ARTICLE
CD4+, CD56+ cutaneous neoplasm is a rare hematological entity recently
individualized [1]. It is characterized by a strong skin tropism, a frequent
bone-marrow infiltration and also an aggressive course. The tumor cells
coexpress CD4 and CD56, CD45 and HLADR and do not express lymphoid
and myeloid lineage markers. We report 3 new cases of CD4+, CD56+
malignancies. The analysis of these cases identifies the key features
that clearly individualize this disease from myeloid/lymphoid proliferations
and the origin of the disease is discussed.
Case reports
Case 1
At the end of December 2000, a 54-year-old woman referred for three infiltrated
purple plaques of the left breast which started two months before. There
were numerous neoplasms in her family: her father presented with a chronic
myelomonocytoid leukemia, her sister a breast adenocarcinoma, her cousin
a prostate adenocarcinoma and her niece a Hodgkin disease. The hemogram
was normal. Staging including bone-marrow biopsy, and total-body computed
tomographic (CT) scan did not show extra-cutaneous lesions. In March 2001,
the patient was treated as if for a lymphoblastic leukemia with LALA-94 protocole.
Induction polychemotherapy consisted of cyclophosphamide, daunorubicin,
vincristine, prednisolone; consolidation treatment consisted of mitoxantrone
and cytosine arabinoside associated with 5 preventive intrathecal
injections with methotrexate, cytarabine, depomedrol and whole brain radiation
(18 grays). In September 2001, complete remission was achieved. In
December 2001, a purple nodule of the left leg and ecchymotic macules
of the right ankle recurred without lymph node enlargement. The bone marrow
was not involved. The histologic features confirmed the recurrence. She
was treated with interferon alpha2a (3 millions UI 3 times a
week) associated with local radiotherapy (33 grays) on the nodule
and topical caryolysine 3 times a week on the ecchymotic macules.
Case 2
In May 2001, an 81-year-old man presented with a 7-month history of multiple
nodules and infiltrated plaques of the trunk, arms and right calf without
lymphadenopathy and hepatosplenomegaly (Fig.
1). Hemogram showed thrombopenia: platelet count was 119 <=> 109
L - 1. Bone-marrow aspiration showed 55% blastic
cells. Total-body CT scan was normal. In August 2001, chemotherapy was
initiated with cyclophosphamide, daunorubicin, vincristine, prednisolone
in conjunction with intrathecal methotrexate injections. Complete remission
was achieved. Three months after the diagnosis the patient died of an
ischaemic stroke.
Case 3
A 60-year-old man presented a subcutaneous nodule of the forehead since
October 2000. He had a history of an adenocarcinoma of the colon operated
in 1998. He referred for an adenopathy of the left parotid gland. Physical
examination showed bilateral lymphadenopathy in the cervical region and
an 8 cm tumor of the forehead associated with multiple purple and
ecchymotic macules of the skull. Bone marrow aspiration showed 95% blastic
cells. Total-body CT scan was normal. In July 2001, the patient was treated
with a COP chemotherapy with cyclophosphamide, vincristine, prednisolone.
Then he was treated with the same protocole as patient 2 followed
by a consolidation treatment with cytosine arabinoside, mitoxantrone and
five intrathecal methotrexate injections. In September 2001, complete
remission was achieved. In November 2001, numerous purple papules appeared
on the trunk associated with a voluminous tumor of the forehead. Bone
marrow smears confirmed the relapse with 29% of tumor cells. Abdominal
echography, brain CT scan and lumbar punction were normal. The patient
underwent another COP regimen. The skin lesions improved but bone marrow
aspiration showed 94% blast cells. In January 2002, the patient died of
cerebral haemorrhage ten months after the diagnosis.
Laboratory investigations
Skin and node histological findings
Tissue specimen and lymph nodes were fixed in 10% neutral buffered formalin,
paraffin embedded and stained with routine H&E. In cases 1 and
2, skin biopsies showed a dense mononuclear infiltrate throughout the
dermis. The papillary dermis was spared. There was neither epidermotropism
nor angiodestruction. The cells were predominantly medium-sized with a
round nucleus and an important amount of cytoplasm. Tissue specimen of
case 3 could not be analysed. In case 3, histological studies of
the lymph nodes showed a diffuse infiltration by small tumors cells with
enlarged nuclei and a small amount of cytoplasm. The normal lymph node
architecture was mainly effaced with a few residual follicules.
Skin and node immunohistochemical findings
Cryostat sections were studied on the skin biopsies of patients 1 and
2 and paraffin sections were studied on the lymph node biopsy of
case 3 with monoclonal antibodies. Case 1 was positive for CD4,
CD45, CD56, CD123 and negative for CD3, CD8, CD10, CD20, CD79a, CD15,
myeloperoxidase, lysozyme, CD30, CD68, CD34. In case 2, skin tumor immunohistochemical
findings were similar to bone marrow cells immunophenotypic analysis except
CD7 and CD33 which were negative. In case 3, node immunohistochemical
findings were similar to bone marrow cells immunophenotypic analysis.
Bone marrow cytological findings
Bone marrow smears were stained with May-Grunwald-Giemsa. Cases 2 and
3 respectively had 55% and 95% blast cells with similar cytologic
features. The cells were medium-sized with a medium nucleus-cytoplasm
ratio. The nuclear configuration was irregular with a fine chromatin and
nucleoli. The cytoplasm had faint basophilia and no azurophilic granulation.
Cells exhibit cytoplasmic vacuoles with an arrangement like a pearl necklace
beside the plasma membrane and pseudopodia-shaped cytoplasmic expansions
(Fig. 2). The MPO and
butyrate esterase cytochemical reactions were negative.
Immunophenotypic analysis of bone marrow cells
Flow cytometric analysis of the blastic cells was performed using monoclonal
antibodies. The immunophenotype of the malignant cells of case 2 were
positive for CD2 (95%), CD4 (90%), CD7 (94%), CD56 (93%), CD33 (88%),
HLADR (97%), CD38 (97%), CD45 (98%); in addition, B and T-cell markers,
comprising surface and cytoplasmic CD3, were negative. The common myelomonocytic
markers, MPO were also negative except CD33. The immunophenotype of case
3 were positive for CD4 (99%), CD7 (90%), CD56 (98%), HLADR (99%),
CD38 (99%), CD45 (99%) and a low positivity for CD36 (34%). All the others,
T-cell, B-cell, and myelomonocytic markers were negative.
Gene rearrangement studies
In case 1, analysis of TCR (T-cell receptor) rearrangement on frozen tumor
tissue, showed a T-cell clonal rearrangement. In cases 2 and 3, TCR
rearrangement was performed on bone marrow cells and showed a weak mono-
allelic rearrangement on locus gamma/delta. B cell clonal rearrangement
was negative.
Cytogenetic studies
Cytogenetic analyses were performed in the three patients on bone marrow.
In case 2, the study was performed in the leukemic phase. The analysis
of 20 metaphases revealed 46, XY, add ?(17)(p13) [20]. In case
3, the study was performed in the leukemic phase. The analysis of 19 metaphases
revealed: 46,XY,del(9)(p13) [14]/46,XY,t(3;11)(q12q14), del(9)(p13) [2]/46,XY
[3].
Discussion
We report 3 cases of a hematological malignancy who presented initially
with purple and ecchymotic cutaneous papules and nodules. Clinically,
they are characterized by an extranodal and notable skin involvement,
an aggressive course with bone marrow infiltration. There is a coexpression
CD4, CD56 and an absence of T, B and myeloid markers; CD7 is sometimes
positive and CD2 is rarely positive. Morphologic analysis of the tumor
cells shows cytoplasmic vacuolations with an arrangement of the vacuoles
as in a pearl necklace. Pseudopodia-shaped cytoplasmic expansions are
also present. Our three patients have the clinical, morphologic and immunophenotypic
features of CD4+ CD56+ malignancies.
CD4 antigen is expressed by peripheral T cells, thymocytes and monocytes/macrophages.
CD56 is not specifically expressed by Natural Killer (NK) cells [2].
It is also expressed in acute myeloid leukemia especially in 67% to 83%
of the acute monocytic leukemia [3, 4]. In these leukemias, Seymour et
al. [4] showed that the positivity for both CD4 and CD56 was
found in 40% of patients with leukemia cutis.
Specific skin lesions often arise in patients presenting with acute myeloblastic
leukemia (AML5) [5-7]. The skin and mucosal lesions are usually large
and purplish nodules and gingival hypertrophy. Histologic examination
shows a monomorphous infiltrate of the upper dermis with a perivascular
and periadnexal aggregation of atypical monocytes with a pale cytoplasm
and an irregular nucleus. Immunohistochemical studies are helpful tools
for the diagnosis of acute monocytic leukemia, with the positivity
of the specific markers for myeloid lineage such as MPO or butyrate esterase,
CD13, CD14, CD15, CD33 and also the positivity of the monocyte markers
such as CD14, CD11b. The markers of the myeloid lineage, myeloperoxidase
and butyrate esterase were negative in our three cases except case 2 who
expressed CD33 antigen.
Chloroma or granulocytic sarcoma is an extramedullary solid tumor composed
of immature myeloid cells. When the disease is limited to the skin, the
diagnosis may be difficult. However, histologic examination shows a pleomorphic
infiltrate of myeloblasts, eosinophils and eosinophilic myelocytes [6].
Immunophenotyping and genetic studies are a good help to establish the
diagnosis: lymphoid-cell markers are negative but lysozyme, MPO, and CD68 are
strongly positive and translocation t(8; 21) is often encountered [8-9].
The characteristic immunophenotype of NK cell is CD3- and CD56+. Because
of the similarity with the phenotype of the blast cells, it raised the
question of a NK cell proliferation and a few diagnoses were discussed.
The nonnasal NK/T cell lymphoma arising on the skin is different from
our cases [10, 11]. Histopathologically, it shows angiocentric features
and the tumor cells contain azurophilic granules in their cytoplasm. The
most common immunophenotype is CD2+, CD56+, cytoplasmic CD3+, surface
CD3-, CD5-, CD4-, CD8-, no expression of T-cell, B-cell and myeloid-cell
antigen receptors and lack of T-cell receptor gene rearrangement [10-12].
The aggressive NK cell lymphoma/leukaemia [13, 14] has a rapid progressive
course with multi-organ involvement but leukemia cutis is rare. The tumor
cells contain azurophilic granules express CD2, CD56 and cytoplasmic
CD3 antigens but do not express surface CD3, CD4, CD5, CD7, CD8.
CD4+, CD56+ malignancies have recently been individualized [1, 15, 16].
Based on clinical, cytological and immunophenotypic criterias identical
to our patients, we found 50 similar cases in the literature [1,
16-29]. Although they coexpressed CD4 and CD56, the cases reported by
Savoia et al. [30] and Wasik et al. [31] were different
from our patients, because CD3 marker was positive. The case published
by Bastian et al. [32] is close to our 3 patients because
PCR yielded a gammadelta TCR clonal rearrangement. When studied, TCR rearrangement
showed germline configuration in most cases. Conversely, a weak T-cell
clone was found in our 3 cases. However, we think our cases are CD4+,
CD56+ hematodermic neoplasms because they share the same clinical, cytologic
and immunophenotypic features. Molecular biology is probably not essential
to establish the diagnosis. Indeed, it was not studied in the largest
series of the literature [16] and therefore the frequency of T-cell clone
cannot be precisely evaluated. In our three cases the malignant infiltrate
was composed of non T-cells but the faint band that was detected is probably
due to an amplification of a few reactive T cells. Moreover, the sensitivity
of the molecular biology technique was important comprised between 10 - 3
and 10 - 4. The 50 cases and our three patients
are characterized by a strong skin tropism. Among the 50 published
cases, 46 (94%) of them presented with a cutaneous disease and 21/34 (65%)
cases presented a cutaneous relapse. Bone marrow was involved in 30 (60%)
patients. There was an aggressive course; relapse occurred between 2 and
28 months, and patients' survival time was comprised between 3 and
96 months with an average survival duration of 10 months. Among
the 50 CD4+ CD56+ malignancies, immunophenotypic criteria were homogenous.
However, CD7 was positive in 38% of cases, CD33 in 16% of cases and
the monocytic lineage markers CD36 and CD68 were positive in
62% and 59% of cases. After staging evaluation and during the course of
the disease, there were 3 cases who had a disease limited to the
skin [1, 19, 21]. The outcome of the disease seemed better when the disease
was exclusively located in the skin. An 82-year-old patient [21] died
24 months after initial diagnosis, and the other two patients [1,
19] were still alive 24 and 32 months after the initial diagnosis.
Our patient no 1 is still alive 24 months after initial diagnosis
although she had cutaneous relapse. Thus it seems to be different subtypes
of CD4+, CD56+, an indolent type limited to the skin and a more aggressive
type with medullar infiltration. When the disease is limited to the skin,
the diagnosis is more difficult because histologic features are not specific.
CD123 antigen seems to be regularly expressed by tumor cells [16,
33]. CD123 is a surface marker of plasmacytoid dendritic cells which
can be used on the skin and the blood cells. It is an interesting tool
which should be used on the skin when the infiltrate coexpresses CD4 and
CD56 without other lineage cell markers especially myelomonocytic
lineage markers. Among 30 patients of related lymphoid or myeloid
malignancies, Petrella et al. [33] demonstrated a coexpression
of CD4, CD56 and CD123 in a chronic myelomonocytic leukemia.
It is suggested that CD123 expression is not sufficient to discriminate
CD4+, CD56+ hematodermic neoplasms. Moreover, to differentiate from NK
proliferation, the lack of expression of TIA1 and granzyme B markers but
also the absence of azurophil granulations in electronic microscopy may
be useful.
CD4+, CD56+ malignancies probably arise from the proliferation of plasmacytoid
dendritic cells. Indeed, Chaperot et al. [15] showed that the malignant
cells from CD4+, CD56+ malignancies produce interferon alpha upon virus
stimulation, differentiate into functional dendritic cells and induce
Th2 polarization in response to IL3. Therefore, these malignant cells
have the same functional properties as the normal plasmacytoid dendritic
cells and they share the same phenotype CD123+, CD4+, CD45RA+, HLA DR+
except CD56, inconstantly CD2+, CD5+, CD7+; conventional T, B and myeloid
markers are absent. Plasmacytoid dendritic cells or dendritic cells type
2 (DC2/pDCs) belong to the heterogenous family of dendritic cells. Normal
DC2/pDCs are expected in the blood, the bone marrow and tonsil but not
in the skin. The origin of DC2 remains unknown. In favour of a lymphoid
origin is that Chaperot et al. [15] found in leukemic cells genes
associated with early T or B precursors such as pre-Talpha, component
of the pre-TCR and lambda pre-B. Interestingly, Petrella et al.
[33] have shown that a rare population of cells called NCAM-expressing
plasmacytoid monocyte like cells exists in peripheral blood of healthy
people after treatment with Flt3 ligand. They all share the same markers
of CD4+ CD56+ malignancies. The authors suggested that these neoplasms
are the result of oncogenic transformation of these cells. CD4+, CD56+
leukemias are associated to six types of cytogenetic abnormalities also
encountered in myeloid and lymphoid malignancies [34]. The most frequent
one is deletion 5q. Our patient no 3 presented with del [9] which
is one of the chromosomal changes defined by the authors [34].
CONCLUSION
This entity raises a diagnostic and therapeutic problem. The diagnosis
is very difficult when the disease is limited to the skin. This disease
has to be recognized because whatever polychemotherapy protocol applied,
although remission is easily obtained, relapse is constant. Novel therapeutic
perspectives may be more interesting such as stem cell or bone marrow
transplantation.
The authors would like to thank Pierre Dubus and Bernard Lenormand.
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