To the Editor,
Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT) is a rare subtype of B-cell non-Hodgkin lymphoma, characterized by a more aggressive clinical course and associated with poorer prognosis compared to its systemic counterpart [1–3]. Due to the limited availability of data, optimal treatment strategies for this entity beyond the use of anthracycline-containing chemoimmunotherapy are not agreed upon [4, 5], especially with respect to the role of consolidation radiation therapy (RT) and the management of central nervous system (CNS) relapse risk [6, 7]. To shed light on these aspects and inform practice, we reviewed our institutional experience in patients with PCDLBCL, LT treated in the rituximab era.
We searched our electronic database and identified 44 patients with PCDLBCL, LT followed at Memorial Sloan Kettering Cancer Center between July 2002 and June 2024. All diagnoses were confirmed through histopathological review, and the study received approval from our center’s Institutional Review Board.
As shown in Table 1, the median age was 75 years (range, 40–96) and 21 patients (48%) were female. Thirty-one (70%) presented with a single lesion while 13 (30%) had multiple cutaneous lesions. No patient exhibited extracutaneous involvement at diagnosis. The disease was localized to the lower extremities in 18 cases (41%), including 10 patients (23%) with a single lesion and 8 (18%) with multiple lesions. All but one patient had an International Prognostic Index (IPI) of 0-2; 30 patients (71%) had a CNS-IPI of 0-1, and 12 (29%) had a CNS-IPI of 2–3; none had high-risk CNS-IPI. Immunohistochemistry (IHC) markers were available for most patients (supplemental Table 1). According to the Hans algorithm, 72% of the 36 evaluable patients exhibited non-GCB phenotype. MUM1 and BCL2 were each expressed in 85% of cases, while BCL6 positivity was observed in 82%. The median Ki-67 index was 85% (IQR, 70%–95%).
Table 1.
Baseline Characteristics and First-line Treatments.
| Characteristics | Overalla | Single lesiona | Multifocala |
|---|---|---|---|
| N = 44 | N = 31 | N = 13 | |
| Median Age | 75 (40, 96) | 76 (40, 89) | 72 (43, 96) |
| Gender | |||
| F | 21 (48%) | 15 (48%) | 6 (46%) |
| M | 23 (52%) | 16 (52%) | 7 (54%) |
| Race | |||
| White | 33 (87%) | 25 (93%) | 8 (73%) |
| Asian | 3 (8%) | 1 (4%) | 2 (18%) |
| African American | 1 (3%) | 1 (4%) | 0 (0%) |
| Other | 1 (3%) | 0 (0%) | 1 (9%) |
| Unknown | 6 | 4 | 2 |
| Ethnicity | |||
| Not hispanic | 38 (97%) | 27 (100%) | 11 (92%) |
| Hispanic or latino | 1 (3%) | 0 (0%) | 1 (8%) |
| Unknown | 5 | 4 | 1 |
| B symptoms | 0 (0%) | 0 (0%) | 0 (0%) |
| ECOG PS | |||
| 0 | 28 (64%) | 21 (68%) | 7 (54%) |
| 1 | 14 (32%) | 8 (26%) | 6 (46%) |
| 2/3 | 2 (4.5%) | 2 (6.5%) | 0 (0%) |
| Skin site | |||
| Lower extremity | 18 (41%) | 10 (32%) | 8 (62%) |
| Other site | 26 (59%) | 21 (68%) | 5 (38%) |
| Bulky mass (>5 cm) | 5 (14%) | 3 (13%) | 2 (15%) |
| Unknown | 7 | 7 | 0 |
| White blood cells * 1000/microL | 7.0 (2.6, 12.6) | 6.8 (4.3, 12.6) | 7.4 (2.6, 10.8) |
| Unknown | 3 | 2 | 1 |
| Hemoglobin, g/dL | 13.4 (9.9,16.1) | 13.5 (11.0, 16.1) | 12.9 (9.9, 15.0) |
| Unknown | 4 | 3 | 1 |
| Platelets * 1000/microL | 218 (126, 453) | 199 (126, 383) | 234 (175, 453) |
| Unknown | 3 | 2 | 1 |
| Albumin, g/dL | 4.2 (3.5, 27.0) | 4.2 (3.8, 27.0) | 4.2 (3.5, 4.7) |
| Unknown | 4 | 3 | 1 |
| Elevated LDH | 8 (19%) | 7 (23%) | 1 (8%) |
| Unknown | 2 | 1 | 1 |
| IPI | |||
| 0/1 | 32 (76%) | 22 (73%) | 10 (83%) |
| 2 | 9 (21%) | 7 (23%) | 2 (17%) |
| 3 | 1 (2%) | 1 (3%) | 0 (0%) |
| Unknown | 2 | 1 | 1 |
| CNS-IPI | |||
| 0/1 | 30 (71%) | 21 (70%) | 9 (75%) |
| 2/3 | 12 (29%) | 9 (30%) | 3 (25%) |
| Unknown | 2 | 1 | 1 |
| Additional cancers | 23 (52%) | 16 (52%) | 7 (54%) |
| Additional skin cancers | 15 (34%) | 10 (32%) | 5 (38%) |
| First-line Treatment | |||
| RT | 11 (25%) | 9 (29%) | 2 (15%) |
| Chemotherapy | 15 (34%) | 10 (32%) | 5 (38%) |
| Chemotherapy + RT | 15 (34%) | 10 (32%) | 5 (38%) |
| Other | 3 (7%) | 2 (6.5%) | 1 (8%) |
| First-line CNS prophylaxis | 6 (14%) | 3 (10%) | 3 (23%) |
PS performance status, LDH lactate dehydrogenase, IPI international prognostic index, CNS central nervous system, RT radiation therapy.
aValues reported as n (%) or as median (range).
As shown in Table 1, patients were treated with a variety of induction strategies including radiation therapy alone (RT group) in 11 patients at doses of 30–45 Gy; R-CHOP immunochemotherapy (CHT group) in 15 (34%); and R-CHOP followed by 30–40 Gy RT (combined modality therapy [CMT] group) in 15 (34%) patients. Three patients received other treatments: one underwent excision alone, one received rituximab after excisional biopsy, and one was managed with best supportive care only. Six patients (14%) received CNS prophylaxis, 5 in the form of intrathecal methotrexate and one high-dose (HD) intravenous methotrexate. Among these patients, CNS-IPI score was 1 in 5 cases and 0 in one.
All 44 patients were evaluable for response, with an overall response rate (ORR) of 86% and complete response (CR) rate of 84%. There was no significant difference in response rates (p = 0.13) among the RT, CHT and CMT groups. Notably, all patients in the CMT group achieved a CR, with disease progression observed at the end of treatment only in the CHT (2 patients) and RT groups (2 patients, supplemental table 2). Among the patients receiving other treatments, one underwent excisional biopsy alone and remained disease-free at the last follow-up. Another patient received four cycles of rituximab following excisional biopsy, achieving stable disease, and subsequently required second-line therapy.
The median follow-up among survivors is 4.8 years (range, 0.6–19.6). The median progression-free survival (PFS) is 4.9 years (95%CI, 2.6-NR), while the median overall survival (OS) is 9.9 years (95%CI, 4.6-NR). A trend toward longer PFS was observed in patients receiving CMT, with a median PFS of 8.5 years (95%CI, 4.9-NR), compared to 4.6 years (95%CI, 1-NR) in the CHT group and 1.6 years (95%CI, 0.98-NR) in the RT group (p = 0.13, Fig. 1B). Similarly, OS was significantly longer in the CMT group, with a median OS of 14 years (95% CI, 14–NR), compared to 9.9 years (95% CI, 3–NR) for CHT and 9.9 years (95% CI, 2.6–NR) for RT (p = 0.051, Fig. 1D).
Fig. 1. Time to event analyses.
Time-to-event outcomes. A Progression-free survival. B Progression-free survival based on treatment group, either radiation therapy (RT), chemotherapy (CHT) or chemotherapy plus radiation therapy (CMT). C Overall Survival D Overall Survival based on treatment group, either radiation therapy (RT), chemotherapy (CHT) or chemotherapy plus radiation therapy (CMT).
In our cohort 31 patients had unifocal disease, while 13 had multifocal disease. No significant differences in response rates (p = 0.4) or PFS (p = 0.8) (supplemental tables 3, 4) were observed between the two groups, while a trend toward improved OS was noted in patients with a single lesion, with a median OS of 14 years (95%CI, 9.9-NR), compared to 4.6 years (95%CI, 2.6-NR) for those with multifocal disease (p = 0.11, supplemental table 5 and supplemental Fig. 1).
Second-line therapies were administered in 12 patients. The majority received rituximab-based immunochemotherapy, including R-CHOP in three patients previously treated with RT. Other regimens included R-ICE, R-GemOx, R-CEPP, rituximab monotherapy and rituximab combined with lenalidomide (one patient each). Four patients received RT alone (30–45 Gy). Consolidation therapy was given to five patients: four received RT, and one underwent high-dose therapy with autologous stem cell support and remains in remission at the time of this writing.
CNS relapse occurred in 5 patients (11%), with involvement of the leptomeninges in 1 case, parenchyma in 2, and both leptomeninges and parenchyma in 2. Of note, none of these patients had received CNS prophylaxis. The 3-year and 5-year cumulative risks of CNS relapse were 7% (95% CI, 2-22%) and 11% (95% CI, 4-29%), respectively (supplemental Fig. 2).
PCDLBCL, LT is an aggressive disease, typically presenting with rapidly growing nodules, plaques, or tumors on the lower extremities. Although considered a separate entity, it shares some molecular features with activated B-cell (ABC)-type DLBCL, including recurrent mutations in CD79B, CARD11, and MYD88 driving NF-κB activation [8]. Our cohort reflects these aspects, with most cases exhibiting a non-GCB phenotype, along with substantial expression of BCL2 and BCL6 and CD10 negativity in almost all cases.
Treatment approaches for PCDLBCL, LT are modeled after those for systemic DLBCL, with R-CHOP being the most commonly used regimen [4]. In previously published reports, the use of R-CHOP resulted in disease-free survival rates comparable to those observed in high-risk systemic DLBCL [5, 9]. In the largest cohorts published to date on the subject (Zinzani et al. [10], 51 patients; Grange et al. [7], 60 patients), rituximab was used in only a small subset of patients. Additionally, those studies did not evaluate the impact of RT consolidation following chemotherapy. In an earlier small report, Kraft et al. [11] suggested improved PFS in PCDLBCL, LT patients receiving R-CHOP plus RT (9 patients, median PFS 58 months, 95% CI 18–112) versus R-CHOP alone (9 patients, median PFS 14 months, 95% CI 5–NR). Our findings support those observations and more strongly suggest that combining chemoimmunotherapy with RT may yield better outcomes than either modality alone [11].
Given the previously described adverse prognostic impact of multiple cutaneous lesions compared to a single lesion [4, 10], we analyzed response rates and survival outcomes by stratifying patients into these two groups. A slightly higher proportion of patients with multifocal disease received CHT and CMT, while RT was more commonly used for single lesions. No statistically significant differences were observed in response rates or PFS between the two groups. However, this finding may be attributed to the retrospective nature and small sample size of the study. Indeed, among the 9 patients with unifocal disease treated with RT, 6 (67%) relapsed, suggesting RT alone is unlikely to provide adequate disease control.
Recent studies have suggested an excess risk of CNS relapse in PCDLBCL, LT patients. This risk is understood in the context of genotypic similarities between PCDLBCL, LT and primary CNS lymphoma, particularly the presence of the non-GCB phenotype and mutations in MYD88 and CD79B genes [8, 12]. In a French series of 13 patients with PCDLBCL, LT and CNS recurrence, 5 out of 6 cases tested positive for the MYD88 mutation [6]. In our study none of the 5 patients with CNS relapse had received CNS prophylaxis. While notable, this observation does not represent a definitive endorsement of the role or method of CNS prophylaxis.
To the best of our knowledge, this represents the largest PCDLBCL, LT cohort treated with rituximab-based chemotherapy in which CNS relapse risk was formally assessed. Our study suggests that existing prognostic tools, such as the IPI and CNS IPI, do not reliably predict CNS relapse in this population, underscoring the need for more accurate predictive markers. In our cohort all CNS-IPI scores were ≤3, yet the cumulative incidence of CNS relapse at 5 years was 11%, which is more reflective of a higher CNS IPI risk category [13]. While none of the patients who received CNS prophylaxis experienced a CNS relapse, analysis of a larger cohort will be necessary to better characterize the role of CNS prophylaxis in patients with PCDLBCL, LT.
Our study has limitations, including its retrospective single-center nature, treatment heterogeneity and overall small sample size, primarily owing to the rarity of PCDLBCL, LT. Nonetheless, our observations support the use of R-CHOP with RT consolidation as preferred frontline treatment for PCDLBCL, LT. Moreover, the higher-than-expected CNS relapse rate, exclusively among those not receiving prophylaxis, suggests a potential benefit of CNS prophylaxis. The introduction of novel therapies, including polatuzumab, CAR-T cells and bispecific antibodies, may further improve outcomes for PCDLBCL, LT patients, and future studies evaluating their impact are warranted [14, 15].
Supplementary information
Acknowledgements
Dr. Falchi’s research was funded in part through a grant from Blood Cancer United (Formerly Leukemia & Lymphoma Society) Dr. Falchi's research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748.
Author contributions
GC and LF conceived the study. GC and LF performed literature search. GC and AQ performed data extraction; ED performed statistical analysis. AD and KJB performed histologic review. LF and GS provided guidance on the methodology. ED, MDE, PH, SMH, EJ, AK, AJM, AN, CO, MLP, ADZ, AD, KJB, JY, GS, MJM edited the manuscript and approved the final version of the article.
Competing interests
Mark D. Ewalt has received speaking fees from Pillar Biosciences. Paul Hamlin has consulted for ADC Therapeutics. JL has consulted for OncLive, Merck. Steven M. Horwitz has consulted for Abcuro, Inc., Arvinas, Autolus, Auxilus Pharma, BlueSphere Bio, Corvus, Daiichi Sankyo, DrenBio, J&J Medicine/Janssen Research & Development, Kyowa Hakko Kirin, March Bio, ONO Pharmaceuticals, Pfizer, SecuraBio, Shoreline Biosciences, Inc., SymBio, Takeda and Yingli Pharma Limited. Has received research funding from ADC Therapeutics, Affimed, Aileron, Celgene, Corvus, Crispr Therapeutics, Daiichi Sankyo, Forty Seven, Inc., Kyowa Hakko Kirin, Takeda, Seattle Genetics, Trillium Therapeutics, Treeline and SecuraBio. Erel Joffe has received honoraria from J&J, abbvie. Anita Kumar has received research funding from Celgene, Seattle Genetics, Adaptive Biotechnologies, Genentech, Abbvie Pharmaceuticals, Loxo/Lily Oncology, Astra Zeneca, Pharmacyclics, Beigene; is a current equity holder in publicly-traded company for BridgeBio; has consulted for Astra Zeneca, Loxo/Lily Oncology, Janssen, Genentech, Kite Pharma. Alison J. Moskowitz has received honoraria from Merck, Seattle Genetics; has received research funding from Bristol-Myers Squibb, Merck, Seattle Genetics, Beigene, Incyte, ADC Therapeutics. Ariela Noy received research funding from Rafael Pharma and Pharmacyclics; has consulted for Pharmacyclics, Medscape, Targeted Oncology, Morphosys, Pharmacyclics and Janssen; received research funding from NIH. Maria L. Palomba has received honoraria from Smart Immune, Cellectar, Seres Therapeutics, Rheos, Juno, Ceramedix, Pluto Immunotherapeutics, Novartis, Garuda Therapeutics, MustangBio, Thymofox, Kite, BMS, Synthekine. Andrew D. Zelenetz has received honoraria from AstraZeneca, Janssen Pharmaceuticals, F. Hoffmann-La Roche Ltd, Pharmacyclics, Gilead, BMS, MEI Pharma Inc; has consulted for AstraZeneca, F. Hoffmann-La Roche Ltd, Janssen Pharmaceuticals, Pharmacyclics, Gilead, BeiGene, BMS, MEI Pharma Inc; has received research funding from Abbvie, F. Hoffmann-La Roche Ltd, Gilead, MEI Pharma Inc; has membership on an entity’s Board of Directors or advisory committees for Lymphoma Research Foundation. Ahmet Dogan has consulted for Seattle Genetics, Takeda, EUSA Pharma, AbbVie, Peerview, Physicans’ Education Resource; has received fundings from Roche/Genentech. Klaus J. Busam has Royalties for textbook published by Elsevier. Gilles Salles has received financial compensations for participating in advisory boards or Data Monitoring Committees: Abbvie, Beigene, BMS, Foresight, Genentech/Roche, Genmab, Janssen, Ipsen Kite/Gilead, Lilly, Merck, Novartis, Pfizer, SERB pharmaceuticals; has received financial compensations for consulting from: Abbvie, Ellipses, Genentech/Roche, Genmab, Incyte, Kite/Gilead; has received research support from Abbvie, Genentech, Genmab Janssen, Ipsen, which was managed by his institution. Matthew J. Matasar has received honoraria from ADC Therapeutics, AstraZeneca, Bayer, BMS, Celgene, Epizyme, IMV Therapeutics, J&J, Kite, Regeneron, Roche, Pfzier; has consulted for Bayer, Genetech, Kite, Roche, Seattle Genetics; has received research funding from Seattle Genetics, Roche, Pharmacyclics, Genentech, J&J, Bayer. Lorenzo Falchi has received research funding from Roche, Genentech, Genmab, AbbVie, Innate Pharma, Beigene, Astrazeneca; has consulted for Roche, Genentech, Genmab, AbbVie, Sanofi, Evolveimmune, Astrazeneca, Merck; was in advisory board of AbbVie, Genentech, ADC therapeutics, Seagen, Ipsen, Johnson & Johnson; received honoraria from Roche, Genmab, AbbVie, Kite; received travel support from Genmab, AbbVie, Roche, Kite. All other authors have no COI.
Footnotes
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Change history
9/29/2025
The Acknowledgement section has been updated as follows: Dr. Falchi’s research was funded in part through a grant from Blood Cancer United (Formerly Leukemia & Lymphoma Society) Dr. Falchi's research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748.
Supplementary information
The online version contains supplementary material available at 10.1038/s41408-025-01354-1.
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