CD30 plays a role in T-dependent immune response and T cell proliferation.

CD30 is a member of the tumor necrosis factor receptor (TNFR) superfamily and expressed in both normal and malignant lymphoid cells. However, the role of CD30 in lymphopoiesis is not known. In this study, we showed CD30 was expressed both in T and B cells, but its deficiency in mice had no effect on T- and B-cell development. In fact, CD30 deficiency attenuated B-cell response to T-cell-dependent antigens. The impaired B cell response in CD30-deficient mice is caused by the reduction of activation-induced cytidine deaminase (AID) expression. Moreover, CD30-deficient mice exhibited decreased TCR-mediated T cell proliferation and slightly impaired TCR signaling. High-throughput RNA sequencing analysis revealed that CD30 deficiency led to a decrease of FOXO-autophagy axis in T cells upon TCR stimulation. Thus, CD30 positively regulates T-cell-dependent immune response and T cell proliferation.

CD30 expression in an emerging group of mesenchymal spindle cell neoplasms with ALK fusion detected by flow cytometry and immunohistochemistry.

An emerging group of spindle cell neoplasms harboring fusions involving NTRK or non-NTRK kinase genes often share characteristic S100 and/or CD34 expression; however, the diagnostic utility of immunohistochemical stains is not well established in this family owing to their lack of specificity. Recently, CD30 expression in spindle cell neoplasms with kinase gene fusions, such as NTRK, BRAF, RAF1, and RET, has been increasingly identified. We herein report a 10-year-old girl with high-grade spindle cell sarcoma of the neck. Prior to histopathological evaluation, flow cytometry (FCM) analysis and touch smear cytology of the tumor tissue revealed CD34+ and dimCD30+ spindle cell populations. Histopathologically, the case was characterized by monomorphic spindle-shaped cytomorphology with CD30, S100, and CD34 positivity and harbored close similarities with spindle cell neoplasms with NTRK or non-NTRK gene fusions. Subsequently, a comprehensive next-generation sequencing sarcoma panel identified a rare PLEKHH2::ALK fusion, and a diagnosis of ALK-rearranged spindle cell neoplasm was made. The patient showed significant tumor response to single-agent treatment with alectinib, an ALK-tyrosine kinase inhibitor. This case supports that CD30 is expressed in an ALK-rearranged mesenchymal neoplasm. The benefit of the early detection of CD30 expression by FCM for a prompt diagnosis and treatment is highlighted in the context of an aggressive clinical course. This case represents a learning experience regarding the need to the check the status of CD30 expression in these tumors and suggests the potential clinical benefits of CD30-targeted therapy.

The Opposite Functions of CD30 Ligand Isoforms.

TNFSF8/CD30 ligand is a TNF superfamily member expressed on several major immune cell types, including activated monocytes, B, and T cells. The signaling of CD30 ligand through its cognate CD30 receptor has been shown to have effects on cell differentiation, cell death/survival, and cytokine production. The signaling pair has been implicated in hematopoietic malignancies and inflammatory disease, and a chemotherapy-CD30 antibody combination for the treatment of Hodgkin and other lymphomas has been developed. There are two recorded isoforms of CD30 ligand. All hitherto studies of CD30 ligand are of the first, canonical isoform, while the second isoform has never been described. This study aims to elucidate the properties and signaling functions of the second CD30 ligand isoform. We have found mRNA expression of both isoforms in the PBMCs of all six healthy donors tested. Through methods in cell biology and biochemistry, we were able to discover that the second CD30 ligand isoform has no discernable pro-inflammatory function and, in fact, isoform 2 can restrict the capacity of the canonical isoform to signal through the CD30 receptor by preventing their interaction. This discovery has implications for the future development of therapeutics targeting the CD30/CD30 ligand signaling pair in cancer and inflammatory disease.

Peripheral T-cell lymphomas expressing CD30 and CD15 expand the spectrum of anaplastic large cell lymphoma, ALK-negative.

Peripheral T-cell lymphomas (PTCL) are morphologically and biologically heterogeneous and a subset expresses CD30, including anaplastic large cell lymphomas (ALCL) and a minority of PTCL, not otherwise specified (PTCL, NOS). ALCL with ALK translocations (ALCL, ALK+) are readily identified by routine diagnostic methods, but differentiating ALCL without ALK translocation (ALCL, ALK-) and PTCL, NOS expressing CD30 (PTCL CD30+) can be challenging. Furthermore, rare PTCL co-express CD30 and CD15 (PTCL CD30+CD15+); some resemble ALCL, ALK- while others resemble classic Hodgkin lymphoma. To explore the relationship between PTCL CD30+CD15+ and ALCL, ALK-, we analysed 19 cases of PTCL with CD30 expression, previously diagnosed as ALCL, ALK- (nine cases) and PTCL CD30+CD15+ (10 cases) for DUSP22/IRF4 rearrangements, coding RNA expression and selected transcriptome analysis using the NanoString nCounter gene expression analysis platform. Unsupervised clustering showed no clear segregation between ALCL, ALK- and PTCL CD30+CD15+. Three cases previously classified as PTCL CD30+CD15+ showed DUSP22/IRF4 rearrangements, favouring a diagnosis of ALCL, ALK-. Our results suggest that cases previously designated PTCL CD30+CD15+, likely fall within the spectrum of ALCL, ALK-; additionally, a subset of ALCL, ALK- with DUSP22/IRF4 rearrangement expresses CD15, consistent with previous reports and expands the immunophenotypic spectrum of this lymphoma subgroup.

Stenotrophomonas maltophilia skin infection in an immunocompetent patient: Primary cutaneous CD30+ T-cell lymphoproliferative disorder or pseudolymphoma?

Cutaneous pseudolymphomas are a wide group of diseases mimicking cutaneous lymphoma. They comprise several skin conditions with different etiopathogenesis, clinical-pathological features, and prognosis, which may occur in the absence of an identifiable trigger factor or after administration of medications or vaccinations, tattoos, infections, or arthropod bites. They present with different manifestations: from solitary to regionally clustered lesions, up to generalized distribution and, in rare cases, erythroderma. They persist variably, from weeks to years, and resolve spontaneously or after antibiotics, but may recur in some cases. CD30+ T-cell pseudolymphomas are characterized by the presence of large, activated lymphoid cells, generally in response to viral infections, arthropod assault reactions, and drug eruptions. Stenotrophomonas maltophilia is a ubiquitous Gram-negative bacillus responsible for opportunistic infections in immunocompromised patients. Infection of intact skin in immunocompetent patients is particularly rare. Here, we report a case of a man presenting an isolated nodule histopathologically mimicking a primary cutaneous CD30+ T-cell lymphoproliferative disorder.

Primary leptomeningeal CD30 positive diffuse large B cell lymphoma disguise as meningioma in a young adult: a case report.

BACKGROUND: Primary leptomeningeal lymphoma (PLML) without brain parenchymal involvement or systemic disease is very rare, comprising of approximately 7% of all primary central nervous system lymphomas (PCNSL). PLML is a diagnosis of exclusion which should be confirmed on biopsy after ruling out metastasis from systemic lymphomas and dissemination from PCNSL. CASE DESCRIPTION: A 21-year-old patient presented with the chief complaints of headache, diplopia, decreased vision for five months, and a swelling on the left side of the forehead for four months. On radiology, a large, lobulated, extra-axial mass lesion along the left frontal region with its base towards dura noted. No parenchymal or subependymal CNS lesions were found on CT/MRI. Histopathology was reported as primary leptomeningeal CD30 positive diffuse large B cell lymphoma. CONCLUSIONS: PLML is a very rare meningeal tumor that requires a very high index of suspicion and is always a diagnosis of exclusion.

Flow Cytometry Analysis in Breast Implant-Associated Anaplastic Large Cell Lymphoma: Three Case Reports.

Breast Implant-Associated-Anaplastic Large Cell Lymphoma (BIA-ALCL) is a rare T-cell non-Hodgkin lymphoma associated with breast prosthetic implants and represents a diagnostic challenge. The National Comprehensive Cancer Network (NCCN) guidelines, updated in 2024, recommend for diagnosis an integrated work-up that should include cell morphology, CD30 immunohistochemistry (IHC), and flow cytometry (FCM). CD30 IHC, although the test of choice for BIA-ALCL diagnosis, is not pathognomonic, and this supports the recommendation to apply a multidisciplinary approach. A close collaboration between pathologists and laboratory professionals allowed the diagnosis of three BIA-ALCLs, presented as case reports, within a series of 35 patients subjected to periprosthetic effusions aspiration from 2018 to 2023. In one case, rare neoplastic cells were identified by FCM, and this result was essential in leading the anatomopathological picture as indicative of this neoplasm. In fact, the distinction between a lymphomatous infiltrate from reactive cells may be very complex in the cytopathology and IHC setting when neoplastic cells are rare. On the other hand, one limitation of FCM analysis is the need for fresh samples. In this study, we provide evidence that a dedicated fixative allows the maintenance of an unaltered CD30 expression on the cell surface for up to 72 h.

Expression and Clinical Significance of CD30 and CD56 in Lymphoblastic Lymphoma: A Retrospective Analysis on Paraffin-Embedded Tissues by Immunohistochemistry.

Background: We evaluated CD30 and CD56 expression in lymphoblastic lymphoma (LBL) and correlated the results with clinicopathological features and prognosis. Methods: Immunohistochemical (IHC) staining was performed on 85 formalin-fixed paraffin-embedded LBL specimens using two CD30 clones and one CD56 antibody clone. Results: Weak and diffuse expression of CD30 was expressed in 4.7% (clone Ber-H2) or 14.1% (clone EPR4102) in LBL, while CD56 was expressed in 24.7%. CD30 and CD56 expression correlated with lactate dehydrogenase levels. CD56-positive expression was closely associated with an unfavorable prognosis. Although CD30 expression exhibited a trend toward poorer overall survival, it did not reach statistical significance. Conclusion: CD56 is a potential negative prognostic marker. These findings suggest that CD30 and CD56 targeted therapies could be potential therapeutic targets for LBL patients.

The oncogenic driving force of CD30 signaling-induced chromosomal instability in adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATL) develops via stepwise accumulation of gene mutations and chromosome aberrations. However, the molecular mechanisms underlying this tumorigenic process are poorly understood. We previously reported the presence of a biological link between the expression of CD30, which serves as a marker for ATL progression, and the actively proliferating fraction of human T-cell leukemia virus type 1 (HTLV-1)-infected cells that display polylobulation. Here, we demonstrated that CD30 signaling induced chromosomal instability with clonal expansion through DNA double-strand breaks (DSBs) via an increase of intracellular reactive oxygen species. CD30+ ATL cells were composed of subclones with additional genomic aberrations compared with CD30- ATL cells in ATL patients. Furthermore, we found an accumulation of copy number loss of DSB repair-related genes as the disease progressed. Taken together, CD30 expression on ATL cells appears to be correlated with genomic instability, suggesting that CD30 signaling is one of the oncogenic factors of ATL progression with clonal evolution. This study provides new insight into the biological roles of CD30 signaling and could improve our understanding of tumorigenic processes of HTLV-1-infected cells.

CD30 induces Reed-Sternberg cell-like morphology and chromosomal instability in classic Hodgkin lymphoma cell lines.

Classic Hodgkin lymphoma (cHL) is characterized by multinucleated cells called Reed-Sternberg (RS) cells and genetic complexity. Although CD30 also characterizes cHL cells, its biological roles are not fully understood. In this report, we examined the link between CD30 and these characteristics of cHL cells. CD30 stimulation increased multinucleated cells resembling RS cells. We found chromatin bridges, a cause of mitotic errors, among the nuclei of multinucleated cells. CD30 stimulation induced DNA double-strand breaks (DSBs) and chromosomal imbalances. RNA sequencing showed significant changes in the gene expression by CD30 stimulation. We found that CD30 stimulation increased intracellular reactive oxygen species (ROS), which induced DSBs and multinucleated cells with chromatin bridges. The PI3K pathway was responsible for CD30-mediated generation of multinucleated cells by ROS. These results suggest that CD30 involves generation of RS cell-like multinucleated cells and chromosomal instability through induction of DSBs by ROS, which subsequently induces chromatin bridges and mitotic error. The results link CD30 not only to the morphological features of cHL cells, but also to the genetic complexity, both of which are characteristic of cHL cells.

CD30 as a therapeutic target in adult haematological malignancies: Where are we now?

CD30 is a transmembrane protein from the tumour necrosis factor receptor superfamily. It is expressed on a small subset of activated T and B lymphocytes, and various lymphoid neoplasms. CD30 is a particularly interesting treatment target because its levels are high in tumours but low in healthy tissues. Several therapeutic strategies targeting CD30 have been developed, including monoclonal antibodies, conjugated antibodies (combination of brentuximab vedotin with chemotherapy or immunotherapy), bispecific antibodies and cell and gene therapies, such as anti-CD30 CAR-T cells in particular. We briefly review the biology of CD30 which makes it a good therapeutic target, and we describe all of the anti-CD30 therapies that have emerged to date.

Anti-CD30 (Ber-H2) epitope requires structural elements as shown by mass spectroscopy and dual-site associated kinetics.

The Ber-H2 mouse monoclonal antibody has been in use for 35 years for detecting the CD-30 biomarker in a variety of lymphomas. Despite the wide use of this clone, we have not been successful in applying synthetic peptides derived from the published epitope sequence and affinity data toward the development of a new Ber-H2-based in vitro diagnostic reagent assay. We found that synthetic peptides based on the published epitope sequence do not function to inhibit antibody-binding activity, thus indicating that the sequence is not the full epitope recognized by Ber-H2. In this report, we used mass spectroscopic analysis of proteolyzed CD30 fragments capable of binding Ber-H2 to identify additional regions within the epitope that participate in binding. Using surface plasmon resonance binding kinetic analyses and immuno-histochemical peptide-inhibition assays, we also demonstrate that the epitope sequence as originally reported is missing two key elements necessary for binding the Ber-H2 antibody.

Frequent CD30 Expression in an Emerging Group of Mesenchymal Tumors With NTRK, BRAF, RAF1, or RET Fusions.

Neurotrophic tyrosine receptor kinase (NTRK) fusions define infantile fibrosarcomas in young children and NTRK-rearranged spindle-cell tumors in older children and adults, which share characteristic spindle-cell histology and CD34 or S100 protein expression. Similar phenotypes were identified in tumors with BRAF, RAF1, or RET fusions, suggesting a unifying concept of "spindle-cell tumors with kinase gene fusions." In this study, we investigated CD30 expression in 38 mesenchymal tumors with kinase gene fusions using immunohistochemistry. CD30 was expressed in 15 of 22 NTRK-rearranged tumors and 12 of 16 tumors with BRAF, RAF1, or RET fusions. In total, CD30 was expressed in 27 of the 38 tumors (71%), with >50% CD30-positive cells in 21 tumors and predominantly moderate or strong staining in 24 tumors. CD34 and S100 protein were also expressed in 71% and 69% of the tumors, respectively. In contrast, CD30 was significantly less frequently expressed in other mesenchymal tumor types that histologically mimic kinase fusion-positive tumors (9 of 150 tumors, 6%), of which none showed >50% or predominantly strong staining. Among these mimicking tumors, malignant peripheral nerve sheath tumors occasionally (30%) expressed CD30, albeit in a weak focal manner in most positive cases. CD30 was also expressed in 3 of 15 separately analyzed ALK- or ROS1-positive inflammatory myofibroblastic tumors. Frequent expression of CD30 enhances the shared phenotype of spindle-cell tumors with NTRK and other kinase gene fusions, and its sensitivity seems similar to that of CD34 and S100 protein. Although moderate sensitivity hampers its use as a screening tool, CD30 expression could be valuable to rapidly identify high-yield candidates for molecular workup, particularly in communities that lack routine genetic analysis and/or for tumors with BRAF, RAF1, or RET fusions.

CD30 expression is frequently decreased in relapsed classic Hodgkin lymphoma after anti-CD30 CAR T-cell therapy.

Chimeric antigen receptor (CAR) T-cells anti-CD30 is an innovative therapeutic option that has been used to treat cases of refractory/relapsed (R/R) classic Hodgkin lymphoma (CHL). Limited data are available regarding the CD30 expression status of patients who relapsed after this therapy. This is the first study to show decreased CD30 expression in R/R CHL in patients (n = 5) who underwent CAR T-cell therapy in our institution between 2018 and 2022. Although conventional immunohistochemical assays showed decreased CD30 expression in neoplastic cells in all cases (8/8) the tyramide amplification assay and RNAScope in situ hybridisation detected CD30 expression at different levels in 100% (n = 8/8) and 75% (n = 3/4), respectively. Hence, our findings document that certain levels of CD30 expression are retained by the neoplastic cells. This is not only of biological interest but also diagnostically important, as detection of CD30 is an essential factor in establishing a diagnosis of CHL.

Anti-CD30 antibody-drug conjugate therapy in lymphoma: current knowledge, remaining controversies, and future perspectives.

CD30 is overexpressed in several lymphoma types, including classic Hodgkin lymphoma (cHL), some peripheral T-cell lymphomas (PTCL), and some cutaneous T-cell lymphomas. The antibody-drug conjugate brentuximab vedotin targets CD30-positive cells and has been evaluated for the treatment of various lymphoma entities. This narrative review summarizes 10 years of experience with brentuximab vedotin for the treatment of CD30-positive lymphomas, discusses novel therapies targeting CD30 in development, and highlights remaining controversies relating to CD30-targeted therapy across lymphoma types. The collective body of evidence for brentuximab vedotin demonstrates that exploitation of CD30 can provide sustained benefits across a range of different CD30-positive lymphomas, in both clinical trials and real-world settings. Preliminary experience with brentuximab vedotin in combination with immune checkpoint inhibitors for relapsed/refractory cHL is encouraging, but further exploration is required. The optimal use of brentuximab vedotin for first-line therapy of PTCL remains to be determined. Further research is required on brentuximab vedotin treatment in high-risk patient populations, and in rare lymphoma subtypes, for which no standard of care exists. Novel therapies targeting CD30 include chimeric antigen receptor therapies and bispecific antibody T-cell engagers, which may be expected to further improve outcomes for patients with CD30-positive lymphomas in the coming years.

Variant histology of pediatric nodular lymphocyte-predominant Hodgkin lymphoma with IgD and CD30 expression.

BACKGROUND: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), recently known as nodular lymphocyte-predominant B-cell lymphoma (NLPBL), accounts for 5%-10% of Hodgkin lymphoma (HL). Different morphologic patterns of NLPBL are identified and categorized as typical patterns (type A and B) and variant histologic patterns (types C, D, E, and F). PATIENTS AND METHOD: We investigated different morphologic patterns, CD30 and IgD expression in pediatric patients with NLPBL diagnosed at the Children's Cancer Hospital Egypt. RESULTS: Forty-six (53%) of the patients exhibited a typical histologic pattern, whereas the remaining (47%) exhibited variant histologic pattern. Variant histology is associated with unfavorable clinical characteristics, such as advanced stages, B-symptoms, and extranodal involvements, particularly bone marrow and bone infiltration, with p-values of .06, .05, and 0.01%, respectively. Additionally, 39% of patients with variant histology experienced disease progression or relapse, compared to only 15.2% of patients with typical patterns (p = .009). Types C and D are related to decreased event-free survival (EFS), as shown by a p-value of .05. The 5-year EFS for patients with variant histology was 94.4% for the rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone (RCHOP) versus 33.3% for the adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD). IgD expression in lymphocyte-predominant (LP) cells was detected in 44 (50%) patients, while CD30 expression in LP cells was found in 39 (44%) patients. CONCLUSION: Variant histology of NLPBL was associated with advanced disease stages and a poor prognosis, while expression of IgD and CD30 in LP cells was not. The poor outcome of variant histology improved with the RCHOP regimen.

CD30 expression in cutaneous B-cell lymphomas.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Neoplastic or inflammatory? A case report of Sweet syndrome with CD30+ cells in a patient with B-lymphoblastic leukemia.

CD30+ cells are typically part of lymphoproliferative disorders but can also be seen in inflammatory dermatoses. We present a case of 47-year-old man with a history of B-lymphoblastic leukemia (B-ALL) who presented with fever, leukocytosis, and papulonodular skin lesions, involving the extremities and trunk. A punch biopsy specimen demonstrated papillary dermal edema with a neutrophilic and histiocytic infiltrate extending into the subcutis. The infiltrate also harbored scattered large cells that were positive for CD30 and demonstrated the immunohistochemical profile of monocytes. A diagnosis of histiocytoid Sweet syndrome with CD30+ cells was made. The case is unique, demonstrating a combination of Sweet syndrome variants with subcutis involvement, histiocytoid morphology, and large CD30+ cells. A prior history of B-ALL and immunohistochemical profile of monocytes with immature morphology broadened the differential diagnosis and added to the diagnostic challenge.

CD30-positive lymphoproliferative disorders-An Australian Clinical Practice Statement from the Peter MacCallum Cancer Centre.

The CD30-postive lymphoproliferative disorders, including lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma, account for up to 30% of all cutaneous T-cell lymphomas (CTCLs) and are the second most common form of CTCLs after mycosis fungoides. Both conditions differ in their clinical presentations; however, they share the expression of the CD30 antigen as a common immunophenotypic hallmark. There is a wide spectrum of management options depending on factors such as extent of disease, staging and treatment tolerability. This Clinical Practice Statement is reflective of the current clinical practice in Australia.

CD30 Expression and Its Functions during the Disease Progression of Adult T-Cell Leukemia/Lymphoma.

CD30, a member of the tumor necrosis factor receptor superfamily, plays roles in pro-survival signal induction and cell proliferation in peripheral T-cell lymphoma (PTCL) and adult T-cell leukemia/lymphoma (ATL). Previous studies have identified the functional roles of CD30 in CD30-expressing malignant lymphomas, not only PTCL and ATL, but also Hodgkin lymphoma (HL), anaplastic large cell lymphoma (ALCL), and a portion of diffuse large B-cell lymphoma (DLBCL). CD30 expression is often observed in virus-infected cells such as human T-cell leukemia virus type 1 (HTLV-1). HTLV-1 is capable of immortalizing lymphocytes and producing malignancy. Some ATL cases caused by HTLV-1 infection overexpress CD30. However, the molecular mechanism-based relationship between CD30 expression and HTLV-1 infection or ATL progression is unclear. Recent findings have revealed super-enhancer-mediated overexpression at the CD30 locus, CD30 signaling via trogocytosis, and CD30 signaling-induced lymphomagenesis in vivo. Successful anti-CD30 antibody-drug conjugate (ADC) therapy for HL, ALCL, and PTCL supports the biological significance of CD30 in these lymphomas. In this review, we discuss the roles of CD30 overexpression and its functions during ATL progression.