The challenge of identifying identical twins: Advances in differentiating lupus erythematosus panniculitis from subcutaneous panniculitis-like T-cell lymphoma
By Warren R. Heymann, MD
Feb. 22, 2018
Did you ever have trouble telling identical twins apart? Most parents can do so by differentiating minor features that others might overlook, such as the way one laughs, wrinkles their nose, or exhibits a subtle smile. Such is the story of differentiating some cases of lupus erythematosus panniculitis (LEP, lupus profundus) from subcutaneous panniculitis-like T-cell lymphoma (SPTCL) that may display clinical and histological overlapping features. I recall rendering a second opinion on a young man referred to me with a diagnosis of LEP, manifesting as deep, depressed, red nodules, unresponsive to hydroxychloroquine. I only considered SPTCL because there was no improvement with treatment; it is easy to say that these disparate disorders should be differentiated (which they must!) — the recipe to do so requires significant skill with a dash of faith. This commentary refers to those cases without clearly defining features for LEP such as classical overlying histological changes of lupus or and/or high titer lupus serologies.
According to LeBlanc et al, it has been suggested that LEP and SPTCL represent opposite ends of a disease spectrum. SPTCL is typically associated with greater morbidity and risk for hemophagocytic lymphohistiocytosis (HLH); therefore, diagnostic distinction is essential. The authors presented the histopathologic, immunophenotypic, and molecular findings with long-term clinical follow-up of 13 patients with SPTCL (median, 64 months follow-up) and 7 with LEP (median, 50 months follow-up) in their multidisciplinary cutaneous oncology clinic. Six SPTCL patients developed HLH, including 2 under the age of 21 years. In the SPTCL group, 2 of 13 patients died of disease. In contrast, there was no mortality or development of HLH in their LEP cohort. They demonstrated that a limited panel (Ki-67, CD3, CD4, and CD8 immunostains) revealed foci of “Ki-67 hotspots” enriched in cytotoxic atypical CD8+ T cells in SPTCL. Ki-67 hotspots were not identified in LEP, thus aiding the distinction of SPTCL from LEP. Lymphocyte atypia combined with adipocyte rimming of CD8+ T cells within Ki-67 hotspots was also highly specific for the diagnosis of SPTCL. Hyaline lipomembranous change, B-cell aggregates, plasmacytoid dendritic cell clusters, and plasma cell aggregates favored the diagnosis of LEP but were identified in some cases of SPTCL including patients with HLH. The authors confirmed that SPTCL and LEP can show significant histologic overlap, and suggested a role for high-throughput sequencing to confirm neoplastic clones, and introduced the concept of SPTCL “Ki-67 hotspots” in evolving disease. (1)
In a histologic review of 19 cases of LEP, Park et al found that most specimens revealed lymphoplasmacytic lobular panniculitis with epidermal and dermal changes of lupus, hyaline fat necrosis, and lymphoid follicles. Immunohistochemistry showed a mixture of T and B cells in the dermis and subcutaneous tissue, with a slight preponderance of T cells. Although the polymerase chain reaction analysis of the T-cell receptor-[gamma] gene rearrangement showed a polyclonal smear in 89.5% of cases, a small portion of specimens demonstrated monoclonality. (2). Rimming of fat lobules by lymphocytes and atypical lymphocytes has been reported as a typical feature of subcutaneous lymphoma, however they have also been described in cases of LEP. (1). There are many cases in the literature describing patients who present with both overlapping features of SPTCL and LEP, yet lack diagnostic features of either, and are categorized as a separate disease entity known as “atypical lymphocytic lobular panniculitis”. (3)
Among the gene expression networks known to influence oncogenic transformation, the one controlled by the proto-oncogene MYC is one of the most frequently deregulated in cancer. (4) MYC interacts with several central cell cycle regulators that control the balance between cell cycle progression and temporary or permanent cell cycle arrest (cellular senescence). Among these are the cyclin E/A/cyclin-dependent kinase 2 (CDK2) complexes, the CDK inhibitor p27KIP1 (p27) and the E3 ubiquitin ligase component S-phase kinase-associated protein 2 (SKP2). (5)
Fernandez-Pol et al performed immunohistochemistry for the MYC oncoprotein on 23 cases of SPTCL and 12 cases of LEP to evaluate if there were quantitative or qualitative differences in protein expression of this marker in these entities. In SPTCL cases, the percentage of all cells that were c-Myc positive ranged from 0.8% to 16%, with a mean of 5.0% and a median of 4.4%. In contrast, in the LEP cases, the percentage of c-Myc-positive cells in the cases ranged from 0.34% to 3.7%, averaged 1.4% and the median was 0.8%. The difference between the means of these two diagnostic categories was statistically significant. Fluorescence in situ hybridization performed on 4 cases of SPTCL with a relatively high level of MYC immunohistochemical staining, however, failed to demonstrate evidence of MYC rearrangement or amplification. The authors concluded that MYC expression levels differ between these two histologic mimics and suggested that this important oncoprotein may play a role in the pathogenesis of SPTCL. (6)
In conclusion, the recent findings of “Ki-67 hot spots” and the presence of the MYC oncoprotein favor the diagnosis of SPTCL over LEP. Despite a mother’s ability to distinguish her twin children, I imagine that occasionally she would get them confused (I was the youngest of three brothers and I found it surprising that my late mother would still call me George, then Andrew, before settling on Warren). Fortunately, we are getting closer to differentiating these two entities. I anticipate that with further molecular advances, we will soon be able to do this with confidence.
1. LeBlanc RE, et al. Useful parameters for distinguishing subcutaneous panniculitis-like T-cell lymphoma from lupus erythematosus panniculitis. Am J Surg Pathol 2016; 40: 745-54.
2. Park HS, et al. Lupus erythematosus panniculitis: Clinicopathological, immunophenotypic, and molecular studies. Am J Dermatopathol 2010; 32: 24-30.
3. He A, et al. Atypical lymphocytic lobular panniculitis: an overlap condition with features of subcutaneous panniculitis-like T-cell lymphoma and lupus profundus. BMJ Case Reports 2016; doi:10.1136/bcr-2016-215335
4. Iaccarino I. IncRNAs and MYC: An intricate relationship. Int J Mol Sci 2017; Jul 12: 18 (7).
5. Hydbring P, et al. MYC modulation around CDK2/p27/SKP2 axis. Gene (Basel) 2017 Jun 30; 8 (7).
6. Fernandez-Pol S, et al. Immunohistochemistry reveals an increased proportion of MYC-positive cells in subcutaneous panniculitis-like T-cell lymphoma compared with lupus panniculitis. J Cutan Pathol 2017; 44: 925-30.
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