Variable loss of CD30 expression by immunohistochemistry in recurrent cutaneous CD30+ lymphoid neoplasms treated with brentuximab vedotin.

AIMS: Brentuximab vedotin is a monoclonal anti-CD30 antibody-drug conjugate that has been used to treat a variety of CD30+ neoplasms. The phenomenon of antigen loss has been observed in patients treated with the anti-CD20 antibody rituximab. This study seeks to assess for antigen loss in the setting of recurrent CD30+ neoplasms treated with brentuximab vedotin. METHODS: We report nine cases of persistent/recurrent cutaneous CD30+ lymphoid neoplasms that demonstrated variable CD30 expression after treatment with brentuximab vedotin. Cases include MF (n = 6), cutaneous T-cell lymphoma, not otherwise specified (n = 1), and anaplastic large cell lymphoma (ALCL), both primary (n = 1) and systemic (n = 1). RESULTS: Immunohistochemical staining revealed decreased CD30 expression following brentuximab vedotin therapy in seven of nine cases. In these seven cases, the pre-treatment percent of tumor cells staining for CD30 ranged from 10% to 100% (mean 50.0%, SD 27.8%), compared to 5% to 50% (mean 14.5%, SD 14.8%, P = 0.003) at recurrence. CONCLUSIONS: This case series highlights the finding that CD30 positivity can be variable in recurrences after treatment with anti-CD30 antibodies. This serves to raise awareness of the phenomenon of antigen loss after treatment with brentuximab vedotin and underscores the utility of performing multiple biopsies and/or employing molecular diagnostic techniques in patients with recurrent/persistent disease.

Large Cells With CD30 Expression and Hodgkin-like Features in Primary Cutaneous Marginal Zone B-Cell Lymphoma: A Study of 13 Cases.

The presence of CD30 cells in cutaneous lymphomas has come to prominence in recent years as a potential diagnostic and therapeutic marker. In primary cutaneous marginal zone B-cell lymphomas, the presence of large CD30 cells with Hodgkin-like features and their significance have not yet been studied. Here we describe the main clinical, histologic, immunophenotypic, and molecular characteristics of 13 cases of primary cutaneous marginal zone lymphomas featuring >10% of CD30 large cells, and analyze their relationship with histologic and clinical progression of the disease and with other morphologic and immunophenotypic features. We report 10 male and 3 female patients, 4 with early-local disease and 8 with locoregional advanced disease without extracutaneous involvement but with a high relapse rate of 69%. We describe an association between a high level of CD30 expression and disease progression, with increased clinical recurrence in cases with >15% of CD30 cells. We also discuss the differential diagnosis with other cutaneous and systemic lymphomas, especially Hodgkin lymphoma.

CD30 expression in a case of intravascular large B-cell lymphoma, cutaneous variant.

Intravascular large B-cell lymphoma (IVLBCL) is one of the rarest B-cell non-Hodgkin lymphomas (NHL), with an aggressive clinical behavior and a poor prognosis; in fact, its treatment is still an unmet clinical need, with a 3-year overall survival (OS) rate of 60% to 81%, and a central nervous system relapse rate of 25%. It usually presents as a widespread disease at diagnosis, with multi-organ involvement. Previously considered as a diffuse large B-cell lymphoma variant, it now represents a different extranodal large B-cell lymphoma entity in the last WHO Classification of tumors of hematopoietic and lymphoid tissues. We hereby describe the case of an 84-year-old Italian woman with an IVLBCL, cutaneous variant, who suffered from early relapse after R-COMP chemotherapy regimen, and was therefore treated with a palliative metronomic chemotherapy. Interestingly, neoplastic cells showed CD30 expression at relapse. CD30 positivity has never been reported in this disease so far, and its expression is known to be involved in NF-kB activation. CD30 expression may be further studied as for prognostic and therapeutic significance; in fact, new therapeutic strategies, such as antibody-drug conjugate targeting CD30, are now available.

Utility of CD30, Ki-67, and p53 in assisting with the diagnosis of mycosis fungoides with large cell transformation.

INTRODUCTION: Mycosis fungoides (MF) with large cell transformation (LCT) is an advanced stage of cutaneous lymphoma with a poor prognosis. Identification of LCT is critical and especially challenging when the number of large abnormal lymphocytes is near but below 25%. We propose that Ki-67 and p53 may be useful in making this diagnosis. METHODS: We identified 17 patients with advanced stage (T3 or T4) MF without LCT and 38 patients with a biopsy-confirmed new diagnosis of MF with LCT treated at our institution's cutaneous lymphoma clinic from 2012 to 2016. Seventeen patients underwent 22 biopsies with advanced stage MF (control), and 38 patients with 46 biopsies of MF with LCT were included in this study. RESULTS: The MF cohort had an average CD30 expression of 4%, while the MF-LCT cohort had an average CD30 expression of 22% (P < 0.05). The MF cohort had an average Ki-67 staining of 13%, while the MF-LCT group had an average Ki-67 staining of 57% (P < 0.05). Forty-seven percent of the MF-LCT group was positive for p53; on the other hand, none of the MF control group showed increased p53 expression (P < 0.05). DISCUSSION: While CD30 shows some value in delineating large cell transformation, Ki-67 and p53 appear to be useful immunohistochemical markers in the diagnosis of LCT.

CD30 expression in neoplastic T cells of follicular T cell lymphoma is a helpful diagnostic tool in the differential diagnosis of Hodgkin lymphoma.

Follicular T cell lymphoma is derived from follicular T-helper cells. In many cases, neoplastic T cells form rosettes around Hodgkin-Reed-Sternberg-like cells, which can lead to the misdiagnosis of classical Hodgkin lymphoma. The aim of the present study was to obtain a better understanding of this rosetting phenomenon and to recognize features that are helpful in the differential diagnosis of classical Hodgkin lymphoma. Sixteen mostly elderly follicular T cell lymphoma patients (mean 66 years) were analyzed. Fifteen of the 16 follicular T cell lymphoma cases presented with Hodgkin-Reed-Sternberg-like cells, which were CD20-positive in 27% of the cases and Epstein-Barr virus-infected in nearly all cases. Frequently, the immunophenotype of rosetting neoplastic T cells differed from the bulk neoplastic cells with less numerous T-follicular helper cell markers expressed, suggesting a modulation of T-follicular helper cell marker expression in the neoplastic T cells. In 75% of the cases, variable CD30 expression was encountered in the neoplastic T cells, likely reflecting an activation state in these cells. Hodgkin-Reed-Sternberg-like cells were positive for CCL17, and follicular T cell lymphoma tumor cells expressed its receptor CCR4 at variable intensity, thus potentially explaining the phenomenon of the tumor cells' rosetting around Hodgkin-Reed-Sternberg-like cells. In summary, this study confirms the presence of Hodgkin-Reed-Sternberg-like cells in a high number of cases of follicular T cell lymphoma, suggesting that Hodgkin-Reed-Sternberg-like cells may contribute to the development of this lymphoma. Hodgkin-Reed-Sternberg-like cells in follicular T cell lymphoma cannot reliably be differentiated from the Hodgkin-Reed-Sternberg cells of classical Hodgkin lymphoma based on their immunophenotype. In contrast, demonstration of a T-follicular helper cell phenotype with CD10 and frequent CD30 expression in the neoplastic T cell population can help to establish the diagnosis of follicular T cell lymphoma, and may even indicate CD30 as a therapeutic target for these patients.

Variant histology, IgD and CD30 expression in low-risk pediatric nodular lymphocyte predominant Hodgkin lymphoma: A report from the Children's Oncology Group.

BACKGROUND: Histologic prognostic factors have been described for nodular lymphocyte predominant Hodgkin lymphoma (NLPHL). This study examines histologic and immunophenotypic variants in a clinical trial for pediatric NLPHL. PROCEDURE: One hundred sixty-eight cases of localized NLPHL were examined for histologic variants, CD30 and immunoglobulin D (IgD) expression, and outcome. Histologic types were scored categorically as 0 = 0, 1 ≤ 25%, and 2 > 25% of the sample. RESULTS: Fifty-eight (35.1%) cases showed only typical nodular with or without serpiginous histology (types A and B). The remainder showed mixtures of histologies. The numbers of patients with score 2 are 85 (50.6%) type A, 21 (12.5%) type B, 46 (27.4%) with extranodular large B cells (type C), 3 with T-cell-rich nodular pattern (type D), 55 (32.7%) with diffuse T-cell-rich (type E) pattern, and 2 (1.2%) with diffuse B-cell pattern (type F). Higher level of types C (P = 0.048) and D (P = 0.033) resulted in lower event-free survival (EFS). Cytoplasmic IgD was found in 65 of 130 tested (50%), did not significantly associate with EFS but positively correlated with types C and E histology (P < 0.0001) and negatively correlated with types A (P = 0.0003) and B (P = 0.006). Seventeen (10%) expressed CD30, with no adverse effect. CONCLUSIONS: Variant histology is common in pediatric NLPHL, especially types C and E, which are associated with IgD expression. Type C variant histology and possibly type D are associated with decreased EFS, but neither IgD nor CD30 are adverse features. Variant histology may warrant increased surveillance, but did not affect overall survival.

Nodular lymphocyte-predominant Hodgkin lymphoma: a unique disease deserving unique management.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare lymphoma entity with an incidence of 0.1 to 0.2/100 000/y. Compared with the more common subtypes of classical Hodgkin lymphoma, NLPHL is characterized by distinct pathological and clinical features. Histologically, the disease-defining lymphocyte predominant cells consistently express CD20 but lack CD30. Clinically, NLPHL mostly has a rather indolent course, and patients usually are diagnosed in early stages. The prognosis of early-stage NLPHL is excellent, with progression-free survival and overall survival rates exceeding 90% after involved-field radiotherapy (IF-RT) alone (stage IA) or combined modality treatment consisting of a brief chemotherapy with 2 cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) chemotherapy followed by IF-RT (early stages other than stage IA). In contrast, patients with advanced disease at diagnosis tend to relapse either with NLPHL histology or with histological transformation into aggressive B-cell non-Hodgkin lymphoma despite more aggressive first-line treatment with 6 to 8 cycles of multiagent chemotherapy. However, even NLPHL patients with multiple relapses successfully respond to salvage therapy in many cases. Salvage therapies range from single-agent anti-CD20 antibody treatment to high-dose chemotherapy followed by autologous stem cell transplantation. Treatment at disease recurrence should be chosen on the basis of various factors, including histology at relapse, time to relapse, extent of disease at relapse, and prior treatment. Because death among NLPHL patients is more often caused by therapy-related late effects than lymphoma-related complications, optimizing the risk-benefit ratio of treatment by decreasing toxicity whenever possible is the major goal of clinical research in this disease.

Roles of Bcl-2 and caspase-9 and -3 in CD30-induced human eosinophil apoptosis.

BACKGROUND/PURPOSE: Activation of cell surface CD30 by immobilized anti-CD30 monoclonal antibodies (mAb) induces strong apoptosis in human eosinophils. This anti-CD30 mAb-induced eosinophil apoptosis is inhibited by the addition of inhibitors of p38, ERK1/2 mitogen-activated protein kinases, and phosphatidylinositol 3-kinase. However, there is little data investigating the role of Bcl-2 and caspases in eosinophil apoptosis induced by anti-CD30 mAb. We sought to determine whether anti-CD30 mAb induces human eosinophil apoptosis via Bcl-2 and caspase pathways. METHODS: Peripheral blood was drawn from 37 healthy volunteers. The CD30 expression on eosinophils was measured at various time points. Eosinophils were then cultured in plates precoated with anti-CD30 mAb (clone Ber-H8), isotype control immunoglobulin G1, interleukin (IL)-5, or dexamethasone. Western blot analysis was performed to determine the expression of Bcl-2, procaspase-8, -9, and -3, and caspase-8, -9, and -3 after cross-linking of CD30. Human eosinophils were also cultured in plates precoated with anti-CD30 mAb (clone Ber-H8) in the presence or absence of caspase-9 or -3 inhibitors. Eosinophil apoptosis was assessed using flow cytometry. RESULTS: The addition of anti-CD30 mAb significantly increased eosinophil apoptosis compared with controls. In western blot analysis, the addition of anti-CD30 mAb significantly decreased the expression of Bcl-2 and procaspase-9 and -3 and increased the expression of caspase-9 and -3. The addition of caspase-9 or -3 inhibitors decreased anti-CD30 mAb-induced human eosinophil apoptosis. Procaspase-8 or caspase-8 expression was not changed in response to various stimuli. CONCLUSION: Anti-CD30 mAb-induced human eosinophil apoptosis is likely to be mediated through Bcl-2 and caspase-9 and -3.

Loss of CD30 expression after treatment with brentuximab vedotin in a patient with anaplastic large cell lymphoma: a novel finding.

Anaplastic large cell lymphoma (ALCL) is an aggressive T-cell lymphoma characterized by strong and uniform expression of CD30. Brentuximab vedotin (BV), an anti-CD30 antibody-drug conjugate has been approved by the U.S. FDA for relapsed/refractory systemic ALCL and achieves improved outcomes. We report a 44-year-old African-American man who presented with lymphadenopathy, lip and chest nodules diagnosed as CD30+, ALK-negative ALCL. The patient was treated with BV upon recurrence. While on treatment, the patient developed new-onset nodules on the chest and back. Skin biopsy showed a diffuse dermal infiltrate of medium-to-large atypical lymphocytes with frequent mitosis and scattered eosinophils. Immunohistochemically, the atypical cells displayed the same immunophenotype as previous specimens (CD3+, CD4-/CD8-, CD56-, ALK- and TCR γ-), except for lack of CD30 expression which was attributed to BV treatment effect. The diagnosis was thought to be consistent with ALK-negative ALCL and the patient was continued on BV along with total skin electron beam radiation and the lesions cleared. The patient relapsed 2 months later with extensive disease and expired. In summary, this is the first report in the literature of loss of CD30 expression in ALCL after BV therapy. Awareness of this may prevent a mistaken diagnosis of a CD30-negative secondary T-cell lymphoma.

Neurotropic Gamma-Delta T-Cell Lymphoma With CD30-Positive Lymphoid Infiltrates.

Primary cutaneous gamma-delta T-cell lymphoma (PCGD-TCL) is a clonal proliferation of gamma-delta T cells with a cytotoxic phenotype that is typically characterized by an aggressive clinical course with ulcerative plaques or subcutaneous nodules. In this report, the authors describe a patient who developed an ulcerated tumor on the left upper extremity and painful papules and nodules on the right lower extremity. Interestingly, several of the papulonodules on the right lower extremity underwent spontaneous involution. A skin biopsy of the papulonodular lesion demonstrated a superficial and deep perivascular interstitial infiltrate with a population of pleomorphic enlarged CD30-positive T cells. These enlarged lymphocytes lacked expression of TCR beta, CD4, CD8, and the pan T-cell antigen CD7, but were positive for TCR gamma, supporting the diagnosis of PCGD-TCL. The patient rapidly developed pain and severe weakness in the left upper limb and MRI revealed extensive neurolymphomatosis of the left brachial plexus. The patient was treated with chemotherapy with complete remission achieved. Unfortunately, her response was transient and the patient relapsed and ultimately died due to her disease. In this article, the authors describe an extraordinary case of a CD30-positive PCGD-TCL to expand the histopathological spectrum of CD30-positive and gamma-delta-positive lymphoproliferative disorders.

Loss of CD30 Expression in Anaplastic Large Cell Lymphoma Following Brentuximab Therapy.

Monoclonal antibody therapy is a new innovation in cancer therapy. Binding of monoclonal antibodies to tumor cells facilitates their destruction by the immune system. Tumor cells with mutated target antigens may escape detection by monoclonal antibodies and exhibit a selective growth advantage. This phenomenon was first recognized in CD20-negative B-cell lymphomas in patients previously treated with the anti-CD20 monoclonal antibody rituximab. We report a cutaneous recurrence of systemic ALCL with an anomalous CD30-negative immunophenotype. The patient had been previously treated with the anti-CD30 monoclonal antibody brentuximab. To our knowledge, we present the first reported case of a cutaneous recurrence of systemic ALCL with an anomalous CD30-negative immunophenotype following chronic brentuximab therapy.

J Drugs Dermatol. 2016;15(7):894-895.

Characterization of the tumor microenvironment in primary cutaneous CD30-positive lymphoproliferative disorders: a predominance of CD163-positive M2 macrophages.

BACKGROUND: The tumor microenvironment is essential for tumor survival, growth and progression. There are only a few studies on the tumor microenvironment in cutaneous CD30-positive lymphoproliferative disorders. METHODS: We assessed the composition of the tumor microenvironment using immunohistochemistry studies in skin biopsies from cases diagnosed with lymphomatoid papulosis (LyP: 18 specimens), primary cutaneous anaplastic large-cell lymphoma (PC-ALCL: 8 specimens), and reactive diseases harboring CD30-positive cells (18 specimens). RESULTS: The predominant cells present in LyP and PC-ALCL were CD163+ M2 macrophages (44.7%, 35%), followed by CD8+ tumor infiltrating lymphocytes (11%, 15%), FOXP3+ T-regulatory cells (9%, 4.5%) and programmed cell death 1(PD-1) + lymphocytes (2.2%, 6.8%). In contrast, CD30-positive reactive inflammatory and infectious disorders were characterized by higher numbers of CD123+ plasmacytoid dendritic cells (6.3%) when compared to LyP (1%), and PC-ALCL (1.1%). CONCLUSIONS: Key differences exist between the microenvironment of CD30-positive lymphoproliferative disorders and reactive conditions harboring CD30-positive lymphocytes. The high number of tumor associated macrophages, and the close vicinity of these immune cells to the CD30-positive tumor cells might suggest that tumor associated macrophages have direct influence on tumorigenesis in LyP and ALCL. Therefore, modulation of M2 macrophages may represent a new therapeutic strategy in cutaneous CD30-positive lymphoproliferative disorders.

Identification of the Ki-1 antigen (CD30) as a novel therapeutic target in systemic mastocytosis.

The Ki-1 antigen (CD30) is an established therapeutic target in patients with Hodgkin lymphoma and anaplastic large-cell lymphoma. We have recently shown that CD30 is expressed abundantly in the cytoplasm of neoplastic mast cells (MCs) in patients with advanced systemic mastocytosis (SM). In the current study, we asked whether CD30 is expressed on the surface of neoplastic MCs in advanced SM, and whether this surface structure may serve as therapeutic target in SM. As assessed by flow cytometry, CD30 was found to be expressed on the surface of neoplastic MCs in 3 of 25 patients (12%) with indolent SM, 4 of 7 patients (57%) with aggressive SM, and 4 of 7 patients (57%) with MC leukemia. The immature RAS-transformed human MC line MCPV-1.1 also expressed cell surface CD30, whereas the KIT-transformed MC line HMC-1.2 expressed no detectable CD30. The CD30-targeting antibody-conjugate brentuximab-vedotin inhibited proliferation in neoplastic MCs, with lower IC50 values obtained in CD30(+) MCPV-1.1 cells (10 µg/mL) compared with CD30(-) HMC-1.2 cells (>50 µg/mL). In addition, brentuximab-vedotin suppressed the engraftment of MCPV-1.1 cells in NSG mice. Moreover, brentuximab-vedotin produced apoptosis in all CD30(+) MC lines tested as well as in primary neoplastic MCs in patients with CD30(+) SM, but did not induce apoptosis in neoplastic MCs in patients with CD30(-) SM. Furthermore, brentuximab-vedotin was found to downregulate anti-IgE-induced histamine release in CD30(+) MCs. Finally, brentuximab-vedotin and the KIT D816V-targeting drug PKC412 produced synergistic growth-inhibitory effects in MCPV-1.1 cells. Together, CD30 is a promising new drug target for patients with CD30(+) advanced SM.

Characterization of primary cutaneous CD8+/CD30+ lymphoproliferative disorders.

CD30 primary cutaneous lymphoproliferative diseases include both lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large cell lymphoma (PCALCL). The neoplastic cell of most primary CD30 lymphoproliferative disorders is CD4 positive. The terminology LyP "type D" has been used to describe a growing number of cases of LyP with a predominantly CD8 infiltrate. PCALCL with a CD8 phenotype has also been described, which presents a particularly difficult diagnostic and management challenge, given the difficulty in distinguishing it histologically from other cytotoxic lymphomas such as primary cutaneous aggressive epidermotropic CD8 cytotoxic T-cell lymphoma and CD8 gamma/delta and natural killer/T-cell lymphoma. We report 7 additional cases of these rare cutaneous CD8/CD30 lymphoproliferative disorders. We also present a unique case of CD8/CD30 LyP with histologic similarities to LyP type B. In all 7 of our cases of CD8 LyP and CD8 anaplastic large cell lymphoma, we found focal to diffuse MUM-1 positivity. We propose that MUM-1 may represent an adjunctive marker for CD8 lymphoproliferative disease. Finally, we review the current literature on cases of CD8 LyP and PCALCL. For the 106 cases examined, we found similar clinical and histologic features to those reported for traditional CD4CD30 LyP and PCALCL.

Mucosal CD30-Positive T-Cell Lymphoproliferative Disorder Arising in the Oral Cavity Following Dental Implants: Report of the First Case.

Mucosal CD30-positive T-cell lymphoproliferative disorder (CD30+ T-cell LPD) is a novel entity with unique clinicopathological features and an indolent behavior. Here we report the first case of mucosal CD30+ T-cell LPD arising in the oral cavity following dental implant. A 70-year-old woman presented with swelling and redness of the oral mucosa of right maxilla and left mandible surrounding dental implants that had been placed 8 years previously. Radiological examination revealed enhancing oral lesions and multiple cervical lymph nodes. Microscopic examination showed diffuse infiltration of large anaplastic cells with characteristic morphology of hallmark cells described in anaplastic large cell lymphoma. These cells were diffusely positive for CD30, CD3, CD4, CD2, CD5, CD7, TIA-1, and TCRßF1, but negative for CD20, CD8, CD45, EMA, ALK, and Epstein-Barr virus. T-cell monoclonality was detected in a TCRγ gene rearrangement study. This a unique case of mucosal CD30+ T-cell LPD with unusual presentation following dental implant.

Prognostic implications of CD30 expression in extranodal natural killer/T-cell lymphoma according to treatment modalities.

Extranodal natural killer/T-cell lymphoma (NKTCL) has aggressive behaviors and poor clinical outcomes. A monomethyl auristatin E-conjugated anti-CD30 antibody (brentuximab vedotin) was recently introduced to treat CD30-positive lymphomas. Thus we investigated the clinicopathological features and prognostic implications of CD30 expression in 72 patients with NKTCL. CD30-positive cases, defined as cases with CD30 expression in more than 1%, 5% and 25% of tumor cells as cut-off values (COVs), accounted for 40 (56%), 27 (38%) and 16 (22%) cases of NKTCL, respectively. CD30 expression was significantly higher in large/anaplastic cell-predominant NKTCL than in small/medium cell-predominant cases. CD30-positive NKTCL showed better responses to non-anthracycline-based therapy. CD30-positive NKTCL with COV of 25% showed a lower rate of relapse. Moreover, in patients treated with non-anthracycline-based chemotherapy, CD30 positivity with COV of 5% was significantly and independently associated with longer overall survival. CD30 may be useful as a prognostic factor and therapeutic target in NKTCL.