Primary cutaneous lymphoma: recommendations for clinical trial design and staging update from the ISCL, USCLC, and EORTC.

The number of patients with primary cutaneous lymphoma (PCL) relative to other non-Hodgkin lymphomas (NHLs) is small and the number of subtypes large. Although clinical trial guidelines have been published for mycosis fungoides/Sézary syndrome, the most common type of PCL, none exist for the other PCLs. In addition, staging of the PCLs has been evolving based on new data on potential prognostic factors, diagnosis, and assessment methods of both skin and extracutaneous disease and a desire to align the latter with the Lugano guidelines for all NHLs. The International Society for Cutaneous Lymphomas (ISCL), the United States Cutaneous LymphomaConsortium (USCLC), and the Cutaneous Lymphoma Task Force of the European Organization for the Research and Treatment of Cancer (EORTC) now propose updated staging and guidelines for the study design, assessment, endpoints, and response criteria in clinical trials for all the PCLs in alignment with that of the Lugano guidelines. These recommendations provide standardized methodology that should facilitate planning and regulatory approval of new treatments for these lymphomas worldwide, encourage cooperative investigator-initiated trials, and help to assess the comparative efficacy of therapeutic agents tested across sites and studies.

Real-world study of pegylated interferon α-2a to treat mycosis fungoides/Sézary syndrome using time to next treatment as a measure of clinical benefit: an EORTC CLTG study.

BACKGROUND: Mycosis fungoides (MF) and Sézary syndrome (SS) are chronic malignant diseases that typically necessitate diverse strategies to achieve remission. Systemic interferon (IFN)-α (subtypes 2a and 2b) has been used to treat MF/SS since 1984; however, its production was recently stopped. The recombinant pegylated (PEG) form of IFN-α-2a remains the only alternative IFN treatment, although it has not been approved for use in MF/SS. OBJECTIVES: To assess the effectiveness and safety of PEG-IFN-α-2a in monotherapy and in combination with other treatments using time to next treatment (TTNT) as a measure of clinical therapeutic benefit in a real-world setting. METHODS: We conducted an international, multicentre retrospective study of patients with MF and SS (of any stage) treated with PEG-IFN-α-2a from July 2012 to February 2022. Patients were included across 11 centres in 10 countries. The primary endpoints were to determine the TTNT of PEG-IFN-α-2a and adverse events (AEs) in MF/SS. RESULTS: In total, 105 patients were included [mean (SD) age 61 (13.1) years]; 42 (40.0%) had stage IA-IIA and 63 (60.0%) had stage IIB-IVB disease. PEG-IFN-α-2a was combined with other therapies in 67 (63.8%) patients, most commonly with extracorporeal photopheresis (36%) and bexarotene (22%). Patients with stage I-IIA disease achieved an overall response rate (ORR) of 57%; the ORR in those with stage IIB-IVB disease was 51%. Combination treatment resulted in a median TTNT of 10.4 months (range 0.6-50.7) vs. 7.0 months (range 0.7-52.4) for those who received monotherapy (P < 0.01). Overall, the mean (SD) TTNT was 9.2 (10.6) months and the ORR was 53.3% (n = 56). A complete response was seen in 13% of patients and a partial response in 40%. AEs were described in 68.6% (n = 72) of patients. Flu-like symptoms (n = 28; 26.7%), lymphopenia (n = 24; 22.9%) and elevated liver function (n = 10; 9.5%) were the most frequently reported. Grade 3-4 AEs were reported in 23 (21.9%) patients, mostly related to myelosuppression. CONCLUSIONS: PEG-IFN-α-2a for MF/SS resulted in an ORR of 53.3% and a mean (SD) TTNT of 9.2 (10.6) months. Combination regimens were superior to monotherapy and doses of 180 µg PEG-IFN-α-2a weekly were related to a higher ORR.

Mycosis fungoides (MF) and Sézary syndrome (SS) are rare types of cancers of the lymphatic system (lymphomas). They result in patches, plaques and/or tumours on the skin that usually need a combination of treatments to be controlled. A drug called interferon alpha (IFN-α) has been used to treat cutaneous lymphomas since 1984, but its production was recently stopped, so another form of it called 'recombinant pegylated IFN α-2a' (PEG-IFN-α-2a) is the only alternative IFN treatment, even though it has not been formally approved for MF/SS. The lack of studies on PEG-IFN-α-2a for MF/SS treatment has meant that its use can vary between institutions. This study aimed to investigate the effectiveness, the safety and how well PEG-IFN-α-2a is tolerated as single treatment or in combination with other MF/SS treatments. We carried out a study of patients with MF/SS treated with PEG-IFN-α-2a between July 2012 and February 2022. In total, 105 patients were included from 10 countries. We found that 53% of the patients responded to PEG-IFN-α-2a treatment. We also found that doses of 180 µg weekly, as well as combining PEG-IFN-α-2a with other treatments, resulted in higher response rates and a longer time until a new treatment needed to be added. However, at least one adverse event occurred in 69% of patients. The most common were flu-like symptoms, a reduction in the number of white blood cells and increased liver function. Severe adverse events occurred in 21% of the patients, mostly related to a reduction in the number of blood cells. Overall, our study findings suggest that PEG-IFN-α-2a is an effective and generally well-tolerated option among the treatments for MF/SS, with patients experiencing a better response when it was used as part of a combination therapy and on doses of 180 µg weekly.

Imbalanced IL-1B and IL-18 Expression in Sézary Syndrome.

Sézary syndrome (SS) is a rare and aggressive type of cutaneous T-cell lymphoma, with an abnormal inflammatory response in affected skin. The cytokines IL-1B and IL-18, as key signaling molecules in the immune system, are produced in an inactive form and cleave to the active form by inflammasomes. In this study, we assessed the skin, serum, peripheral mononuclear blood cell (PBMC) and lymph-node samples of SS patients and control groups (healthy donors (HDs) and idiopathic erythroderma (IE) nodes) to investigate the inflammatory markers IL-1B and IL-18 at the protein and transcript expression levels, as potential markers of inflammasome activation. Our findings showed increased IL-1B and decreased IL-18 protein expression in the epidermis of SS patients; however, in the dermis layer, we detected increased IL-18 protein expression. In the lymph nodes of SS patients at advanced stages of the disease (N2/N3), we also detected an enhancement of IL-18 and a downregulation of IL-1B at the protein level. Moreover, the transcriptomic analysis of the SS and IE nodes confirmed the decreased expression of IL1B and NLRP3, whereas the pathway analysis indicated a further downregulation of IL1B-associated genes. Overall, the present findings showed compartmentalized expressions of IL-1B and IL-18 and provided the first evidence of their imbalance in patients with Sézary syndrome.

Extraordinary Case: Unique Presentation of an Aggressive Epstein-Barr Virus-Positive Mucocutaneous Ulcer.

ABSTRACT: Epstein-Barr virus-positive mucocutaneous ulcer is a recent and unusual type of lymphoproliferation, mostly associated with various forms of immunosuppression. In most cases, they regress spontaneously, but an increasing number of reports describe a spectral behavior of the lesion, which ranges from a simple ulcer with eosinophilia to aggressive ulcers. In these cases, Epstein-Barr virus-related lymphomas are the main differential diagnosis. We report a unique observation of this rare disease with mandibular involvement. Due to bone erosion, the patient was treated with 6 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) with complete healing of the ulcer on clinical examination and PET-scan control.

The Role of Tumor Microenvironment in the Pathogenesis of Sézary Syndrome.

Sézary syndrome is an aggressive leukemic variant of cutaneous T-cell lymphomas, characterized by erythroderma, lymphadenopathy, and peripheral blood involvement by CD4+ malignant T-cells. The pathogenesis of Sézary syndrome is not fully understood. However, the course of the disease is strongly influenced by the tumor microenvironment, which is altered by a combination of cytokines, chemokines, and growth factors. The crosstalk between malignant and reactive cells affects the immunologic response against tumor cells causing immune dysregulation. This review focuses on the interaction of malignant Sézary cells and the tumor microenvironment.

Development of a clinical scale to assess the severity of striae distensae.

BACKGROUND AND OBJECTIVE: There is no validated instrument to assess the clinical severity of striae distensae. Here, we aimed to develop a striae distensae severity scale. MATERIAL AND METHODS: After a Delphi-based consensus, 15 items related to striae severity were assessed in 110 areas (breasts, abdomen, and buttocks) from 45 participants. The items were analyzed through a partial least squares model to select the most important variables. To assess the reliability of the scale, 43 areas were retested. RESULTS: Of the 110 areas evaluated, 34 were breasts, 24 abdomens, and 52 buttocks. Striae were considered mild in 30% of the evaluations, moderate in 33%, severe in 21%, and extremely severe in 16%. The final model was composed by: width of the widest striae, width of the striae with the most frequent pattern, atrophy, number of affected quadrants, distribution (multiple or isolated), hypo or hyperchromia and topography. The scores of the scale demonstrated a high correlation with the clinical classification (rho = 0.77). There was a high agreement in the scores from the reassessed areas (intraclass correlation coefficient = 0.90). CONCLUSION: An objective and reliable scale to assess the clinical severity of striae distensae on the breasts, abdomen, and buttocks was developed.

Taxane-induced scleroderma. Report of two cases.

Taxanes are a class of chemotherapeutic agents with common associated dermatologic adverse events, such as skin hyperpigmentation, hand-foot skin syndrome, paronychia and onycholysis. Taxane-induced scleroderma is rare. Few cases with skin findings resembling systemic sclerosis, have been reported after the administration of these agents. We report two cases with stage IV breast cancer, aged 66 and 71 years, who developed sclerodermic skin lesions in their extremities after starting treatment with placlitaxel and nabplaclitaxel respectively.

Poikilodermatous Mycosis Fungoides: Comparative Study of Clinical, Histopathological and Immunohistochemical Features.

BACKGROUND: Poikilodermatous mycosis fungoides (pMF) is characterized by poikiloderma areas, typically involving the major flexural areas and trunk. Its presentation can be generalized or admixed with other forms of MF. Previous studies fail to correlate the clinical presentation with prognosis and laboratory findings. Some reports show pityriasis lichenoides chronica (PLC) preceding the poikiloderma. OBJECTIVES: Correlate prognostic, histopathological and molecular aspects of pMF with its clinical presentation. METHODS: Retrospective analysis of 14 cases of generalized pMF (GpMF), 22 of localized pMF (LpMF) and 17 of pMF admixed with other forms of MF (mix-pMF). RESULTS: Female predominance and lower age at diagnosis was found in all groups compared to classic MF, a high prevalence of PLC-like lesions in the GpMF group and a high rate of hypopigmented lesions in the mix-pMF group. There were 2 deaths within the GpMF group. Histology was similar to previously reported findings, as was the prevalence of CD4 T-cell infiltrate, compared to CD8. The T-cell clonality positivity was lower in the GpMF group, compared to other groups (27% GpMF, 80% LpMF and 100% mix-pMF). DISCUSSION: This is the first article to categorize the different forms of pMF and correlate them with clinical and laboratory findings. The dermatological presentation differs among the groups. There was a high frequency of PLC-like lesions within the GpMF group and of hypopigmented lesions in mix-pMF. The histological and immunohistochemical findings were similar to those previously reported. Aggressive treatments are not recommended due to the good prognosis of all pMF forms. The low positivity of T-cell clonality in the GpMF group should be investigated.

Cutaneous manifestations of adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive peripheral T-cell lymphoma caused by the human T-lymphotropic virus type-1 (HTLV-1). The skin is affected in approximately half of ATLL patients, and it may be the first manifestation of the disease. The skin lesions of ATLL are polymorphous, and depending on the type of skin eruption, it is possible to predict the prognosis of the disease. Besides specific skin lesions, other non-specific lesions and increased risk of cutaneous and systemic infections are observed. In this article, we describe the different skin lesions of ATLL patients (specific, non-specific, and infectious lesions), the different histopathological patterns, and the association of clinicopathological characteristics with prognosis. Recognition of ATLL skin lesions is essential for the correct management and the search for the virus, even in non-endemic regions, where global migration may bring HTLV-1 infected individuals.

A case report of erythroderma in a patient with borderline leprosy on reversal reaction: a result of the exacerbated reaction?

BACKGROUND: Erythroderma is characterized by erythema and scaling affecting more than 90% of the body surface area. Inflammatory, neoplastic and, more rarely, infectious diseases may culminate with erythroderma. Diagnosis of the underlying disorder is therefore crucial to institute the appropriate therapy. Leprosy is a chronic infectious disease that is endemic in Brazil. Here we present an unusual case of leprosy and reversal reaction causing erythroderma, and we discuss the underlying immunological mechanisms which could contribute to the generalized skin inflammation. CASE PRESENTATION: We report a case of a patient with reversal reaction (RR) in borderline borderline leprosy presenting with erythroderma and neural disabilities. Histopathology of the skin showed regular acanthosis and spongiosis in the epidermis and, in the dermis, compact epithelioid granulomas as well as grouped and isolated bacilli. This duality probably reflects the transition from an anergic/multibacillary state to a state of more effective immunity and bacillary control, typical of RR. Leprosy was successfully treated with WHO's multidrug therapy, plus prednisone for controlling the RR; the erythroderma resolved in parallel with this treatment. Immunologic studies showed in situ predominance of IFNγ + over IL-4+ lymphocytes and of IL-17+ over Foxp3+ lymphocytes, suggesting an exacerbated Th-1/Th-17 immunoreactivity and poor Th-2 and regulatory T-cell responses. Circulating Tregs were also diminished. We hypothesize that the flare-up of anti-mycobacteria immunoreactivity that underlies RR may have triggered the intense inflammatory skin lesions that culminated with erythroderma. CONCLUSIONS: This case report highlights the importance of thorough clinical examination of erythrodermic patients in search for its etiology and suggests that an intense and probably uncontrolled leprosy RR can culminate in the development of erythroderma.

Evaluation of the 2008 World Health Organization classification for non-mycosis fungoides, non-Sezary syndrome T/NK-cell lymphomas with primary cutaneous involvement.

BACKGROUND: Cutaneous non-mycosis fungoides non-Sezary syndrome T/NK cell lymphomas (non-MF/non-SS CTCL) are rare. In 2005, a consensus of the World Health Organization (WHO) and European Organization for Research and Treatment of Cancer (EORTC) classifications for primary cutaneous lymphomas was established. These guidelines were then adopted into the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 2008. This study aims to assess the applicability of the WHO 2008 classification in a retrospective series of CTCL cases registered in a reference academic center in Brazil. METHODS: Twenty-seven patients with non-MF/non-SS CTCL were studied. Clinical, histopathological and immunophenotypical features based on an extensive panel of antibodies were applied to classify the cases according to the WHO, 2008. RESULTS: Overall, diagnostic categories included eight (29.6%) cutaneous anaplastic large-cell lymphoma, five (18.5%) lymphomatoid papulosis, six (22.2%) extranodal natural killer (NK)/T-cell lymphoma, nasal type, five (18.5%) adult T-cell leukemia/lymphoma, one (3.7%) cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma and two (7.4%) of peripheral T-cell lymphoma not otherwise specified (NOS). CONCLUSIONS: The WHO classification (2008) was applicable to most cases of non-MF/non-SS CTCL, while some cases remained unclassified and were considered NOS-peripheral T-cell lymphoma. An unexpected high frequency of NK/T-cell lymphoma nasal type was observed.

Hypopigmented mycosis fungoides versus mycosis fungoides with concomitant hypopigmented lesions: same disease or different variants of mycosis fungoides?

BACKGROUND: Hypopigmented mycosis fungoides (HMF) is a rare subtype of mycosis fungoides (MF). We compared patients with exclusive hypopigmented lesions with a group of MF patients with concomitant different lesions. METHODS: 20 patients with HMF only and 14 patients with hypopigmented lesions concomitant with other types of lesions (mixed MF, MMF) were selected. Clinical-epidemiological analysis as well as histological and immunohistochemical studies were performed. RESULTS: HMF and MMF preserve some similarities, like predilection for dark-skinned persons and slow progression, but they also present differences: the exclusive variant is associated with early onset and a clear CD8+ immunophenotype, whereas MMF patients tend to present a predominance of CD4+ cell infiltrates. Histological analysis revealed similar findings; relapsing courses were common. CONCLUSION: Whether patients are suffering from exclusive HMF or MMF, the presence of hypopigmented lesions can be considered a marker of good prognosis in MF, since both groups presented similar data, such as staging and disease duration.