Dermatological Findings in Turkish Paediatric Haematology-Oncology Patients

Objective: Diagnoses of skin, mucosae, hair and nail manifestations in malignant diseases are often challenging because of life-threatening drug reactions, opportunistic infections or skin involvement of primary processes. Description of morphology, configuration and distribution of lesions is important in order to differentiate the self-healing eruptions from serious side effects of chemotherapy. There are case reports from Turkey including dermatological manifestations of malignancies and case series in adult patients but there are no published large group studies assessing all manifestations in children. The aim of this study was to evaluate the morphological features of dermatological findings in children with haemato-oncological diseases. Materials and Methods: The study was performed at the Erciyes University, Faculty of Medicine Pediatric Hematology-Oncology Clinic, Turkey. Three dermatologists daily consulted all patients admitted to the clinic during a one-year period. Results: The study group comprised of 157 children (79 female/78 male) aged 1-16 years (mean 7.19±4.63). Detailed dermatological examinations were performed, including oral-genital mucosae, hair and nails. Thorough skin examination revealed that 70% of the patients exhibited at least one dermatological finding. Generalized xerosis and hyperpigmentation were the most common findings among patients undergoing chemotherapy (24.19%). Multiple nevi on at least 10 covered areas were very frequent among patients undergoing long-term chemotherapy (18.47%). Three were identified as dysplastic nevus, but malignant transformation was not observed during the one-year study period. Conclusion: Regular dermatological consultation may help resolve the diagnostic and therapeutic problems in paediatric haemato-oncology clinics.


Introduction
Diagnoses of skin, mucosae, hair and nail manifestations in malignant diseases are often challenging because of lifethreatening drug reactions, opportunistic infections or skin involvement of primary processes.Description of morphology, configuration and distribution of lesions are important in order to differentiate self-healing eruptions from serious side effects of chemotherapy, such as acral erythema and intertriginous eruption [1][2][3][4].
There are case reports from Turkey including dermatological manifestations of malignancies and case series in adult patients, but there are no published large group studies assessing all manifestations in children.The aim of this study was to evaluate the morphological features of dermatologic findings in children with haemato-oncological diseases.

Materials and Methods
The study was performed at the Erciyes University, School of Medicine Pediatric Hematology-Oncology Clinic, Turkey.The study protocol was approved by the Erciyes University Local Research Ethics Committee.Written informed consent was obtained from all patients' parents.Three dermatologists daily consulted all patients admitted to the clinic during a one-year period.The study group comprised of 157 children (79 female/78 male) aged 1-16 years (mean 7.19±4.63).Detailed dermatological examinations were performed, including oral-genital mucosae, hair and nails.Skin biopsy, smear, bacterial and fungal cultures and diascopy were also performed, if needed.Treatment protocols and laboratory findings were noted and relations with dermatological findings were investigated.
Data were analyzed on Statistical Packages for the Social Sciences 13.0 (SPSS Inc.; Chicago, IL, USA) software.

Results
Diagnoses are shown in tables 1 and 2. Thorough skin examinations showed that 70% of the patients exhibited at least one dermatological finding.Generalized xerosis and hyperpigmentation were the most common findings among patients undergoing chemotherapy.Generalized hyperpigmentation was observed in two patients and attributed to chemotherapy, but no correlation was determined with specific drug-therapy.Localized hyperpigmentation in the genital area was not related to therapy.Multiple nevi on at least 10 covered areas were very frequent among patients undergoing long-term chemotherapy (Table 3).Diascopic examination revealed that the most acquired pigmented nevi was globular patterned.Three cases were identified as dysplastic nevus, but malignant transformation was not observed during the one-year study period (Table 4).Intertriginous eruption and acral erythema was observed not only during chemotherapy, but also after the cessation of drug therapy (Figure 1).Intertriginous eruption showed no bacterial or fungal growth and resolved spontaneously within one week with desquamation and hyperpigmentation.Acral erythema showed recurrences, but no correlation was determined with drug therapy.Drug-induced eruptions were observed as a nonspecific maculopapular rash in 8 patients and were related to the use of antibiotics.There was no serious drug reaction in any patient.Oral mucosae exhibited paleness, gingival bleeding and painful mucositis (Table 5).Candida albicans colonization was almost always determined, despite prophylactic fluconazole therapy.
Nail changes exhibited a strong correlation with chemotherapy sessions, in the form of regular parallel bands of Beau or Muehrcke lines (Table 6).
Diffuse anagen alopecia was observed in several patients and is known to be a classic side effect of chemotherapy.Hypertrichosis related to drug therapy was frequently observed in post-pubescent children (Table 7).In one case, skin lesions, a classic indicator of Sweet syndrome, exhibited an atypical course and initially presented a diagnostic challenge.Multiple urticarial papules and erythematous concentric plaques were observed on the second day (Figure 2).Typical Sweet syndrome lesions appeared on the third day, and skin biopsy was diagnostic.

Discussion
We report the results of dermatological consultations of 157 Turkish children in our institution.Several cutaneous signs associated with malignancy and chemotherapy are described.Side effects range from common to unusual and may be confused with other dermatoses.The consulting dermatologist is required to decide whether symptoms necessitate laboratory investigation and/or discontinuation of the current therapy, and must therefore be able to rule out cutaneous manifestations of malignancy, opportunistic infections, GVH (graft versus host) disease, and drug reactions due to chemotherapy or concomitant therapeutics.
The results of this research are supported by those of previous studies, which have commonly reported xerosis, generalized hyperpigmentation, ecchymosis and purpura.Local hyperpigmentation, especially in the scrotal area, was not related to disease or drug therapy.We identified intertriginous eruption in 10 children with different malignancies.All intertriginous areas, especially on inguinal folds, exhibited asymptomatic deep erythematous patches.Fungal and bacterial cultures were negative, and the eruption healed spontaneously with post-inflammatory hyperpigmentation within one week.We did not perform skin biopsy, and there was no recurrence.It has also been reported that drugs can be concentrated in eccrine glands [5].
Acral erythema was observed in our cases during or after the cessation of chemotherapy.Patients reported painful erythema of the fingertips, but blister formation was not observed.Lesions healed within 48 hours without treatment, but recurred many times.This finding may be associated with primary disease in our patients, in contrast to the cases reported in the literature, which were related to high-dose methotrexate [6,7].Allergic drug reactions were neither as frequent as expected, nor as serious.
The level of patients with acquired multiple melanocytic nevi was 18.47%, higher than the nevi count in healthy Turkish children [8].All occurred on covered areas of skin and were not related to exposure to sun.Three were dysplastic nevus, but malignant transformation was not observed during the one-year period.However, multiple nevi may be a sign of immunosuppression [9].
Mucositis is a significant problem in cancer patients.Contributory factors include Candida albicans, poor oral hygiene and dehydration.Daily oral care by nursing staff and antifungal therapy are useful, but antifungal resistance is becoming an increasing problem, as observed in our study group.An antifungal resistance test before therapy can be helpful.Opportunistic fungal infections, such as Aspergillus, Rhizopus and Mucor species can be life-threatening [10][11][12][13][14].One case in our study group showed Zygomycosis of the sinus and face did not respond to parenteral amphotericin B treatment, and proved fatal.
Lesions typical of Sweet syndrome have sometimes been reported to resemble other dermatoses and may initially pose a diagnostic problem.Skin biopsy is helpful in evaluating atypical lesions [15].Diffuse anagen alopecia, striae and steroid acne are common dermatoses and require no treatment [16].
Allergic drug eruptions were not as frequent as reported in adult studies.We observed only two allergic skin eruptions, which were related to the use of antibiotics.
Nail changes are usually related to chemotherapy [17,18].We observed nail signs only in haematological malignancies with long-term chemotherapy.
We did not perform skin biopsy, as the main aim of this study was to evaluate the morphological findings of skin lesions.
In conclusion, effective diagnosis of skin problems likely to be seen in haematology-oncology patients and is vital, not only for paediatricians and dermatologists, but also for nursing staff, in order to ensure optimum patient care.