Prognostic Factors in Primary Cutaneous Anaplastic Large Cell Lymphoma: Clinical and Molecular Characterization of a Subset with Worse Outcome.
Authors: Woo Denise , Jones Chris , Vanoli-Storz Monique , Kohler Sabine , Reddy Sunil , Advani Ranjana , Hoppe Richard , Kim Youn 
Published: April 2020

Abstract
Background and Objectives: Primary cutaneous anaplastic large cell lymphoma (pcALCL) has an overall favorable prognosis. However, we have previously suggested that patients with extensive limb involvement may have a worse outcome (J Am Acad Dermatol49:1049, 2003). The primary objective was to assess the potential prognostic factors in pcALCL, in particular the role of extensive regional single-limb disease (ERSL-D), defined as presentation with or progression to T2b or T2c involvement of a single limb, or T3b involvement of &gt; 3 contiguous body regions. Our secondary objectives were to study the gene expression profiles and treatment responses of our patients with pcALCL that may correlate with clinical outcome.
Patients and Methods: This was a retrospective study involving 48 patients with pcALCL diagnosed and managed at Stanford from 1990–2005. The potential prognostic factors for overall and disease-specific survivals (OS and DSS) were analyzed using the KM method and univariate and multivariate Cox regression. Cox regression was also used to identify risk factors for progresson to extracutaneous disease. Gene expression profiles were studied using cDNA microarrays.
Results: The OS and DSS rates of the entire cohort were 76% and 85% at 5 yrs and 70% and 85% at 10 yrs, respectively. Our univariate analysis demonstrated age, ERSL-D, and progression to extracutaneous disease (as a time-dependent variable) as significant prognostic factors for OS, while ERSL-D and progression to extracutaneous disease were significant for DSS. Sex, presence of spontaneous regression, and lesion site were not significantly assoicated with OS or DSS. Patients with T1 (solitary skin lesion) disease had an overall more favorable OS and DSS compared to those with T2 (regional skin involvement) and T3 (generalized skin involvement) disease, although the differences were not statisticlly significant. In our multivariate analysis, age (HR 1.83, 95% CI 1.02–3.26) and progression to extracutaneous disease (HR 6.42, 95% CI 1.39–29.68) remained significant for OS, while ERSL-D (HR 29.31, 95% CI 1.72–500.82) and progression to extracutaneous disease (HR 13.12, 95% CI 1.03–167.96) remained independent prognostic factors for DSS. Presentation with T3 disease was a significant risk factor for progression to extracutaneous disease (HR 10.20, 95% CI 1.84–56.72). Microarray studies of 14 samples from 3 ERSL-D and 7 classic pcALCL patients were performed. The patients with ERSL-D and classic pcALCL formed distinct, separate clusters. Classic pcALCL showed concurrent upregulation of epidermal genes analogous to normal skin, while ERSL-D lacked this signature. Genes upregulated in ERSL-D (after subtraction of epidermal genes) included STAT5A, IL2Rα, HIPK2, WDR10 and those down-regulated included RXRA. These gene profiling data suggest that targeting IL2R (denileukin diftitox) or STAT5 (HDAC inhibitors) may be appropriate in ERSL-D while therapeutic resistance to bexarotene may be linked to lack of RXRA gene expression.
Conclusion: Our data suggest that patients with ERSL-D have a worse clinical outcome associated with a distinct gene expression profile. More aggressive and targeted treatments may be indicated in this subgroup.