Myelodysplasia Cutis Versus Leukemia Cutis

Abstract

Abbreviations: AML, acute myeloid leukemia; FISH, fluorescent in situ hybridization; IPSS, International Prognostic Scoring System; MDS, myelodysplastic syndrome; OS, overall survival

Full text

Gabriela Petrof
1
, Su M. Lwin
1
,
Magdalena Martinez-Queipo
1
,
Alya Abdul-Wahab
1
, Simon Tso
1
,
Jemima E. Mellerio
1,2
,
Ineke Slaper-Cortenbach
3
,
Jaap J. Boelens
4
, Jakub Tolar
5,6
,
Paul Veys
7
, Mercy Ofuya
8
,
Janet L. Peacock
8
, Anna E. Martinez
2
and John A. McGrath
1
1
St John’s Institute of Dermatology, King’s
College London (Guy’s Campus), London, UK;
2
Department of Dermatology, Great Ormond
Street Hospital for Children NHS Foundation
Trust, London, UK;
3
Cell Therapy Facility,
Department of Clinical Pharmacology,
University Medical Centre Utrecht, Utrecht,
The Netherlands;
4
Department of Pediatrics,
Blood and Marrow Transplantation Program,
Wilhelmina Children's Hospital, University
Medical Centre Utrecht, Utrecht, The
Netherlands;
5
Department of Pediatrics, Blood
and Marrow Transplant, Medical School,
University of Minnesota, Minneapolis,
Minnesota, USA;
6
Stem Cell Institute,
University of Minnesota, Minneapolis,
Minnesota, USA;
7
Blood and Marrow
Transplantation Department, Great Ormond
Street Hospital, London, UK and
8
Division of
Health and Social Care Research, King’s
College London, London, UK
E-mail: john.mcgrath@kcl.ac.uk
SUPPLEMENTARY MATERIAL
Supplementary material is linked to the online
version of the paper at http://www.nature.com/jid
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Myelodysplasia Cutis Versus Leukemia Cutis
Journal of Investigative Dermatology (2015) 135, 2321–2324; doi:10.1038/jid.2015.146; published online 14 May 2015
TO THE EDITOR
Skin lesions in myelodysplastic syn-
drome (MDS) include neutrophilic
dermatoses (Vignon-Pennamen et al.,
2006), leucocytoclastic vasculitis,
infections, drug reactions, and leukemia
cutis (Avivi et al., 1999). In MDS patients,
leukemia cutis, a blastic myeloid cell
infiltration of the skin (Cho-Vega et al.,
2008), has a poor prognosis (Aractingi
et al.,1995;Kadduet al.,1999),witha
rapid development of acute myeloid
leukemia (AML) and death (Longacre
et al., 1993). The prognostic value of
skin lesions infiltrated only by non-
blastic MDS tumor cells has not yet
been characterized.
We studied 24 MDS patients with
non-blastic skin infiltrate and compared
them with 20 leukemia cutis patients.
This study adheres to the declaration of
Helsinki principles, and patient consent
for experimentals was not required
because the French laws consider human
tissue left over from surgery as discarded
material. Detailed patient data are given
in Supplementary Table S1 online.
Between 1995 and 2012, 800
patients were diagnosed with MDS in
Hôpital-Saint-Louis, Paris. One hundred
and fifty patients underwent skin biopsy,
and we identified 24 skin involvements
by non-blastic tumor cells, defined as
medium-sized immature myeloid cells
(Figure 1) with (i) abundant eosinophilic
cytoplasm and (ii) twisted nuclei or
pseudo-Pelger-Huet anomaly, a speci-
fic myelodysplasia marker on blood
smears (Shetty et al., 2001). The tumor
cells had a combined myeloid and
monocytic phenotype, expressing
both myeloperoxydase (100% of
cases) and CD163 (100%) or CD68
(96%). They did not express CD34,
CD117, or CD56. The proliferative
index with Mib-1 was low (o10%
positive cells) in 56% of cases, or
intermediate (10 to 66% positive
cells) in 44% of cases, but never high
(≥66% positive cells). Mature neutro-
phils and normal CD3+lymphocytes
were numerous (46% and 100% of
cases, respectively) and edema was
frequent (67%).
Accepted article preview online 10 April 2015; published online 14 May 2015
Abbreviations: AML, acute myeloid leukemia; FISH, fluorescent in situ hybridization; IPSS, International
Prognostic Scoring System; MDS, myelodysplastic syndrome; OS, overall survival
A Osio et al.
Myelodysplasia Cutis Versus Leukaemia Cutis
www.jidonline.org 2321

Nineteen of the 24 MDS cases were
tested for bone marrow cytogenetics.
Abnormalities were found in 6 of them
(32%). To determine whether the
same genetic abnormalities were also
found in the skin tumor cells, fluores-
cent in situ hybridization (FISH) ana-
lyses were performed on 4 μm-thick
paraffin-embedded skin sections using
relevant probes and the Histology-FISH-
Accessory-Kit (Dako, Denmark). Scoring
of the hybridization signals, performed on
200 consecutive morphologically intact
nuclei with a 10% normal cutoff value
(Haralambieva et al, 2002), showed
common cytogenetic abnormalities in
thebonemarrowandthenon-
blastic myeloid cells in 4/6 patients
(Supplementary Figure S2 online). This
demonstrated that the immature tumor
cells in the skin were clonally related to
the myeloid malignancy. A clonal
relationship of this sort has so far
only been demonstrated in neutrophilic
dermatoses associated with AML (Sujobert
et al., 2013).
In all the 24 patients, the median
overall survival (OS) from skin diagnosis
was 62 months, longer compared with
the 52 months expected OS calculated
with the International Prognostic Scoring
System (IPSS; Greenberg et al., 1997).
Twenty percent of the patients (5/24)
developed AML below the 30%
reported risk of MDS progression to
AML (Mufti et al., 2008).
In 16 cases, the patients received
hydroxychloroquine, dapsone, colchi-
cine, or thalidomide, with no signi-
ficant benefit. High-dose oral predni-
sone provided complete response in
18 patients, most often with steroid
dependence.
We thus characterized a skin condi-
tion in the course of MDS with non-
blastic tumor cell skin infiltrate and a
lower risk of progression to AML than
for leukemia cutis.
We further compared these 24
patients with “myelodysplasia cutis”
with 20 true leukemia cutis, in the
course of AML (7 with previous MDS).
Histologically, leukemia cutis was
defined by a skin infiltration by blast
cells with (i) medium to large mono-
morphous cytoplasm, (ii) large round
nuclei, and (iii) expression of the
myeloid or monocytic markers, myelo-
peroxydase (80% of cases), CD163
(85%), and CD68 (95%).
Discriminant features, using Fisher’s
t-test (Figure 2) were, for histopathology,
the positivity of CD34, CD56, or
CD117 for leukemia cutis (Po0.05)
and the presence of CD3+lymphocytes
(Po0.001), edema (Po0.01), and a lower
Mib-1 proliferative index (Po0.05) for
myelodysplasia cutis.
Clinical discriminant features were
the presence of nodules for leukemia
cutis (Po0.01) and the presence of
erythematous plaques (Po0.001),
annular pattern (Po0.05), fever, or
arthralgia (Po0.01) for myelodysplasia
cutis.
Regarding evolution, persistent nodules
were the hallmark of leukemia cutis,
whereas flares and relapses character-
ized evolution in myelodysplasia cutis.
In most myelodysplasia cutis patients
(14/24), skin lesions occurred before the
bone marrow MDS diagnosis, with
a mean time-lapse of 41 months (range
2–108). In the other 10/24 patients, skin
lesions occurred during MDS evolution
with a shorter time-lapse of 15 months
Myelodysplasia cutis Leukemia cutis
CD68 CD34
CD56MPO
CD68 CD34
CD56MPO
Figure 1. Myelodysplastic syndrome patients with non-blastic tumor cell infiltrate (“myelodysplasia cutis”)
and leukemia cutis patients had different clinical, histological, and immuno-phenotypical features.
In myelodysplasia cutis patients (a) erythematous plaques, frequently annular, were predominant,
corresponding to (b) a skin infiltrate composed of myeloid cells with the pseudo-Pelger-Huet anomaly
(nucleus with “pince-nez”appearance at high magnification, arrows), mixed with lymphocytes. (c) The
myeloid cells expressed myelomonocytic markers CD68 and myeloperoxydase but not blastic markers
CD34 and CD56. In contrast, in leukemia cutis patients, (a) nodules were predominant, corresponding
to (b) a skin infiltrate composed of monomorphous blastic cells (with large round nuclei at high
magnification). (c) These cells expressed both myelomonocytic markers CD68 and myeloperoxydase and
blastic markers CD34 and CD56. Scale bars =b100 μm, high magnifications 25 μm; c50 μm.
A Osio et al.
Myelodysplasia Cutis Versus Leukaemia Cutis
2322 Journal of Investigative Dermatology (2015), Volume 135

(range 6-19). Skin lesions in all 20
leukemia cutis patients occurred after
the bone marrow diagnosis of the
hemopathy.
Regarding survival, OS from the skin
diagnosis was considerably longer in
myelodysplasia cutis patients than in
leukemia cutis patients (62 vs. 5 months,
Po0.001). In the seven leukemia cutis
patients with previous MDS, the skin
lesions occurred when MDS evolved to
AML, with a 2-month OS after the
occurrence of the skin lesions, similar
to the time-lapse reported by Longacre
et al., (1993).
Using the Cox multivariate hazard
model, the blastic versus non-blastic
nature of the skin infiltrate in MDS
patients was associated with survival,
independently from IPSS. In Cox
univariate analysis, the blastic versus
non-blastic nature of the skin infiltrate
was significantly associated with survival
(Po0.005), whereas IPSS was not
(P=0.17).
Altogether, we identified clinical and
pathological features discriminating
myelodysplasia cutis from leukemia
cutis, with a significantly longer survival
for myelodysplasia cutis.
Retrospective analysis of the relevant
literature enabled us to find reports
of “histiocytoid Sweet’s syndrome”
(Requena et al., 2005) that could
match myelodysplasia cutis when they
were associated with MDS (Chavan
et al., 2014): patients had plaques with
fever and arthralgia and a myeloid
histiocytoid non-blastic skin infiltrate
with edema, mixed neutrophils, and
CD3+lymphocytes––i.e., five of the
eight discriminant features we identified
(the three others being not specified).
In addition, in two MDS cases
without AML, the same cytogenetic
abnormality was found in the skin and
the bone marrow, as in four of our
myelodysplasia cutis. Therefore, we
think that cases reported as “histiocy-
toid Sweet’s syndrome”in the course of
MDS may be better classified as
myelodysplasia cutis.
One of the original results of our
study is to highlight the fact that skin
lesions in myelodysplasia cutis can pre-
cede by months or years MDS diagnosis
in the bone marrow. This underlines the
value of a long follow-up, particularly in
elderly patients with a normal initial bone
marrow examination. More studies will
be necessary to identify peculiar mar-
kers involved in non-blastic MDS cells
skin homing, as it has been described
for blast cells (Blakst et al., 2011).
The discriminant features we identi-
fied between myelodysplasia cutis
and leukemia cutis have translational
value, given the far better prognosis of
myelodysplasia cutis.
CONFLICT OF INTEREST
The authors state no conflict of interest.
ACKNOWLEDGMENTS
We thank Dr C. Juillard, Dr F. Cordoliani, and
Dr M. Rybojad who provided patient data and Angela
Swaine Verdier who edited the English language.
A. Osio
1,2,3
, M. Battistella
1,2,3
,
J-P Feugeas
1,4
,W.Cuccuini
5
,
M-E Noguera
1,5
,T.Petrella
6
,E.Raffoux
7
,
A. Janin
1,2,3
and Vignon Pennamen
1,2,3
1
Université Paris Diderot, Sorbonne Paris Cité,
UMR-S 1165, Paris, France;
2
INSERM, U1165-
Paris, Paris, France;
3
Laboratoire de pathologie,
Hôpital Saint-Louis, AP-HP, Paris, France;
4
INSERM, U1137-Paris, Paris, France;
5
Laboratoire d’hématologie, Hôpital Saint-
Louis, AP-HP, Paris, France;
6
Laboratoire de
pathologie, Plateau technique de biologie,
CHU Dijon, Dijon, France and
7
Service
24 patients with
myelodysplasia cutis
24 Myelodysplasia cutis patients
20 patients with
leukemia cutis
20 Leukemia cutis patients
P-value
Clinical criteria
Plaques 96
71
12.5
42
100
67
0
037
40
10
35
0
70
10
10 <0.001
<0.01
<0.01
<0.05
<0.001
<0.01
<0.05
<0.05
P<0.001
1.0
0.8
0.6
0.4
0.2
0.0
0 50 100 150 200
Month
Estimated probability of overall survival
Fever and/or arthralgia
Nodules
1
2
3
4
5
6
7
8
Annular pattern
CD3+ T cells
Edema
CD34 or CD117 or CD56 cells
Mib-1 >66%
Histopathological criteria
(%)(%)
Figure 2. Statistical analyses comparing 24 myelodysplasia cutis patients and 20 leukemia cutis patients.
(a) Using Fisher’st-test with R-software (R 3.1.2 The R Foundation for Statistical Computing R, Vienna,
Austria) and after correction for multiple comparison, eight clinical and histopathological discriminant
features were identified. We performed a quantitative study of cells labeled with CD163, CD68,
myeloperoxydase, CD117, CD56, CD34, and CD3 in the skin sections. We analyzed a minimum of three
different fields at an original magnification 250 ×and counted the percentage of stained cells in one
hundred tumor cells for CD163, CD68, myeloperoxydase, CD117, CD56, CD34, and lymphocytes for
CD3. The cutoff value was 80% positive cells for CD163, CD68, and myeloperoxydase, 50% for CD117,
CD56, and CD34, and 20% for CD3. (b) Plotting Kaplan–Meier curves for the overall survival (OS) in
myelodysplasia cutis patients versus leukemia cutis patients, and comparing them with the log-rank test,
showed that myelodysplasia cutis patients had a significantly longer OS compared with patients with
leukemia cutis (62 vs. 5 months, Po0.001).
A Osio et al.
Myelodysplasia Cutis Versus Leukaemia Cutis
www.jidonline.org 2323

d’hématologie, Hôpital Saint-Louis, AP-HP,
Paris France
E-mail: amelie.osio@sls.aphp.fr or
anne.janin1165@gmail.com
SUPPLEMENTARY MATERIAL
Supplementary material is linked to the online
version of the paper at http://www.nature.com/jid
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Der p1 and Der p2-Specific T Cells Display a Th2, Th17,
and Th2/Th17 Phenotype in Atopic Dermatitis
Journal of Investigative Dermatology (2015) 135, 2324–2327; doi:10.1038/jid.2015.162; published online 28 May 2015
TO THE EDITOR
Atopic dermatitis (AD) represents an
inflammatory, relapsing, non-conta-
gious, and itchy skin disorder affecting
up to 30% of children and 2–10%
of adults in industrialized countries
(Bieber, 2008). It is well established
that allergen-specific T cells display a
Th2 polarization in allergic donors
(Bateman et al., 2006; Macaubas
et al., 2006; Wambre et al., 2008)
with a tendency to develop into Th1
in chronic AD (Thepen et al., 1996;
Werfel et al., 1996). The high
proportion of Th2-polarized T cells
seems to be the key factor in allergic
inflammation (Werfel, 2009), and
allergen-specific Th2 cells are reduced
after successful specific immunotherapy
(Wambre et al., 2012; Wambre et al.,
2014). However, the classical paradigm
of a Th2-polarized allergen-specificT
cell has been questioned, as Th17 and
Th22 polarizations have been described
in allergic diseases (Aggarwal et al.,
2003; Langrish et al., 2005; Eyerich
et al., 2009). Especially, the responses
to house dust mite (HDM) allergens differ
between atopic diseases. Although in
allergic asthma this seems to be
influenced by lipopolysaccharide (LPS)-
toll-like receptor4 (TLR4) signaling, in
allergic rhinitis TLR2 responses may
rather have a role (Ryu et al., 2013).
High-titered HDM-specific IgE can
be detected particularly often in older
children, adolescents, and adults
with AD. This study aimed to charac-
terize Dermatophagoides pteronyssinus
(Der p)-1–and Der p2–specific T-helper
cells in patients suffering from AD.
Thirty adult consecutive patients with
AD fulfilling the criteria of Hanifin
and Rajka (Hanifin and Rajka, 1980)
from our Department who were IgE
sensitized to HDM were included in
this study. These showed various IgE
sensitizations and a mild-to-severe dis-
ease activity (scoring atopic dermatitis
(SCORAD) 2.5–70.5; mean 33.4, see
Supplementary Table S1). Median CAP
class of our patient cohort was class 5
(D. pteronyssinus) and class 4 (Der p1
and Der p2), respectively. One further
AD patient was included who suffered
Accepted article preview online 28 April 2015; published online 28 May 2015
Abbreviations: AD, atopic dermatitis; Der p, Dermatophagoides pteronyssinus; HDM, house dust mite;
LPS, lipopolysaccharide; MHC, major histocompatibility complex; PBMC, peripheral blood
mononuclear cell; SCORAD, scoring atopic dermatitis; TLR, toll-like receptor
LM Roesner et al.
HDM-Specific T Cells in AD
2324 Journal of Investigative Dermatology (2015), Volume 135