Open Journal of Blood Diseases, 2012, 2, 95-99 Published Online December 2012 (
CD4+/CD56+ Hematodermic Neoplasm Presenting in
the Skin: A Tunisian Case Report and Current
Review of the Literature
Yosra Ben Youssef1, Nessrine Ben Sayed1, Kmira Zahra1, Abir Gmidène2, Naouel Ben Salah3,
Atef Ben Abdelkader4, Nejia Brahem5, Hlima Sennana2, Colanda Belajouza6, Abderrahim Khelif1
1Department of Clinical Hematology, Farhat Hached University Hospital, Sousse, Tunisia; 2Department of Cytogenetics, Farhat
Hached University Hospital, Sousse, Tunisia; 3Department of Cytology, Aziza Othmana University Hospital, Tunis, Tunisia; 4De-
partment of Anatomopathology, Farhat Hached University Hospital, Sousse, Tunisia; 5Department of Cytology, Farhat Hached Uni-
versity Hospital, Sousse, Tunisia; 6Department of Dermatology, Farhat Hached University Hospital, Sousse, Tunisia.
Received October 10th, 2012; revised November 15th, 2012; accepted November 25th, 2012
The CD4+/CD56+ hematodermic neoplasm is a rare aggressive systemic neoplasm for which effective therapies have
not yet been established, it is clinically characterized by cutaneous involvement with spread to bone marrow, blood and
poor prognosis with current chemotherapy regimens. Our objective is to report diagnosis and treatment difficulties of
CD4+/CD56+ hematodermic neoplasm. We describe here a Tunisian man who presented with subcutaneous ulcerated
lesion localized in the right leg and multiples generalized nodules. Skin biopsy showed an atypical lymphoid cell infil-
tration with an angiocentric pattern and extensive necrosis by immuno-histochemical analysis, these cells were positive
for CD4, CD56, granzyme B and negative for CD8, CD123, CD20 and CD30. T-cell rearrangement and Ep-
stein-Barr-virus (EBV) in situ hybridation studies were negative. The patient underwent 5 cycles chemotherapy SMILE
regimen monthly sandwiched with radiotherapy on the residual lesions of the right leg with great tolerance but he re-
lapsed within 8months with skin, blood, bone marrow, lung, and cerebrospinal involvement. Based on these findings,
the patient was diagnosed with CD4+/CD56+ hematodermic neoplasm (blastic NK-like T-cell lymphoma) treated with
one course of hyper-CVAD regimen, he died within 20 days with a septic chok. Despite the use of L-Asparaginase and
radiotherapy the prognosis is very poor; we suggest the exploration for highly active drugs, hematopoietic stem cell
transplantation (HSCT) is crucial to improve survival.
Keywords: Blastic NK-Like T-cell Lymphoma; Hyper-CVAD; SMILE; Prognosis; Treatment
1. Introduction
Since the early 1990s, several cases of CD4+ CD56+
hematodermic neoplasm’s (HN) (WHO-EORTC) have
been reported. Based on the lymphoid morphology of
tumor cells, expression of CD56 (also known as neural
cell adhesion molecule NCAM) and the absence of the
T-cell receptor or surface CD3, a natural killer (NK) ori-
gin has been suggested, despite the negativity of most
NK-associated markers and the absence of azurophilic
granulations. These tumors fell under the designation of
blastic NK-like T-cell lymphoma (WHO) without an
evidence of a NK-cell origin [1]. From 1993 to 2011, 64
cases of cutaneous lymphoma were diagnosed in our
hospital, with only one case of blastic NK-like T-cell
lymphoma of the skin in 2011. Due to the rarity of this
entity, we report a case of a 49-year old man with blastic
NK-like cell lymphoma with skin, bone marrow, blood,
cerebrospinal fluid involvement and reviewed clinical
manifestations, treatment and prognosis of this condition.
2. Case Report
A 49-year-old Tunisian man developed slowly growing
subcutaneous 15 cm nodules secondly ulcerated localized
in the right leg. Subsequently similar nodules appeared
on the trunk, back, the other leg and upper extremities.
At the time of evaluation, about 10 red nodules from in-
dex finger seized to thumb seized and homolateral in-
guinal lymphadenopathy were noted (Figures 1(A)-(C)).
Skin biopsy showed atypical lymphoid cell infiltration
with an angiocentric pattern and extencive necrosis. These
cells were positive for CD4, CD56, CD123 granzyme B,
and negative for CD8, terminal deoxynucleotidyl trans-
Copyright © 2012 SciRes. OJBD
CD4+/CD56+ Hematodermic Neoplasm Presenting in the Skin: A Tunisian Case
Report and Current Review of the Literature
Figure 1. Skin lesions before treatment. (A) Ulcerated nod-
ules with a fibrinous base of the right leg before chemo-
therapy; (B) Violaceous skin nodules on the back before
chemotherapy; (C) Skin nodules on the trunk before che-
ferase (TdT), CD20 and CD30. T-cell rearrangement and
Epstein-Barr-virus (EBV) in situ hybridation studies
were negative (Figure 2).
Thus the diagnosis of CD4+ CD56+ hematodermic
neoplasm was established. Laboratory evaluation reveal-
ed normal level of lactate deshydrogenase (LDH = 332
UI/L); serum titers for EBV antibodies were negative for
IgM and positive for IgG; completed tomographic (CT)
scan showed an infracentimetric mediastinal lymphade-
nopathy. Bone narrow biopsies as well as complete ORL
examination were normal. His clinical stage was deter-
mined as T3bN1M0 according to the TNM classification.
The decision was to treat the patient with 6 courses of
SMILE therapy sandwiched with radiotherapy. The pa-
tient underwent 3 cycles chemotherapy SMILE regimen
monthly based on: Dexamethasone (40 mg, day 2 - 4),
Etoposide (100 mg/m2, day 2 - 4), Methotrexate (2 g/m2
day 1), Ifosfamide (1.5 g/m2, day 2 - 4), L-asparginase
(6000 UI/ m2, day 8, 10, 12, 14, 16, 18 and 20) with ra-
diotherapy on residual lesion after 2 cycles. At the end of
the first 3 cycles of chemotherapy only 2 smalls violet
papules measuring 6 cm and 3 cm respectively in the
right leg remained (Figure 3).
Four weeks later he received external radiotherapy at
the dose of 45 Gy through direct field on the residual
lesions with great tolerance, than he received the other
cycles of SMILE chemotherapy. Physical examination
revealed no evidence of disease with a follow up of 8
months. While the patient received the fifth cycle of
SMILE therapy he presented with erythematous nodules
on the trunk and chronic cough, a second skin biopsy
demonstrated relapsed dermal lymphoid infiltration. Whole
body computed tomography (CT) scan found 2 lung
nodules on the median right lobe and 3 left posterior lung
Figure 2. Morphologic and immunohistochemical analysis
of the blastic-NK cell lymphoma of the skin. (A) Dense
lymphoid infiltrate diffusely involving dermis (Hematoxy-
lin-eosin stain; original 50× magnification); (B) Lymphoid
cells staining strongly positive with CD56 marker (original
400× magnification; (C) Lymphoid cells staining strongly
positive with CD4 marker (original stain 400× magnifica-
tion); (D) Lymphoid cells staining strongly positive with
granzyme marker (original stain 400× magnification).
Figure 3. Skin lesions after treatment. (A) Skin lesions of
the back after 3 cycles of chemotherapy; (B) Skin lesions of
the right leg after chemoradiotherapy.
nodules, bone marrow biopsy was normal. Laboratory
investigations, including complete blood count, liver
enzymes, serum LDH were within normal limits. Two
weeks after achieving the fifth course of chemotherapy,
the patient developed weakness, fatigue, fever and dyspnea.
Laboratory data was notable for leukocytosis (WBC
count 41.9 × 109/L, with 33% transformed, apparently
lymphoid cells medium sized, basophilic cytoplasm ir-
regular nuclei) (Figure 4(A)), anemia (hemoglobin 8.8
g/dl), thrombocytopenia (platelet count 93 × 109/L), an
increase serum LDH level of 1667 UI/L. Circulating ma-
lignant cells in the peripheral blood displayed the follow-
ing phenotype by flow cytometry: CD45+, CD38+,
CD56+, CD7+, surface CD3, cytoplasmic CD3+, CD4,
CD8, CD57, CD16, cMPO, CD13, CD33 TCR
gama/delta. Bone marrow aspiration showed infiltration
Copyright © 2012 SciRes. OJBD
CD4+/CD56+ Hematodermic Neoplasm Presenting in the Skin: A Tunisian Case
Report and Current Review of the Literature
with 10% centroblastoid cells with irregular nuclei and
inconspicuous nucleoli (Figure 4(B)). Bone marrow bi-
opsy showed massive infiltration with medium-sized
blasts (Figure 4(C)).
Examination of cerebrospinal fluid showed infiltration
with lymphoid blastic cells. Cytogenetic analysis re-
vealed complex karyotype with 46, XY, del (11)(p14),
del (12)(p13) [4]/45, XY, add (1)(p36), del (12)(p13),
22 [3]/45, XY, add (2)(p24), del (12)(p13), 15 [2]/46,
XY [11]. Based on these findings, the patient received
the first course of hyper-CVAD regimen (fractionated
cyclopho-sphamide, vincristine, doxorubicin, and dexa-
methasone), with central nervous system prophylaxis
using intrathecal methotrexate/cytarabine, he died within
20 days with a septic chok.
3. Discussion
Natural killer (NK) and NK-like T-cell lymphoma are
aggressive hematologic malignancies that have an ex-
tranodal presentation. The main affected organ sites in-
clude the gastrointestinal tract, skin and nasal cavities.
These neoplasms are categorized into nasal versus non
nasal type; they can present initially in the skin and/or
involve the skin as a part of a multiorgan disseminated
lymphoma. In both NK and NK-like T-cell lymphomas,
the neoplastic cells express CD2 and CD56. The distinc-
tion of NK versus NK-like T-cell lymphoma is based on
the T-cell receptor (TCR) β and/or γ gene rearrangement
and surface CD3 expression; those that lack these fea-
tures are categorized by NK lymphomas, those that
manifest surface CD3 and exhibit a TCR rearrangement
are considered NK-like T-cell lymphomas. The expre-
ssion of CD4 is designed as blastic NK-like T-cell lym-
phoma. More recently, it has been established that the
Figure 4. Morphologic analysis of the blastic NK-cell lym-
phoma in the blood and bone marrow; (A) Lymphoid me-
dium-sized cells, basophilic cytoplasm, irregular nuclei
(Blood) (May-Grunwald-Giemsa staining); (B) Bone mar-
row aspiration: centroblastoid cells with irregulae nuclei,
in-conspicuous nucleoi (May-Grunwald-Giemsa staining);
(C) Medium-sized blasts infiltrating the bone marrow bi-
opsy (hematoxylin eosin, ×100).
cell of origin is a plasmacytoid/dendritic cells, cones-
quently the term “blastic NK-like T-cell lymphomas has
been supplanted by the term “CD4+ CD56+ hematoder-
mic neoplasm” in the WHO/EORTC classification but is
now termed blastic plasmacytoid dendritic cell neo-
plasm(BPDCN) [2,3]. Blastic NK-like T-cell lymphoma
can arise at any age including childhood, but it tends to
present in middle aged or elderly patients with a median
age of 52 years [3-5]. It affects predominantly man than
woman with a sex ratio 3:1 [5], there is no racial predi-
lection [6]. Similar to acute leukemia, blastic NK-cell
leukemia/lymphoma has a multiorgan involvement, lym-
phadenopathy, splenomegaly with a rapid blood and
bone marrow involvement [7]. Cutaneous lesions may be
solitary or multiple nodules or tumors, or have petechial
appearance witch tend to be generalized [3,7-9]. Skin
biopsy reveals a dense dermal infiltration by medium
malignant cells without epidermal involvement with fo-
cal angiocentric accentuation and necrosis [2,4,7]. Im-
munophenotypically, blastic NK-cell lymphoma is typi-
cally CD45+, CD2+, surface CD3, cytoplasmic CD3+,
CD4+, CD56+, CD5, CD7+/, TdT+/TCR genes are
in germline configuration [2,7]. The absence of positivity
for myeloperoxidase, CD13 and CD33 in bone marrow
cells excluded the diagnosis of CD56+ myeloid leukemia
[4,10]. In contrast with aggressive NK-cell leukemia and
extranodal NK/T-cell lymphomas, EBV DNA in tumor
cells is negative, so the possibility of extranodal NK/
T-cell lymphoma nasal type is excluded and the positiv-
ity of EBV might serve as a key point for differential
diagnosis from mature NK cell malignancies [8,9]. Cy-
togenetic analysis reveals a complex karyotype, such as
deletion of chromosomes 9, 13, 15, deletion of the 5q,
12p and 6q abnormalities, but no recurring abnormalities
were identified [7]. Deletion of 12p and add 1 were
found in our patient. Suzuki et al. reported 4 cases of
blastic NK cell lymphoma, only one patient had cytoge-
netic abnormalities [10]. Differential diagnosis includes
other CD56+ lymphomas with cutaneous involvement.
These include extranodal NK/T-cell lymphoma (ENKTL)
nasal type, CD56+ myeloid leukemia, cutaneous CD30+
lymphoproliferation with CD56 expression and cutane-
ous granulocytic sarcoma [2,8]. The prognosis of patients
with blastic NK-like T-cell lymphoma is poor with a me-
dian survival of 14 months, 2 and 5 years overall survival
of 33% and 6% respectively [7,8]. There is no standard
treatment for this malignancy, response to combination
chemotherapy such as CHOP, is minimal or transient and
early progression is common. Radiotherapy is effective
for localized disease only [8]. More aggressive therapies
directed to allogenic stem cell transplantation are proba-
bly superior with long term remission [8]. Several studies
showed efficacy of regimens containing L-Asparaginase.
Copyright © 2012 SciRes. OJBD
CD4+/CD56+ Hematodermic Neoplasm Presenting in the Skin: A Tunisian Case
Report and Current Review of the Literature
The rationale is based on reports that L-Asparaginase is
effective in the treatment of NK/T-cell lymphoma [8,11].
L-Asparaginase induced selective apoptosis of NK-lym-
phoma cells in vitro, these results in fast inhibition of
DNA and RNA synthesize in lymphocytes [5]. Etoposide
has demonstrated in vitro and in vivo efficacy. Increased
expression of a multidrug resistant (MDR) phenotype has
been correlated with aggressive behavior in these lym-
phomas [3,5,6,10]. MDR phenotype and P53 mutation
also can be associated with a poor prognosis and may
help predict response to the treatment. [3,5,6,10]. The
components of SMILE protocol are MDR unrelated
agents and EBV associated lymphoproliferative disorders.
Motoko et al. reported an overall response rate at 67%
for six Japanese patients with advanced-stage, relapsed
or refractory ENKT-CL and leukemia treated with six
courses of chemotherapy SMILE regimen with sand-
wiched radiotherapy after three courses [12]. Hyper-
CVAD regimen is used mainly for therapy of acute lym-
phocyte leukemia and high-grade lymphomas. Shapiro et
al. reported successfully achieved complete remissions in
two patients using the hyper-CVAD regimen [7]. Among
five patients with CD4+/CD56+ HN, one patient treated
with the hyper-CVAD regimen achieved a complete re-
sponse and remain alive with a follow-up of over than 38
months [13]. Allogenic HSCT, with the potential benefit
of graft-versus lymphoma effect is a second option for
patients with advanced disease, long remission of blastic
NK-cell lymphoma was reported after autologous pe-
ripheral blood stem cell transplantation. Therefore al-
logenic or autologous, or cord blood stem cell transplant-
tation is a promising treatment strategy, but small series
have shown that it is a potentially curative option [7,8,
14,15]. Age 40 years, presentation with only skin le-
sions, initial treatment with transplantation directed
regimens and TdT expression by >50% of the neoplastic
cells were associated with better prognosis [2].
4. Conclusion
CD56+ CD4+ HN’s are an extremely difficult group, for
pathologists and clinicians. For pathologists, correct clas-
sification of these lymphomas is difficult, expensive and
time-consuming, it requires application of several com-
plimentary techniques such as extensive phenotyping,
EBV analysis and T-cell receptor TCR gene rearrange-
ment studies. Clinicians are confronted with an aggres-
sive clinical behavior and a fatal outcome often within 1
year after diagnosis, and may consider more intensive
therapies, as in acute leukemias, as initial therapy. Pro-
spective data on larger series of patients treated homo-
geneously also with innovative approaches are needed in
order to establish the best treatment for this disease.
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Report and Current Review of the Literature
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