-cell lymphoma (nDLBCL) in Germinal Center type (GCB) and non-GCB subtypes may be applied to Primary Cutaneous B-cell lymphoma (PCBCL) too, and which of these algorithms performs better on PCBCL. DesignRetrospective case control study. SettingPathology Department of the University Hospital “San Giovanni di Dio e Ruggi d′Aragona” Salerno, Italy. ParticipantsFourteen PCBCL, including Primary Cutaneous follicle centre lymphoma (PCFCL) and primary cutaneous diffuse large B-cell lymphoma, Leg type (PCDLBCL-LT) and 14 nDLBCL were evaluated for 7-year period (January 2011 to December 2017). Primary cutaneous marginal zone cell lymphoma (PCMZL) cases were not included in the present study. InterventionEvaluation of immunohistochemical CD10, BCL6, MUM1/IRF4, BCL2, MYC and Ki-67 expression and classification according to three different algorithms. Gene expression profiling (GEP) was performed on the same series using Lymph2Cx assay (Nanostring). The data obtained were compared and analysed. ResultsAll the IHC algorithms showed 13 GCB and 15 non-GCB. GEP showed 12 GCB, 12 activated B cell–type and 4 unclassified. ConclusionsThe PCBCL were classifiable as GCB and non-GCB like the nDLBCL as IHC algorithms were concordant to GEP and produced the same results.

Cell-of-origin classification using the Hans and Lymph2Cx algorithms in primary cutaneous large B-cell lymphomas

Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) and primary cutaneous follicle center lymphoma with a diffuse population of large cells (PCFCL-LC) are both primary cutaneous B-cell lymphomas with large-cell morphology (CLBCL) but with different clinical characteristics and behavior. In systemic diffuse large B-cell lymphoma, not otherwise specified (DLBCL-NOS), gene-expression profiling (GEP) revealed two molecular subgroups based on their cell-of-origin (COO) with prognostic significance: the germinal center B-cell-like (GCB) subtype and the activated B-cell-like (ABC) subtype. This study investigated whether COO classification is a useful tool for classification of CLBCL. For this retrospective study, 51 patients with PCDLBCL-LT and 15 patients with PCFCL-LC were analyzed for their COO according to the immunohistochemistry-based Hans algorithm and the NanoString GEP-based Lymph2Cx algorithm. In PCFCL-LC, all cases (100%) classified as GCB by both Hans and Lymph2Cx. In contrast, COO classification in PCDLBCL-LT was heterogeneous. Using Hans, 75% of the PCDLBCL-LT patients classified as non-GCB and 25% as GCB, while Lymph2Cx classified only 18% as ABC, 43% as unclassified/intermediate, and 39% as GCB. These COO subgroups did not differ in the expression of BCL2 and IgM, mutations in MYD88 and/or CD79B, loss of CDKN2A, or survival. In conclusion, PCFCL-LC uniformly classified as GCB, while PCDLBCL-LT classified along the COO spectrum of DLBCL-NOS using the Hans and Lymph2Cx algorithms. In contrast to DLBCL-NOS, the clinical relevance of COO classification in CLBCL using these algorithms has limitations and cannot be used as an alternative for the current multiparameter approach in differentiation of PCDLBCL-LT and PCFCL-LC.

A rare case of primary cutaneous diffuse large B cell lymphoma, leg type with metastasis

<p class="abstract">Primary cutaneous diffuse large B cell lymphoma, leg type (PCDLBCL-LT) is a rare and aggressive type of primary cutaneous B cell lymphoma (PCBCL), which represents 10-20% cases of PCBCL. It has a 40-50% recurrence rate and 5 year survival rate of 50%. Here, we present a case of an 86 year old female who presented to us with complaints of slightly tender annular plaques with an oedematous base present over bilateral lower limbs and pitting oedema. Histopathological examination from the annular lesion showed normal epidermis, grenz zone and a dense lymphoid infiltrate involving almost the entire dermis. Immunohistochemistry confirmed histological findings, atypical cell were positive for CD20 and MUM1 protein with focal expression of BCL 6 which is rare. Based on the above findings, we made a diagnosis of diffuse large B cell lymphoma-leg type and started her on palliative radiotherapy. As PCBCL-LT is rare and aggressive lymphoma, we present this case to review literature and summarise its clinical features.</p>

Clinical and Histological Spectrum of Primary Cutaneous B-Cell Lymphoma in an Ethnically-Diverse Group of Patients: A Case Series

Primary cutaneous lymphomas, which are diagnosed with only skin involvement, can be of B or T cell origin. Due to their varied origin as well as their diverse presentations, these groups have been divided further into more descriptive and representative groups. The subtypes are primary cutaneous marginal zone lymphoma (PCMZL), primary cutaneous follicle center lymphoma (PCFCL), primary cutaneous diffuse large B cell lymphoma, leg type (PCDLBCL-LT) and intravascular large B-cell lymphoma. Here, we present the cases of three ethnically diverse patients with distinct clinical and histological forms of cutaneous B cell lymphoma.

Primary cutaneous diffuse large B-cell lymphoma, leg type: case report

ABSTRACT The report describes the clinic of an aggressive non-Hodgkin lymphoma, primary cutaneous diffuse large-B cell lymphoma, leg type (PCDLBCL-LT), and shows its relevance for addressing the case of a rare lymphoma, with complex diagnosis and, in most cases, late as there are few studies reported on the subject. Since it is an aggressive pathology, it is essential to have the dissemination of knowledge to assist in the early diagnosis of the disease and, consequently, in the choice of a more effective treatment. Therefore, we seek to demonstrate the main clinical characteristics, as well as the diagnostic approach, staging, and the symptomatic and specific treatment of PCDLBCL-LT.

Primary cutaneous diffuse large B-cell lymphoma, leg-type: The Mayo Clinic experience.

e20044 Background: Primary Cutaneous Diffuse Large B-cell Lymphoma, Leg-type (PCDLBCL) is a rare lymphoma comprising 4% of all cutaneous lymphomas with an aggressive clinical course. We investigated disease characteristics and outcomes among patients PCDLBCL. Methods: Following IRB approval, we identified patients retrospectively with PCDLBCL treated at the Mayo Clinic Cancer Center 1998-2019. Results: 45 pts were identified with a median age of 71 years (Range- 48-95) and 28 (62%) were female. Disease locations were legs (62%), arms (22%), head (11%), trunk (2%) and multiple sites (2%). At diagnosis, (51%) had a single lesion, (29%) had multiple lesions in 1-2 contiguous regions, (16%) had multiple lesions in non-contiguous regions or > 2 regions and data was not available (4%). Immunohistochemistry showed positive staining for BCL-2 (92%), BCL-6 (76%), c-MYC (62%), MUM1 (95%), CD10 (11%), and cytoplasmic IgM (8/9- 89%). By Han’s criteria, (95%) had activated B cell lymphoma (ABC). Median Ki-67 was 90% (range, 50,100%). 9/12 (75%) were positive for MYD88 L265P mutation. 13/21 (62%) were double expressor and 3/22 (14%) had double hit lymphoma. 37/45 (82%) had ECOG < 2. LDH was elevated in 13/37 (35%). The median number of therapies was 1 (range; 1-11). The initial treatments were chemo-radiation (30%), chemo alone (38%), rituximab alone (11%), radiation (RT) alone (16%), rituximab-RT (2.5%), and surgical (2.5%). The median follow-up time for the whole cohort was 80 months (95% CI; 32, 169). The median progression free survival and overall survival (OS) were 20 months (95% CI; 12, 34) and 80 months (95% CI; 48, 119). 22/45 (49%) are alive. The cause of death was disease-related in 11/23 (48%). The median number of relapses was 1 (range; 0, 11) with (60%) relapsed after first line. 4/45 pts had autologous stem cell transplant after relapse. 7/45 (16%) had a systemic relapse at a median time of 35 months from diagnosis (range; 16, 112). Age above 60 years was associated with worse OS; 70 months (95% CI; 30, 99) vs NR (95% CI; 135, NR), p = 0.025. ECOG performance status < 2 was associated with better OS, NR months (95% CI; 80, NR) vs 48 months (95% CI; 3.3, 88),p = 0.0003. 1 pt received Ibrutinib on 11th relapse and had 3 years of PFS. Conclusions: PCDLBCL is predominantly ABC type, affects elderly pts and is characterized by multiple cutaneous relapses followed in some cases by systemic relapses. Increased age and poor performance status had a negative impact on OS. High incidence of MYD88 L265P mutation is observed in PCDLBCL similar to immune-privileged site lymphomas.

Transformation from Indolent Primary Cutaneous Marginal Zone Lymphoma to Aggressive Primary Cutaneous Diffuse Large B-Cell Lymphoma: A Rare Case and Review of the Literature

Introduction Primary cutaneous B-cell lymphomas (PCBCLs) arise within the skin without evidence of extracutaneous involvement at the time of diagnosis. The incidence of PCBCL is rare, and PCBCLs are less common than primary cutaneous T-cell lymphomas. There are three subgroups of PCBCL: primary cutaneous marginal zone lymphoma (PCMZL), primary cutaneous follicle-cell lymphoma (PCFCL), and primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT). The 5-year survival rates of the former two subtypes exceed 90%, whereas PCDLBCL-LT is approximately 50% (Wilcox 2015). We describe a rare case of indolent PCMZL transforming into the more aggressive PCDLBCL-LT as well as a review of literature and case series. Case A 62-year-old man with history of PCMZL refractory to external beam radiation and rituximab chemotherapy presented with a two-month history of an enlarging rash and three nodules on his left leg. On physical exam, two violaceous, infiltrative plaques with distinct borders were present on the left leg, resembling his past PCMZL. Three new lesions were described as deep-seated 2 cm erythematous nodules (Fig 1). Histologic review of the new nodules revealed a diffuse, dermal-based atypical lymphoid infiltrate extending from the papillary dermis into the subcutis. The atypical lymphoid cells contained mostly round nuclei, vesicular chromatin, and prominent nucleoli consistent with an immunoblastic and centroblastic morphology (Fig 2). They expressed B-cell markers such as CD79a and CD19, and were negative for CD20 most likely due to prior treatment with rituximab. Immunohistochemistry demonstrated positivity for Bcl-2 and MUM1. Discussion Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is a rare and aggressive B-cell lymphoma. This subtype is positive for CD20 and CD79, negative for CD5 and CD10, and strongly positive for Bcl-2 and MUM1. It has the gene expression profile of the ABC subtype. A nodule on the lower leg is an ominous sign given this subtype's predilection for lower extremities. This subtype affects the elderly as opposed to the indolent subtypes that arise in middle age (Willemze 2005). Prognosticating PCDLBCL-LT is challenging, as survival rates vary from 40 to 70% (Willemze 2005). Additionally, the aggressive nature of PCDLBCL-LT confers use of more aggressive, systemic chemotherapy regimens. Rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R-CHOP) chemotherapy followed by external beam irradiation is recommended, though no large prospective clinical trials have been performed to date. If lesions remain refractory to R-CHOP, the treatment goal should be redirected to treat as a refractory systemic diffuse large B-cell lymphoma which may require bone marrow transplant or targeted agents with known activity in the ABC subtype such as lenalidomide or ibrutinib. Transformation from PCMZL to PCDLBCL-LT is a rare event and has only been described in 2 case series (Table 1). In our review of the prior cases, the age group was heterogenous ranging from 29 years-old to 80 years-old. There was no consensus treatment, however, the majority of patients did receive at least CHOP-based regimen. Survival ranged from 24 months to 180 months, showing the heterogeneity of the disease process. In our patient, he underwent R-CHOP but progressed and then received salvage R-ICE with CR. He then underwent bone marrow transplantation but unfortunately had recurrence 36 days post-transplantation, proven PCDLBCL-LT, and he died 161 days following his allogeneic transplant. Conclusion Although PCMZL and PCFCL frequently recur despite treatment, transformation to PCDLBCL-LT is unusual. To date, transformation from PCMZL to PCDLBCL-LT has been described rarely in the literature (Table 1). PCMZL is indolent and is treated with external beam radiation therapy or surgical excision with excellent prognosis, the aggressive PCDLBCL-LT subtype has a poor outcome and requires systemic chemotherapy. Because of the vast difference in prognosis and treatment between PCMZL and PCDLBCL-LT, early recognition and exhaustive work-up is beneficial to the patient. Considering this transformation is both rare and diagnostically challenging, clinicians should have heightened concern for new nodular lesions in the setting of recurrent indolent primary cutaneous B-cell lymphomas. Disclosures Yazbeck: Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.