Schrader, Anne M.R., de Groen, Ruben A.L., Willemze, Rein, Jansen, Patty M., Quint, Koen D., van Wezel, Tom, van Eijk, Ronald, Ruano, Dina, Diepstra, Arjan, van den Berg, Anke, Kakiailatu, Naomi, Vermeer, Maarten H., and Vermaat, Joost S.P.
Primary cutaneous follicle center lymphoma (PCFCL) is characterized by lesions on the trunk and head-and-neck region consisting of centrocytes and admixed centroblasts. In general, PCFCL has an indolent behaviour with a 5-year disease-specific survival of 95%. Local radiotherapy results in a complete remission in 99% of the patients, however, cutaneous relapses are frequent (30%) and 10% of the patients develop progressive disease with extracutaneous dissemination or large-cell transformation. As it is difficult to identify these patients, the aim of this study was to identify 'clues' in clinical presentation, histopathology, immune phenotype, and genetic profile of PCFCL patients at time of diagnosis that may help to identify patients at risk for disease progression. In total, 15 patients with progressive PCFCL and 15 patients with indolent PCFCL (without disease progression and a follow-up duration of at least 5 years) were selected from the Dutch Registry of Cutaneous Lymphoma. Clinical presentation and histopathology were reviewed and immune phenotyping and molecular analysis, including targeted next-generation sequencing (NGS) with a 200 B-cell lymphoma-related gene panel, were performed. At diagnosis, all patients presented with classic PCFCL lesions on the trunk or head-and-neck region. Histology showed a characteristic predominance of centrocytes with admixed centroblasts. The median follow-up duration was 65 (range, 30 to 193) months with a progression-free survival of 26 (range, 4 to 147) months, during which five patients died of progressive PCFCL and one patient died of cardiac disease. In patients with progressive disease, IgM was significantly more often expressed compared with patients with indolent disease (53% vs. 7%; p=0.005). Targeted NGS demonstrated one or multiple PCFCL-like mutations in TNFRSF14, IRF8, CREBBP, EP300, EZH2, SETD2, SOCS1, STAT6 in 6 of 11 (55%) patients with indolent disease and in 9 of 12 (75%) patients with progressive disease. In 7 of 9 of these patients with progressive disease, however, additional non-PCFCL-like alterations were detected that were absent in patients with indolent disease, including MYC rearrangements in two patients and ERBB4, ZEB2, ARID1A, and ITBKB mutations in four patients as well as MYD88, CD79B, PIM1, and TBL1XR1 mutations in one of these patients. In three patients with progressive disease but without a PCFCL-like profile, we detected mutations in MYD88, PIM1, and TBL1XR1 in one patient, a MYD88 non-L265P mutation amongst others in one patient, and mutations in BRAF and CIITA in one patient, of which CIITA was also detected in one of the indolent patients. In conclusion, expression of IgM at diagnosis might represent a clue for a progressive disease course in PCFCL and may warrant additional genetic analysis and closer clinical follow-up of these patients. As this observation was made on a limited number of patients, these results need validation in an independent cohort. [ABSTRACT FROM AUTHOR]