ARTICLE
Auteur(s) : M Janusch1, M Fischer2,
WCH Marsch2, H-J Holzhausen3, T
Kegel1, P
Helmbold2,4,*
1Department of Medicine IV, Martin Luther University
Halle – Wittenberg, Halle (Saale), Germany
2Department of Dermatology, Martin Luther University
Halle – Wittenberg, Ernst-Kromayer-Straße 5 – 6, 06097 Halle
(Saale) Germany
3Institute of Pathology, Martin Luther University Halle
– Wittenberg, Halle (Saale), Germany
4Department of Dermatology, University of Heidelberg,
Germany
accepté le 1 Mars 2006
The hand-foot syndrome (HFS) (palmoplantar erythrodysesthesia) is
an acute-onset symptom complex affecting the palms and soles of the
feet, which is strongly associated with antineoplastic
chemotherapy. Originally the term was applied to similar clinical
changes in sickle-cell disease. However, it is unclear whether the
pathomechnism is the same. Elicitation of an HFS by antineoplastic
chemotherapies was first observed in the 1970s in treatment with
the organochlorine mitotane (o,p’-dichlorodiphenyldichloroethane),
which is still used for the chemotherapy of adrenocortical
carcinomas [1]. Later, there was such an increase in reports on the
development of HFS-like diseases under treatment with 5-fluoruracil
(5-FU) that this drug was considered the main HFS-eliciter [2].
Meanwhile, however, it is known that HFS can be caused by other
cytostatics (table 1). For this reason, the protocols of most
clinical antineoplastic therapy trials now include monitoring of
HFS [3].Despite the general knowledge of this disease among
oncologists experienced in 5-FU therapy, difficulties are often
encountered in delineation from other differential diagnoses and
recognition is often delayed in therapy with substances other than
5-FU. Little is known about the histopathological changes
underlying the disease and the pathogenesis is unclear. The present
article presents the clinical symptoms, differential diagnoses,
histopathological and ultrastructural changes and options for
disease management.
Clinical symptoms
( Table 1 )Typical early symptoms, which
lead the patient to consult the doctor, are a sense of tension,
tingling, burning or stabbing pains in the palms of the hands,
fingers, soles of the feet or plantar areas of the toes. Often,
symmetrical, large areas of livid erythema follow, which may be
accompanied in severe cases with coarse-lamellar scaling, edema,
blistering, erosions or, infrequently, ulcerations (( figure 1 )). Indicative is
the dysesthesia, which differentiates the disease from other
erythematous, but usually itching or subjectively symptom-free
diseases of the hand or soles of the feet. HFS always occurs in
temporal association under or shortly after chemotherapy with the
various potential eliciters (table 1). It is typical that the
complete pattern develops after several therapy-cycles and becomes
worse from cycle to cycle, while at least at the start of disease
it may even heal during the therapy-free intervals. After
withdrawal of the eliciter, the unpleasant subjective symptoms
abate in from one to a few days, and heal over the course of days
or (rarely) weeks. Healing, as long as there was no ulceration, is
without scars.
Superinfections with Staphylococci or gram-negative bacteria or
the occurrence of erysipelas have been observed as complications.
This may prolong the healing time. But it is rare that these
infections lead to deterioration of the healing result. The
severity of HFS can be rated based on the WHO-classification of
chemotherapy-related adverse events (Common Toxicity Criteria,
CTC), whereby life-threatening, or lethal courses of HFS (Grades IV
and V) are unknown to date and therefore not taken into account
[4]. For clinical practice, different staging systems are used: CTC
adapted staging of the Expanded Toxicity Criteria of the National
Cancer Institute of Canada by Lotem et al. (table 2( Table 2 )) has proven most useful [5]. Other
staging systems like that of the Cancer Therapy Evaluation Program
Common Terminology Criteria for Adverse Events [3] are not very
suitable because of impracticable combinations of visible and
subjective symptoms.
Table 1 Eliciters of HFS discussed to date in the
literature
|
Frequent
|
|
5-Fluorouracil (5-FU) [4]
|
- Capecitabine [3]
- Tegafur [23]
- Emitefur [24]
|
|
Vinorelbin [10]
|
|
Liposomal encapsulated-doxorubicin [11]
|
|
Rare
|
|
Irinotecan (Camplothecin Derivative) [25]
|
|
Doxorubicin [26]
|
|
Cytarabin [27]
|
- FUDR (Floxuridin) [28]
- Sorafenib [29]
|
Table 2 Clinical severity grades of HFS (modified from
[5]), adapted to the five-grade Common Toxicity Criteria (CTC) of
the WHO
|
Grade I
|
Mild dysesthesia or/and mild erythema, swelling, or desquamation
not precluding normal physical activity
|
|
Grade II
|
Painful erythema, swelling, blistering, erosion, or swelling
interfering with regular activity, including ability to wear
clothing
|
|
Grade III
|
Diffuse or local blistering and ulceration causing infections or
bedridden state, severe pain
|
|
Grade IV/Va
|
-
|
aLife-threatening side effects or death have not been
reported so far in the literature.
Histology and ultrastructural changes
Histological findings are nonspecific and consistent with a basal
keratinocyte toxicity [6, 7]. The epidermis is hyperplastic and
shows a marked tendency to premature keratinization (dyskeratosis)
with pronounced eosinophilia in the Stratum spinosum and isolated
hyaline keratinocyte necrobioses (( figure 2 )) [5].
Keratinocyte proliferation rate is usually high. Basal dyskeratosis
and hyperproliferation are not equally distributed. This produces
an imbalanced pattern in which the pronounced eosinophilic segments
in the HE-slide may nearly give the impression that the Stratum
basale is almost absent, alternating with orthologically-layered
epidermis segments. Broadly dilated capillaries with pericyte
proliferation can be found in the Stratum papillare of the dermis,
but usually only slight perivascular lymphocytic infiltration.
Immunohistologically, the premature keratinization can be
demonstrated by cytokeratin-10 positive keratinocytes in the
Stratum basale.
Ultrastructurally, the keratinocyte differentiation disorder
presents as a basal and suprabasal increase of keratin filament
bundles with perinuclear aggregation and vacuolic degeneration (
(figure 3) ).
Isolated keratinocyte necrobioses and multinuclear basal
keratinocytes are to be found. Activation (swelling) of endothelial
cells and multinuclear pericytes can be recognized in the
microvessels of the upper dermis (own observations). The basal
lamina seems to be intact and eccrine sweat gland or duct damage
appears to be absent [8].
Incidence
The incidence of HFS varies widely in dependence on the cytostatic
therapy. Due to various ratings of severity in the literature, a
precise description of the incidence is difficult. HFS occurs most
frequently in therapy with 5-Fluoruracil (5-FU) or its derivates,
whereby there are clear differences between a continuous infusion
therapy (incidence 34%) and a bolus infusion (incidence 13%) [4].
An incidence of 5-20% (related to clinical severity grade 3) is
reported in the literature for therapy with oral fluoropyrimidines
(capecitabine), which are 5-FU pro-drugs [1, 3, 9]. A continuous
infusion therapy with vinorelbin may elicit HFS in 6-7% [10]. HFS
must be expected under therapy with liposomal-encapsulated
doxorubicin as one of the main limiting toxicities [11].
There is no evidence in the literature that HFS prefers a race
or population group. It can occur in children and adults, and there
are no known gender differences.
Differential diagnoses
Palmoplantar erythemas of other origins (hepatic, cardiac,
pregnancy associated) are common and differ from HFS in that they
already exist prior to the start of chemotherapy, do not become
worse under chemotherapy and are not accompanied by dysesthesia
(burning, pain, tingling).
Mechanical altering or cumulative-subtoxic contact eczema (due
for example to manual labour, long hikes or working with irritative
chemicals) certainly may imitate HFS, may be painful, but can be
identified by the anamnesis, possible asymmetry of the skin
manifestations, limitation to either only the feet or only the
hands and the lack of association to therapy cycles.
An allergic contact eczema, unlike HFS, is almost always
characterized by itching, is frequently asymmetric and forms
papules.
Allergic drug-induced exanthemas are only rarely limited
exclusively to the skin on palms and soles of the feet and they
often itch.
Mycoses and gram-negative foot infections show hardly anything
in common with HFS except the same localization. The erythemas are
not as distributed as HFS, and there is interdigital
accentuation.
Hand-Foot-Mouth Disease is a rare disease caused by
Coxackie-viruses, which may also affect the mouth and appears on
the palms and soles initially as small (up to 5 mm) maculae,
which may be confluent or form blisters and may be painful. The
clinical course of about one week has, however, no connection to
the chemotherapy cycles.
Hyperhidrosis manuum et pedum may become worse under
chemotherapy (subjectively or objectively) and also be accompanied
by erythemas. However, greatly increased sweat secretion is
untypical for HFS.
Acrokeratosis Bazex occurs as a facultative paraneoplasia in
bronchial carcinomas and is characterized by hyperkeratoses of the
palms and soles, but not by the symptoms typical for HFS.
The Hand-Foot Syndrome in sickle-cell anemia hardly differs
clinically from a chemotherapy-associated HFS. Here, the clinical
long-lasting course without temporal association to chemotherapy,
hemoglobin electrophoresis, and the erythrocytic changes are
indicative.
Erythema scarlatiniforme desquamativum recidivans localisatum
and Erytheme multiforme (type inversa) should be added to the
differential diagnostic considerations.
Pathogenesis
The precise mechanisms which lead to the onset of HFS are largely
unknown to date. Cyclooxigenase 2 (COX-2) overexpression might be a
potential mediator for development of HFS [12]. It would appear
that cytostatic therapy may mediate a toxic effect on the basal
keratinocytes [13]. The high turnover rate of these cells
apparently makes them particularly susceptible to the toxic effects
of chemotherapy [14]. This hypothesis is supported by our
histological and ultrastructural investigations, in which we found
a compensatory hyperproliferation of the basal epidermis in
addition to irregular premature and not stratum-typical
keratinization. Why these pathological changes appear primarily on
the palms of the hands and soles of the feet has not yet been
clarified. Possibly, an elevated keratinocyte turn-over rate plays
a role in this preferential localization. Different
microvascularization, a high frequency of eccrine glands, or
temperature differences have additionally been discussed [6, 15].
There might be a genetic background for HFS. In Korean patients, a
IVS14+1G → A point mutation was identified to correlate with the
degree of HFS [16].
There is evidence that an elevated level of
dihydropyrimidin-dehydrogenase (DPD), the initial, rate-limiting
enzyme in the metabolism of fluorouracil (5-FU), increases HFS, and
that inhibition of DPD reduces HFS as a complication of 5-FU
administration. Thus, HFS is seldom observed under UFT combination
therapy (1-(2-tetrahydrofuryl)-5-fluorouracil (FT) and uracil)
[17]. The uracil component of UFT apparently inhibits DPD activity
sufficiently to prevent HFS. Variances in DPD activity obviously
account for much of the variability observed with therapeutic use
of 5-FU (including inter-individual differences in 5-FU levels,
individual pharmacokinetics, bioavailability, toxicity, and drug
resistance). To reduce this variability, DPD inhibitors were
developed to modulate 5-FU metabolism resulting in a new subclass
of orally-administered fluoropyrimidines (DPD-inhibiting
fluoropyrimidines, DIF) [18].
Diagnostics
In most cases, diagnosis can be established by the clinical picture
and the course of the disease. Histology is rather unspecific but
may exclude a variety of differential diagnoses. It should be used
in cases with vague history or misleading symptoms (e.g.
confrontation of localized skin disorders with neuropathies, which
might induce dysesthesia).
Therapy
In treatment schedules with an expected rate of HFS, it is
important that patients are able to recognize early symptoms in
order to start therapy or treatment modification without delay.
Dose modification, systemic or local symptomatic approaches can be
used [19].
Dose reduction or interruption of therapy is often necessary.
After the first episode of HFS, once the symptoms have abated,
therapy can usually be restarted according to the original scheme.
If HFS recurs or occurs even more severely, dose adjustment is
mandatory. Repeated occurrence of HFS with toxicity grade three
makes dose adjustment or discontinuation of therapy necessary
(table 3( Table 3 )).
Systemic strategies. Pyridoxine (vitamin B6) has also been found
beneficial as therapy. Complete disappearance of the HFS is
reported under pyridoxine with doses of 50 to 150 mg/d. In other
patients, however, pyridoxine therapy has no effect. The precise
mechanism of action is still unknown. Pyridoxine can also be use
preventively [20]. Cyclooxygenase (COX)-2 inhibition has also been
shown effective as a systemic approach for prophylaxis of
chemotherapy-associated HFS [12].
Local therapy. High-potency corticosteroids and a
wet-disinfectant treatment of blisters and erosions have been found
effective as topical therapy. Preventive administration of
glucocorticoids, by contrast, shows no success. In grade 1 HFS,
avoiding mechanical irritation of the skin on the palms and soles
and mild emollient creams or gels are sufficient. Cooling the
affected areas using a cooling battery or cooling hand and foot
baths (without intensive washing) relieve the symptoms. An
interesting approach is the prophylactic use of local
vaso-constrictive nicotine patches (1 h before until 1 h
after 5-FU infusion) [21]. No sufficient effect could be
demonstrated for therapy with DMSO (dimethylsulfoxide) [22].
Depending on the severity of HFS, healing occurs after a matter of
days or weeks.
Table 3 Recommendations for therapeutic intervention on
occurrence of HFS
|
Onset of HFS
|
Toxicity grade 1
|
Toxicity grade 2
|
Toxicity grade 3
|
|
First occurrence
|
No dose adjustment
|
Interruption of therapy until reaching Grade 0-1, then re-start
with initial dose.
|
Interruption of therapy, then re-start with 75% of the initial
dose.
|
|
Second occurrence
|
No dose adjustment
|
Interruption of therapy, then re-start with 75% of the initial
dose
|
Interruption of therapy, then re-start with 50% of the initial
dose.
|
|
Third occurrence
|
No dose adjustment
|
Interruption of therapy, then re-start with 50% of the initial
dose.
|
Withdrawal of therapy
|
Conclusion
HFS is a common and dose-dependant erythro-dysesthesia reaction of
the hairless skin of the palms and soles under systemic cytostatic
chemotherapy. Histological investigations indicate that the
pathological skin changes are mainly elicited by a toxic effect on
the basal keratinocytes and upper dermal microvessels. HFS can be
brought well under control therapeutically by dose adjustment of
the cytostatics, additional topical therapy and pyridoxine. HFS is
usually completely reversible. Early recognition can be crucial in
the management of the patients.
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