International Society For Cutaneous Lymphomas Research Articles

P54 Blood tumour burden does not correlate with skin tumour burden in early-stage mycosis fungoides: analysis of the PROspective Cutaneous Lymphoma International Prognostic Index international registry

Abstract Blood involvement B1, defined as absolute counts 250–1000 IU of an aberrant CD4+CD7– or CD4+CD26– phenotype, may be found in early-stage mycosis fungoides (MF). There is a suggestion that B1 blood involvement is a poor prognostic marker, but there is limited evidence investigating the prognostic significance of B0 or B1 blood involvement in early-stage MF. Loss of CD26 and/or CD7 expression on CD4 cells may occur in MF; however, it is unclear whether loss of either one of these immunophenotypic markers bears more significance on prognosis. For B2 blood involvement (> 1000 IU), the International Society for Cutaneous Lymphomas (ISCL) criteria define Sézary syndrome as CD26 loss of > 30% or CD7 loss of > 40%. Understanding the impact of B1 and comparative loss of CD26 and/or CD7 in early-stage MF may allow patients at higher risk of stage progression to be identified and selected for better therapeutic options. The aims of this study were to analyse B0 vs. B1 blood involvement at diagnosis in patients with early-stage MF (IA–IIA) and evaluate the relative CD4+CD7– and CD4+CD26– absolute cell counts. Prospective data from the PROCLIPI registry were analysed. Ninety-four patients with early-stage MF were identified from our database, 67 (71%) of whom were B0 [stage IA, n = 23 (34%); stage IB, n = 24 (36%); stage IIA, n = 20 (30%)] and 27 (29%) were B1 [stage IA, n = 12 (44%); stage IB, n = 10 (37%); stage IIA, n = 5 (18%)]. Median age at diagnosis in B0 patients was 59 years (range 20–91) vs. 61 years (range 21–81) in B1 patients. Median CD4+CD7– cell count was 16.4% (range 0–41%) in patients with B0 involvement and 28.1% (range12–45%) in B1 patients. Median CD4+CD26– cell count was 16% (range 0–39.1%) in B0 and 28% (range 0–44%) in B1 patients. The Median Modified Severity-Weighted Assessment Tool score in B1 patients was 11 (range 1–73) vs. 20 (range 0.5–100) in B0 patients. There was no significant difference in progression to the advanced stage between B0 and B1 (P = 0.112) patients or overall survival between B0 and B1 patients during median follow-ups of 49 months and 45 months, respectively. These results suggest that blood tumour burden in early-stage MF, measured by the percentage aberrancy in CD4+CD7– and CD4+CD26– cell counts, does not correlate with clinical stage, skin tumour burden or stage progression. This suggests that in B1 involvement, atypical lymphocytes may lose their skin-homing properties. Interestingly, levels of CD4+7– and CD26– are similar in B1 involvement, despite the ISCL criteria defining B2 involvement as a lower relative loss of CD26–. Identifying B1 patients is important as certain therapeutic options such as extracorporeal photopheresis and mogamulizumab may be indicated in patients with early-stage MF, refractory to skin-directed therapies.

International Society for Cutaneous Lymphomas Pandemic Section (ICLYPS) analysis of cutaneous T-cell lymphoma outcomes during the COVID-19 pandemic: A retrospective cohort study

To the Editor: Outcomes of patients with cutaneous T-cell lymphoma (CTCL), a diverse group of non-Hodgkin lymphomas, during the COVID-19 pandemic are unknown. Patients with CTCL require active management and rely on various local and systemic therapies administered in-hospital or in-office, representing an increased risk for contracting COVID-19. There are no established maintenance protocols for cutaneous lymphomas. The COVID-19 pandemic served as an “experiment of nature” to understand the effects of reduced regimens and maintenance therapy. The professional societies developed emergency guidelines for the management of patients with cutaneous lymphomas during the pandemic to ensure patient safety.1Zic J.A. Ai W. Akilov O.E. et al.United States Cutaneous Lymphoma Consortium recommendations for treatment of cutaneous lymphomas during the COVID-19 pandemic.J Am Acad Dermatol. 2020; 83: 703-704Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar,2Papadavid E. Scarisbrick J. Ortiz Romero P. et al.Management of primary cutaneous lymphoma patients during COVID-19 pandemic: EORTC CLTF guidelines.J Eur Acad Dermatol Venereol. 2020; 34: 1633-1636Crossref PubMed Scopus (11) Google Scholar The International Society for Cutaneous Lymphomas created an International Cutaneous Lymphomas Pandemic Section to collect data to assess the impact of these guidelines. Using these data, we can determine if these measures were effective in preventing COVID-19 infection, what the impact was of maintenance therapy, and how delays in treatment affected disease outcomes in CTCL patients. We performed a retrospective analysis of data from the electronic medical records at 9 international academic medical centers in 7 countries from March to October 2020, including 149 patients, actively managed with an established diagnosis of cutaneous lymphoma. Patient demographics, date of diagnosis, staging details, treatment details, delays or changes to treatment regimens, disease outcomes, and COVID-19 disease history including the source of transmission were recorded (Fig 1). Treatment was delayed for 53.0% of patients for a mean of 3.2 months (range: 10 days-10 months). Adjusting for age, race, biological sex, COVID-19 status, and disease stage, treatment delay was associated with a significant risk of disease relapse or progression across all stages (odds ratio 5.00; 95% confidence interval [2.38, 11.0], P value < .001) and, for each additional month that a patient experienced treatment delay, the odds of disease progression increased by 37.0% (odds ratio 1.37; 95% confidence interval [1.14, 1.70], P value < .001) (Table I). A total of 28 (18.8%) patients with CTCL were diagnosed with COVID-19, none acquired from outpatient office visits. Patients who contracted COVID-19 did not have a statistically significant increase in odds of disease progression compared to COVID-19–negative patients (odds ratio 0.41; 95% confidence interval [0.15, 1.08], P value = .07).Table IDemographic and outcomes by treatment delay statusTreatment delay (n = 79) N (%)No treatment delay (n = 70) N (%)Total (N = 149) N (%)Age Mean6459 Median (IQR)65 (53, 78)62 (48, 72) Range28, 9522, 88Biological sex Male43 (54.4)40 (57.1)83 (55.7) Female36 (45.6)30 (42.9)66 (44.3)Race White60 (75.9)44 (62.9)104 (69.8) Black/African American8 (10.1)19 (27.1)27 (18.1) Other/unknown/declined11 (13.9)7 (10.0)18 (12.1)Stage IA-IIA40 (50.6)37 (52.9)77 (51.6) IIB11 (13.9)12 (17.1)23 (15.4) IIIA-IIIB4 (5.1)2 (2.8)6 (4.0) IVA1 (SS)19 (24.1)16 (22.9)35 (23.5) IVA2-IVB3 (3.8)3 (4.3)6 (4.0) PC CD30+ LPD2 (2.5)0 (0.0)2 (1.3)COVID-19 status Positive18 (22.8)10 (14.3)28 (18.8) Negative61 (77.2)60 (85.7)121 (81.2)Length of treatment delay (mo) Mean3.200.00 Median (IQR)3.00 [1.05, 4.00]0.00 [0.00, 0.00] Range0.30, 10.000.00, 0.00 Unknown20Outcomes Improvement of disease5 (6.3)10 (14.3)15 (10.1) Stable disease15 (19.0)36 (51.4)51 (34.2) Disease progression/relapse52 (65.8)22 (31.4)74 (49.7) Deceased7 (8.9)2 (2.9)9 (6.0) Open table in a new tab Based on the results of this study, we conclude the following:1.Adequate safety measures and protocols can prevent transmission of COVID-19 at physicians' offices as no outpatient office-acquired infections were reported.2.Patients with cutaneous lymphomas who develop COVID-19 do not have worse outcomes than expected according to their risk factors.3.As the pandemic continues, our data reveals the need to re-evaluate the initial recommendations made by the USCLC and EORTC-CLTG, and it provides reassurance that our current COVID-19–conscious management practices are safe and effective.4.Delays in therapy lead to adverse clinical outcomes and should be avoided, as the risk of contracting COVID-19 in the outpatient setting did not outweigh the risk of morbidity and mortality due to disease progression.5.Ensuring continuity of treatment and maintenance therapy appears critical to avoiding disease progression, underscoring the importance of maintenance therapy for CTCL. None disclosed.

Application of the current diagnostic algorithm for early mycosis fungoides to a single center cohort: Identification of challenges and suggestions for modification.

Diagnosing early-stage mycosis fungoides (MF) remains a significant challenge. The International Society for Cutaneous Lymphomas (ISCL) proposed an algorithm for diagnosing early MF incorporating clinical and histopathologic characteristics, as well as immunohistochemistry and molecular studies. Here we aim to examine the diagnostic utility of the ISCL algorithm. In this single-center retrospective review, the ISCL algorithm was applied to 28 patients diagnosed with early-stage MF. Immunohistochemistry and molecular studies were not performed for all patients, so a subgroup analysis was conducted including 18 patients in whom both studies had been performed. We calculated the diagnostic sensitivity of the algorithm. Subsequently, we examined how modifying the algorithm's histopathologic criterion from epidermotropism without spongiosis to epidermotropism influenced its sensitivity. Forty-three percent (12/28) of the cohort and 50% (9/18) of the subgroup met the algorithm's diagnostic threshold. When the algorithm was modified, 71% of the cohort and 89% of the subgroup met the algorithm's threshold. While the ISCL algorithm is useful in diagnosing early-stage MF, its sensitivity remains suboptimal. Further refinement of the algorithm to capture spongiotic subtypes of MF may improve its diagnostic value.

Poor prognostic factors of Sézary syndrome: A retrospective single‐center study from Japan

AbstractObjectivesAlthough the prognosis of Sézary syndrome (SS) is highly unfavorable, the prognostic factors have not been fully understood. In this study, we tried to investigate the prognostic factors in Japanese SS patients for the first time.MethodsWe performed a retrospective cohort study of 19 SS patients who visited our hospital between January 1, 1999, and December 31, 2019. The collected clinical findings were age, gender, performance status (PS), and TNMB staging at diagnosis. TNMB staging was determined according to the International Society for Cutaneous Lymphomas and the cutaneous task force of the European Organization of Research and Treatment of Cancer criteria. The collected hematological findings were serum levels of soluble IL‐2 receptor (sIL‐2R), lactate dehydrogenase (LDH), thymus and activation‐regulated chemokine (TARC), and immunoglobulin E (IgE), Sézary cell count, Sézary cell ratio among white blood cells, and eosinophil count in peripheral blood at diagnosis.ResultsWe analyzed the correlations between overall survival and various clinical and hematological findings. In the log‐rank test, PS1‐3, N2‐3 stage, higher serum levels of LDH (≥355 IU/L), sIL‐2R (≥1729 U/ml) and TARC (≥19,867 pg/ml), and higher Sézary cell count (≥7480/μl) and Sézary cell ratio among white blood cells (≥52%) at diagnosis were associated with decreased overall survival.ConclusionsThis is the first report evaluating prognostic factors in Asian SS patients. This study may contribute to selecting the treatment strategy and improving survival and quality of life of Asian SS patients.

Sézary syndrome preceded by mycosis fungoides and complicated by tumor lysis syndrome and macrophage activation syndrome

Sir, Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common malignancies of cutaneous T-cell lymphoma [1]. Herein, we report a case of SS complicated by tumor lysis syndrome and macrophage activation syndrome. A 54-year-old patient, followed since October 2017 for mycosis fungoides and undergoing various treatments (PUVA therapy, methotrexate, chlorambucil + prednisone), presented with an aggravation of lesions toward extensive and intensely pruritic. A clinical examination revealed dry erythroderma, scratch marks, wart plaques, an accentuation of frontal wrinkles and nasolabial folds (leonine facies), palmoplantar fissuring keratoderma, xanthopachyonychia of all nails, and a carapace-like appearance of the scalp (Figs. 1 – 3). Generalized lymphadenopathy, hepatomegaly, and a state of anasarca-type edema caused by hypoalbuminemia were also found. A skin biopsy revealed lymphoproliferation of CD4+ T-cells and an aberrant loss of pan-T antigens. The CD4-to-CD8 ratio was at 48.5% and Sézary cells were 6960 (absolute value). A lymph node biopsy showed a dense infiltration of Sézary cells. A PET scan revealed hypermetabolism in the entire skin and at the lymph node level. Tumor lysis syndrome was evident, with high levels of blood uric acid (at 182 mg/L), elevated LDH (at 924 U/L), and functional kidney failure. Macrophage activation syndrome was also present, with fever, anemia and thrombocytopenia, liver cytolysis, hypertriglyceridemia, and hyperferritinemia. The patient received an albumin infusion, oral corticosteroid therapy to treat the syndrome, and rasburicase for hyperuremia. Despite this, the patient died before multiagent chemotherapy could have been started. On rare occasions, SS may be preceded by a prior history of classic MF. The International Society for Cutaneous Lymphomas (ISCL) recommends that such cases be designated “SS preceded by MF” [2]. Traditionally, SS is defined as a leukemic form of CTCL associated with erythroderma. Sézary cells are a population of large lymphocytes in the peripheral blood, with grooved and lobulated nuclei, in the case of SS, numbering 1000 cells/mL or more [2]. The histopathologic findings in the skin often resemble those observed in MF, with less prominent epidermotropism. As in MF, immunohistochemical studies showing a CD4 predominance and loss of pan-T-cell markers may be helpful. Lymph node involvement is characterized by the complete effacement of the nodal architecture by the infiltrating Sézary cells (2). The poor prognostic factors in Sézary syndrome include an advanced stage of the disease, an older age at onset, and large cell transformation [3]. While high response rates may be achieved with systemic chemotherapy, they are frequently short-lived and associated with significant toxicities [2]. The management of SS is complicated and requires multidisciplinary collaboration between dermatologists, hematologists, biologists, and reanimators.

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

AbstractThe 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.

Primary cutaneous T-cell lymphomas in childhood and adolescence.

Primary cutaneous lymphomas are extranodal non-Hodgkin lymphomas of T- or B- cell origin, that predominantly affect older patients but have been reported in all age groups and as early as in the first years of life. Diagnosis of cutaneous lymphomas is challenging and requires high clinical suspicion and close collaboration between dermatologists, pediatric oncologists and pathologists. Skin involvement of non-Hodgkin lymphomas in children or adolescents can either be primary cutaneous or secondary due to an underlying nodal lymphoma. The most common primary cutaneous lymphomas encountered in children are of T-cell origin, with mycosis fungoides being the most prevalent cutaneous T-cell lymphoma, followed by CD30+ lymphoproliferative disorders. While cutaneous lymphomas share clinicopathologic characteristics between juvenile and adult forms, there are important differences in terms of clinical presentation, diagnosis and treatment. The hypopigmented variant of mycosis fungoides seems to be overrepresented in the pediatric age group. Prognosis and treatment of mycosis fungoides are stage dependent. The majority of children present with early-stage disease and respond well to topical corticosteroids and phototherapy.

Determination of immunophenotypic aberrancies provides better assessment of peripheral blood involvement by mycosis fungoides/Sézary syndrome than quantification of CD26- or CD7- CD4+ T-cells.

Blood involvement by mycosis fungoides (MF)/Sézary syndrome (SS) influences prognosis and therapeutic decisions. MF/SS blood stage is currently determined by absolute CD4 + CD26- or CD4 + CD7-cell counts, which quantification method may overestimate MF/SS by including CD26- or CD7- normal CD4+ T-cells, or underestimate disease burden when MF/SS cells show incomplete loss of CD26 and/or CD7. Recently, through the standardization effort led by the International Clinical Cytometry Society (ICCS), recommendation was made to quantify MF/SS by enumerating immunophenotypically aberrant CD4+ T-cells, rather than CD26- or CD7- in isolation. We compared these two quantitation methods in 309 MF/SS patients who had blood samples analyzed by flow cytometry immunophenotyping (FCI) over a 1-year period. Using the European Organization of Research and Treatment of Cancer (EORTC)/International Society for Cutaneous Lymphomas (ISCL) criteria, 221 (71.5%) patients had a blood stage corresponding to B0, 57 (18.4%) to B1, and 31 (10%) to B2. By FCI analysis, a total of 62 patients (20.0%) were found positive for MF/SS. Among EORTC B0 patients, 11/221 (5%) were positive by FCI (false negatives), and among EORTC Stage B1 patients, 35/57 (61%) were negative by FCI (false positives). Regarding patients positive for MF/SS cells by FCI, there was an overall excellent correlation (r = .999, p < .001) between the EORTC/ISCL method and FCI method; however, four (6.5%) patients would have an altered B stage between B0 and B1. The MF/SS cell quantification method using immunophenotypic aberrancies, as recommended by the ICCS, allows to distinguish MF/SS cells from background benign T-cells and enables for more accurate staging, especially among patients currently being considered to have B0 and B1 stage diseases.

Reflectance confocal microscopy may be included as part of the diagnostic algorithm of early-stage mycosis fungoides.

Reflectance confocal microscopy (RCM), a noninvasive, real-time technique of computed tomography, has been widely used for pigmentary, inflammatory, and tumor diseases of the skin. Our main purpose was to analyze the consistency between pathological and RCM characteristics of early-stage mycosis fungoides (MF) and the utility of RCM in the diagnosis of early-stage MF. According to the RCM features of MF in the early stage, the biopsy sites of 40 cases of suspected MF and 20 cases of chronic inflammatory skin diseases clinically were preliminarily located. Histopathologic and immunohistochemical examinations were performed to make a diagnosis based on the diagnostic algorithm proposed by the International Society for Cutaneous Lymphomas. Among the 60 patients observed, there were 12 confirming cases of MF, 14 suspecting cases, 6 not completely excluding cases, and 28 eliminating cases according to the diagnostic algorithm, as well as characteristics of RCM were typical in 8 cases, suspected in 16 cases, not excluded in 3 cases, and excluded in 33 cases. The kappa value was 0.769 (P<.01), which means there is a strong consistency between the classification by RCM and the diagnosis algorithm. MF in patch stage and plaque stage (IA to IIB) has typical characteristics of RCM, respectively. RCM can be used as an objective and convenient auxiliary means to diagnose early-stage MF and may be included as part of the diagnostic algorithm of early-stage MF.

Brentuximab Vedotin (BV) and Lenalidomide (Len) in Relapsed and Refractory (r/r) Cutaneous (CTCL) and Peripheral (PTCL) T-Cell Lymphomas; A Planned Interim Analysis of Phase II Trial

Background: Patients with r/r tumor stage CTCL and/or PTCL have a poor prognosis. BV is currently FDA approved for CD30 positive CTCL and anaplastic large cell lymphoma (ALCL) with single agent activity in additional PTCL subtypes. Len also has single agent activity in patients with r/r CTCL/PTCL. The safety of the combination was established in a phase I trial in patients with r/r diffuse large B-cell lymphoma. Methods: We conducted a single-institution phase II trial to determine the safety and efficacy of BV+Len combination in patients with r/r CTCL/PTCL. Simon's 2-stage optimal design was followed to test the null hypothesis of overall response rate (ORR) ≤0.3 versus the alternative hypothesis of ORR≥0.5. Patients with ≥ 1 line of systemic therapy or 2 lines of skin directed therapy, at least stage IB (for CTCL), and no prior progression on BV were eligible regardless of CD30 staining. All patients were treated with BV 1.2 mg/kg IV and Len 20 mg PO daily q3 weeks for a maximum 16 cycles. After 7 patients were treated, we reduced Len to 10 mg given safety/tolerability concerns. Responses are assessed by the International Society for Cutaneous Lymphomas and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (ISCL/EORTC) Global response criteria (for CTCL) and Cheson year criteria (for PTCL). The effect of treatment on quality of life is assessed by Skindex-16. Results: As of July 1, 2019, 17 subjects were treated; 10 (59%) with mycosis fungoides (MF), 2 (12%) with Sezary syndrome (SS), 2 (12%) with CD30+ lymphoproliferative disorder, and 3 (18%) with PTCL. Median age was 60 (49-90) years and 76% were males. CD30 was completely negative (&lt;1%) in 3 (18%) of patients and median CD30 staining (by immunohistochemistry) was 7.5% (range 1-75%). Of 12 patients with MF/SS, 5 (42%) had evidence of large cell transformation at accrual. Of 14 patients with CTCL, median baseline mSWAT was 54.5 (range 4.4-190). Median number of prior therapies was 5 (range 1-9). Grade 3 adverse events (AEs) were reported in 11/17 patients; including neutropenia (4), thrombocytopenia (1), bronchitis (1), dyspnea (1), abdominal pain (2), vertigo (1), , DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) syndrome (1), urinary tract infection (1), and tumor flare (2). Median number of cycles received was 4 (range 1-17). Best response in 14 evaluable patients were 2 (14%) complete response, 3 (21%) partial response, and 8 (57%) stable disease with ORR of 33% (95% confidence interval:12-62%). Of 17 patients, 5 (29%) remain on treatment, and 12 (71%) discontinued treatment because of disease progression (7; 58%), AEs (4; 33%), or patient preference (1; 2%). Median duration of response was 3.2 (range 2.5-13) months. Of note, 7/14 patients (50%) patients with CTCL had &gt;50% reduction in their Skindex-16 scores after a median of 2 cycles (range 1-3). Conclusions: BV + Len is combination is safe and efficacious in a heavily pre-treated patients with T-cell lymphomas. Len doses higher than 10 mg daily are poorly tolerated and associated with excess tumor flare. Recruitment of both CTCL and PTCL patients for this trial is ongoing. Disclosures William: Guidepoint Global: Consultancy; Kyowa Kirin, Inc.: Consultancy; Defined Health: Consultancy; Techspert: Consultancy; Celgene Corporation: Consultancy. Brammer:Verastem, Inc: Research Funding; Viracta Therapeutics, Inc.: Research Funding; Bioniz Therapeutics, Inc.: Research Funding. Grantier:Pharmacyclics LLC and Janssen Oncology: Other: Advisory Board. Hoffman:Pharmacyclics LLC and Janssen Oncology: Other: Advisory Board. Baiocchi:Prelude: Consultancy. Epperla:Pharmacyclics: Honoraria; Verastem Oncology: Speakers Bureau. Christian:Triphase: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Immunomedics: Research Funding; Acerta: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Cephalon: Research Funding; Merck: Research Funding; Janssen: Research Funding; Millennium Pharmaceuticals Inc: Research Funding. Maddocks:BMS: Research Funding; Merck: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Brentuximab vedotin is being used off-label for CD30 negative peripheral and cutaneous T-cell lymphoma. Lenalidomide is being used off-label for both conditions (within a phase II clinical trial)

Primary cutaneous lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Primary cutaneous lymphomas (PCLs) are defined as non-Hodgkin lymphomas that present in the skin with no evidence of extracutaneous disease at the time of diagnosis. After gastrointestinal lymphomas, PCLs are the second most common group of extranodal non-Hodgkin lymphomas, with an estimated annual incidence of 1/100 000 in Western countries. PCLs must be distinguished from nodal or systemic malignant lymphomas involving the skin secondarily, which often have another clinical behaviour, have a different prognosis and require a different therapeutic approach. In recent lymphoma classifications, PCLs are therefore included as separate entities. Within the group of PCLs, distinct types of cutaneous T cell lymphoma (CTCL) and cutaneous B cell lymphoma (CBCL) can be distinguished [1.Willemze R. Jaffe E.S. Burg G. et al.WHO–EORTC classification for cutaneous lymphomas.Blood. 2005; 105: 3768-3785Crossref PubMed Scopus (3224) Google Scholar, 2.WHO Classification of Tumours Haematopoietic and Lymphoid Tissues.in: Swerdlow S.H. Campo E. Harris N.L. 4. IARC, Lyon2017Google Scholar]. In the Western world, CTCLs constitute ∼75%–80% of all PCLs [with mycosis fungoides (MF) as the most common type of CTCL] and CBCL ∼20%–25% [1.Willemze R. Jaffe E.S. Burg G. et al.WHO–EORTC classification for cutaneous lymphomas.Blood. 2005; 105: 3768-3785Crossref PubMed Scopus (3224) Google Scholar]. However, different distributions have been observed in other parts of the world. In Southeast Asian countries, CTCLs other than MF [in particular Epstein–Barr virus-associated natural killer (NK)/T cell lymphomas] are much more common than in Western countries, while CBCLs are much more uncommon [3.Tan S.H. Sim C.S. Ong B.H. Cutaneous lymphomas other than mycosis fungoides in Singapore: a clinicopathological analysis using recent classification systems.Br J Dermatol. 2003; 149: 542-553Crossref PubMed Scopus (30) Google Scholar, 4.Park J.H. Shin H.T. Lee D.Y. et al.World Health Organization–European Organization for research and treatment of cancer classification of cutaneous lymphoma in Korea: a retrospective study at a single tertiary institution.J Am Acad Dermatol. 2012; 67: 1200-1209Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar]. PCLs are rare diseases and patients should ideally be seen by a multidisciplinary team of dermatologists, pathologists, haematologists and radiation oncologists. The diagnosis and classification of PCLs should always be based on a combination of clinical, histological, immunophenotypical and genetic data. Demonstration of clonal T cell receptor or immunoglobulin gene rearrangements in lesional skin or peripheral blood may be a valuable adjunct in selected cases. However, clinical and histopathological features are, in most cases, the most important deciding factors for therapeutic planning. PCLs should be classified according to the criteria of the revised 2017 World Health Organization (WHO) classification ( see Table 1) [2.WHO Classification of Tumours Haematopoietic and Lymphoid Tissues.in: Swerdlow S.H. Campo E. Harris N.L. 4. IARC, Lyon2017Google Scholar].Table 1WHO-EORTC classification for cutaneous lymphomasCutaneous T cell lymphomaMycosis fungoides (MF)Variants of MF•Folliculotropic MF•Pagetoid reticulosis•Granulomatous slack skinSézary syndromePrimary cutaneous CD30+ lymphoproliferative disorders•Primary cutaneous anaplastic large cell lymphoma•Lymphomatoid papulosisSubcutaneous panniculitis-like T cell lymphomaExtranodal NK/T cell lymphoma, nasal-typePrimary cutaneous peripheral T cell lymphoma-not otherwise specified•Primary cutaneous γ/δ T cell lymphoma•Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T cell lymphomaaProvisional entities.•Primary cutaneous acral CD8+ T cell lymphomabNew provisional entity in the revised 2017 WHO classification [2].•Primary cutaneous CD4+ small/medium T cell lymphoproliferative disorderaProvisional entities.Cutaneous B cell lymphomaPrimary cutaneous marginal zone lymphomaPrimary cutaneous follicle centre lymphomaPrimary cutaneous diffuse large B cell lymphoma, leg typeEORTC, European Organization of Research and Treatment of Cancer; NK, natural killer; WHO, World Health Organization.Adapted from [1.Willemze R. Jaffe E.S. Burg G. et al.WHO–EORTC classification for cutaneous lymphomas.Blood. 2005; 105: 3768-3785Crossref PubMed Scopus (3224) Google Scholar] with permission.a Provisional entities.b New provisional entity in the revised 2017 WHO classification [2.WHO Classification of Tumours Haematopoietic and Lymphoid Tissues.in: Swerdlow S.H. Campo E. Harris N.L. 4. IARC, Lyon2017Google Scholar]. Open table in a new tab EORTC, European Organization of Research and Treatment of Cancer; NK, natural killer; WHO, World Health Organization. Adapted from [1.Willemze R. Jaffe E.S. Burg G. et al.WHO–EORTC classification for cutaneous lymphomas.Blood. 2005; 105: 3768-3785Crossref PubMed Scopus (3224) Google Scholar] with permission. In all cases, adequate staging should be carried out to exclude the presence of extracutaneous disease. Recommendations for the initial staging of patients with MF/Sézary syndrome (SS) are presented in Table 2. Flow cytometry of the peripheral blood is usually recommended for all stages of MF. However, it is debatable whether this test is justified in patients who are not suspected to have SS. Computed tomography (CT) and/or fluorodeoxyglucose-positron emission tomography (FDG-PET) scans are optional in early-stage MF. Bone marrow examination is usually not indicated in patients with MF/SS.Table 2Recommendations for staging evaluation in patients with MF/SS [6.Olsen E. Vonderheid E. Pimpinelli N. et al.Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).Blood. 2007; 110: 1713-1722Crossref PubMed Scopus (1084) Google Scholar]Complete physical examination including:•Determination of type(s) of skin lesions•Identification of any palpable lymph node, especially those ≥ 1.5 cm in largest diameter or firm, irregular, clustered or fixed•Identification of any organomegalySkin biopsy•Most indurated area if only one biopsy•Routine histology and immunophenotyping•Evaluation for clonality of TCR gene rearrangement (optional)Blood tests•CBC with manual differential, liver function tests, LDH, comprehensive chemistries•TCR gene rearrangement and relatedness to any clone in skin (optional)•Analysis for abnormal lymphocytes by either Sézary cell count with determination absolute number of Sézary cells and/or flow cytometry (including CD4+/CD7– or CD4+/CD26–) (optional)Radiological tests•CT scans of chest, abdomen and pelvis alone ± FDG-PET (optional in patients with early-stage MF)Lymph node biopsy•Excisional biopsy in patients with a node that is either ≥ 1.5 cm in diameter and/or is firm, irregular, clustered or fixed•Routine histology, immunohistochemistry and TCR gene rearrangement analysisCBC, complete blood count; CT, computed tomography; FDG-PET, fluorodeoxyglucose-positron emission tomography; LDH, lactate dehydrogenase; MF, mycosis fungoides; SS, Sézary syndrome; TCR, T cell receptorAdapted from [6.Olsen E. Vonderheid E. Pimpinelli N. et al.Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).Blood. 2007; 110: 1713-1722Crossref PubMed Scopus (1084) Google Scholar] with permission from the American Society of Hematology; permission conveyed through Copyright Clearance Center, Inc. Open table in a new tab CBC, complete blood count; CT, computed tomography; FDG-PET, fluorodeoxyglucose-positron emission tomography; LDH, lactate dehydrogenase; MF, mycosis fungoides; SS, Sézary syndrome; TCR, T cell receptor Adapted from [6.Olsen E. Vonderheid E. Pimpinelli N. et al.Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).Blood. 2007; 110: 1713-1722Crossref PubMed Scopus (1084) Google Scholar] with permission from the American Society of Hematology; permission conveyed through Copyright Clearance Center, Inc. Initial work-up for patients with a PCL other than MF/SS also includes complete physical examination, representative skin biopsy, complete and differential blood cell count, routine serum biochemistry with lactate dehydrogenase (LDH) and appropriate imaging studies (CT and/or FDG-PET scans) [5.Kim Y.H. Willemze R. Pimpinelli N. et al.TNM classification system for primary cutaneous lymphomas other than mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).Blood. 2007; 110: 479-484Crossref PubMed Scopus (354) Google Scholar]. In PCLs with a predominantly subcutaneous presentation, such as subcutaneous panniculitis-like T cell lymphoma (SPTCL) and primary cutaneous gamma/delta T cell lymphoma (PCGD-TCL), FDG-PET is essential to evaluate the extent of disease. In patients with typical lymphomatoid papulosis (LyP) or primary cutaneous CD4+ small/medium T cell lymphoproliferative disorder (LPD), CT and FDG-PET scans are not required. Bone marrow biopsy and aspirate should be carried out in cutaneous lymphomas with an intermediate or aggressive clinical behaviour but is not required in cutaneous lymphomas with an indolent clinical behaviour, unless indicated by other staging assessments [5.Kim Y.H. Willemze R. Pimpinelli N. et al.TNM classification system for primary cutaneous lymphomas other than mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).Blood. 2007; 110: 479-484Crossref PubMed Scopus (354) Google Scholar, 6.Olsen E. Vonderheid E. Pimpinelli N. et al.Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).Blood. 2007; 110: 1713-1722Crossref PubMed Scopus (1084) Google Scholar]. Bone marrow examination is not indicated in patients with primary cutaneous marginal zone lymphoma (PCMZL), but its significance in primary cutaneous follicle centre lymphomas (PCFCLs) is controversial [5.Kim Y.H. Willemze R. Pimpinelli N. et al.TNM classification system for primary cutaneous lymphomas other than mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).Blood. 2007; 110: 479-484Crossref PubMed Scopus (354) Google Scholar, 7.Senff N.J. Kluin-Nelemans H.C. Willemze R. Results of bone marrow examination in 275 patients with histological features that suggest an indolent type of cutaneous B-cell lymphoma.Br J Haematol. 2008; 142: 52-56Crossref PubMed Scopus (53) Google Scholar]. Prognosis is extremely variable depending on the type of PCLs and the stage of disease. For clinical staging of MF and SS, the revised tumour, node, metastasis and blood (TNMB) staging system should be used (Tables 3 and 4) [6.Olsen E. Vonderheid E. Pimpinelli N. et al.Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).Blood. 2007; 110: 1713-1722Crossref PubMed Scopus (1084) Google Scholar]. Apart from clinical stage, older age, large cell transformation and increased LDH values have been identified as independent unfavourable prognostic factors in MF [8.Agar N.S. Wedgeworth E. Crichton S. et al.Survival outcomes and prognostic factors in mycosis fungoides/Sézary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer staging proposal.J Clin Oncol. 2010; 28: 4730-4739Crossref PubMed Scopus (569) Google Scholar, 9.Scarisbrick J.J. Prince H.M. Vermeer M.H. et al.Cutaneous Lymphoma International Consortium study of outcome in advanced stages of mycosis fungoides and Sézary syndrome: effect of specific prognostic markers on survival and development of a prognostic model.J Clin Oncol. 2015; 33: 3766-3773Crossref PubMed Scopus (266) Google Scholar, 10.Alberti-Violetti S. Talpur R. Schlichte M. et al.Advanced-stage mycosis fungoides and Sézary syndrome: survival and response to treatment.Clin Lymphoma Myeloma Leuk. 2015; 15: e105-e112Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar]. For PCLs other than MF/SS, a separate TNM classification system has been published [5.Kim Y.H. Willemze R. Pimpinelli N. et al.TNM classification system for primary cutaneous lymphomas other than mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).Blood. 2007; 110: 479-484Crossref PubMed Scopus (354) Google Scholar]. This staging system is primarily meant to document extent of disease and cannot be used as a prognostic guide.Table 3Revised TNMB classification of MF/SS [6.Olsen E. Vonderheid E. Pimpinelli N. et al.Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).Blood. 2007; 110: 1713-1722Crossref PubMed Scopus (1084) Google Scholar]T (skin)T1Limited patch/plaque (involving < 10% of total skin surface)T2Generalised patch/plaque (involving ≥ 10% of total skin surface)T3Tumour(s)T4ErythrodermaN (lymph node)N0No clinically abnormal peripheral lymph nodesN1Clinically abnormal peripheral lymph nodes; histologically uninvolvedN2Clinically abnormal peripheral lymph nodes; histologically involved (nodal architecture uneffaced)N3Clinically abnormal peripheral lymph nodes; histologically involved [nodal architecture (partially) effaced]NxClinically abnormal peripheral lymph nodes; no histological confirmationM (viscera)M0No visceral involvementM1Visceral involvementB (blood)B0No circulating atypical (Sézary) cells (or < 5% of lymphocytes)B1Low blood tumour burden (≥ 5% of lymphocytes are Sézary cells, but not B2)B2High blood tumour burden (≥ 1000/µl Sézary cells and positive clone)MF, mycosis fungoides; SS, Sézary syndrome; TNMB, tumour, node, metastasis, blood.Reprinted from [6.Olsen E. Vonderheid E. Pimpinelli N. et al.Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).Blood. 2007; 110: 1713-1722Crossref PubMed Scopus (1084) Google Scholar] with permission from the American Society of Hematology; permission conveyed through Copyright Clearance Center, Inc. Open table in a new tab Table 4Revised clinical staging system for MF/SS [6.Olsen E. Vonderheid E. Pimpinelli N. et al.Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).Blood. 2007; 110: 1713-1722Crossref PubMed Scopus (1084) Google Scholar]Clinical stageIAT1N0M0B0-1IBT2N0M0B0-1IIAT1–2N1-2M0B0-1IIBT3N0–2M0B0-1IIIT4N0–2M0B0-1IVA1T1–4N0-2M0B2IVA2T1–4N3M0B0-2IVBT1–4N0–3M1B0-2MF, mycosis fungoides; SS, Sézary syndrome. Reprinted from [6.Olsen E. Vonderheid E. Pimpinelli N. et al.Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).Blood. 2007; 110: 1713-1722Crossref PubMed Scopus (1084) Google Scholar] with permission from the American Society of Hematology; permission conveyed through Copyright Clearance Center, Inc. Open table in a new tab MF, mycosis fungoides; SS, Sézary syndrome; TNMB, tumour, node, metastasis, blood. Reprinted from [6.Olsen E. Vonderheid E. Pimpinelli N. et al.Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).Blood. 2007; 110: 1713-1722Crossref PubMed Scopus (1084) Google Scholar] with permission from the American Society of Hematology; permission conveyed through Copyright Clearance Center, Inc. MF, mycosis fungoides; SS, Sézary syndrome. Reprinted from [6.Olsen E. Vonderheid E. Pimpinelli N. et al.Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).Blood. 2007; 110: 1713-1722Crossref PubMed Scopus (1084) Google Scholar] with permission from the American Society of Hematology; permission conveyed through Copyright Clearance Center, Inc. The choice of treatment depends on the type of PCL and the stage of disease. Due to their heterogeneity and rarity, controlled clinical trials in PCLs are almost non-existent, with a few exceptions mainly concerning recently marketed drugs. Recommendations are therefore largely based on (retrospective) cohort studies and expert opinions discussed during consensus meetings of the European Organization of Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Group, the International Society for Cutaneous Lymphomas (ISCL), the United States Cutaneous Lymphoma Consortium (USCLC) and the International Lymphoma Radiation Oncology Group (ILROG), including consensus recommendations for clinical end points and response criteria in MF/SS [11.Olsen E.A. Whittaker S. Kim Y.H. et al.Clinical end points and response criteria in mycosis fungoides and Sézary syndrome: a consensus statement of the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer.J Clin Oncol. 2011; 29: 2598-2607Crossref PubMed Scopus (457) Google Scholar]. Since early aggressive chemotherapy (ChT) is associated with considerable side effects but does not improve survival, a stage-adapted conservative therapeutic approach is recommended for MF and its variants [12.Kaye F.J. Bunn Jr, P.A. Steinberg S.M. et al.A randomized trial comparing combination electron-beam radiation and chemotherapy with topical therapy in the initial treatment of mycosis fungoides.N Engl J Med. 1989; 321: 1784-1790Crossref PubMed Scopus (427) Google Scholar, 13.Trautinger F. Eder J. Assaf C. et al.European Organisation for Research and Treatment of Cancer consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome – update 2017.Eur J Cancer. 2017; 77: 57-74Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar, 14.National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology; Mycosis fungoides/Sézary syndrome (Version 2.2018 – January 2, 2018). https://www.nccn.org/professionals/physician_gls/pdf/t-cell.pdf (8 January 2017, date last accessed).Google Scholar, 15.Whittaker S. Hoppe R. Prince H.M. How I treat mycosis fungoides and Sézary syndrome.Blood. 2016; 127: 3142-3153Crossref PubMed Scopus (88) Google Scholar]. Patients with only patches and/or plaques covering < 10% (stage IA) or ≥ 10% of the skin surface (stage IB) should be treated with skin-directed therapies, including topical steroids, psoralens plus ultraviolet A (PUVA), narrow-band ultraviolet B (nb-UVB) and topical cytostatic agents, such as mechlorethamine (nitrogen mustard) (Figure 1). nb-UVB is recommended for patients with patches or very thin plaques but PUVA is preferred for patients with thicker plaques [III, A] [13.Trautinger F. Eder J. Assaf C. et al.European Organisation for Research and Treatment of Cancer consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome – update 2017.Eur J Cancer. 2017; 77: 57-74Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar, 15.Whittaker S. Hoppe R. Prince H.M. How I treat mycosis fungoides and Sézary syndrome.Blood. 2016; 127: 3142-3153Crossref PubMed Scopus (88) Google Scholar]. Topical steroids can be recommended as monotherapy for stage IA disease with patches/flat plaques. In stage IB, topical steroids can be used as adjuvant therapy for selected skin lesions. Topical application of mechlorethamine, either in aqueous solution or in an ointment-based preparation, has been used successfully for decades in the treatment of early-stage MF. A commercial 0.02% gel preparation was approved by the European Medicines Agency (EMA) as an orphan drug for the treatment of early stage MF [II, B] [16.Lessin S.R. Duvic M. Guitart J. et al.Topical chemotherapy in cutaneous T-cell lymphoma: positive results of a randomized, controlled, multicenter trial testing the efficacy and safety of a novel mechlorethamine, 0.02%, gel in mycosis fungoides.JAMA Dermatol. 2013; 149: 25-32Crossref PubMed Scopus (122) Google Scholar]. In patients developing one or few infiltrated plaques or tumours (stage IIB), additional low-dose local radiotherapy (RT) may suffice [III, A] [17.Neelis K.J. Schimmel E.C. Vermeer M.H. et al.Low-dose palliative radiotherapy for cutaneous B- and T-cell lymphomas.Int J Radiat Oncol Biol Phys. 2009; 74: 154-158Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar]. Local RT can be curative in patients with early localised disease, particularly in patients with unilesional MF and pagetoid reticulosis [IV, A]. In such patients, local RT is most commonly administered with electrons (energy dependent on the thickness of the lesion), with bolus to achieve full skin dose, a margin of ≥ 2 cm and a total dose of 20–24 Gy [IV, A] [18.Specht L. Dabaja B. Illidge T. et al.Modern radiation therapy for primary cutaneous lymphomas: field and dose guidelines from the International Lymphoma Radiation Oncology Group.Int J Radiat Oncol Biol Phys. 2015; 92: 32-39Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar]. For patients with more extensive infiltrated plaques and tumours, or patients refractory to skin-directed therapies, systemic therapy with interferon alpha (IFNα) or retinoids (including bexarotene), commonly combined with PUVA or other skin-directed therapies, or a combination of IFNα and retinoids or total skin electron beam therapy (TSEBT), can be considered [III, B] [13.Trautinger F. Eder J. Assaf C. et al.European Organisation for Research and Treatment of Cancer consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome – update 2017.Eur J Cancer. 2017; 77: 57-74Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar, 15.Whittaker S. Hoppe R. Prince H.M. How I treat mycosis fungoides and Sézary syndrome.Blood. 2016; 127: 3142-3153Crossref PubMed Scopus (88) Google Scholar, 19.Quaglino P. Maule M. Prince H.M. et al.Global patterns of care in advanced stage mycosis fungoides/Sezary syndrome: a multicenter retrospective follow-up study from the Cutaneous Lymphoma International Consortium.Ann Oncol. 2017; 28: 2517-2525Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar]. TSEBT was often given to total doses of 30–36 Gy, but lower doses (10–12 Gy) have been employed with the advantages of shorter duration of the treatment period, fewer side effects and opportunity for re-treatment [III, A] [20.Hoppe R.T. Harrison C. Tavallaee M. et al.Low-dose total skin electron beam therapy as an effective modality to reduce disease burden in patients with mycosis fungoides: results of a pooled analysis from 3 phase-II clinical trials.J Am Acad Dermatol. 2015; 72: 286-292Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar, 21.Kamstrup M.R. Gniadecki R. Iversen L. et al.Low-dose (10-Gy) total skin electron beam therapy for cutaneous T-cell lymphoma: an open clinical study and pooled data analysis.Int J Radiat Oncol Biol Phys. 2015; 92: 138-143Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar]. In patients with advanced and refractory disease, gemcitabine or liposomal doxorubicin may be considered, but responses are generally short-lived [II, B] [22.Marchi E. Alinari L. Tani M. et al.Gemcitabine as frontline treatment for cutaneous T-cell lymphoma: phase II study of 32 patients.Cancer. 2005; 104: 2437-2441Crossref PubMed Scopus (153) Google Scholar, 23.Dummer R. Quaglino P. Becker J.C. et al.Prospective international multicenter phase II trial of intravenous pegylated liposomal doxorubicin monochemotherapy in patients with stage IIB, IVA, or IVB advanced mycosis fungoides: final results from EORTC 21012.J Clin Oncol. 2012; 30: 4091-4097Crossref PubMed Scopus (79) Google Scholar]. Other agents like the fusion toxin denileukin diftitox and histone deacetylase (HDAC) inhibitors, such as vorinostat and romidepsin, have been approved in the United States by the Food and Drug Administration (FDA) for patients with relapsed and refractory CTCL, but have not yet been registered for CTCL in Europe [24.Prince H.M. Duvic M. Martin A. et al.Phase III placebo-controlled trial of denileukin diftitox for patients with cutaneous T-cell lymphoma.J Clin Oncol. 2010; 28: 1870-1877Crossref PubMed Scopus (184) Google Scholar, 25.Olsen E.A. Kim Y.H. Kuzel T.M. et al.Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma.J Clin Oncol. 2007; 25: 3109-3115Crossref PubMed Scopus (877) Google Scholar, 26.Whittaker S.J. Demierre M.F. Kim E.J. et al.Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma.J Clin Oncol. 2010; 28: 4485-4491Crossref PubMed Scopus (543) Google Scholar]. Multi-agent ChT is only indicated in patients with effaced lymph nodes or visceral involvement (stage IV), or in patients with widespread tumour stage MF, which cannot be controlled with skin-targeted and immunomodulating therapies or who failed single-agent ChT, but—similar to single-agent ChT—responses are generally short-lived [IV, B] [27.Hughes C.F.M. Khot A. McCormack C. et al.Lack of durable disease control with chemotherapy for mycosis fungoides and Sezary syndrome: a comparative study of systemic therapy.Blood. 2015; 125: 71-81Crossref PubMed Scopus (150) Google Scholar]. Local palliation of cutaneous as well as extracutaneous lesions may be achieved with local RT to doses ≥ 8 Gy [III, A] [17.Neelis K.J. Schimmel E.C. Vermeer M.H. et al.Low-dose palliative radiotherapy for cutaneous B- and T-cell lymphomas.Int J Radiat Oncol Biol Phys. 2009; 74: 154-158Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar]. Recent studies report high response rates of brentuximab vedotin (BV; an anti-CD30 monoclonal antibody coupled to the anti-tubulin agent monomethyl auristatin E) in patients with advanced MF/SS expressing CD30 [II, B] [28.Duvic M. Tetzlaff M.T. Gangar P. et al.Results of a phase II trial of brentuximab vedotin for CD30+ cutaneous T-cell lymphoma and lymphomatoid papulosis.J Clin Oncol. 2015; 33: 3759-3765Crossref PubMed Scopus (220) Google Scholar, 29.Kim Y.H. Tavallaee M. Sundram U. et al.Phase II investigator-initiated study of brentuximab vedotin in mycosis fungoides and Sézary syndrome with variable CD30 expression level: a multi-institution collaborative project.J Clin Oncol. 2015; 33: 3750-3758Crossref PubMed Scopus (208) Google Scholar, 30.Prince H.M. Kim Y.H. Horwitz S.M. et al.Brentuximab vedotin or physician’s choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial.Lancet. 2017; 390: 555-566Abstract Full Text Full Text PDF PubMed Scopus (358) Google Scholar]. In a phase II trial including 28 patients with CD30+ relapsed or refractory MF, BV showed a 54% overall response rate (ORR) with a median time to response of 12 weeks and a median duration of response of 32 weeks in patients with MF, independent of the degree of CD30 expression [28.Duvic M. Tetzlaff M.T. Gangar P. et al.Results of a phase II trial of brentuximab vedotin for CD30+ cutaneous T-cell lymphoma and lymphomatoid papulosis.J Clin Oncol. 2015; 33: 3759-3765Crossref PubMed Scopus (220) Google Scholar]. Another phase II study reported an ORR of 70% in a group of 32 patients with relapsed or refractory MF/SS with a wide range of CD30 expression levels [29.Kim Y.H. Tavallaee M

SALT II: A new take on the Severity of Alopecia Tool (SALT) for determining percentage scalp hair loss

To the Editor: The percentage scalp surface area (SSA) involved in various hair loss disorders is of interest for a variety of reasons including potential staging of a given condition, prognostic implications for hair regrowth, amount of drug application necessary for treatment, and efficacy assessments. We previously published a tool for determining degree of hair loss based on the percentage of SSA involved on the top, back, and each side of the scalp (Fig 1) that is used in the assessment of the Severity of Alopecia Tool (SALT) score for alopecia areata (AA).1Olsen E.A. Hordinsky M.K. Price V.H. et al.Alopecia areata investigational assessment guidelines – part II.J Am Acad Dermatol. 2004; 51: 440-447Abstract Full Text Full Text PDF PubMed Google Scholar We have updated this figure (SALT II) to include smaller increments of scalp coverage to facilitate the assessment of hair loss: (a) where small patches of hair loss predominate, such as in AA or cicatricial alopecia; and (b) where only certain areas of the scalp are involved, such as in male pattern hair loss (MPHL) and frontal fibrosing alopecia (FFA) (Fig 2). This reflects incorporation of earlier figures published by Olsen2Olsen E.A. Female pattern hair loss.J Am Acad Dermatol. 2001; 45: S70-S80Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar in 2001 and Olsen et al3Olsen E.A. Canfield D. Canfield W. Budris K. A novel method for assessing regional scalp hair density in male pattern hair loss.in: Van Neste D. Hair science and technology. Skininterface, Tournai (Belgium)2003: 251-254Google Scholar in 2003.Fig 2SALT II aid for determining scalp surface area more precisely. The SALT score, using either the original SALT I or SALT II, is determined by adding the percentage hair loss in the various areas of the scalp. With the addition of hair density, SALT II can also be used to establish patterns of hair loss germane to different hair loss conditions.View Large Image Figure ViewerDownload Hi-res image Download (PPT) To determine total and 1% SSA, we determined the head circumferences of 26 female [53-58 cm (mean 56 cm)] and 26 male [54.5-62 cm (mean 58 cm)] subjects. We then categorized the head circumference into small, medium, and large and measured the total SSA of 2 male subjects from each category. We used a conversion factor derived from these 6 male subjects to interpolate the SSA for the remaining subjects. The SSA results for all 52 subjects ranged from 607 cm2 (smallest head) to 842 cm2 (largest head) or an average of 705 cm2. In all, 1% of the SSA was approximately 7 cm2 with the sections of the SALT II diagram reflecting percentages of the total SSA, rounded to the nearest whole integer. These tools are analogous to the “rule of nines” and the palm plus 5 fingers used to determine percentage body surface area in various body regions in cutaneous lymphoma.4Olsen E.A. Vonderheid E. Pimpinelli N. Willemze R. Kim Y. Knobler R. et al.Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Study Group of the European Organization of Research and Treatment of Cancer (EORTC).Blood. 2007; 110: 1713-1722Crossref PubMed Scopus (1084) Google Scholar The new figure of the scalp can be used successfully to quantitate both total scalp hair loss or can be used specifically on one area of the scalp only, such as the central aspect of the scalp, to assess involvement of MPHL, female pattern hair loss (FPHL), and central centrifugal cicatricial alopecia (CCCA) or the frontal and temporal hair loss in FFA. Patterns of hair loss can also be defined with this figure for AA, MPHL, FPHL, CCCA, and FFA. Efficacy assessments can be done by noting the density in each of the areas of the involved scalp: for that purpose, we refer the reader to the method of combining region and density rating published on MPHL in 2003.3Olsen E.A. Canfield D. Canfield W. Budris K. A novel method for assessing regional scalp hair density in male pattern hair loss.in: Van Neste D. Hair science and technology. Skininterface, Tournai (Belgium)2003: 251-254Google Scholar We think this new tool will be extremely useful both in clinical practice and in clinical trials of hair loss. Given the new interest in treatments for AA, it is important to introduce this figure for potential use in Food and Drug Administration–sponsored studies for that hair loss condition in particular.

Editorial introductions

Current Opinion in Oncology was launched in 1989. It is one of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of psychiatry is divided into 15 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Journal's Section Editors for this issue. SECTION EDITORS Robert PirkerRobert PirkerRobert Pirker is currently Professor of Medicine and Program Director for Lung Cancer at the Department of Medicine I, Medical University of Vienna, Austria. He obtained a master's degree in Biochemistry in 1978 and his medical degree in 1979 from the University of Vienna. Robert Pirker trained in Internal Medicine, Hemato-Oncology and Nuclear Medicine at the University of Vienna. He also worked as NIH Visiting Fellow at the Laboratory of Molecular Biology (Chief: Dr Ira Pastan), National Cancer Institute, Bethesda, MD, USA (1983–86). He specialises in hemato-oncology. His research focuses on drug resistance mechanisms in patients with cancer, chemotherapy and targeted therapy of lung cancer, predictive factors in lung cancer, and anaemia management in patients with cancer. As a member of the IALT-Bio and LACE-Bio groups, he has been involved in the characterization of predictive factors with regard to adjuvant chemotherapy in patients with completely resected NSCLC. He was also the world-wide Co-ordinating Investigator of the FLEX trial. Robert Pirker has published more than 150 articles, reviews or book chapters. He is an editorial board member of Lung Cancer, ESMO faculty member on Chest Tumors, and has been a member including Chair of the IASLC Education Committee. He was Congress President of the 8th Central European Lung Cancer Congress in 2002 and Chair of the Scientific Committee of the European Multidisciplinary Conference on Thoracic Oncology in 2009. He will be Congress President of the 14th Central European Lung Cancer Congress in 2014 and the 17th World Congress on Lung Cancer in 2016 in Vienna, Austria. He is also Chair of the Steering Committee of the recently launched Central European Initiative against Lung Cancer. Robert Pirker has received several scientific awards and has been a member of ESMO, ASCO and other scientific societies for many years. Reinhard DummerReinhard DummerProfessor Reinhard Dummer is Professor of the University of Zurich and Vice-Chairman of the Department of Dermatology in the University Hospital of Zürich, Switzerland and is a key thought leader in worldwide cutaneous oncology. Currently he is head of the Skin Cancer Unit and the Clinical Trial Unit of the Department of Dermatology. Professor Dummer began his medical education in haematology and oncology before successfully completing his dermatology residency in Würzburg, Germany, and Zürich in 1992. He is Board Certified in allergology, clinical immunology, dermatology and dermatopathology. Professor Dummer's principal research interests are molecular biology, immunology and immunotherapy of cutaneous malignancies, including cutaneous lymphomas and melanomas. He has published more than 560 papers with a cumulative impact factor of more than 4790. He has been President of the Melanoma Project Group of the Swiss Institute for Applied Cancer Research since 1999, is board member of the Society for Melanoma Research and past President of the International Society for Cutaneous Lymphomas. He is a founding and board member of the European Association of Dermato-Oncology (EADO), and past President of the European Society for Dermatological Research (ESDR).

Cutaneous T-cell lymphoma (CTCL): Current practices in blood assessment and the utility of T-cell receptor (TCR)-Vβ chain restriction

Accurate quantification of malignant cells in the peripheral blood of patients with cutaneous T-cell lymphoma is important for early detection, prognosis, and monitoring disease burden. We sought to determine the spectrum of current clinical practices; critically evaluate elements of current International Society for Cutaneous Lymphomas (ISCL) B1 and B2 staging criteria; and assess the potential role of T-cell receptor-Vβ analysis by flow cytometry. We assessed current clinical practices by survey, and performed a retrospective analysis of 161 patients evaluated at Yale (2011-2014) to compare the sensitivity, specificity, positive predictive value, and negative predictive value of parameters for ISCL B2 staging. There was heterogeneity in clinical practices among institutions. ISCL B1 criteria did not capture 5 Yale cohort cases with immunophenotypic abnormalities that later progressed. T-cell receptor-Vβ testing was more specific than polymerase chain reaction and aided diagnosis in detecting clonality, but was of limited benefit in quantification of tumor burden. Because of limited follow-up involving a single center, further investigation will be necessary to conclude whether our proposed diagnostic algorithm is of general clinical benefit. We propose further study of modified B1 criteria: CD4/CD8 ratio 5 or greater, %CD4(+) CD26(-) 20% or greater, or %CD4(+) CD7(-) 20% or greater, with evidence of clonality. T-cell receptor-Vβ testing should be considered in future diagnostic and staging algorithms.

Defining early mycosis fungoides: validation of a diagnostic algorithm proposed by the International Society for Cutaneous Lymphomas.

Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma and is often difficult to diagnose. Early-stage disease is particularly challenging and requires clinical and histopathologic correlation to make an accurate diagnosis. In order to facilitate the diagnosis of early MF, an algorithm has been proposed by the International Society for Cutaneous Lymphomas (ISCL) whereby clinical and histopathologic characteristics as well as immunohistochemistry and T-cell receptor gene rearrangement studies may be applied to suspected cases of MF. The diagnostic utility of this algorithm has not yet been validated. We sought to determine the validity of the proposed algorithm via an investigator-blinded, retrospective, case-control study. A total of 34 cases were randomly selected from the database of a clinic for cutaneous T-cell lymphomas and included patients with MF and patients with clinicopathologic mimics. The proposed diagnostic algorithm was systematically applied to the entire cohort. Each case was assigned a composite score based on the parameters in the proposed algorithm. Among the 24 cases of MF, 21 cases achieved four or more points through application of the algorithm. Among the 10 cases of MF mimics, only four achieved four or more points. This difference was significant (Fisher's exact test, p = 0.009). The sensitivity of the 4-point threshold for a diagnosis of MF was 87.5% and the specificity was 60%. The diagnostic algorithm proposed by the ISCL is a statistically valid method for defining cases of early MF and distinguishing these cases from other benign dermatoses. However, the clinical utility of the algorithm may be limited by its low specificity. Further refinement of the algorithm may improve its accuracy.

Treatment options for primary cutaneous T-cell lymphoma

Primary cutaneous T-cell lymphoma (CTCL) represents a group of diseases characterized by the abnormal proliferation of lymphocytes derived from the skin,with mycosis fungoides (MF) as the most common type.The choice of treatment for CTCL is mainly based on the tumor-node-metastasis-blood (TNMB) classification and staging system for cutaneous lymphomas proposed by the International Society for Cutaneous Lymphomas (ISCL)-World Health Organization-European Organization for Research and Treatment of Cancer (EORTC) in 2007.Other factors to be considered should include the time to onset of action and duration of sustained remission,as well as tolerability,side effects,convenience and cost of treatment.Supportive and local therapies are recommended for early CTCL,while systemic chemotherapy,with or without immunomodulatory therapy,is recommended for advanced CTCL.Some specific cytokines,monoclonal antibodies,and fusion toxins have been tried to treat CTCL. Key words: Lymphoma, T-cell, cutaneous;  Therapeutic uses

Prognostic factors in 105 Japanese cases of mycosis fungoides and Sézary syndrome: Clusterin expression as a novel prognostic factor

BackgroundThe analysis of prognostic factors in Japanese cases of cutaneous T-cell lymphoma (CTCL) is scarce. Clusterin is a ubiquitous 80kDa heterodimeric glycoprotein expressed on tumor cells of systemic and primary cutaneous anaplastic large cell lymphoma. The expression of clusterin in mycosis fungoides (MF) and Sézary syndrome (SS) has only been sporadically reported in a small number of cases. ObjectiveTo determine the long-term prognosis of Japanese patients with MF and SS, to identify clinical and pathological factors predictive of survival, and to evaluate the prognostic significance of the International Society for Cutaneous Lymphomas (ISCL) revised staging system (2007). MethodsWe performed a retrospective cohort study of 105 Japanese patients with MF and SS managed at the Department of Dermatology Asahikawa Medical University from 1976 to 2011. Formalin-fixed, paraffin-embedded sections of MF and SS were immunostained for clusterin, CD30, and Ki-67. ResultsNo statistically significant difference in survival was found between stages IA–IIA and IIIA patients. The significant prognostic factors in the univariate analysis were higher age, TNMB classification, clinical staging, performance status, increased serum LDH level, dermal Ki-67-positive cells, and clusterin expression. In the multivariate analysis, T classification, extracutaneous disease, increased serum LDH level, clusterin expression, and performance status were the significant independent prognostic factors. ConclusionJapanese stage IIIA MF/SS patients contain a subpopulation with a favorable prognosis. The most significant prognostic factor for survival of MF and SS was the presence of extracutaneous disease. Clusterin expression was shown to be a novel unfavorable prognostic factor.

Time course, clinical pathways, and long‐term hazards risk trends of disease progression in patients with classic mycosis fungoides

Mycosis fungoides (MF) is an indolent primary cutaneous T-cell lymphoma. To the authors' knowledge, no data currently are available regarding the evolution over time of the risk of developing specific pathways of disease progression. This retrospective study analyzed 1422 patients with MF who were diagnosed and followed from 1975 through 2010 in 27 Italian Study Group for Cutaneous Lymphoma centers. The primary objectives were to ascertain the time course, pathways, and hazards risk trends of cutaneous/extracutaneous disease progression; to evaluate whether different tumor-lymph node-metastasis-blood (TNMB) stages have different pathways of disease progression; and to analyze differences between tumor-stage and erythrodermic MF with regard to clinical onset, disease evolution, and prognosis. The secondary objective was to provide a further validation for the revised International Society for Cutaneous Lymphomas and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (ISCL/EORTC) classification. The median follow-up was 14.5 years; stage progression occurred in 29.7% of patients and blood involvement was the most frequent extracutaneous site of disease progression. Patients with stage IA to stage IB disease demonstrated a steady low annual incidence of disease progression to tumor-stage (1%-2%); patients with stage IIA disease had a higher risk within the first years (up to 9.4%). Erythroderma evolved with a significantly higher frequency from patches/plaques (13.9%/28.2%) than tumors (P = .028 and P = .013, respectively). Hazards rates of extracutaneous involvement were low (< 1%). The T-score was found to be associated with extracutaneous involvement site, tumor-stage disease with lymph node/visceral lesions, and erythroderma with blood involvement. TNMB classification and stage progression resulted as independent prognostic variables being detected on multivariate analysis; the type of extracutaneous involvement was found to affect survival . The data from the current study support the need for a stage-tailored follow-up, suggest that the classification of tumor-stage disease at a stage below erythroderma could be modified, and offer a further validation for the revised TNMB classification.

Molecular Markers of Early-Stage Mycosis Fungoides

The lack of a specific marker differentiating early mycosis fungoides (eMF) from benign inflammatory dermatitis presents significant difficulties in the assessment and management of suspected MF patients, which often leads to delayed diagnosis and improper medical approaches. To address this, an investigation was carried out to characterize positive identification markers for eMF by comparing eMF lesions with healthy skin and benign inflammatory dermatitis, using high-throughput genomic transcription profiling. A total of 349 genes were differentially expressed in eMF lesions compared with normal skin. These genes belong to pathways associated with inflammation, immune activation, and apoptosis regulation. Most of them (N=330) also demonstrated significant upregulation in chronic dermatitis, making them nonideal markers for eMF. Among them, 19 genes with specific enrichment in eMF lesions were identified that showed no significant upregulation in chronic dermatitis. Two of them, TOX and PDCD1, showed high discrimination power between eMF lesions and biopsies from benign dermatitis by RNA expression. Furthermore, TOX demonstrated highly specific staining of MF cells in eMF skin biopsies in immunohistochemistry and immunofluorescence, including the early epidermotropic cells in Pautrier's microabscesses. This study demonstrates the potential of eMF-enriched genes, especially TOX, as molecular markers for histological diagnosis of eMF, which currently is a major diagnostic challenge.

Cutaneous T-Cell Lymphomas: A Review of New Discoveries and Treatments

Treatment regimens of patients with CTCL vary widely based on clinician preference and patient tolerance. Skin directed therapies are recommended for patients with early stage IA and IB MF, with combinations used in refractory cases. While no regimen has been proven to prolong survival in advanced stages, immunomodulatory regimens should be used initially to reduce the need for cytotoxic therapies. In more advanced stages of disease, treatment efforts should strive for palliation and improvement of quality of life. With many new therapies and strategies on the horizon, the future looks promising for CTCL patients. Unfortunately, other than allogeneic HCT, there are no potential curative therapies for CTCL. Clinical trials are currently underway to identify new therapies to improve quality of life for patients, and researchers are hard at work to identify novel pathways and genes for prognostication and as targets for therapies. Importantly, collaborative clinical trials to enhance rates of accrual need to be conducted, and improved interpretation of data via standardizing end points and response criteria should be an emphasis. Recently, the International Society for Cutaneous Lymphomas (ISCL), the United States Cutaneous Lymphoma Consortium (USCLC), and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer (EORTC) met to develop consensus guidelines to facilitate collaboration on clinical trials. These proposed guidelines consist of: recommendations for standardizing general protocol design; a scoring system for assessing tumor burden in skin, lymph nodes, blood, and viscera; definition of response in skin, nodes, blood, and viscera; a composite global response score; and a definition of end points. Although these guidelines were generated by consensus panels, they have not been prospectively or retrospectively validated through analysis of large patient cohorts.