Most rare subtypes of cutaneous lymphoma display variable CD30 expression: analysis of the German Cutaneous Lymphoma Network
Authors: U. Wehkamp, C. Mitteldorf, S. Stendel, R. Stranzenbach, J.P. Nicolay, M. Wobser, M. Weichenthal, R. Schneiderbauer, C.‐D. Klemke, U. Hillen, W. Kempf, C. Assaf
Journal: British Journal of Dermatology (2021)

Dear Editor, CD30, also known as tumour necrosis factor receptor 8 (TNF-R 8), was initially called Ki-1 and is a cell-surface molecule that was first described by a group of pathologists from Kiel in 1982.1 CD30 can be targeted with the drug brentuximab vedotin (BV), which is approved for relapsed or refractory CD30+ cutaneous T-cell lymphoma (CTCL) including primary cutaneous anaplastic large-cell lymphoma and CD30+ mycosis fungoides and Sézary syndrome. Treatment for rare cutaneous lymphoma (CL) subtypes such as primary cutaneous diffuse large B-cell lymphoma (PCDLBCL) may be challenging, and clinical trials in these indications are scarce. Detection of CD30 expression in the rare subtypes could provide the rationale for treatment with targeted therapy. In the present study, 105 biopsies of 101 patients with rare CL from 10 centres (Berlin-Neukölln, Göttingen, Karlsruhe, Kiel, Krefeld, Ludwigshafen, Mannheim, Minden, Würzburg and Zurich) were collected. All patients were diagnosed with a rare CL and staged according to the current classification of the European Organization for the Research and Treatment of Cancer and International Society for Cutaneous Lymphomas: In total, 100 rare CL cases were evaluable for CD30 expression study; CD30 stains were performed in one centre and evaluated by six dermatologists/dermatopathologists. Overall, a third of patients died due to the lymphoma itself, illustrating the aggressiveness of many of the rare skin lymphoma subtypes. In more than two-thirds of the cases, CD30 expression was detectable (71 of 100; 71%) (see Table 1). The expression in most cases was low [< 1–5% (59 of 71; 83·1%)] and limited to the dermal area. None of the cases displayed an epidermal expression of CD30. Only 11·3% (eight of 71) cases revealed an expression of CD30 in more than 10% of the lymphocytic infiltrate. Two of these cases had NK-TCL (10% and 14%). Staining intensity was regarded mainly as weak or moderate (61 of 71; 85·9%). Expression was detected predominantly in the cytoplasm with or without combined membrane and/or Golgi-reactivity (64 of 71; 90·1%). Eight representative cases (two PCDLBCLs, one NK-TCL, two SPTCLs, one γ/δ TCL, one BPDCN and one CD4+ SMTCL) were double-stained with CD30 and Pax-5 to see if the B-cell population in the infiltrate was positive for CD30. None of the cases displayed an expression of both markers on identical cells. The question of how much CD30 expression is needed for a valuable clinical response to a CD30-targeted therapy is still not finally resolved. In the ALCANZA trial (ClinicalTrials.gov trial no. NCT01578499) that led to FDA approval for BV in relapsed or refractory CD30+ CTCL, a cutoff of 10% CD30 expression was used as inclusion criterion. However, this cutoff is arbitrary and Kim et al. reported treatment of patients with lower CD30 expression levels who also showed treatment responses.2 In addition, recent reports of patients with CTCL demonstrating no or less than 1% of CD30 expression in their biopsy samples described complete remissions after application of BV, indicating that the detection and description of single CD30+ cells in CL samples is crucial and could be relevant for the patients’ outcome.3, 4 Even very low levels of CD30 expression seem to prove sufficient for successful treatment of CL. The explanation attempts for the successful treatment with BV in cases with no to low CD30 expression vary over technical aspects – including the use of different antibodies or detection methods – to interobserver variability.5, 6 However, biological reasons such as variability of CD30 expression of lesions within the same patient could also play a role. Furthermore, cells of the tumour microenvironment expressing CD30, e.g. tumour-associated macrophages, might represent a target structure in addition to CD30+ tumour cells.2, 7 The results of our analysis describing the expression of CD30 in many of the rare CL subtypes, viewed in conjunction with the recent promising results of the ECHELON-2 study in systemic peripheral TCL,8 showed that the targeted treatment might be a valid treatment option in cases of rare CL even with low CD30 expression, especially for the aggressive variants, when standard treatment options do not exist or have not led to a remission of the disease. A clinical study for these rare CL subtypes would be optimal to determine the response in relation to the CD30 expression and also in relation to the entity of CL. the authors thank Christel Martensen-Kerl for excellent technical assistance. Open Access funding enabled and organized by ProjektDEAL. Ulrike Wehkamp: Conceptualization (lead); Data curation (lead); Formal analysis (lead); Investigation (lead); Methodology (lead); Project administration (lead); Writing-original draft (lead). Christina Mitteldorf: Formal analysis (equal); Investigation (equal); Writing-review & editing (supporting). Sarja Stendel: Data curation (supporting); Formal analysis (supporting); Project administration (equal); Writing-review & editing (supporting). René Stranzenbach: Formal analysis (supporting); Investigation (supporting); Writing-review & editing (supporting). Jan Nicolay: Formal analysis (supporting); Investigation (supporting); Writing-review & editing (supporting). M. Wobser: Formal analysis (equal); Investigation (equal); Writing-review & editing (supporting). Michael Weichenthal: Project administration (supporting); Writing-review & editing (supporting). Roland Schneiderbauer: Formal analysis (equal); Investigation (equal); Writing-review & editing (supporting). Claus-Detlev Klemke: Formal analysis (supporting); Investigation (supporting); Writing-review & editing (supporting). Uwe Hillen: Formal analysis (equal); Investigation (equal); Writing-review & editing (supporting). Werner Kempf: Formal analysis (supporting); Investigation (supporting); Writing-review & editing (supporting). Chalid Assaf: Conceptualization (equal); Data curation (equal); Formal analysis (equal); Investigation (equal); Methodology (equal); Supervision (lead); Writing-review & editing (equal).