Primary Cutaneous Anaplastic Large Cell Lymphoma-A Review of Clinical, Morphological, Immunohistochemical, and Molecular Features.

Primary cutaneous anaplastic large cell lymphoma (ALCL) is the second most common cutaneous T-cell lymphoma after mycosis fungoides and belongs to the spectrum of cutaneous CD30+ T-cell lymphoproliferative disorders. Although primary cutaneous ALCL usually presents as a localized nodule or papule with or without ulceration, multifocal lesions may occur in up to 20% of cases. Histologically, primary cutaneous ALCL consists of a diffuse dermal infiltrate of medium to large anaplastic/pleomorphic cells with abundant amphophilic-to-eosinophilic cytoplasm, horseshoe-shaped nuclei, strong and diffuse expression of CD30, and with focal or no epidermotropism. The neoplastic infiltrate may show angiocentric distribution and may extend to the subcutis. Patients with localized or multifocal disease have a similar prognosis with a 10-year overall survival rate of 90%. Approximately 30% of primary cutaneous ALCLs harbor a DUSP22 (6p25.3) gene rearrangement that results in decreased expression of this dual-specific phosphatase, decreased STAT3 activation, and decreased activity of immune and autoimmune-mediated mechanisms regulated by T-cells.

Use of flow cytometry and cytology to differentiate breast implant-associated anaplastic large cell lymphoma from reactive seromas in Brazilian patients.

INTRODUCTION: The combination of cytology and multiparametric flow cytometry (MFC) may be useful in the diagnosis of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) and may be a practical way to differentiate lymphoma from benign and reactive seromas. Although the Brazilian breast implant market is the second largest in the world, with several manufacturers and the almost exclusive use of textured implants, the occurrence of BIA-ALCL in Brazil is underreported. METHODS: One hundred seventeen sequential collections of suspicious periprosthetic fluid (PF) from 105 Brazilian patients registered between March/2018 and March/2021 were evaluated by routine cytomorphology and flow cytometry. The combination of CD30, HLA-DR, and CD25 was used together with T and B lymphocyte and monocyte evaluation. The PF samples were divided into positive, acute reactive (neutrophilic exudate), or chronic reactive (macrophage or lymphocyte rich), and unavailable samples. RESULTS: Nine BIA-ALCL positive cases (7.7%) were identified, with typical morphology and increased FSC/SSC dispersion, bright expression of CD30, CD25 and HLA-DR, and absence or weakness of T-cell antigens (CD3, CD8, CD4, CD5, and CD7). Reactive samples were acute (n = 18, 15.4%) and chronic (n = 70, 59.8%). Twenty samples were excluded. The mean age of BIA-ALCL patients was 50 years (31-57 years) and 35 years in reactive patients (20-69 years). CONCLUSION: Use of MFC with a comprehensive antibody panel consisting of CD30 in conjunction with CD25 and HLA-DR can discriminate anaplastic cells of BIA-ALCL from lymphoid or neutrophilic reactive cells and should be considered in the initial evaluation of seroma.

CD30 Expression in Oral and Oropharyngeal Diffuse Large B Cell Lymphoma, not Otherwise Specified.

Diffuse large B cell lymphoma, not otherwise specified (DLBCL, NOS) is the most frequent non-Hodgkin lymphoma subtype. This aggressive neoplasm may variably express the CD30 protein, which may be used as a therapeutic target for this tumor. However, CD30 expression in DLBCL NOS arising from the oral cavity and the oropharynx has not been investigated. Therefore, this study aims to determine the frequency of CD30 expression and its prognostic significance for patients affected by oral/oropharyngeal DLBCL NOS. Fifty cases were retrieved from pathology files and submitted to immunohistochemistry against CD30. Reactivity was accessed by two oral pathologists using two cut-off values (> 0% and > 20% of tumor cells) to determine positivity in each case. Clinical data were obtained from the patients' medical files to investigate the prognostic potential of the protein. Seven high-grade B cell lymphomas and two EBV-positive DLBCL NOS were identified. We found one CD30-positive case in each of these two groups of lymphomas. Among the remaining 41 DLBCL NOS, other four cases (three in the oral cavity and one in the oropharynx) were positive for CD30, but only two expressed the protein in > 20% of tumor cells, both in the oral cavity. Survival analysis demonstrated that CD30-positive cases had a higher five-year overall survival rate (75%) than CD30-negative cases (32.3%), although a statistically significant result was not achieved (p = 0.19). Only a minor subset of oral and oropharyngeal DLBCL NOS express CD30 and these patients seems to have a higher survival rate.

Prognostic significance of CD30 expression in diffuse large B-cell lymphoma: A systematic review with meta-analysis.

BACKGROUND: CD30 is variably expressed in diffuse large B-cell lymphoma (DLBCL), but its prognostic potential for the affected patients remains debatable and unclear. Therefore, we aimed to determine the frequency of CD30 expression in DLBCL and its potential for prognostic determination. METHODS: An electronic systematic review was performed using multiple databases, followed by a quantitative meta-analysis to assess the frequency of CD30 expression with positivity cut-off values of >0% and >20%, and to determine its association with clinicopathological features and patients' survival. RESULTS: Using a cut-off value >0%, we observed that 3.5%-59.1% of the cases were considered positive for CD30. There was a significant association of the protein expression with a lower number of extra-nodal sites affected by the neoplasm, with Ann Arbor advanced stage, the absence of B-symptoms, the lack of MYC and BCL2 translocations, and a lower ECOG performance. Using a cut-off value >20%, we observed that 2.5%-36.7% of the cases were considered positive for CD30, being significantly associated with a lower number of extra-nodal sites affected by the neoplasm, Ann Arbor stages III/IV, non-GCB tumours, the lack of MYC and BCL2 translocations, and a lower ECOG value. CD30 expression was significantly associated with a better survival rate, regardless of what cut-off parameter was used. CONCLUSION: Despite variations in the cut-off values used to determine CD30 positivity in DLBCL, the expression of this protein seems to be associated with a higher survival rate and better prognosis.

Linfoma anaplásico de células grandes associado a implante mamários: um desafio diagnóstico / Breast implant-associated anaplastic large cell lymphoma: a diagnostic challenge

O linfoma anaplásico de células grandes associado a implante mamário (BIA-ALCL ) é uma entidade provisória com características morfológicas e imunofenotípicas indistinguíveis do linfoma anaplásico de células grandes (ALCL) ALK negativo. Ao contrário do ALCL, o BIA-ALCL surge principalmente em associação ao implante mamário. A confirmação diagnóstica do BIA-ALCL pode ser difícil e a associação de características morfológicas e patológicas com citometria de fluxo e imuno-histoquímica pode auxiliar no diagnóstico. O objetivo deste relatório é descrever um caso de BIA-ALCL no qual a análise citológica e imunofenotipológica utilizando citometria de fluxo sugeriu a presença de grandes células positivas para CD30 no líquido de derrame.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a provisional entity with morphological and immunophenotypic characteristics indistinguishable from ALKnegative anaplastic large cell lymphoma (ALCL). Unlike ALCL, BIA-ALCL arises mainly in association with breast implantation. Diagnostic confirmation of BIA-ALCL can be difficult and associating morphological and pathological hallmarks with flow cytometry and immunohistochemistry can assist in the diagnosis. The objective of this report is to describe a case of BIA-ALCL in which cytological and immunophenotypological analysis using flow cytometry suggested the presence of large CD30-positive cells in the effusion fluid.

Clinicopathologic and microenvironmental analysis of primary cutaneous CD30-positive lymphoproliferative disorders: a 26 year experience from an academic medical center in Brazil.

BACKGROUND: Primary cutaneous CD30+ lymphoproliferative disorders (pc-CD30-LPD) are a group of clonal T cell lymphoproliferative disorders that despite very similar tumor histology follow different and characteristic clinical courses, suggesting a homeostatic role of the tumor microenvironment. Little is known about tumor microenvironment and there is almost no literature about PD-L1 expression in pc-CD30-LPD. METHODS: This retrospective study presents a fully clinicopathologically characterized series of pc-CD30-LPDs from an academic medical center in Brazil, including 8 lymphomatoid papulomatosis (LyP), 9 primary cutaneous anaplastic large cell lymphoma (pcALCL) and 4 borderline lesions. All the cases were scored for FOXP3+ regulatory T-cells (Treg) and CD8+ cytotoxic tumor infiltrating lymphocytes (TIL) densities, as well as PD-L1 expression in tumor cells and tissue associated macrophages. The CD8+/FOXP3+ ratio was also evaluated. RESULTS: Among the 21 cases of pc-CD30-LPD, PD-L1 expression is frequent in both tumor cells and tissue associated macrophages in pc-CD30-LPD across categories, suggesting that the PD-L1 axis may be a common feature of pc-CD30-LPDs. While reactive T cell infiltrates vary widely from case to case, a common feature across pc-CD30-LPDs is higher density of CD8 than FOXP3 + T cells. The distribution of T cells within the lesions however differed between LyP and pcALCL: we found that LyP lesions tend to be permeated by CD8+ and FOXP3+ T cells, whereas pcALCL tend to be surrounded by a rim of CD8+ TIL and FOXP3+ Tregs with relatively lower density infiltrates in the center of the lesion. CONCLUSIONS: LyP has a trend to have denser immune cells throughout the lesion, with higher FOXP3+ Treg and CD8+ TIL in the center than the edge comparing with pcALCL. PD-L1+ is frequent in tumor cells and tissue associated macrophages in pc-CD30-LPD. The differential distribution of CD8+ and FOXP3+ TILs in LyP as compared to pcALCL could provide a clue to the relapsing/remitting course of LyP as compared to the less frequent spontaneous regression of pcALCL.

Linfoma anaplásico de células T grandes primario cutáneo CD30+. Serie de nueve casos.

INTRODUCTION: CD30+ anaplastic large T cell lymphoma is a cutaneous primary lymphoma in which there is no evidence of systemic disease; histopathological study is required for its diagnosis. OBJECTIVE: To present the cases diagnosed with primary cutaneous CD30+ anaplastic large T-cell lymphoma over a 24-year period in Hospital General "Dr. Manuel Gea González" Department of Dermatology. METHOD: Retrospective study. Descriptive statistics was carried out. Information was collected on gender, age, clinical characteristics, complementary test results, previous and current treatments, histopathological studies reports and immunohistochemistry test results. RESULTS: Of 29 309 records, nine patients (0.000034%) with a diagnosis of CD30+ anaplastic T cell lymphoma were found. Histopathological and immunohistochemical diagnosis was confirmed by two certified dermatopathologists. Average age was 61.2 years, and there was a predominance of the female gender, with initial clinical presentation as a papular or nodular lesion and varied topography. CONCLUSIONS: The prognosis of CD30+ anaplastic large T cell lymphoma in the studied population was dependent on clinical stage. The treatment at early stages has favorable results.

INTRODUCCIÓN: El linfoma anaplásico de células T grandes CD30+ es un linfoma primario cutáneo en el cual no hay evidencia de enfermedad sistémica; para su diagnóstico es necesario el estudio histopatológico. OBJETIVO: Presentar los casos diagnosticados en el Departamento de Dermatología del Hospital General "Dr. Manuel Gea González" con linfomas anaplásicos de células T grandes primarios cutáneos CD30+ durante un periodo de 24 años. MÉTODO: Estudio retrospectivo en el que realizó estadística descriptiva. Se recopiló información de sexo, edad, características clínicas, resultados de pruebas complementarias, tratamientos previos y actuales, reportes de los estudios histopatológicos y de inmunohistoquímica. RESULTADOS: Entre 29 309 expedientes, se encontraron nueve casos (0.000034 %) con diagnóstico de linfoma anaplásico de células T CD30+. Se hizo la confirmación del diagnóstico histopatológico e inmunohistoquímico por dos dermatopatólogos certificados. La edad promedio fue de 61.2 años, hubo predominio del sexo femenino y de lesión papular o nodular y topografía variada como presentación clínica inicial. CONCLUSIONES: El pronóstico del linfoma anaplásico de células T grandes CD30+ en la población estudiada fue dependiente del estadio clínico. El tratamiento en etapas tempranas tiene resultados favorables.

Linfoma anaplásico de células T grandes primario cutáneo CD30+. Serie de nueve casos / Primary cutaneous CD30+ anaplastic large T-cell lymphoma. Series of nine cases

Resumen Introducción: El linfoma anaplásico de células T grandes CD30+ es un linfoma primario cutáneo en el cual no hay evidencia de enfermedad sistémica; para su diagnóstico es necesario el estudio histopatológico. Objetivo: Presentar los casos diagnosticados en el Departamento de Dermatología del Hospital General "Dr. Manuel Gea González" con linfomas anaplásicos de células T grandes primarios cutáneos CD30+ durante un periodo de 24 años. Método: Estudio retrospectivo en el que realizó estadística descriptiva. Se recopiló información de sexo, edad, características clínicas, resultados de pruebas complementarias, tratamientos previos y actuales, reportes de los estudios histopatológicos y de inmunohistoquímica. Resultados: Entre 29 309 expedientes, se encontraron nueve casos (0.000034 %) con diagnóstico de linfoma anaplásico de células T CD30+. Se hizo la confirmación del diagnóstico histopatológico e inmunohistoquímico por dos dermatopatólogos certificados. La edad promedio fue de 61.2 años, hubo predominio del sexo femenino y de lesión papular o nodular y topografía variada como presentación clínica inicial. Conclusiones: El pronóstico del linfoma anaplásico de células T grandes CD30+ en la población estudiada fue dependiente del estadio clínico. El tratamiento en etapas tempranas tiene resultados favorables.

Abstract Introduction: CD30+ anaplastic large T cell lymphoma is a cutaneous primary lymphoma in which there is no evidence of systemic disease; histopathological study is required for its diagnosis. Objective: To present the cases diagnosed with primary cutaneous CD30+ anaplastic large T-cell lymphoma over a 24-year period in Hospital General "Dr. Manuel Gea González" Department of Dermatology. Method: Retrospective study. Descriptive statistics was carried out. Information was collected on gender, age, clinical characteristics, complementary test results, previous and current treatments, histopathological studies reports and immunohistochemistry test results. Results: Of 29 309 records, nine patients (0.000034%) with a diagnosis of CD30+ anaplastic T cell lymphoma were found. Histopathological and immunohistochemical diagnosis was confirmed by two certified dermatopathologists. Average age was 61.2 years, and there was a predominance of the female gender, with initial clinical presentation as a papular or nodular lesion and varied topography. Conclusions: The prognosis of CD30+ anaplastic large T cell lymphoma in the studied population was dependent on clinical stage. The treatment at early stages has favorable results.

Mycosis fungoides preceding lymphomatoid papulosis

Lymphomatoid papulosis (LyP) is defined as a chronic, recurrent, self-healing papulonecrotic or papulonodular skin disease with histologic features suggestive of a (CD30-positive) malignant lymphoma. In up to 20% of patients, LyP are preceded by, associated with, or followed by another type of cutaneous or systemic lymphoma, generally mycosis fungoides (MF), primary cutaneous anaplastic large cell lymphoma (C-ALCL). In this case, we describe a case of MF that preceded and continued to coexist with LyP type C.(AU)

A papulose linfomatóide (LyP) é definida como uma doença cutânea papulonecrótica ou papulonodular crônica, recorrente, com características histológicas sugestivas de linfoma maligno (CD30-positivo). Em até 20% dos pacientes, o LyP é precedido por, associado ou seguido por outro tipo de linfoma cutâneo ou sistêmico, geralmente micose fungóide (MF), linfoma cutâneo primário de células grandes anaplásicas (C-ALCL). Neste caso, descrevemos um caso de MF que precedeu e continuou a coexistir com LyP tipo C. (AU)

The role of CD30 and CD153 (CD30L) in the anti-mycobacterial immune response.

The establishment of a protective T-cell response against mycobacterial infections involves different co-stimulatory molecules and their respective ligands. Among these molecules the Tumor Necrosis Factor Receptor Super-family (TNFRSF) and the Tumor Necrosis Factor Super-family (TNFSF) are known to be important members. This review analyzes the evidence that CD30 and CD153 (CD30L), members of the TNFRSF and TNSF, play key roles in the T cell-dependent anti-mycobacterial immune response. Mice deficient in either CD30 or CD153, or treated with antibodies blocking the effects or CD30 and CD153, and infected with M.avium or M.bovis BCG exhibit higher bacterial burden, abnormal inflammatory responses with decreased Th1 responses, this is evidenced by the reduced number of IFN-γ-producing cells. Recent evidence also showed that CD30+ CD153+ Tγδ cells participate in the early stages of M.bovis BCG infection by producing IL-17A. In humans, stimulation of T-cells with mycobacterial antigens induces CD30 expression mainly by CD4+ cells; CD30+ cells have been demonstrated in tissues of patients with tuberculosis (TB) and in positive tuberculin skin test reactions. In addition, the levels of soluble CD30 are increased in serum and BAL of TB patients and these levels seems to correlate with the severity of the disease. These findings suggest that CD30/CD153 interactions during the anti-mycobacterial immune response are important for the establishment and maintenance of a protective response. Further studies would be required to determine whether these molecules may be good clinical biomarkers or potential targets for immune manipulation.

IL-15 controls T cell functions through its influence on CD30 and OX40 antigens in Celiac Disease.

AIM: To evaluate the ability of interleukin (IL)-15 to control T cell functions through its influence on CD30 and OX40 expressing cells in Celiac Disease (CD). In peripheral blood (PB), by examining the expression of OX40 in conventional effectors cells and T cells with a phenotypic specialization of regulatory cells [CD4+CD25high forkhead box protein 3 (Foxp3)+], and the co stimulation of IFN-γ and IL-4 production within CD30 and OX40 positive subsets of T cells. At the duodenal mucosa, by assessing the expression of CD30 and OX40 in intraepithelial (IE) and lamina propria (LP) lymphocytes (IEL, LPL). PATIENTS AND METHODS: PB and duodenal mucosal biopsies were obtained from 38 patients with classic CD (Cel) and 38 healthy controls (HC). Analysis of cell surface and/or intracellular antigens was performed in anti-CD3-treated PB mononuclear cells (PBMC) before and after treatment with recombinant IL-15 (rIL-15), and in IE and LP cellular suspensions prepared from duodenal biopsies pre-treated with/without rIL-15. RESULTS: A subpopulation of CD3+OX40+ T blasts was induced in Cel and HC by a 3days treatment of PBMC with anti-CD3 and decreased its size thereafter, regardless of the presence of rIL-15. However, the addition of rIL-15 to T blasts distinctively induced the survival of T cells with a regulatory phenotype that expresses OX40 antigen in Cel (p<0.05). Celiac patients showed higher frequencies of IFN-γ-producing CD3+CD30+ blasts before and after treatment with rIL-15 (p<0.05, vs. HC). IL-15 increased the frequencies of CD3+CD30+ LPL (HC: p<0.05, Cel: p<0.05) but not of CD3+OX40+ LPL, and CD30 or OX40 positive IEL. CONCLUSIONS: The distinctive control of OX40+ cells with a T regulatory phenotype mediated by the influence of IL-15 comes out as new function of this cytokine in the context of CD. The higher production of IFN-γ by a subpopulation of peripheral CD3+CD30+ cells contributes to the type I biased immune response.

Association of high post-transplant soluble CD30 serum levels with chronic allograft nephropathy.

The purpose of this study was to evaluate the association of post-transplant soluble CD30 (sCD30) levels, isolated or in combination with of anti-HLA class II antibodies and of serum creatinine levels, with kidney graft loss due to chronic allograft nephropathy (CAN), and type of lesions in graft biopsies for cause. The study comprised 511 first kidney graft recipients, transplanted at a single center, with a graft functioning for at least 2.8 years. A single blood sample was collected from each patient. sCD30 levels were determined by ELISA, and HLA antibodies by Luminex assay. The minimum follow-up after testing was 9.3 years. High sCD30 levels, set at sCD30 ≥ 34.15 ng/mL, the presence of HLA class II antibodies, and serum creatinine ≥ 1.9 mg/dL were independently associated with CAN-graft loss (P values <0.0001, 0.05, <0.0001, respectively), and the combined hazard ratio for CAN-graft loss was 20.2. Analyses of 166 biopsies for cause showed that high sCD30 levels and creatinine were independently associated with interstitial lesions. Post-transplant sCD30 serum levels, especially in conjunction with information regarding HLA class II antibodies and serum creatinine levels, provide valuable information regarding graft outcome and could be useful for the management of kidney transplant recipients.