- Email: [email protected]
Survival in Mycosis Fungoides and Sezary Syndrome: How Can We Predict Outcome?
COMMENTARY develop with the psoriatic phenotype could have important effects on both of these variables. Prior studies suggested that L-SNAs could penetrate to the dermis in explants of psoriatic skin (Lewandowski et al., 2017), but the efficiency of this process is unknown. In the current models, L-SNA treatment of essentially normal skin in these prevention models reduced IL-17RA mRNA by 57% in mouse skin and as much as 72% in cytokine-treated human 3D skin cultures, and the reductions were time dependent. In established psoriasis, the barrier is more pronounced, the epidermis is thicker, target keratinocytes are more numerous, and IL-17A receptor expression is upregulated, all of which suggest greater challenges for effective L-SNA delivery. It is difficult to predict how much and how often topical LSNA application will be required for clinical efficacy. Limitations in current psoriasis models suggest that these issues can only be addressed through clinical trials, which are now underway. Despite remaining challenges, the current studies provide important proof of concept for the future development of topical L-SNA therapies for the treatment of psoriasis. They also support the feasibility of L-SNA delivery for the treatment of other skin diseases. In particular, L-SNA delivery has the potential to be effective for skin pathologies in which the skin barrier may be normal or compromised, and, thereby, presents less of an obstacle to delivery, such as wound healing, immunobullous diseases, and disorders of the hair follicle. L-SNA delivery has the potential to be an enabling technology for the topical delivery of molecularly-targeted therapies, dramatically expanding the scope of topical interventions available to dermatologists and other healthcare providers. ORCIDs Emrullah Korkmaz: https://orcid.org/0000-00028808-5445 Louis D. Falo: https://orcid.org/0000-0001-98130433
CONFLICT OF INTEREST LDF is a scientific advisor for and holds an equity position in BrainStage and SkinJect. EK states no conflict of interest.
ACKNOWLEDGMENTS LDF is supported by National Institutes of Health grants R01AR074285, R01AR071277, R01AR0 68249, and P50CA121973.
REFERENCES Korkmaz E, Friedrich EE, Ramadan MH, Erdos G, Mathers AR, Ozdoganlar OB, et al. Therapeutic intradermal delivery of tumor necrosis factor-alpha antibodies using tip-loaded dissolvable microneedle arrays. Acta Biomater 2015;24:96e105. Lee JH, Jung YS, Kim GM, Bae JM. A hyaluronic acid-based microneedle patch to treat psoriatic plaques: a pilot open trial. Br J Dermatol 2018;178:e24e5. Lewandowski KT, Thiede R, Guido N, Daniel WL, Kang R, Guerrero-Zayas MI, et al. Topically delivered tumor necrosis factor-a-targeted gene regulation for psoriasis. J Invest Dermatol 2017;137:2027e30. Liu H, Kang RS, Bagnowski K, Yu JM, Radecki S, Daniel WL, et al. Targeting the IL-17 receptor
using liposomal spherical nucleic acids as topical therapy for psoriasis. J Invest Dermatol 2020;140:435e44.e4. Mirkin CA, Letsinger RL, Mucic RC, Storhoff JJ. A DNA-based method for rationally assembling nanoparticles into macroscopic materials. Nature 1996;382:607e9. Moos S, Mohebiany AN, Waisman A, Kurschus FC. Imiquimod-induced psoriasis in mice depends on the IL-17 signaling of keratinocytes. J Invest Dermatol 2019;139:1110e7. Prausnitz MR, Langer R. Transdermal drug delivery. Nat Biotechnol 2008;26:1261e8. Wraight CJ, White PJ. Antisense oligonucleotides in cutaneous therapy. Pharmacol Ther 2001;90: 89e104. Zheng D, Giljohann DA, Chen DL, Massich MD, Wang XQ, Iordanov H, et al. Topical delivery of siRNA-based spherical nucleic acid nanoparticle conjugates for gene regulation. Proc Natl Acad Sci USA 2012;109: 11975e80.
See related article on pg 495
Survival in Mycosis Fungoides and Sezary Syndrome: How Can We Predict Outcome? Julia J. Scarisbrick1 Early-stage mycosis fungoides (MF) has been associated with long survival. A recent meta-analysis including 6,279 patients with MF and Sezary syndrome found that about 10e20% of stage IB patients don’t survive 5 years, whereas patients with advanced-stage MF and Sezary syndrome have a 5-year survival chance of about 20e60%. Identifying prognostic markers to better identify those at risk of limited survival may allow improved management choices and this, coupled with newer treatments, could improve survival. Journal of Investigative Dermatology (2020) 140, 281e283. doi:10.1016/j.jid.2019.08.440
Cancer staging systems are used to estimate the survival of patients with specific cancers and help to determine best management. However, there are ranges of survival within individual cancer stages. Mourad and Gniadecki (2019) performed a systematic review and metanalysis of overall survival (OS) in patients with stage IBeIVB mycosis fungoides (MF) and Sezary syndrome (SS). They identified 10 studies including 6,279 patients. All were
retrospective cohort studies that were mostly limited to single centers, and thus there is no uniformity in definitions. The median age at diagnosis ranged from 52e62 years and all studies had a male predominance of 1.6 (male:female ratio 6:4) in accordance with previous reports (Willemze et al., 2005). The authors concentrated on OS because detailed information on cause of death was not available. This is a logical approach in retrospective
1
Department of Dermatology, University Hospital Birmingham, Birmingham, United Kingdom
Correspondence: Julia J. Scarisbrick, Department of Dermatology, University Hospital Birmingham, Birmingham, B15 2TH, United Kingdom. E-mail: [email protected] ª 2019 The Author. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology.
www.jidonline.org
281
COMMENTARY
Clinical Implications Survival in stage IB mycosis fungoides is significantly reduced in up to one in five patients, with death within 5 years of diagnosis. Survival is poor in advanced mycosis fungoides and Sezary syndrome, and 5-year survival rates range from 20e60%. Identifying risk factors for poorer survival may allow individualized treatment choices.
cohort studies when data may be inconsistently defined between centers or incomplete. Mourad and Gniadecki (2019) reported a median survival and included best- and worst-case scenarios. The authors achieved this by calculating median 5-year OS rates and then defining best case as the upper 10th percentile for each stage and worst case as the lower 10th percentile. They showed OS to be 85.8% in stage IB, reflecting significant mortality in these patients with early-stage MF, with a best case of 88.8% and a worst case of 82.1%. The authors showed that development of tumors (progression from stage I to IIB), Se´zary syndrome (stage IVA1), nodal effacement (stage IVA2), and metastatic spread (stage IVB) had powerful, negative impacts on survival. However, these features are reflected in the staging algorithm and don’t give additional information on the patients’ clinical or pathological phenotypes, which may provide further prognostic information. The Prospective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) study is a global prospective effort collecting clinical, pathological, genotypic, treatment, and healthrelated quality of life (HRQoL) data on all stages of MF and SS with the aim to develop a prognostic index to stratify patients for better management decisions and to improve survival. PROCLIPI recently reported the median age of diagnosis of stage IB MF as 57 years (interquartile range ¼ 45e67yrs) (Scarisbrick et al., 2019). As the reported 5-year OS by Mourad et al. (2019) is 85.8% in stage IB MF, this shows that some patients with stage IB MF have considerable reductions in life expectancy. Longer survival data (10- to 20-year OS) was not reported, but it is known that many patients with stage I MF have a long survival (Willemze 282
et al., 2005). It would be useful to identify prognostic markers in stage IB that could predict those with a more aggressive phenotype but also provide reassurance for those with a less aggressive phenotype. In PROCLIPI, factors being tracked as possible poor prognostic markers in stage IB include folliculotropic MF (FMF; recorded in 24.8% of patients with stage IB MF), large cell transformation (LCT) in skin (which is defined as >25% overall or microscopic nodules of atypical lymphocytes being greater than normal size [recorded in 1.7% of patients with stage IB MF]), low level blood involvement with circulating aberrant lymphocytes (typically CD4þ, CD7-, or CD26-) between 250 and 1000 IU as defined by B1 (recorded in 26.1% of patients with stage IB MF), and raised serum lactate dehydrogenase (LDH; recorded in 8.9% of patients with stage IB MF). Factors that are possibly associated with improved survival include the clinical variants manifesting poikiloderma (recorded in 15.2% of patients with early-stage MF) and hypopigmentation (recorded in 8.0% of patients with early-stage MF), malignant lymphocytes which are CD4-CD8þ by immunohistochemical staining (recorded in 4.6% of patients with early-stage MF), and the association with lesions of lymphomatoid papulosis (Scarisbrick et al., 2019). Advanced stages of MF and SS present more often at older ages than early stages, with a median age at diagnosis of w63 years (range ¼ 8e98 years) (Scarisbrick et al., 2015; Talpur et al., 2012). Advanced stages of MF and SS are comprised of stages IIBeIVB and are associated with a worse prognosis than early-stage disease. Median survival historically has been quoted at about 3 years (Willemze et al., 2005). Individual studies reporting 5-year survival in the advanced cohort reported by Mourad and Gniadecki (2019) found a 5-year
Journal of Investigative Dermatology (2020), Volume 140
OS ranging from 41e68.5% and a 10year OS of 25e58.8%, indicating that not all advanced patients have a poor outcome and that some patients may survive more than a decade. The metaanalysis reported a median 5 year-OS in stage IIB as 62.2% (best 67.9%, worst 56%), 59.7% in stage IIIA (best 67.6%, worst 50.7%), 54% in stage IIIB (best 63.4%, worst 43.3%), 52.5% in stage IVA1 (best 52.5%, worst 43.2%), 34% in stage IVA2 (best 46.3%, worst 22.1%), and 23.3% in stage IVB (best 39.7%, worst 10%) (Mourad et al., 2019). These results will allow more detailed information on OS to be available for patients but also show a 10e20% difference in the best- and worst-case scenarios. This may be confusing for patients until we can identify those factors that may better differentiate survival risks. It is likely patients will want to know if they are more likely to survive >10 years for future life and family planning. Deciding how best to inform patients regarding 5-year OS may also be challenging for physicians, especially in metastatic disease (stage IVB) where the best-case scenario gives a 40% 5-year OS compared with just 10% in the worst case. Factors previously reported to be associated with worsened survival in advanced stages of MF include age greater than 60 years at diagnosis, partially or completely effaced nodal involvement (N3), B2 blood involvement (as defined by 1000 IU aberrantly circulating lymphocytes), visceral involvement, LCT in skin, and raised serum LDH (Benton et al., 2013; Scarisbrick et al., 2015). PROCLIPI is recording these factors as well as histological markers such as CD30% and Ki-67 (Gru et al.,2018). Variation in survival within the stages of MF and SS is acknowledged and the importance of poor prognostic indices outside the staging system has been recognized. The International Society for Cutaneous Lymphoma and European Organisation for Research and Treatment of Cancer Cutaneous Lymphoma Task Force recommend the tracking of patients with FMF or LCT to determine if either warrants a different staging system from classical MF and SS. A staging system that relates to prognosis is vital, as this dictates treatment choices for patients with MF or
COMMENTARY SS. Patients with early-stage MF (stages IAeIIA) are treated with skin-directed therapy. Patients with advanced-stage MF or SS (stages IIBeIVB) typically require immunotherapy or chemotherapy, and sequential treatments are given as the disease progresses (https:// www.nccn.org/professionals/physician_ gls/pdf/primary_cutaneous.pdf). Treatment is frequently palliative and decided on an individual patient basis. Allogeneic stem cell transplant may be considered for eligible patients with poor survival risk. It produces some good responses, but careful consideration is required as transplant-related mortality at year 1 is significant (w34%) (Duarte et al., 2010). Treatment of MF and SS rarely results in complete responses, and partial responses or stable disease is common (https://www.nccn.org/professionals/ physician_gls/pdf/primary_cutaneous. pdf). Patients therefore live for long periods with significant morbidity from skin tumor burden, which impacts quality of life. Molloy et al. (2019) recently reported on HRQoL, as measured by Skindex-29, in patients with MF and SS. HRQoL was found to be worse in women, patients with SS, patients with alopecia, those with high skin tumor burden, and those in advanced-stage disease. Female sex and alopecia were the only independent predictors of worsened global HRQoL. Item-level analysis showed that the HRQoL impairment in women occurred because of a higher impact of the symptoms of burning/stinging, pruritus, and irritation and worse emotional scores of depression, shame, embarrassment, and annoyance with their diagnosis of MF or SS (Molloy et al., 2019). The likely survival outcomes of individual patients is often their greatest concern. Identifying prognostic markers
will provide more relevant personalized information for patients than stage alone and allow better management decisions. More specifically, if prognostic markers can be modeled into a prognostic index, this may provide individualized survival outcomes and allow personalized management choices. A prognostic index for aggressive non-Hodgkin lymphoma was developed in 1993, and it has been widely used to stratify patients for treatment (Shipp, 1994). Development of a useful prognostic index requires international collaboration, and it must be done prospectively with welldefined criteria to ensure comparable measures. Retrospective data may be flawed because of poor recording, differing definitions, and inaccurate recall. The PROCLIPI study provides an established registry with centrally reviewed clinicopathological data (Gru et al., 2018) with the aim of producing a prognostic index in MF and SS to stratify patients according to survival. It is hoped that such an international prognostic index will provide an improved basis for selecting patients for appropriate therapies and for stratification into clinical trials, and that it will improve survival in this group of patients with poor outcome. Mourad and Gniadecki (2019) have provided a useful data source that can be used to give guidance to patients and treating physicians in the likely survival outcomes of patients with MF and SS according to stage. ORCID Julia J. Scarisbrick: https://orcid.org/0000-00028011-4408
CONFLICT OF INTEREST The author states no conflict of interest.
REFERENCES Benton EC, Crichton S, Talpur R, Agar NS, Fields PA, Wedgeworth E, et al. A cutaneous
lymphoma international prognostic index (CLIPi) for mycosis fungoides & Sezary syndrome. Eur J Cancer 2013;49:2859e68. Duarte RF, Canals C, Onida F, Gabriel IH, Arranz R, Arcese W, et al. Allogeneic haematopoietic cell transplantation for patients with mycosis fungoides and Sezary syndrome: a retrospective analysis of the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol 2010;28: 4492e9. Gru A, Battistella M, Kim J, Pulitzer M, Guitart J, Hong E, et al. The use of digital slide scanning as a tool for central pathology review in patients with advanced stage mycosis fungoides and Sezary syndrome: a multi-institutional and international pathology study. Am J Surg Pathol 2018;42:726e34. Molloy K, Jonak C, Woei-A-Jin FJSH, Guenova E, Busschots AM, Bervoets A, Hauben E, et al. Characteristics associated with significantly worse quality of life in mycosis fungoides/Se´zary syndrome from the Prospective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) study [epub ahead of print]. Br J Dermatol 2019. https://doi.org/10.1111/bjd.18089 (accessed 13 September 2019). Mourad A, Gniadecki R. Overall survival in mycosis fungoides: A systematic review and meta-analysis [e-pub ahead of print]. J Invest Dermatol 2020;140:495e7.e5. Scarisbrick JJ, Prince HM, Vermeer MH, Quaglino P, Horwitz S, Porcu P, et al. Cutaneous Lymphoma International Consortium (CLIC) study of outcome in advanced stages of mycosis fungoides & Se´zary syndrome: effect of specific prognostic markers on survival and development of a prognostic model. J Clin Oncol 2015;33:3766e73. Scarisbrick JJ, Quaglino P, Prince HM, Papadavid E, Hodak E, Bagot M, et al. The PROCLIPI international registry of early stage mycosis fungoides identifies substantial diagnostic delay in most patients. Br J Dermatol 2019;181:350e7. Shipp MA. Prognostic factors in aggressive nonHodgkin’s lymphoma: who has ‘high-risk’ disease? Blood 1994;83:1165e73. Talpur R, Singh L, Daulat S, Liu P, Seyfer S, Trynosky T, et al. Long-term outcomes of 1,263 patients with mycosis fungoides and Se´zary syndrome from 1982 to 2009. Clin Cancer Res 2012;18:5051e60. Willemze R, Jaffe ES, Burg G, Cerroni L, Berti E, Swerdlow SH, et al. WHO/EORTC classification for cutaneous lymphomas. Blood 2005;105:3768e85.
www.jidonline.org
283
CONFLICT OF INTEREST LDF is a scientific advisor for and holds an equity position in BrainStage and SkinJect. EK states no conflict of interest.
ACKNOWLEDGMENTS LDF is supported by National Institutes of Health grants R01AR074285, R01AR071277, R01AR0 68249, and P50CA121973.
REFERENCES Korkmaz E, Friedrich EE, Ramadan MH, Erdos G, Mathers AR, Ozdoganlar OB, et al. Therapeutic intradermal delivery of tumor necrosis factor-alpha antibodies using tip-loaded dissolvable microneedle arrays. Acta Biomater 2015;24:96e105. Lee JH, Jung YS, Kim GM, Bae JM. A hyaluronic acid-based microneedle patch to treat psoriatic plaques: a pilot open trial. Br J Dermatol 2018;178:e24e5. Lewandowski KT, Thiede R, Guido N, Daniel WL, Kang R, Guerrero-Zayas MI, et al. Topically delivered tumor necrosis factor-a-targeted gene regulation for psoriasis. J Invest Dermatol 2017;137:2027e30. Liu H, Kang RS, Bagnowski K, Yu JM, Radecki S, Daniel WL, et al. Targeting the IL-17 receptor
using liposomal spherical nucleic acids as topical therapy for psoriasis. J Invest Dermatol 2020;140:435e44.e4. Mirkin CA, Letsinger RL, Mucic RC, Storhoff JJ. A DNA-based method for rationally assembling nanoparticles into macroscopic materials. Nature 1996;382:607e9. Moos S, Mohebiany AN, Waisman A, Kurschus FC. Imiquimod-induced psoriasis in mice depends on the IL-17 signaling of keratinocytes. J Invest Dermatol 2019;139:1110e7. Prausnitz MR, Langer R. Transdermal drug delivery. Nat Biotechnol 2008;26:1261e8. Wraight CJ, White PJ. Antisense oligonucleotides in cutaneous therapy. Pharmacol Ther 2001;90: 89e104. Zheng D, Giljohann DA, Chen DL, Massich MD, Wang XQ, Iordanov H, et al. Topical delivery of siRNA-based spherical nucleic acid nanoparticle conjugates for gene regulation. Proc Natl Acad Sci USA 2012;109: 11975e80.
See related article on pg 495
Survival in Mycosis Fungoides and Sezary Syndrome: How Can We Predict Outcome? Julia J. Scarisbrick1 Early-stage mycosis fungoides (MF) has been associated with long survival. A recent meta-analysis including 6,279 patients with MF and Sezary syndrome found that about 10e20% of stage IB patients don’t survive 5 years, whereas patients with advanced-stage MF and Sezary syndrome have a 5-year survival chance of about 20e60%. Identifying prognostic markers to better identify those at risk of limited survival may allow improved management choices and this, coupled with newer treatments, could improve survival. Journal of Investigative Dermatology (2020) 140, 281e283. doi:10.1016/j.jid.2019.08.440
Cancer staging systems are used to estimate the survival of patients with specific cancers and help to determine best management. However, there are ranges of survival within individual cancer stages. Mourad and Gniadecki (2019) performed a systematic review and metanalysis of overall survival (OS) in patients with stage IBeIVB mycosis fungoides (MF) and Sezary syndrome (SS). They identified 10 studies including 6,279 patients. All were
retrospective cohort studies that were mostly limited to single centers, and thus there is no uniformity in definitions. The median age at diagnosis ranged from 52e62 years and all studies had a male predominance of 1.6 (male:female ratio 6:4) in accordance with previous reports (Willemze et al., 2005). The authors concentrated on OS because detailed information on cause of death was not available. This is a logical approach in retrospective
1
Department of Dermatology, University Hospital Birmingham, Birmingham, United Kingdom
Correspondence: Julia J. Scarisbrick, Department of Dermatology, University Hospital Birmingham, Birmingham, B15 2TH, United Kingdom. E-mail: [email protected] ª 2019 The Author. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology.
www.jidonline.org
281
COMMENTARY
Clinical Implications Survival in stage IB mycosis fungoides is significantly reduced in up to one in five patients, with death within 5 years of diagnosis. Survival is poor in advanced mycosis fungoides and Sezary syndrome, and 5-year survival rates range from 20e60%. Identifying risk factors for poorer survival may allow individualized treatment choices.
cohort studies when data may be inconsistently defined between centers or incomplete. Mourad and Gniadecki (2019) reported a median survival and included best- and worst-case scenarios. The authors achieved this by calculating median 5-year OS rates and then defining best case as the upper 10th percentile for each stage and worst case as the lower 10th percentile. They showed OS to be 85.8% in stage IB, reflecting significant mortality in these patients with early-stage MF, with a best case of 88.8% and a worst case of 82.1%. The authors showed that development of tumors (progression from stage I to IIB), Se´zary syndrome (stage IVA1), nodal effacement (stage IVA2), and metastatic spread (stage IVB) had powerful, negative impacts on survival. However, these features are reflected in the staging algorithm and don’t give additional information on the patients’ clinical or pathological phenotypes, which may provide further prognostic information. The Prospective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) study is a global prospective effort collecting clinical, pathological, genotypic, treatment, and healthrelated quality of life (HRQoL) data on all stages of MF and SS with the aim to develop a prognostic index to stratify patients for better management decisions and to improve survival. PROCLIPI recently reported the median age of diagnosis of stage IB MF as 57 years (interquartile range ¼ 45e67yrs) (Scarisbrick et al., 2019). As the reported 5-year OS by Mourad et al. (2019) is 85.8% in stage IB MF, this shows that some patients with stage IB MF have considerable reductions in life expectancy. Longer survival data (10- to 20-year OS) was not reported, but it is known that many patients with stage I MF have a long survival (Willemze 282
et al., 2005). It would be useful to identify prognostic markers in stage IB that could predict those with a more aggressive phenotype but also provide reassurance for those with a less aggressive phenotype. In PROCLIPI, factors being tracked as possible poor prognostic markers in stage IB include folliculotropic MF (FMF; recorded in 24.8% of patients with stage IB MF), large cell transformation (LCT) in skin (which is defined as >25% overall or microscopic nodules of atypical lymphocytes being greater than normal size [recorded in 1.7% of patients with stage IB MF]), low level blood involvement with circulating aberrant lymphocytes (typically CD4þ, CD7-, or CD26-) between 250 and 1000 IU as defined by B1 (recorded in 26.1% of patients with stage IB MF), and raised serum lactate dehydrogenase (LDH; recorded in 8.9% of patients with stage IB MF). Factors that are possibly associated with improved survival include the clinical variants manifesting poikiloderma (recorded in 15.2% of patients with early-stage MF) and hypopigmentation (recorded in 8.0% of patients with early-stage MF), malignant lymphocytes which are CD4-CD8þ by immunohistochemical staining (recorded in 4.6% of patients with early-stage MF), and the association with lesions of lymphomatoid papulosis (Scarisbrick et al., 2019). Advanced stages of MF and SS present more often at older ages than early stages, with a median age at diagnosis of w63 years (range ¼ 8e98 years) (Scarisbrick et al., 2015; Talpur et al., 2012). Advanced stages of MF and SS are comprised of stages IIBeIVB and are associated with a worse prognosis than early-stage disease. Median survival historically has been quoted at about 3 years (Willemze et al., 2005). Individual studies reporting 5-year survival in the advanced cohort reported by Mourad and Gniadecki (2019) found a 5-year
Journal of Investigative Dermatology (2020), Volume 140
OS ranging from 41e68.5% and a 10year OS of 25e58.8%, indicating that not all advanced patients have a poor outcome and that some patients may survive more than a decade. The metaanalysis reported a median 5 year-OS in stage IIB as 62.2% (best 67.9%, worst 56%), 59.7% in stage IIIA (best 67.6%, worst 50.7%), 54% in stage IIIB (best 63.4%, worst 43.3%), 52.5% in stage IVA1 (best 52.5%, worst 43.2%), 34% in stage IVA2 (best 46.3%, worst 22.1%), and 23.3% in stage IVB (best 39.7%, worst 10%) (Mourad et al., 2019). These results will allow more detailed information on OS to be available for patients but also show a 10e20% difference in the best- and worst-case scenarios. This may be confusing for patients until we can identify those factors that may better differentiate survival risks. It is likely patients will want to know if they are more likely to survive >10 years for future life and family planning. Deciding how best to inform patients regarding 5-year OS may also be challenging for physicians, especially in metastatic disease (stage IVB) where the best-case scenario gives a 40% 5-year OS compared with just 10% in the worst case. Factors previously reported to be associated with worsened survival in advanced stages of MF include age greater than 60 years at diagnosis, partially or completely effaced nodal involvement (N3), B2 blood involvement (as defined by 1000 IU aberrantly circulating lymphocytes), visceral involvement, LCT in skin, and raised serum LDH (Benton et al., 2013; Scarisbrick et al., 2015). PROCLIPI is recording these factors as well as histological markers such as CD30% and Ki-67 (Gru et al.,2018). Variation in survival within the stages of MF and SS is acknowledged and the importance of poor prognostic indices outside the staging system has been recognized. The International Society for Cutaneous Lymphoma and European Organisation for Research and Treatment of Cancer Cutaneous Lymphoma Task Force recommend the tracking of patients with FMF or LCT to determine if either warrants a different staging system from classical MF and SS. A staging system that relates to prognosis is vital, as this dictates treatment choices for patients with MF or
COMMENTARY SS. Patients with early-stage MF (stages IAeIIA) are treated with skin-directed therapy. Patients with advanced-stage MF or SS (stages IIBeIVB) typically require immunotherapy or chemotherapy, and sequential treatments are given as the disease progresses (https:// www.nccn.org/professionals/physician_ gls/pdf/primary_cutaneous.pdf). Treatment is frequently palliative and decided on an individual patient basis. Allogeneic stem cell transplant may be considered for eligible patients with poor survival risk. It produces some good responses, but careful consideration is required as transplant-related mortality at year 1 is significant (w34%) (Duarte et al., 2010). Treatment of MF and SS rarely results in complete responses, and partial responses or stable disease is common (https://www.nccn.org/professionals/ physician_gls/pdf/primary_cutaneous. pdf). Patients therefore live for long periods with significant morbidity from skin tumor burden, which impacts quality of life. Molloy et al. (2019) recently reported on HRQoL, as measured by Skindex-29, in patients with MF and SS. HRQoL was found to be worse in women, patients with SS, patients with alopecia, those with high skin tumor burden, and those in advanced-stage disease. Female sex and alopecia were the only independent predictors of worsened global HRQoL. Item-level analysis showed that the HRQoL impairment in women occurred because of a higher impact of the symptoms of burning/stinging, pruritus, and irritation and worse emotional scores of depression, shame, embarrassment, and annoyance with their diagnosis of MF or SS (Molloy et al., 2019). The likely survival outcomes of individual patients is often their greatest concern. Identifying prognostic markers
will provide more relevant personalized information for patients than stage alone and allow better management decisions. More specifically, if prognostic markers can be modeled into a prognostic index, this may provide individualized survival outcomes and allow personalized management choices. A prognostic index for aggressive non-Hodgkin lymphoma was developed in 1993, and it has been widely used to stratify patients for treatment (Shipp, 1994). Development of a useful prognostic index requires international collaboration, and it must be done prospectively with welldefined criteria to ensure comparable measures. Retrospective data may be flawed because of poor recording, differing definitions, and inaccurate recall. The PROCLIPI study provides an established registry with centrally reviewed clinicopathological data (Gru et al., 2018) with the aim of producing a prognostic index in MF and SS to stratify patients according to survival. It is hoped that such an international prognostic index will provide an improved basis for selecting patients for appropriate therapies and for stratification into clinical trials, and that it will improve survival in this group of patients with poor outcome. Mourad and Gniadecki (2019) have provided a useful data source that can be used to give guidance to patients and treating physicians in the likely survival outcomes of patients with MF and SS according to stage. ORCID Julia J. Scarisbrick: https://orcid.org/0000-00028011-4408
CONFLICT OF INTEREST The author states no conflict of interest.
REFERENCES Benton EC, Crichton S, Talpur R, Agar NS, Fields PA, Wedgeworth E, et al. A cutaneous
lymphoma international prognostic index (CLIPi) for mycosis fungoides & Sezary syndrome. Eur J Cancer 2013;49:2859e68. Duarte RF, Canals C, Onida F, Gabriel IH, Arranz R, Arcese W, et al. Allogeneic haematopoietic cell transplantation for patients with mycosis fungoides and Sezary syndrome: a retrospective analysis of the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol 2010;28: 4492e9. Gru A, Battistella M, Kim J, Pulitzer M, Guitart J, Hong E, et al. The use of digital slide scanning as a tool for central pathology review in patients with advanced stage mycosis fungoides and Sezary syndrome: a multi-institutional and international pathology study. Am J Surg Pathol 2018;42:726e34. Molloy K, Jonak C, Woei-A-Jin FJSH, Guenova E, Busschots AM, Bervoets A, Hauben E, et al. Characteristics associated with significantly worse quality of life in mycosis fungoides/Se´zary syndrome from the Prospective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) study [epub ahead of print]. Br J Dermatol 2019. https://doi.org/10.1111/bjd.18089 (accessed 13 September 2019). Mourad A, Gniadecki R. Overall survival in mycosis fungoides: A systematic review and meta-analysis [e-pub ahead of print]. J Invest Dermatol 2020;140:495e7.e5. Scarisbrick JJ, Prince HM, Vermeer MH, Quaglino P, Horwitz S, Porcu P, et al. Cutaneous Lymphoma International Consortium (CLIC) study of outcome in advanced stages of mycosis fungoides & Se´zary syndrome: effect of specific prognostic markers on survival and development of a prognostic model. J Clin Oncol 2015;33:3766e73. Scarisbrick JJ, Quaglino P, Prince HM, Papadavid E, Hodak E, Bagot M, et al. The PROCLIPI international registry of early stage mycosis fungoides identifies substantial diagnostic delay in most patients. Br J Dermatol 2019;181:350e7. Shipp MA. Prognostic factors in aggressive nonHodgkin’s lymphoma: who has ‘high-risk’ disease? Blood 1994;83:1165e73. Talpur R, Singh L, Daulat S, Liu P, Seyfer S, Trynosky T, et al. Long-term outcomes of 1,263 patients with mycosis fungoides and Se´zary syndrome from 1982 to 2009. Clin Cancer Res 2012;18:5051e60. Willemze R, Jaffe ES, Burg G, Cerroni L, Berti E, Swerdlow SH, et al. WHO/EORTC classification for cutaneous lymphomas. Blood 2005;105:3768e85.
www.jidonline.org
283