Off-chemotherapy dermatitis.
A new entity?

Bonifazi E., Garofalo L., Mazzotta F., Gelmetti C.*

Pediatric Dermatology Unit, University of Bari (Italy)

*Institute of Dermatological Sciences, University of Milan (Italy)

Summary

The Authors report 11 cases of a characteristic disorder arising in leukemic children by one month from withdrawing the chemotherapy. The disorder is characterized by eczema-like lesions that spontaneously regress within 3 months. It is not caused by infectious agents and is not related with atopy. However, it is reminiscent of seborrheic dermatitis. The Authors propose the name "off-chemotherapy dermatitis" for this disorder, that is not reported in the relevant literature.

Key words

Leukemia, chemotherapy, dermatitis.

Skin manifestations are frequent in patients with leukemia (4). They can be caused by the disease itself, the drugs used in its treatment and finally by the altered reactivity of the organism, that is secondary to the disease itself or to the antineoplastic drugs. However, the skin manifestations occurring in leukemic patients cannot be easily classified because they often lack typical clinical and pathological findings.

The infectious and specific skin manifestations can be more easily recognized and classified. On the other hand, the classification of the so-called drug eruptions is more difficult, due to both the lack of clinical and pathological criteria (2) and the rise of new clinical entities (7). The latter are only partially due to the introduction of new drugs (3, 11, 6). Nixon (14) subdivides the skin eruptions due to antineoplastic drugs as follows: cytotoxic, pigmentary and exanthematous. Among the exanthematous manifestations, the Authors include urticaria, erythema multiforme-like, toxic necrolysis-like and other hardly classifiable eruptions. In the last group new clinical disorders such as acral erythema (3) and the so-called lymphocyte recovery eruption -LRE- (7) have been recently isolated.

We here reported a cutaneous eruption, that is characterized by rather typical time of onset, evolution and clinical features. The eruption is mainly characterized by its onset within 4 weeks after the last course of chemotherapy in children affected by acute lymphoblastic leukemia (ALL).

Case report

11 patients (8 males and 3 females), aged 3-14 years (with an average age of 8.1 years) were visited in the out-patient department of Pediatric Dermatology in the period 1988-’93. These patients presented a subacute dermatitis characterized by erythematous and scaling lesions. The lesions were mainly localized on the face (Fig. 1, 2), the scalp and the upper part of the trunk. In 3 cases similar lesions also affected the upper limbs (Fig. 3). Erythema ranged between pink and red, and scales were pityriasis-like. Most patient reported moderate itching. However, scratch marks were not observed. All the children came from the Pediatric Oncohematology, where they had undergone chemotherapy as affected by ALL for a period of about two years.

Chemotherapy included vincristine, daunorubicin, asparaginase, methotrexate, 6-mercaptopurine and prednisone, according to the protocols of the Italian Association of Pediatric Oncohematology (AIEOP).

In 10/11 cases the eruption arose after withdrawing the chemotherapy, more precisely 7-30 days (with a 18-day average interval) after the last course of antiblastic treatment, while leukemia was in phase of remission. In one case the cutaneous eruption arose 15 days after a course of methotrexate, that had been given due to an ocular and central nervous system relapse.

In all the patients the eruption spontaneously regressed within 15-110 days (with an average period of 40 days). 5 children who presented a significant scaling of the face and were symptomatic (itching), were given a mild emollient treatment.

These patients were followed up for a period of time of 3-7 years after the withdrawal of the chemotherapic protocol. 5 males died due to the relapse of leukemia with central nervous system, bone and eye localization. On the other hand, after 3 to 18 months (with an average period of 8 months), 4 out of survivors presented endocrinological problems as follows: a 12-year-old girl presented micropolycystic ovary, a 10-year-old girl obesity, a 9-year-old girl (all the females survived) precocious puberty and finally a 10-year-old boy a transitory Cushing syndrome.

The clinical features and itching led us to perform particular investigations. In 10/10 cases eosinophils were within normal limits (1-4%), with an average value of 2.8%. In 6/6 cases the total IgE levels were within normal limits. No specific IgE were detected in these cases and the skin tests did not show any reactivity against the most common environmental allergens. A skin biopsy was never performed, because the clinical features were not consistent with infectious complications or specific leukemic manifestations.

Comment

The here reported eruption is characterized by moderately itchy eczema-like lesions, mainly involving the head and the upper part of the trunk. The ruption starts by one month from stopping the chemotherapy in children with ALL and spontaneously regresses by a little more than one month.

We observed this eruption only in children with ALL. However, one should consider that ALL is the most frequent malignancy in children, accounting for 80% of cases (13).

This disorder must be first of all differentiated from drug induced eruptions (14), for instance actinomycin D (10). The differential diagnosis is easy enough, due to the peculiar clinical features of off-chemotherapy dermatitis, the interval, sometimes longer than one month, between its onset and the end of the last course of chemotherapy and finally because it follows different therapeutic protocols employing different drugs.

Off-chemotherapy dermatitis must be also differentiated from demodicidosis a recently reported eruption, that also involves seborrheic regions and affects immunocompromised (1, 9) or immunocompetent (15) subjects. Although mainly affecting the face, demodicidosis is different from a morphological point of view, because it is characterized by pustules and does not start, moreover, after the withdrawal of chemotherapy.

Off-chemotherapy dermatitis should be finally differentiated from an eruption reported by Horn et Al. (7) with the name of LRE in 1989. The latter was observed in adults with leukemia, 6-21 days after the onset of chemotherapy, at the time of bone marrow recovery. LRE is associated with fever, is more acute and, in the cases reported, does not specifically involve the face. With regard to its causative factors, the Authors rule out drugs and viruses and hypothesize as responsible factor the bone marrow recovery.

Recently, Horn (8) underlined the relationship between a cutaneous eruption and transient, chemotherapy-induced bone marrow aplasia at the moment of the return to the normality. Accor-ding to Horn, LRE could be induced by the granulocyte macrophage-colony-stimulating factor (GM-CSF). This eruption is clinically characterized by macular and papular, sometimes roundish, annular lesions. These lesions appear during the treatment with GM-CSF and rapidly regress when the drug is stopped (18). According to some Authors (16) the pathological findings of LRE are typical and characterized by an increased number of dermal macrophages, many of which may contain ingested elastin. According to other Authors (6), the pathological findings of LRE are characterized by modest epidermal spongiosis and large macrophages in the dermis. According to other Authors (18), the presence of leukemic cells in the dermis is a clue to the diagnosis of LRE, in spite of the lack of atypical cells in the peripheral blood and in the bone marrow. Finally, other Authors (5) showed in LRE syndrome pathological findings reminiscent of mycosis fungoides with Pautrier’s microabscesses. These heterogeneous pathological findings support the view (2), according to which the skin biopsy is rarely useful in the classification of these cutaneous eruptions. However, the cases here reported did not undergo a stimulating treatment with GM-CSF.

Off-chemotherapy dermatitis can be easily differentiated from other eruption reported in the relevant literature. To our knowledge, it has not been so far reported in the literature. However, it is probably not exceptional. We observed off-chemotherapy dermatitis at least 20 years ago, thanks to the close relationship existing between the Unit of Pediatric Dermatology and that one of Pediatric Oncohematology. Moreover, we simultaneously and independently observed it in Bari e Milan. We would like also to say that, when a poster regarding this eruption was presented in the Congress of the European Society for Pediatric Dermatology in September ’96, some colleagues (17, 12), working in units of Pediatrics Dermatology, told us that they too had observed similar eruptions.

We suggest for this apparently new clinical disorder the name of "off-chemotherapy dermatitis", to empasize the close relationship between the stop of chemotherapy and the onset of the skin eruption. With regard to the pathogenesis of this disorder, we rule out the possibility of an infectious complication or a specific leukemic manifestation, thanks to the clinical features and the laboratory investigations.

The eczema-like appearance and the sites affected suggest a relationship with atopic dermatitis and seborrheic dermatitis. With regard to the former, the history, laboratory investigations and follow-up do not support the role played by atopy. On the other hand, the relationship with seborrheic dermatitis is supported by the sites involved -face and upper part of the trunk-, the peripuberal age and the later appearance of endocrinologic disorders in 4 out of the 6 survivors. The endocrinological disorders are, however, more frequent at the peripuberal age in leukemic children who had undergone chemotherapy protocols (13). Moreover, the involvement of the forearms and the moderate pruritus do not support the hypothesis of seborrheic dermatitis.

To conclude, we reported a transient and self-healing but rather characteristic cutaneous eruption, that arises after stopping the chemotherapy. Its pathogenesis will be better clarified in a larger series of cases.

Address to:

Prof. E. Bonifazi

Clinica Dermatologica

Università di Bari - Policlinico

Piazza G. Cesare 11 - 70124 Bari

Fig. 1, 2, 3: Off-chemotherapy dermatitis is characterized by erythematous and scaling, not exudative, eczema-like lesions. The lesions are mainly located on the face (Fig. 1, 2) and the upper part of the trunk, sometimes on the upper limbs (Fig. 3).

References

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Bonifazi et Al.

Off-chemotherapy dermatitis