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 ef-
ficiency of this process is unknown. In
the current models, L-SNA treatment of
essentially normal skin in these pre-
vention 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 L-
SNA application will be required for
clinical efficacy. Limitations in current
psoriasis models suggest that these is-
sues 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 sup-
port the feasibility of L-SNA delivery for
the treatment of other skin diseases. In
particular, L-SNA delivery has the po-
tential to be effective for skin pathol-
ogies 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 tech-
nology for the topical delivery of
molecularly-targeted therapies,
dramatically expanding the scope of
topical interventions available to der-
matologists and other healthcare
providers.
ORCIDs
Emrullah Korkmaz: https://orcid.org/0000-0002-
8808-5445
Louis D. Falo: https://orcid.org/0000-0001-9813-
0433
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 using liposomal spherical nucleic acids as
LDF is supported by National Institutes of Health topical therapy for psoriasis. J Invest Dermatol
grants R01AR074285, R01AR071277, R01AR0 2020;140:435e44.e4.
68249, and P50CA121973. Mirkin CA, Letsinger RL, Mucic RC, Storhoff JJ.
A DNA-based method for rationally assembling
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intradermal delivery of tumor necrosis factor-alpha Kurschus FC. Imiquimod-induced psoriasis in
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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 es- retrospective cohort studies that were
timate the survival of patients with mostly limited to single centers, and
specific cancers and help to determine thus there is no uniformity in defini-
best management. However, there are tions. The median age at diagnosis
ranges of survival within individual ranged from 52e62 years and all
cancer stages. Mourad and Gniadecki studies had a male predominance of 1.6
(2019) performed a systematic review (male:female ratio 6:4) in accordance
and metanalysis of overall survival (OS) with previous reports (Willemze et al.,
in patients with stage IBeIVB mycosis 2005). The authors concentrated on
fungoides (MF) and Sezary syndrome OS because detailed information on
(SS). They identified 10 studies cause of death was not available. This is
including 6,279 patients. All were 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: Julia.Scarisbrick@uhb.nhs.uk
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) re-
ported 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), Sézary syndrome
(stage IVA1), nodal effacement (stage
IVA2), and metastatic spread (stage IVB)
had powerful, negative impacts on sur-
vival. However, these features are re-
flected in the staging algorithm and
don’t give additional information on the
patients’ clinical or pathological phe-
notypes, which may provide further
prognostic information.
The Prospective Cutaneous Lym-
phoma International Prognostic Index
(PROCLIPI) study is a global prospective
effort collecting clinical, pathological,
genotypic, treatment, and health-
related 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 de-
cisions and to improve survival. PRO-
CLIPI recently reported the median age
of diagnosis of stage IB MF as 57 years
(interquartile range ¼ 45e67yrs)
(Scarisbrick et al., 2019). As the re-
ported 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 Journal of Investigative Dermatology (2020), Volume 140
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 lym-
phocytes 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-) be-
tween 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 immunohis-
tochemical staining (recorded in 4.6%
of patients with early-stage MF), and the
association with lesions of lymphoma-
toid papulosis (Scarisbrick et al., 2019).
Advanced stages of MF and SS pre-
sent 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
OS ranging from 41e68.5% and a 10-
year 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 meta-
analysis 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 chal-
lenging 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 involve-
ment (as defined by 1000 IU aber-
rantly 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 his-
tological 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 Euro-
pean Organisation for Research and
Treatment of Cancer Cutaneous Lym-
phoma 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 treat-
ment choices for patients with MF or

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 chemo-
therapy, and sequential treatments are
given as the disease progresses (https://
www.nccn.org/professionals/physician_
gls/pdf/primary_cutaneous.pdf). Treat-
ment 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 consider-
ation 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 re-
sponses 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 indepen-
dent 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, pru-
ritus, 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 indi-
vidual 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 in-
dex for aggressive non-Hodgkin lym-
phoma was developed in 1993, and it
has been widely used to stratify patients
for treatment (Shipp, 1994). Develop-
ment of a useful prognostic index re-
quires international collaboration, and it
must be done prospectively with well-
defined 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 stratifica-
tion into clinical trials, and that it will
improve survival in this group of patients
with poor outcome. Mourad and
Gniadecki (2019) have provided a use-
ful data source that can be used to give
guidance to patients and treating physi-
cians in the likely survival outcomes of
patients with MF and SS according to
stage.
ORCID
Julia J. Scarisbrick: https://orcid.org/0000-0002-
8011-4408
CONFLICT OF INTEREST
The author states no conflict of interest.
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COMMENTARY
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