ARTICLE
Auteur(s) :, Claudio Fozza*, F
Dore, S Bonfigli, L Podda, M Longinotti
Istituto di Ematologia, Università di Sassari, Viale San Pietro
12, 07100 Sassari, Italy
accepté le 5 Octobre 2004
The real risk of lymphoproliferative disease in patients with a
history of psoriasis has not yet been defined. In particular, it is
not clear if this disease, independently of the therapies
performed, is related to an increased risk of developing lymphoid
malignancies. The use of cyclosporine A (CsA) for the treatment of
severe psoriasis was controversial until a few years ago, however
its efficiency has now been established [1, 2]. As a lot of studies
have reported an increased incidence of non Hodgkin lymphoma (NHL)
in transplant recipients treated with CsA [3, 4], a long-term use
of immunosuppressive therapy is per se potentially associated with
a high risk of neoplasm. To the best of our knowledge, only a few
studies describing the occurrence of NHL in psoriatic patients
undergoing CsA therapy have been published [5-9] but data about the
occurrence of chronic lymphoproliferative disorders have never been
reported. In this paper we describe the development of hairy cell
leukemia and Waldenstrom macroglobulinemia in two psoriatic
patients treated with CsA.
Case 1
A 44-year-old woman had had a 24-year story of diffuse psoriasis
which had been treated for 21 years with topical drugs. Three years
before our first observation, because of a worsening of the skin
lesions, she began treatment with CsA 200 mg/day. At that moment,
haematological parameters turned out to be normal. This
immunosuppressive therapy was prolonged for nineteen months, until
August 1999. In June 2001, twenty-two months later, the patient was
admitted to our hematologic ward for pancytopenia. However, she had
complained of worsening asthenia for almost one year. In
particular, significant laboratory data included severe anaemia (Hb
8.3 g/dL), leukopenia (WBC 2 400/mcL) and trombocytopenia
(PLTS 63 000/mcL). Physical examination detected only
splenomegaly, confirmed by ultrasonography (170 × 100 mm). 14%
of the peripheral cells had peripheral hairy projections resembling
hairy cell. Bone marrow examination was consistent with hairy cell
leukaemia and flow cytometric analysis showed CD19 76%, CD22 73%,
CD25 75%, CD11c 72%, CD103 68% and FMC7 65%. The patient is being
treated with interferon-alpha, which is allowing a good control of
the hematological parameters, without a worsening of psoriatic
lesions.
Case 2
A 38-year-old woman had been treated for 11 years with topical
drugs for psoriasis localised only on the knees. She had responded
well until her first pregnancy, when psoriatic plaques became
diffuse, involving her trunk, legs and arms. From 1997 the patient
received a treatment of 100 mg/day of CsA. At that time, no signs
of haematological disease were present. This immunosuppressive
therapy resulted in a remarkable improvement of skin lesions.
Despite some interruptions due to side effects, this treatment was
prolonged for five years, until our first observation. In fact, in
January 2002, the patient was admitted to our hematologic ward for
severe anaemia. She complained of asthenia, obfuscation of vision
and hypacusia. Significant laboratory data included severe anaemia
(Hb 6.8 g/dL) and immuno-electrophoresis revealed a highly elevated
IgM (6120 mg/dL) and immunoglobulin light chain λ. Physical
examination detected splenomegaly and cervical lymphadenopathy.
Total body CT scan demonstrated a phagedenic lesion, localised in
the sphenoid. A bone marrow examination and a cervical lymph node
biopsy showed a diffuse infiltration of mainly mature lymphocytes,
positive for CD45, CD79a, CD20, IgM, immunoglobulin light chain λ
and bcl-2 at immunohistochemical analysis. Therefore, a diagnosis
of Waldenstrom macroglobulinemia was made. The patient, after a
polychemotherapy with fludarabine, cyclofosfamide and prednisone,
was in complete remission.
Discussion
The real risk of developing lymphoproliferative malignancies in
psoriatic patients remains controversial. Two factors above all
could be advocated as possible explanations for the occurrence of
these diseases: the broad immune activation that characterises the
pathophysiology of this disease and the administration of an
immuno-suppressive treatment.
Regarding the former, a generalised systemic activation in the
course of psoriasis, involving not only T but also B lymphocytes,
is suggested by the demonstration of an elevated number of
proliferating B cells, T cells and monocytes in the blood of
psoriatic patients compared with normal volunteers [10]. Several
studies have tried to demonstrate, with contradictory findings,
whether psoriasis is associated or not with a high relative risk of
NHL [11-13]. Interestingly, a recent paper by Gelfand et al.
demonstrated a 3-fold increase in the rate of lymphoma in psoriatic
patients [14].
As regards the latter, it is important to underline that
long-term use of immunosuppressive therapy is potentially
associated with a high risk of neoplasm. In particular, many
studies have reported an increased incidence of NHL in transplant
recipients treated with CsA [3, 4]. B-cell proliferation due to
primary or reactivated Epstein Bar virus infection is often
advocated as a possible connection between the immunosuppressive
therapy and the occurrence of lymphoid disorders [15]. Actually, an
increased risk of malignancies in patients treated with CsA for
psoriasis has been recently demonstrated only for skin cancer, with
an incidence of non skin malignancies, including NHL, not
significantly higher than in the general population [11]. It is
also interesting to report some cases of benign lymphocytic dermal
infiltrates in association with CsA therapy for inflammatory skin
diseases. However, these lesions resolved in all patients when
therapy was discontinued [16, 17].
To the best of our knowledge, only a few studies describing the
onset of NHL in psoriatic patients undergoing CsA therapy have been
published [5-9]. In these patients the immunosuppressive therapy
was carried out for a period varying from a few months to some
years and the histology of these disorders was usually
characterised by a high grade of malignancy. On the other hand,
data about the development of chronic lymphoproliferative
disorders, like hairy cell leukemia and Waldenstrom
macroglobulinemia, have never been reported. A case of hairy cell
leukemia which developed during treatment of psoriasic
polyarthritis with methotrexate has been described [18].
We hypothesize that the occurrence of lymphoproliferative
disorders in our cases represents more than a coincidence. Our
patients had had a 27-year and 16-year story of psoriasis before
the diagnosis of hairy cell leukemia and Waldenstrom
macroglobulinemia. Both subjects had been treated with CsA. The
immunosuppressive therapy had been started five and three years
before the diagnosis and carried out for nineteen and sixty months
respectively. No signs of EBV infection were detected in either of
our cases, however in most of the reported cases regarding
psoriatic patients the association with EBV was not evident or the
data about this relationship are lacking. Moreover, it is
interesting to point out that these two neoplastic diseases, both
arising from a mature B-cell, although typical of a more advanced
age, occurred in young patients with a common underlying disease,
which is considered as a potential risk factor for the development
of lymphoid malignancies.
Neither of our patients presented cutaneous manifestations of
their B cell lymphoproliferative disorder. It is also interesting
to mention that some of the cases of lymphoma reported in patients
undergoing CsA therapy for psoriasis were not characterized by skin
localisation of the malignancies [7, 8]. Moreover, hairy cell
leukemia and Waldenstrom macroglobulinemia are much more rarely
associated with cutaneous infiltration [19, 20] than non Hodgkin
lymphoma.
It remains unclear in our cases of chronic lymphoproliferative
disease, as well as in the reported cases of psoriatic patients who
develop lymphomas, whether psoriasis or the immunosuppressive
treatment could play a role, although we suggest it is not possible
to exclude a synergism between these factors. In conclusion, the
use of immunosuppressive therapy, a potential risk factor for the
development of lymphoid malignancies, should be carefully
considered in patients affected by psoriasis, which could be per se
related to an increase in the rate of lymphoproliferative
diseases.
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