Leg Type Research Articles

Thermoelectric performance and mechanical analysis of inner-arc type leg applied in solar thermoelectric generator

The solar thermoelectric generator (STEG) is capable of converting solar energy directly into electricity. To solve the contradictory relationship between thermoelectric efficiency and thermal stress, a new type of internal-arc thermoelectric leg is proposed. A mathematical model of STEG is established, and the effects of leg structure on the thermoelectric performance and thermal stress of STEG are analyzed. The results show that the new thermoelectric leg has excellent power output, which is 10.82% higher than that of rectangular leg. At the same time, it has lower thermal stress, which is 3.82% lower than that of rectangular leg. As the indicator of STEG structure optimization, this study uses the critical power density that can reach 113.63 × 105W/m3 for the inner-arc type thermoelectric leg, which is 146.97% of the X-type leg. Taking into account the thermoelectric performance and thermal stress, the best configuration is X-type thermoelectric leg when the concentration ratio is between 0 ∼ 72.5, and the inner-arc type is preferred when the concentration ratio is between 72.5 ∼ 89.8. By conducting further optimization of the inner-arc type leg, it is possible to achieve an enhancement in the critical power density, amounting to a notable increase of 64.63%. These findings hold significant implications for guiding the structural design of STEG.

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.

Clinical characteristics and efficacy analysis of 11 patients with primary cutaneous diffuse large B-cell lymphoma, leg type

Clinical characteristics and efficacy analysis of 11 patients with primary cutaneous diffuse large B-cell lymphoma, leg type

Clinician's perspective on the diagnosis of primary cutaneous B-cell lymphoma.

Of all cutaneous lymphomas, 25% are primary cutaneous B-cell lymphomas (PCBCLs). Of these, primary cutaneous follicle center lymphoma (PCFCL), primary cutaneous marginal zone B-cell lymphoma (PCMZL), and primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) are the most common subtypes. For the diagnosis of PCBCLs, a biopsy combined with immunohistochemistry and histological examination is the gold standard. PCBCLs are categorized into indolent or intermediate to aggressive subtypes based on their clinical behavior in a clinically oriented approach. PCDLBCL-LT has an aggressive course that spreads to extracutaneous sites in about 45% of cases, whereas PCFCL and PCMZL are indolent diseases. As a result, instrumental staging is advised for PCDLBCL-LT but not for extracutaneous disease after a diagnosis of PCMZL or PCFCL. Lastly, dermatoscopy may offer a novel diagnostic tool to improve the clinical recognition of various PCBCL subtypes when used in conjunction with a strong clinical suspicion.

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.

Cutaneous B-cell lymphomas: 2023 update on diagnosis, risk-stratification, and management.

Approximately one-fourth of primary cutaneous lymphomas are B-cell derived and are generally classified into three distinct subgroups: primary cutaneous follicle center lymphoma (PCFCL), primary cutaneous marginal zone lymphoma (PCMZL), and primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT). Diagnosis and disease classification is based on histopathologic review and immunohistochemical staining of an appropriate skin biopsy. Pathologic review and an appropriate staging evaluation are necessary to distinguish primary cutaneous B-cell lymphomas from systemic B-cell lymphomas with secondary skin involvement. Disease histopathology remains the most important prognostic determinant in primary cutaneous B-cell lymphomas. Both PCFCL and PCMZL are indolent lymphomas that infrequently disseminate to extracutaneous sites and are associated with 5-year survival rates that exceed 95%. In contrast, PCDLBCL, LT is an aggressive lymphoma with an inferior prognosis. PCFCL and PCMZL patients with solitary or relatively few skin lesions may be effectively managed with local radiation therapy. While single-agent rituximab may be employed for patients with more widespread skin involvement, multiagent chemotherapy is rarely appropriate. In contrast, management of patients with PCDLBCL, LT is comparable to the management of patients with systemic DLBCL.

1421 Primary cutaneous diffuse large B-cell lymphoma–leg type masquerading as a mucocele

1421 Primary cutaneous diffuse large B-cell lymphoma–leg type masquerading as a mucocele

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)

Design Scheme of Intelligent Robot Based on Crawler Sports Chassis

The chassis structure design of mobile robots is currently separated into four categories: wheel type, mechanical leg type, McNair wheel type, compound type, and crawler type, with wheel leg type, common crawler type, and wheel crawler type being under compound type. A formula Complex application scenarios frequently limit the robot's passibility throughout the actual application process. A new robot design plan is offered to overcome this problem: an intelligent robot built on a crawler-type moving chassis. To achieve the robot's astute observation of the surrounding environment, the advantages of wheeled and legged robots will be organically merged, and intelligent control terminals will be included in the hardware design. The mechanical framework will be built on a traditional crawler chassis, with leg guiding added. The crawler actuator of the structure will drive the crawler actuator of the leg-guided design to enable the robot to get out of problems in the face of challenging terrain conditions such as stairs, steps, and steep slopes. This work proposes an intelligent robot design strategy based on crawler motion chassis with high practicability, novelty, and broad applicability.

Violaceous Lesions on the Leg: What Else Apart from Kaposi Sarcoma? Differential Diagnosis with a Narrative Review of the Literature

With this work, we aimed to review the principal benign and malignant tumors (including vascular, keratinocytic/epidermal, melanocytic, hematopoietic, and lymphoid origin), primarily affecting the leg’s skin. The lesions’ location can also help focus on a spectrum of differential diagnoses in clinical practice. All the diseases present the same clinical presentation characterized by erythematous to violaceous nodules. Despite the same clinical presentation, each disease’s prognostic outcome and therapeutic management can be somewhat different. Since clinical diagnosis may sometimes be challenging, histology and immunohistochemistry play a fundamental role in recognizing and staging these types of lesions. Molecular studies can help to determine the exact nature of lesions with no specific characteristics. Kaposi’s sarcoma is an angioproliferative neoplasm that typically occurs in the lower limbs and can enter into differential diagnosis with several other rarer skin diseases. The principal differential diagnosis concerns primary cutaneous lymphomas, of which mycosis fungoides represent the most frequent primary cutaneous T-cell lymphoma. Other rare forms include primary cutaneous B-cell lymphomas, which can be divided into indolent and aggressive forms, such as the primary cutaneous diffuse large B-cell lymphoma, leg type, and lymphomatoid papulomatosis (LyP). In the case of indolent lesions, skin-directed therapies, limited-field radiotherapy, and surgical approaches can be good options. At the same time, different management, with systemic chemotherapy and allogenic bone marrow transplant, is required with aggressive neoplasms, such as blastic plasmacytoid dendritic cell neoplasia or advanced mycosis fungoides. The dermatologist’s role can be crucial in recognizing such diseases and avoiding misdiagnosis, giving the pathologist the correct clinical information for an accurate diagnosis, and starting the suitable therapy.

Distribution and clinical features of lymphomas involving skin in Taiwan.

A wide variety of primary and secondary lymphoma types involves the skin. However, reports with comparisons between both groups are limited in Taiwan. We retrospectively enrolled all cutaneous lymphomas and evaluated their clinicopathologic features. There were 221 cases of lymphoma: 182 (82.3%) primary and 39 (17.7%) secondary. Mycosis fungoides was the most common primary T-cell lymphoma, 92 (41.7%) cases, followed by CD30-positive T-cell lymphoproliferative disorders including lymphomatoid papulosis (n=33, 14.9%) and cutaneous anaplastic large cell lymphoma (n=12, 5.4%). The most frequent primary B-cell lymphomas were marginal zone lymphoma (n=8, 3.6%) and diffuse large B-cell lymphoma (DLBCL), leg type (n=8, 3.6%). DLBCL including variants was the most common secondary lymphoma involving skin. Most primary lymphomas presented at low-stage (T-cell, 86%; B-cell, 75%), whereas the majority of secondary lymphomas presented at high-stage (T-cell, 94%; B-cell, 100%). Patients with secondary lymphomas had an older mean age, more frequent B symptoms, lower serum albumin and hemoglobin, and a higher frequency of atypical lymphocytes in blood than those with primary lymphomas. In primary lymphomas, older age, lymphoma types, decreased lymphocyte counts and atypical lymphocytes in blood were poorer prognostic factors. In secondary lymphoma patients, lymphoma types, high serum lactate dehydrogenase and low hemoglobin levels predicted poorer survival. We found that the distribution of primary cutaneous lymphomas in Taiwan mirrors that of other Asian countries but shows some differences as compared with Western countries. Primary cutaneous lymphomas have a better prognosis than secondary lymphomas. Histologic classification of lymphomas highly correlated with disease presentation and prognosis.

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 ).

Cutaneous lymphomas—fast facts about an orphan disease—a short review

SummaryCutaneous lymphomas are a rare group of primary skin lymphoproliferative disorders, divided into T and B cell lymphomas. They differ substantially in clinical course and therapy. The two main subtypes of primary cutaneous T‑cell lymphomas include mycosis fungoides, which is the most common, and Sézary syndrome, the rare leukemic variant. Skin lesions seen in mycosis fungoides patients are erythematous patches, plaques, or tumors. Most patients remain at patch/plaque (early) stage, while some progress to tumor (advanced) stage during their clinical course. Sézary syndrome is characterized by erythroderma and involvement of lymph nodes and the peripheral blood. Treatment is dependent on the disease stage. Therapeutic options include skin-directed and systemic therapies. In localized, early stage mycosis fungoides, prognosis is usually good which changes in advanced stages. Significant progress has been made in recent years in the clinical management of progressive or relapsed cutaneous T‑cell lymphomas by the approval of new targeted therapies. Although there are no curative treatment options apart from allogeneic transplantation, response rates are often encouraging, in particular when using combination therapies. Primary cutaneous B cell lymphomas are rare and three main subtypes are recognized: primary cutaneous marginal zone lymphoma, primary cutaneous follicle center lymphoma, and primary cutaneous diffuse large B‑cell lymphoma, leg type. An accurate diagnosis of the subtype is important for therapeutic management. The most common clinical presentations are red-to-violaceous cutaneous nodules and papules. Primary cutaneous marginal and follicle center lymphoma have excellent 5‑year survival rates of 95–99%.

Primary Cutaneous Diffuse Large B Cell Lymphoma, Leg Type: A Rare Neoplasm Masquerading as Squamous Cell Carcinoma

Primary Cutaneous Diffuse Large B Cell Lymphoma, Leg Type (PCDLBCL, LT) comprises 4% of all cutaneous lymphomas, and it presents as an aggressive form of lymphoma. Rarely do pathologist/cytologists find specimens of PCDLBCL, LT on Fine Needle Aspiration Cytology (FNAC). The mimickers on FNAC are metastatic small cell carcinoma, Merkel Cell Carcinoma (MCC), Malignant Melanoma (MM), Cutaneous Alveolar Rhabdomyosarcoma and Primary Cutaneous Ewing's Sarcoma (PCES). A 75-year-old female patient presented in the Department of Surgery with multiple nodules on the leg for three months. On cytology small round cell tumour with possibility of non hodgkin lymphoma was given and biopsy was advised. The confirmation of PCDLBCL, LT on cytology is not recommended however, it is emphasised that it can be picked up on FNAC and distinguished from its mimickers. Because of the aggressive nature and poor prognosis with the frequent relapses and tendency for extracutaneous spread, it is considered to be a distinct type of cutaneous lymphoma which needs to be diagnosed and treated as early as possible.

Primary cutaneous diffuse large B-cell lymphoma, leg type, in an 80-year-old female patient. Clinical case

Primary cutaneous diffuse large B-cell lymphoma, leg type, is diagnosed in 20-25 % cases of all primary cutaneous B-cell lymphomas, primarily in elderly women (older than 70 years). The disease has aggressive recurrent progression and worse prognosis than other variants. The standard antitumor drug therapy are such regimens as R-CHOP and CHOP-like programs including anthracycline antibiotics. Use of these programs can be limited by the presence of cardiovascular and other concomitant disorders.Due to the limited variety of combinations of antitumor agents, low frequency of diagnosis of this immunomorphological variant of lymphoproliferative disease and absence of a single algorithm of drug therapy, every clinical case is interesting and informative.In the presented clinical case, an 80-year-old female patient with primary cutaneous diffuse large B-cell lymphoma, leg type, and concomitant pathology of the cardiovascular system underwent 2 courses of R-CVP regimen drug therapy without anthracyclines. A significant antitumor clinical effect was achieved in the form of complete tumor regression. Treatment was not accompanied by significant toxicity which allowed to complete therapy.

433 Single-cell characterization of primary cutaneous B-cell lymphomas reveals distinct clonal properties of marginal zone, follicle center and leg-type lymphomas

Primary cutaneous B-cell lymphomas (CBCL) comprise a group of extranodal non-Hodgkin lymphomas that are primarily confined to the skin. Primary cutaneous marginal zone lymphoma (MZL) and follicle center lymphoma (FCL) are associated with a rather indolent tumor behavior, while diffuse large B-cell lymphoma, leg type (DLBCL-LT) shows an aggressive clinical course. Besides distinct clinical and immune-histological features, the underlying molecular tumor biology is still only insufficiently understood.

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.

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.