Abstract
Background
Cutaneous lymphoma (CL) diagnosed after anti-tumor necrosis factor (TNF)α therapy has been reported in the literature, yet a clear link between both events remains elusive.
Objective
To review our experience with CL diagnosed during or after the use of anti-TNFα therapies.
Methods
This is a multicenter retrospective study and a literature review.
Results
Twenty-two cases, including 20 cutaneous T-cell lymphomas (CTCL) and 2 cutaneous B-cell lymphomas (CBCL), were identified. In the CTCL group, 75% of the patients received an anti-TNFα agent for a presumed inflammatory skin condition. Mycosis fungoides and Sézary syndrome were the most common subtypes of CTCL diagnosed. Advanced disease (IIB – IVA) was commonly seen at time of diagnosis requiring aggressive therapy, including stem cell transplant in three patients. Two patients diagnosed with CBCL had an indolent course. A total of 31 cases were gathered from a literature search.
Limitations
This is a retrospective study.
Conclusions
Our findings suggest that most of the identified patients were misdiagnosed as having psoriasis or eczema; therefore, a comprehensive morphological and molecular review of skin biopsies and peripheral blood should be considered prior to initiation of anti-TNFα therapy in patients with poorly defined dermatitis or atypical presentations of “psoriasis”.
Keywords: anti-tumor necrosis factor alpha agents, cutaneous lymphoma, immunosuppression, large cell transformation, psoriasiform dermatitis, spongiotic dermatitis
Introduction
Cutaneous lymphomas (CL) are rare cancers characterized by proliferation of malignant T or B-lymphocytes in the skin. Cutaneous T-cell lymphomas (CTCL) are more common than B-cell lymphomas, with mycosis fungoides (MF) being the most common subtype. The initial presentation of MF can mimic inflammatory skin conditions such as eczema, pigmented purpura, pityriasis lichenoides chronica, and psoriasis. This mimicry of benign dermatoses is a major challange for clinicians and pathologists that can lead to misdiagnosis and to the use of potentially harmful immunosuppressive agents in these patients.
Additionally, there is an increased risk of lymphoma with chronic use of immunosuppressive therapy such as cyclosporine, mercaptopurine, or anti-tumor necrosis factor (TNF)α agents, yet the effects of these agents on CL remains controversial.1, 2 Approximately 30 cases of CL arising after anti-TNFα therapy have been reported in the literature.1, 3–20 Some of those cases were eventually diagnosed as MF resembling psoriasis or eczema, with an unmasking of the lymphoma after receiving the anti-TNFα agent. Herein, we describe our multi-institutional set of patients diagnosed with cutaneous lymphomas after being exposed to anti-TNFα therapy.
Materials and methods
This is a case series derived from a multicenter retrospective chart review. Upon Institutional Review Board approval, patients diagnosed with CL after therapy with anti-TNFα agents were included. A literature search of case series and case reports with the same inclusion criteria was also performed. Clinical data were collected from the electronic medical records system, including gender, race, age of diagnosis of CL, disease for which the anti-TNFα agent was prescribed, other immunosuppressive treatment received, type of anti-TNFα agent received, time since anti-TNFα therapy was started until CL diagnosis, type of CL diagnosed, blood parameters at diagnosis such as lactate dehydrogenase (LDH), flow cytometry of peripheral blood, Sézary cell count, T-cell receptor (TCR) gene rearrangement in the blood and skin, initial TNM for non-MF/Sézary syndrome (SS) cases or TNMB staging for MF/SS cases, treatment received for CL, and outcome. Follow-up was assessed from diagnosis to the most recent point in time for which adequate patient data existed. Skin biopsies performed prior to and after receipt of anti-TNFα therapy were reviewed along with immunohistochemistry data, when available. Descriptive statistics including median (with range) were performed. The same data were also collected from published case series and case reports.
Results
A total of 22 patients, 15 male and 7 female, were included in the study. Twenty patients were diagnosed with CTCL and 2 with CBCL.
CTCL
Clinical, histologic, and therapeutic details of the 20 CTCL patients are reported in Table 1. The male-to-female ratio was 2:1, and the median age was 63 years (ranging from 21 to 76 years). Fifteen patients were White, 3 Black, and 2 Hispanic. A primary skin disorder was the indication for the use of anti-TNFα agents in 75% of patients. Most of these cases had been clinically diagnosed as psoriasis, psoriasiform dermatitis, or idiopathic erythroderma. Of the remaining 5 (25%) patients were diagnosed with rheumatoid arthritis (RA) in 2 patients, Crohn’s disease (CD) in another 2 patients and sarcoidosis in one patient prior to use of anti-TNFα therapy. Of note, three of the five patients had a concomitant, but unspecified dermatitis prior to the initiation of the anti-TNFα agent.
Table 1.
Demographic, clinical and follow up data of patients diagnosed with CTCL.
| Case | age/gender /race |
Condition prior anti-TNFα agent (years) |
Skin biopsy prior to anti-TNFα agent |
Therapy prior to anti-TNFα agent |
Anti-TNFα agents (months) |
CTCL | Stage | Treatments | Outcome | F/u (months) |
|---|---|---|---|---|---|---|---|---|---|---|
| 124 | 69/F/B | Psoriasis (1) | Yes, psoriasiform dermatitis | MTX acitretin,MMF, P | Adalimumab (1) | CTCL NOS | T3N3M0 | HDAC | DOD | 7 |
| 2 | 63/M/W | Crohn’s disease/Psoriasis (6 and 30 years) | Yes, inconclusive | NB-UVB | Adalimumab (1) | CTCL NOS | T3N2M0 | PUVA, methotrexate, gemcitabine,NB-UVB | AWD | 27 |
| 3 | 46/F/W | Crohn’s disease (30) | N/A | 6-MP, AZA | Adalimumab (8) | CTCL NOS | T2N0M0 | Self-resolved | AWOD | 33 |
| 4 | 72/M/W | Rheumatoid arthritis/derm atitis (uk and 6 years), | None | Leflunomide, sulfasalazine, AZA | adalimumab, etanercept, infliximab (UK) | FMF | IIB | Acitretin, XRT | AWD | 12 |
| 5 | 29/F/B | Psoriasis (13) | Yes, N/A | MTX | Adalimumab,ustekinumab | FMF | IIB | INF, PUVA, BXT, HDAC, PXT, NM, TSEBT, FM, AHSCT | AWD | 24 |
| 6 | 76/F/W | Psoriasis (20) | None | None | Etanercept (6) | FMF | IIB | MTX, GM, BXT | DOD | 31 |
| 7 | 63/M/W | Psoriasis (3) | Yes, psoriasis | MTX | Etanercept (2) | FMF (LCT) | IIB | XRT, NB-UVB, acitretin, INF, BXT | AWD | 26 |
| 8 | 72/F/W | Rheumatoid arthritis (40) | N/A | None | Etanercept (12) | MF | IA | NBUVB, MTX | AWOD | 137 |
| 9 | 21/M/W | Psoriasis (UK) | Yes, psoriasis | None | Adalimumab (20) | MF | IA | NB-UVB, acitretin | AWD | 27 |
| 10 | 64/F/W | Erythroderma (2) | Yes, chronic lymphocytic dermatitis | P, MTX, NB-UVB | Adalimumab, infliximab (UK) | MF | IIIA | ECP, DXR, MTX, NB-UVB, P, MOGA, HDAC, ALZ, AHSCT | AWOD | 96 |
| 11 | 66/M/W | Eczema(since childhood) | None | MTX, NB-UVB, PUVA | Infliximab (UK) | MF | IIIA | TSEBT, HDAC, acitretin, GM, erlotinib, DXA, capecitabine | AWD | 24 |
| 12 | 58/M/H | Psoriasis (2) | Yes, N/A | None | Adalimumab (4) | MF | IVA2 | XRT, PUVA, HDAC, NM | AWD | 6 |
| 13 | 49/M/W | Psoriasis (40) | Yes, psoriasiform dermatitis | None | Adalimumab (24) | MF | IB | CHOEP, HDAC, BM, PTX, MTX. | AWOD | 20 |
| 14 | 75/M/W | Erythroderma (5) | Yes, spongiotic dermatitis | Systemicsteroids | Adalimumab (UK) | MF (LCT) | IIIA | UK | Lost to f/u | UK |
| 15 | 72/F/H | Eczema vs psoriasis(UK) | Yes, spongiotic dermatitis | Systemic steroids, NB-UVB | Apremilast, etanercept, adalimumab (UK) | MF (LCT) | UK | UK | Lost to f/u | UK |
| 16 | 41/M/W | Erythroderma (9) | Yes, inconclusive | INF, NB-UVB, Thalidomide,AZA | Etanercept (8) | MF/LyPoverlap | IVA2 | INF, DXR, DXA, GM, AHSCT | AWOD | 137 |
| 17 | 27/M/B | Psoriaticarthritis/Psoriasis(1.5) | Yes, psoriasis | CsA, MTX | Adalimumab, ustekinumab (4) | PCAEC-TCL | T3N0MX | NBUVB, MTX, EPOCH, GM, HDAC, Brentuximab | DOD | 13 |
| 18 | 42/M/W | Sarcoidosis (1.5) | Yes, granulomatous panniculitis | P, minocycline, hydroxicloroqui ne | Infliximab (1) | PCγδTCL | T3NXM0 | CHOEP, CsA, Brentuximab, AHSCT | AWOD | 5 |
| 19 | 64/M/W | Psoriasis (4) | Yes, psoriasis | UK | Adalimumab, ustekinumab (24) | SS | IVA1 | ECP, BXT, INF | AWD | 4 |
| 20 | 40/M/W | Psoriasis (7) | Yes, psoriasis | MTX, CSA | Apremilast, Adalimumab (UK) | SS | IVA1 | Acitretin, INF | AWD | 3 |
6-MP: 6-mercaptopurine; ALZ: alemtuzumab; AWD: alive with disease; AWOD: alive without disease; AZA: azathioprine; BXT: bexarotene; CHOEP: etoposido, prednisone, vincristine, doxorrubicine; CsA: cyclosporine A; DOD: dead of disease; DXA: dexamethasone; ECP: photopheresis; EPOCH: etoposide, prednisone, vincristine, doxorubicin; f/u: follow-up; FM: fludarabine/melfalan; GM: gemcitabine; HDAC: histone deacetylase inhibitor (romidepsin); INF: interferon; MMF: mycofenolate mophetil; MOGA: mogalimumab; MTX: methotrexate; N/A: non-available/non-applicable; NB-UVB: narrow band-ultraviolet; NM: nitrogen mustargen; P: prednisone; PUVA: psoralen-ultraviolet; PXT: praletexate; AHSCT: allogeneic hematopoietic stem cell transplant; TSEBT: total skin electron beam therapy; UK: unknown; XRT: radiation therapy.
Of the 18 patients with a skin disorder prior to anti-TNFα agent initiation, 15 had a skin biopsy performed. The most common histologic finding (46%) was “psoriasis” or “psoriasiform dermatitis” with some cases revealing striking similarity to psoriasis vulgaris including acanthosis, parakeratosis and exocytosis of neutrophils. Biopsies of the remaining 7 patients were reported as chronic spongiotic dermatitis, chronic lymphocytic dermatitis, or granulomatous dermatitis. We had the opportunity to retrospectively review 6 of these biopsies, which in some cases showed rare atypical lymphocytes but for the most part failed to fulfill histological or immunohistological criteria for CL. Only two patients with extensive skin disease had peripheral blood assessment performed before anti-TNFα therapy initiation. Both had an abnormal population of <200 cells, one by morphology and the other by flow cytometry, deemed clinically non-significant.
The median time from disease onset to initiation of anti-TNFα therapy was 6 years (ranging from 1 to 40 years). Thirteen patients received adalimumab, 6 etanercept, 4 infliximab, and 7 patients received more than 1 biologic agent. Fourteen patients received a median of 2 other immunosuppressive treatments prior to biologic agents, most commonly methotrexate and/or systemic steroids. A total of 3 patients had been treated with 6-mercaptopurine and/or azathioprine, and another one received cyclosporine A. Phototherapy had been given to 38% (5/13) of patients during their treatment course.
After anti-TNFα initiation, the majority of cases experienced worsening of skin disease, and three patients developed new skin eruptions. One of them was a 21-year-old patient with symmetrically distributed erythematous and scaly plaques, and biopsy-proven psoriasis, with a family history of psoriasis who developed de novo erythematous patches with a different distribution compared to his psoriasis (Case 9).
The median time from the start of anti-TNFα agent to CTCL diagnosis was 6 months (ranging from 1 to 24). Thirteen patients were diagnosed with MF, including 4 cases with the folliculotropic (FMF) variant, 2 patient with Sézary syndrome (SS), 3 patients with CTCL not otherwise specified (NOS), 1 patient with primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphoma (PCAEC-TCL), and 1 patient with primary cutaneous gamma-delta T-cell lymphoma (PCGD-TCL). Stages are detailed in Table 1. Limited blood involvement (B1 stage) was observed in 5 (45%) patients on blood smear and, 2 of which were confirmed by flow cytometry. One patient with CTCL NOS had an abnormal population of more than 3,000 cells, with a CD4-/CD8-null-phenotype that did not coincide with the phenotype of the atypical lymphocytes of the skin biopsy (Case 1). This patient died 2 months after the administration of the anti-TNFα agent from the CTCL.21
At diagnosis of CTCL, serum LDH was abnormal in 7 patients (70%), all of whom had advanced disease. Eighty-one percent of the patients had a T-cell clone present in the skin biopsy, and 58% had a T-cell clone present in peripheral blood. Same clonality in skin and blood was detected in one MF patient as well as the 2 patients with SS. Histological features and phenotype of the diagnostic skin biopsies are shown in Table 2. At the time of CTCL diagnosis, three biopsies consistent with MF showed features of large cell transformation (LCT), and large cell morphology was observed in one patient with CTCL NOS (Case 2).
Table 2.
Immunohistochemical findings of CTCL diagnosis.
| Case | Diagnosis | Main histological findings | CD2 | CD3 | CD4 | CD5 | CD7 | CD8 | CD30 | TIA-1 | EBER | BF1 | GM1 | CD4:CD8 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | CTCL NOS | Psoriasiform features with AL | N/A | + | + | + | + | − | N/A | 10% | N/A | + | 10% | 8:1 |
| 2 | CTCL NOS (large cells) | Spongiotic epidermis, superficial and mid dermis with AL | N/A | + | largecells | + | loss | − | 10% | − | − | + | − | 5:1 |
| 3 | CTCL NOS | Lobular panniculitis with AL | − | + | − | − | − | − | − | + | − | + | − | 4:1 |
| 4 | FMF | Folliculotropism of AL | N/A | + | + | − | N/A | N/A | 25% | N/A | N/A | + | − | 10:1 |
| 5 | FMF | Folliculotropism and syringotropism of AL | + | + | − | + | + | − | − | 3: 1 | ||||
| 6 | FMF | Folliculotropism of AL, psoriasiform features | N/A | + | + | N/A | N/A | N/A | − | N/A | N/A | N/A | N/A | 10:1 |
| 7 | FMF (LCT) | Folliculotropism with AL, psoriasiform features, large cells | N/A | + | + | N/A | 50% | − | + | − | N/A | N/A | N/A | 10:1 |
| 8 | MF | Band-like infiltrate with epidermotropism of AL | + | + | + | 50% | − | N/A | N/A | − | N/A | N/A | 5:1 | |
| 9 | MF | Band-like infiltrate with insterstitial AL | + | + | + | loss | loss | − | + | N/A | 10:1 | |||
| 10 | MF | Band-like infiltrate with epidermotropism of AL | N/A | + | + | + | N/A | N/A | few large cells | N/A | N/A | N/A | N/A | 7:1 |
| 11 | MF | Outside biopsy (N/A) | N/A | N/A | N/A | N/A | N/A | N/A | N/A | N/A | N/A | N/A | N/A | N/A |
| 12 | MF | Band-like infiltrate with epidermotropism of AL | − | + | + | − | − | − | 20% | − | − | − | − | 6: 1 |
| 13 | MF | Psoriasiform dermatitis with AL | N/A | + | + | + | − | − | N/A | N/A | N/A | + | N/A | 4:1 |
| 14 | MF (LCT) | Dense dermal infiltrate with syringotropism of large AL | − | + | + | + | − | − | 10% | − | N/A | N/A | N/A | N/A |
| 15 | MF (LCT) | Dense dermal infiltrate with large AL | + | + | + | + | N/A | − | + | N/A | N/A | N/A | N/A | |
| 16 | MF/LyP | Band-like infiltrate with epidermotropism of AL | + | − | + | − | + | − | 50% | N/A | N/A | N/A | N/A | 10:1 |
| 17 | PCAEC-TCL | Dense intraepidermal infiltrate of AL | − | + | − | + | − | − | scattered | + | − | − | − | N/A |
| 18 | PCγδTCL | Patchy infiltrate of AL in dermis and lobular panniculitis | + | + | − | − | − | − | + | + | − | − | − | N/A |
| 19 | SS | Psoriasiform features with AL | N/A | + | + | N/A | N/A | − | N/A | N/A | N/A | N/A | N/A | 10:1 |
| 20 | SS | Psoriasiform features with AL | Few+ | Few+ | + | + | − | − | − | N/A | N/A | + | − | 4:1 |
LCT: large cell transformation; N/A: non-available; AL: atypical lymphocytes
The median time of follow-up for patients with available data (16 patients) was 25 months (ranging from 4 to 137). After discontinuation of the anti-TNFα agent, all patients received treatment according to their CTCL stage, except for one patient in whom subcutaneous nodules resolved spontaneously 7 months after the anti-TNFα agent was withdrawn (Case 3). Six patients achieved complete remission, 5 patients partial response, and 4 patients had no significant improvement with CTCL therapy. Three patients died from progressive disease (Table 1).
CBCL
One patient was a 29-year-old white man who presented with enlarged erythematous plaques on bilateral lower legs after 8 months on etanercept for RA. Skin biopsy showed features consistent with primary cutaneous marginal zone lymphoma (PCMZL) with Ig kappa light chain restriction and absence of Epstein-barr virus encoded RNA1 (EBER-1). Bone marrow biopsy was negative for lymphoma. After treatment with radiation, CHOP (cyclophosphamide, vincristine, doxorubicin, and prednisone) and bortezomib, the patient achieved complete remission during a follow-up time of 3 years.
The second patient was a 53-year-old white man diagnosed with primary cutaneous follicular B-cell lymphoma (PCFL) after 1 month on adalimumab for psoriasis and psoriatic arthritis. This patient received methotrexate, phototherapy, and acitretin prior to biologic therapy. Etanercept was prescribed initially and after several years was switched to adalimumab to treat recalcitrant cutaneous psoriasis. Four weeks after this switch, he developed an erythematous plaque on the scalp, histologically consistent with PCFL with large cell morphology. Cells were positive for Bcl-6 and negative for MUM1, Bcl-2, and EBER-1. Bone marrow biopsy showed no evidence of involvement by lymphoma. After radiation, the patient achieved complete remission and was restarted on etanercept for psoriasis/psoriatic arthritis without recurrence of the PCFL at 9 years of follow-up.
Literature review (Table 3)
Table 3.
Comparison of demographics, clinical data, and outcomes between our cohort and literature cohort.
| Our cohort (n=22) | Literature cohort (n=31) | ||
|---|---|---|---|
| Male:Female | 15:7 | 21:9, 1 not specified | |
| Median age (range), years | 63 (21 – 72) | 63 (28 – 75) | |
| Disease for anti-TNFα agents | Skin disease | 16 | 11 |
| Systemic disease* | 6 | 20 | |
| Anti-TNFa used | Adalimumab (14), etanercept (7), infliximab (4) | Infliximab (12), etanercept (11), adalimumab (8) | |
| Skin biopsy prior to anti-TNFα agent used | 15/18** | 11/16** | |
| CL diagnosis (number of patients) | MF/SS (15), CTCL NOS (3), Cytotoxic CTCL (2), CBCL (2) | MF/SS (19), Cytotoxic CTCL (5), CD30 CLPD (2), cutaneous HD (2), SM PTCL (2), ATLL (1) | |
| Disease stage in MF/SS patients (number of patients) | IA (2), IB (1), IIB (4), IIIA (2), IVA (4) | IA or IB (13), IIB (2), IVA (4) | |
| Median time of follow-up (range), months | 25 (4 – 137) | 11 (0.7 – 19) | |
| Outcome (number of patients) | CR (9), PR (6), SD (3), PD (2) | CR (12), PR (9), SD (2), PD (1), Died (5) | |
Crohn’s disease, Rheumatoid arthritis, Spondyloarthropathy, psoriatic arthritis
Skin biopsies/total of patients with skin disorder
TNFα: tumor necrosis factor alpha; MF: mycosis fungoides; SS: Sézary syndrome; CD30 CLPD: CD30 cutaneous lymphoproliferative disorder; SMPTCL: small/medium pleomorphic T-cell lymphoma; ATLL: adult T-cell lymphoma/leukemia, CR: complete remission; PR: partial response; SD: stable disease, PD: progressive disease.
We identified 31 additional cases published in which CL was diagnosed after anti-TNFα agent exposure.3, 5–7, 9–14, 16–20, 22–27 Twenty of these previously published patients received an anti-TNFα agent for treatment of a systemic disease such as rheumatoid arthritis, inflammatory bowel disease, spondyloarthropathy, or psoriatic arthritis. Six of the 20 patients had a concurrent poorly characterized skin eruption. Eleven patients received an anti-TNFα agent for treatment of psoriasis, psoriasiform dermatitis, or non-specific dermatitis. Among the 17 patients with any type of dermatosis, over half either did not have a biopsy or had a biopsy with inconclusive results prior to anti-TNFα agent initiation. The median time on anti-TNFα agent until CL diagnosis was 5.5 months, ranging from 0.5 to 96 months. Nineteen patients were diagnosed with MF/SS, 3 of whom had the folliculotropic variant and 4 of whom had LCT. Cytotoxic lymphomas were diagnosed in 5 patients including subcutaneous panniculitis-like T-cell lymphoma, PC-GDTCL, dermal CD8+ T-cell lymphoma, and PCAEC-TCL. Two developed a CD30+ lymphoproliferative disorder. Other CLs were found in the remaining 5 patients including 2 with cutaneous Hodgkin’s lymphoma, 2 with small/medium pleomorphic T-cell lymphoma, and 1 with chronic adult T-cell leukemia/lymphoma. Seventeen of the 19 patients with MF/SS had stage data available. Thirteen presented with early stage disease (IA or IB), 2 with stage IIB, and 4 with stage IVA. The median time of follow-up was 11 months (ranging from 0.7 to 19 months), and the majority of the patients achieved complete remission or partial response. Only one developed progressive disease from patch to tumor stage. Six patients died, mostly due to reasons unrelated to CL or due to CL treatment complications.
Discussion
We describe a cohort of patients with CL diagnosed after exposure to anti-TNFα agents. Compared to the cohort identified from the literature, a higher frequency of advanced disease was observed in our patient population. This difference might be explained by the inclusion criteria of the selected cohort. While our inclusion criteria considered all cases diagnosed with CL after anti-TNFα therapy, some case series specifically excluded patients misdiagnosed with psoriasis or eczema prior to use of biologic therapy. It is known that addition of immunosuppressive therapy in patients with CL often leads to disease progression.20, 28 Our data underscore the risk of progression of previously undiagnosed CL when anti-TNFα therapy is used with the intent to treat a nonmalignant skin condition, likely due to the immunosuppressive properties of the treatment. Similar findings were observed in a recent publication that included CTCL cases exposed to any type of immunosuppression treatment, including cyclosporine, azathioprine, mycophenolate mofetil and anti-TNFα agents.20
Skin biopsies of the reported cases showed a high prevalence of LCT in biopsies with MF/SS, and large cell morphology in biopsies of other types of CL, consistent with our findings. This corroborates prior reports of aggressive histological features that indicate CL progression among patients given immunosuppressive therapy.20, 28–31
The rarity of CTCL relative to more common conditions like psoriasis and eczema combined with the fact that CTCL (most commonly MF) can clinically and histologically mimic these conditions increases the risk of misdiagnosis. In addition, a clinical diagnosis of psoriasis is often not confirmed with skin biopsy. It has been suggested that chronic lymphocyte-driven inflammatory states of psoriasis and atopic dermatitis plus the use of immunosuppressive therapies may help to select a malignant T-cell clone, provoking the development of CTCL.28, 32 Controversy surrounds the true prevalence of CL in patients with atopic dermatitis and psoriasis. One group reported a significant increased risk of CTCL in patients with moderate to severe psoriasis independent of the systemic therapy received (adjusted hazard ratio of 9.25 [CI: 95%]). Another group cites misdiagnosis of CTCL as eczema as a major confounding factor in reporting the true prevalence of CTCL in patients with atopic dermatitis.33–35 We acknowledge the occasional difficulty in differentiating clinically and histologically between MF and psoriasis or eczema and have seen a similar situation with fatal disease progression in case 1 of this series. Indeed, MF/SS are known to occasionally require multiple skin biopsies for its diagnosis. Thus, close clinical monitoring and repeat biopsies with the use of immunohistochemistry and TCR gene rearrangement should be considered in ambiguous or atypical cases. In patients with extensive skin disease or erythroderma, flow cytometry and TCR gene rearrangement studies of peripheral blood can aid in diagnosis.36
There are no previous case reports in the literature of CBCL diagnosed during or after anti-TNFα therapy. It is difficult to definitively establish a causal relationship between the development of CL and the use anti-TNFα agents in our patients. However, the temporal association noted in the first case presented, in which erythematous plaques that were stable for 11 years enlarged with anti-TNFα therapy, suggests that adalimumab-induced immunosuppression can accelerate a previously quiescent low grade primary CL. The patient in the second case was treated with etanercept for several years, with PCFL appearing after 1 month of adalimumab therapy. After achieving complete remission, etanercept was re-started again without CL recurrence. Reinitiating anti-TNFα therapy after remission of CTCL is controversial, supported by only one case report of a patient with short-term follow-up.22 Whether anti-TNFα agents can be safely restarted in patients with remission of a low grade CL requires further investigation. A balance between benefits and risks of using anti-TNFα therapy after a diagnosis of CL in patients with systemic diseases such as CD or RA must be carefully assessed.
Our series highlights a variety of CL presentations associated with anti-TNFα agents. Most cases had a preceding dermatitis that was possibly mistaken for psoriasis or eczema due to lack of definitive features of CTCL or early evolution of disease. The use of anti-TNFα therapy down-regulates innate and adaptive immunity that might normally control proliferation of malignant lymphocytes, thereby unmasking the lymphoma. This may explain why most of the patients in our series had a more advanced stage, often with large cell morphology or transformation at the time of diagnosis.
These findings underscore the need for all physicians prescribing anti-TNFα therapy to include a review of any cutaneous symptoms and a thorough skin exam prior to starting biologic therapy. A word of caution to avoid the use of anti-TNFα agents in erythrodermic patients in which there is any doubt of the psoriatic nature of the erythroderma has already been given. Moreover, the diagnosis must be reconsidered if erythroderma worsens after an anti-TNFα agent has been administered.37 In selected cases, skin biopsy and specific peripheral blood studies such as flow cytometry and T-cell rearrangement, should be considered to exclude CL before initiating immunosuppressive therapies. In addition, close monitoring and repeat biopsy of de novo skin eruptions or worsening of pre-existing dermatosis is strongly recommended in patients receiving any immunosuppressive therapy.
Capsule summary.
CL diagnosed after anti-TNFα therapy is most commonly associated with a misdiagnosis of “psoriasis”
Anti-TNFα therapy can accelerate the CL course.
Prior to initiating anti-TNFα therapy, skin biopsies and peripheral blood analysis should be considered in patients with atypical presentation of psoriasis in order to exclude a CL.
Acknowledgments
This research project is approved by the IRB of Northwestern University under the cutaneous lymphoma umbrella project.
Funding source: none
ABBREVIATIONS
- CBCL
Cutaneous b-cell lymphoma
- CD
Crohn’s disease
- CL
cutaneous lymphoma
- CTCL
Cutaneous t-cell lymphoma
- EBER-1
Epstein-barr virus encoded RNA1
- FMF
folliculotropic mycosis fungoides
- LCT
large cell transformation
- LDH
lactate dehydrogenase
- MF
mycosis fungoides
- NOS
not otherwise specified
- PCAEC-TCL
primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphoma
- PCFL
primary cutaneous follicular B-cell lymphoma
- PCGD-TCL
primary cutaneous gamma-delta T-cell lymphoma
- PCMZL
primary cutaneous marginal zone lymphoma
- RA
rheumatoid arthritis
- SS
Sézary syndrome
- TCR
T-cell receptor
- TNF
tumor necrosis factor
Footnotes
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