CD30-positive primary cutaneous lymphoproliferative disorders: molecular alterations and targeted therapies

Abstract

Primary cutaneous CD30-positive T-cell lymphoproliferative disorders are the second most common subgroup of cutaneous T-cell lymphomas. They include two clinically different entities with some overlapping features and borderline cases: lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma. Molecular studies of primary cutaneous anaplastic large cell lymphoma reveal an increasing level of heterogeneity that is associated with histological and immunophenotypic features of the cases and their response to specific therapies. Here, we review the most significant genetic, epigenetic and molecular alterations described to date in primary cutaneous CD30-positive T-cell lymphoproliferative disorders, and their potential as therapeutic targets.

Figure 1.

“Classic”, ALK-, DUSP22-, TP63- (triple negative) primary cutaneous anaplastic large cell lymphoma. (A) Clinical picture showing two adjacent tumoral erythematous nodules located in the scapular region simulating dermatofibrosarcoma protuberans. (B,C) (×40), Hematoxylin & eosin stain showing the dermal infiltration consisting of a circumscribed infiltrate, composed of arranged large lymphoid cells with absent or subtle epidermotropism. (D,E) (×40), CD30 stain showing positivity in the membrane and Golgi of the tumoral large cells.

Figure 2.

ALK-negative primary cutaneous anaplastic large cell lymphoma with DUSP22 rearrangements. (A) Clinical picture of a large ulcerated tumor in the left malar region of an elderly woman showing (B) the typical CD30 staining of a case of pcALCL with DUSP22 rearrangement (Ref. , courtesy of Onaindia et al.), evidencing extensive epidermotropism with CD30⁺ small-to-medium-sized T-lymphocytes that simulate pagetoid reticulosis lesions. (C) Hematoxylin & eosin-stained panoramic view of the case in (E) and (F) showing the tumor nodule with profuse dermal involvement. (D) Detail, stained with hematoxylin & eosin, of another case exemplifying the biphasic epidermal and dermal lymphocytic infiltrate. (E,F) (×40), CD3 stain highlights the intraepidermic neoplastic T cells in another case with DUSP22 rearrangement.

Figure 3.

ALK-positive primary cutaneous anaplastic large cell lymphoma. (A) Clinical picture of a large ulcerated tumor located on the back. (B) Fluorescence in situ hybridization image showing an ALK reciprocal translocation with gain of one or two copies of the ALK gene. (C,D) Hematoxylin & eosin stain showing the morphology of large T cells (E,F) (×40), with CD30 positivity and (G,H) (×40), nuclear and cytoplasmic ALK positivity in tumor T cells.

Figure 4.

New targeted therapies in advanced primary cutaneous anaplastic large cell lymphoma. Brentuximab vedotin is a drug composed of a chimeric anti-CD30 antibody linked to four monomethyl auristatin (MMAE) molecules (on average) (1). This antibody-drug conjugate first binds to CD30 on the surface of pcALCL cells (2). It is then internalized by a receptor-mediated endocytosis process (3 and 4). The resultant vesicle fuses with lysosomes (4), leading to proteolytic cleavage of the dipeptide linker and the presence of free MMAE molecules, which inhibit tubulin polymerization of the cellular cytoskeleton and arrest growth of pcALCL tumor cells. Gamma-secretase (γ-secretase) inhibitors prevent release of intracellular NOTCH1 (ICN1) from membrane-tethered heterodimeric NOTCH1 protein. This causes the downregulation of the tumor cell nuclear factor-kB (NFKB) pathway and the inactivation of survival genes. JAK1/2/3 inhibitors are effective in vitro for controlling pcALCL cell growth. This mechanism involves oncogenic JAK1 or STAT3 mutations associated with the hyperactive pSTAT3 shown in pcALCL with an NPM1-TYK2 gene fusion and oncogenic STAT3 activation. In addition, anti-ALK molecules such as crizotinib, alectinib, and ceritinib in pcALCL patients with ALK rearrangements could downregulate the STAT3 pathway, ultimately inducing tumor-cell death. IPH4102 is a humanized monoclonal antibody directed against the cellular receptor KIR3DL2 (CD158K). This receptor has been shown to be aberrantly expressed in advanced pcALCL. IPH4140 targets KIR3DL2 in tumor cells and promotes cell lysis after linking to the CD16 activating receptor through antibody-dependent, cell-derived cytotoxicity mediated by NK cells. At the epigenetic level, histone deacetylase (HDAC) inhibitors and demethylating agents have demonstrated a degree of effectiveness at inducing cell-cycle arrest, differentiation and/or apoptosis of tumor cells.