ARTICLE
Auteur(s) :, Sarah FRIEDRICH, Kerstin RAFF, Michael
LANDTHALER, Sigrid KARRER*
Department of Dermatology, University of Regensburg,
Franz-Josef-Strauss Allee 11, 93053 Regensburg, Germany
*Sigrid Karrer, Fax: (+49)-941-944 9657. E-mail:
sigrid.karrer@klinik.uni-regensburg.de sarah.friedrich@gmx.de
accepté le 1 Mars 2004
In 1869, hydroxyurea was first synthesized by Dressler and Stein in
Germany by hydroxylating a molecule of urea [1]. Although the
suppressive effect of hydroxyurea on bone marrow was demonstrated
in 1928 [2], it was not until the 1960s that its effectiveness as
an antineoplastic drug was shown [3, 4]. Hydroxyurea inhibits DNA
synthesis and acts upon the enzyme ribonucleotide reductase causing
cell death in the S-phase of the cell cycle [5]. Hydroxyurea is
commonly used to treat myeloproliferative disorders (i.e. chronic
myelocytic leukemia, polycythemia vera, essential thrombocythemia,
myelofibrosis) [6], but was also used in the 1960s and 1970s to
treat solid tumours such as primary brain tumors, renal cell
carcinoma, head and neck cancers, melanoma and breast cancer [7].
Less common indications for hydroxyurea are: sickle-cell anaemia,
severe cases of refractory psoriasis [8, 9] and as an adjunctive
therapy in HIV disease reducing the viral load [10-12].Hydroxyurea
is a generally well tolerated chemotherapeutic agent and severe
adverse reactions are rare. Dermatologic side-effects occur quite
often and are frequently described in association with therapy of
myeloproliferative disorders. These side-effects include xerosis,
scaling, acral erythema, alopecia, hyperpigmentation, atrophy,
photosensitization, keratotic lesions, dermatomyositis-like
eruptions and oral ulceration. Ulcerations of the skin are rarely
seen.We describe a patient who developed painful cutaneous ulcers
on his hands and heels as well as multiple keratoses of the skin
during long-term hydroxyurea therapy.
Case Report
In November 2002, a 71-year-old man with a Philadelphia
chromosome-positive chronic myelocytic leukemia (CML) presented
with extremely painful ulcerations over the knuckles of both hands
(Figs 1 and 2) and on both heels. On both forearms
reticular hyperpigmentations with superficial erosions could be
seen (( Fig. 2 )). His
face showed multiple actinic keratoses on atrophic skin and a
1.0 × 1.0 cm hyperkeratotic tumour on the left
preauricular region. In February 1999, three and a half years
before admission, the diagnosis of chronic myelocytic leukemia
(CML) had been made. Since then the patient was treated with
hydroxyurea (Litalir®) at doses of 1-3 g/day. About one
and a half years after initiation of hydroxyurea therapy
erythematous changes on the face and hands as well as
hyperpigmentations on both forearms appeared. Two years after these
first changes, painful ulcerations on the knuckles of both hands
and on both heels were observed. Despite intensive local treatment
the ulcers continued to worsen and were resistant to therapy.
Physical examination was otherwise unremarkable and the mucous
membranes were not involved. His previous medical history included
arrhythmia absoluta due to atrial fibrillation, sigmoid
diverticulosis, arterial hypotension and an incomplete
posttraumatic paraplegia. Medication upon admittance was:
digitoxine 0.07 mg/d, aspirin 100 mg/d, famotidine
40 mg/d, hydroxyurea 1.5 g/d. The patient admits having
had intense sun exposure throughout his life.
The dermatohistopathological examination of a skin biopsy taken
from one of the ulcerations on the dorsa of the hands revealed
dyskeratotic cells in the epidermis and a few lymphocytes within
the basal layer of the epidermis. In the upper dermis there was
local fibrosis and a dense population of mainly perivascular
inflammatory cell infiltrates.
The histopathological examination of biopsy specimens from the
face showed actinic keratoses and on the left preauricular region a
squamous-cell carcinoma.
Bone marrow examination showed cytomorphologically the chronic
phase of CML. Analysis of the chromosomes: male karyotype with
mosaic of two pathologic cell lines with Philadelphia-
translocation and an additional aberration. Bcr/abl-rearrangement
positive.
Initial laboratory data showed extreme leukocytosis of 92.31/nl
(reference interval 4.80-10.80/nl), lymphocytopenia 3.4% (reference
interval 22.4-47.9%), elevated neutrophilic granulocytes 91.1%
(reference interval 41.2-70.1%), an increase of mean cell volume
118. 9 fl (reference interval 80-100 fl) and mean cell
haemoglobin 40.0 pg (reference interval 28-32 pg) as well as
slightly elevated liver enzymes (alanine-amino transferase
26 U/l [reference interval <22 U/l], gamma-glutamyl
transpeptidase 32 U/l [reference interval 6-28 U/l]) and
reduced renal function (creatinine 1.35 mg/dl [reference
interval 0.50-1.10 mg/dl], urea 61 mg/dl [reference interval
10-50 mg/dl]). Furthermore antistreptolysin titre 833.0 IU/ml
(reference interval 0-200 IU/ml) and phosphatidyl-IgM antibodies
16.9 U/ml (reference interval <10 U/ml) were increased
and the rheumatoid factor Waaler-Rose was positive. Following test
results were within normal ranges: electrolytes, blood glucose,
coagulation factors, pemphigus and pemphigoid titer, rheumatoid
factor-Latex, antimitochondrial antibodies, antinuclear antibodies
(ds-DNA, histones, SS-A(Ro), SS-B(La), RNP, Sm, Jo1, Scl 70,
c-ANCA), anticardiolipin antibodies. The patient did not reveal any
other co-morbid conditions that could account for ulceration and
there was no clinical evidence of vascular insufficiency or
vasculitis. No signs of infection in a smear test. Furthermore no
drugs taken could be held responsible for the development of the
skin ulcers. Despite diligent wound care no improvement was
achieved.
Due to these findings, the clinical observation and history, the
diagnosis of hydroxyurea induced ulcerations of the skin and skin
tumours was made.
Therapy with hydroxyurea was discontinued and switched to
Imantinib (Glivec®) 400mg/day. Only a few weeks later
clear improvement of the cutaneous ulcers and a decline of the
leukocyte count was observed. Actinic keratoses were removed by
curettage and the squamous-cell carcinoma was excised (( Fig. 3 )).
Three months after suspension of hydroxyurea the ulcerations on
both hands and heels had completely healed. The patient was in a
good clinical condition and hematological control.
Discussion
Hydroxyurea is a cytostatic agent used to treat myeloproliferative
disorders and other malignant and non-malignant conditions. Toxic
effects on the skin occur quite frequently and comprise
dermatological side-effects such as xerosis [13, 14], scaling,
acral erythema, alopecia [13], cutaneous and ungual
hyperpigmentation [13-15], photosensitization, stomatitis,
keratotic lesions such as actinic keratoses, basal cell carcinomas
and squamous cell carcinomas [14, 16-18] as well as brittle and
thinned nails and dermatomyositis-like eruptions [15, 19, 20].
Ulcerations of the skin, in particular of the legs, have been
reported but generally represent rare complications of long-term
hydroxyurea therapy [21-24]. Montefusco et al. [21]
described 17 and Best et al. [23] described
14 patients with painful hydroxyurea-induced leg ulcers after
long-term hydroxyurea therapy. Ulcers located on the hands have
only been described in a few cases [18, 24]. Table I( Table I ) summarizes the main
dermatologic side-effects associated with long-term hydroxyurea
treatment.
We describe a patient with CML who developed extremely painful
cutaneous ulcers and also skin tumours while on long-term therapy
with hydroxyurea. The ulcers occurred on the dorsae of the hands
and both heels, suggesting trauma as a possible initiating factor.
The patient did not have other medical conditions responsible for
acral ulceration. The doses of hydroxyurea prior to the occurrence
of cutaneous lesions varied between 1-3 g/day. Three months after
discontinuation of hydroxyurea all ulcers had healed.
Cutaneous side-effects of hydroxyurea mainly develop during
long-term therapy with doses of more than 1 g hydroxyurea per
day [21-23, 25]. First lesions of the skin have been described to
appear after about 1-9 years after initiation of hydroxyurea
therapy [23, 26]. In one case a 65-year-old man developed a lichen
planus-like dermatitis on the dorsa of his hands just after
15 days of treatment [24]. To date the exact mechanisms of
action and the pathogenesis of hydroxyurea-induced ulcers and skin
carcinomas remain unclear. It has been suggested that skin ulcers
are the direct consequence of the cutaneous toxicity of hydroxyurea
[26]. By inhibiting DNA-synthesis hydroxyurea causes damage to
basal keratinocytes. This may result in epidermal atrophy [5, 27]
and in severe cases in epithelial skin carcinomas in light exposed
areas [16-18]. Hydroxyurea also leads to photosensitization [16,
18] and inhibits DNA-repair mechanisms [5, 28, 29] impairing
healing of the skin. Epidermal atrophy and repeated mechanical
injury could explain ulcerations on the hands and heels, both areas
of common trauma. Another hypothesis considers the morphological
effect of hydroxyurea on erythrocytes [29]. Due to the increased
mean corpuscular volume (MCV) the erythrocytes are hindered from
easily passing capillaries. The local decrease of oxygen impairs
epidermal proliferation and causes vasodilatation in peripheral
tissue. Vasodilatation, especially in combination with epidermal
atrophy, can make skin vulnerable and prone to injury.
In the literature different approaches to treating
hydroxyurea-induced ulcers of the skin have been described. These
vary from local or systemic antibiotic therapy [23, 30] to
administration of pentoxifylline, hyperbaric oxygen, warfarin,
prednisone, and to application of topical wound dressings [23].
Some studies postulate that cessation of hydroxyurea is necessary
for cutaneous ulcers to heal [21, 23, 30] whereas others report
that dose reduction [23] or meticulous wound care suffice [22].
Irrespective of the treatment chosen other factors conditioning leg
ulcers such as cardial or vascular leg edema should be
excluded.
In our case hydroxyurea therapy was discontinued and all ulcers
had healed within 3 months of cessation. This period concurs
with figures quoted in the literature varying between 3-24 months
[23, 26, 30].
In summary, cutaneous ulcerations represent a rare complication
of long-term hydroxyurea therapy and their origin is often
recognized too late. The ulcers typically occur spontaneously, in
areas of common trauma, are extremely painful and heal poorly.
Discontinuation of treatment is often the only solution.
Table I Main dermatologic side-effects of
hydroxyurea (Litalir ®)
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• Xerosis, scaling, pruritus
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• Skin atrophy
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• Erythema, teleangiectasias
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• Hyperpigmentation (nails and skin)
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• Alopecia
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• Dermatomyositis-like eruptions
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• Brittle and thinned nails
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• Ulcerations (lower legs, malleoli, hands)
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• Keratotic lesions, skin tumours (basal and squamous cell
carcinoma)
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References
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2 Rosenthal , Wislicki , Kollek Über die beziehungen von
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3 Stock , Clarke , Philips , Barclay Sarcoma
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Clin Experimental Dermatol 26 2001 141-148
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