How to cite this article: Pulido-Díaz N, Medina G, Palomino N, Peralta F. Cutaneous manifestations of leukemia. Rev Med Inst Mex Seguro Soc. 2015;53 Supl 1:S30-5.
Received: October 22nd 2014
Accepted: March 6th 2015
bUnidad de Investigación en Epidemiología Clínica
cDepartamento de Dermatología, Hospital de Especialidades, Centro Médico Nacional La Raza, Instituto Mexicano del Seguro Social, Distrito Federal
a,bDivisión de Estudios de Posgrado, Facultad de Medicina, Universidad Nacional Autónoma de México, Distrito Federal, México
dDivisión Académica de Ciencias de la Salud, Universidad Juárez Autónoma de Tabasco, Tabasco, México
Communication with: Nancy Pulido
Telephone: (55) 5724 5900, extensión 24085
Background: To describe the type and frequency of cutaneous manifestations of leukemia
Methods: Observational, descriptive study. We included patients over 16 years of age, with confirmed diagnosis of leukemia from the Hematology and Dermatology Departments of the outpatient clinic and from in-patients. Patients with bone marrow transplantation were excluded. A complete history and physical examination of the skin and appendages was performed, with biopsy and cultures if required. The cutaneous manifestations were classified as infection or drug-related, leukemic infiltration, associated dermatosis to leukemia and non-specific lesions. Descriptive statistics was employed.
Results: We included 142 patients (62 females, 80 males) with the following diagnoses: acute myeloid leukemia (n = 36), acute lymphoblastic leukemia (n= 52), chronic myeloid leukemia (n = 21), chronic lymphocitic leukemia (n = 30) and hairy cells leukemia (n = 3). 42 % of patients (n = 60) presented some dermatoses. There were 36 non-specific dermatoses, 21 drug-related, 20 infectious, 3 infiltrative and none associated.
Conclusions: Cutaneous manifestations directly related to leukemia are frequent, being the non-specific ones, the most commonly observed. However, a thorough dermatologic examination is important in these patients as part of an overall evaluation.
Keywords: Leukemia, Dermatology, Stem cells.
Leukemia is a neoplastic proliferation of the progenitor cells of hematopoietic origin. These cells lose their ability to mature and differentiate, proliferating in a disorderly manner, replacing the normal elements of the bone marrow. Cell proliferation can infiltrate other organs, including the skin. They are divided according to their origin into myeloid and lymphoid, and generally into acute and chronic.1,2
Among the systemic clinical manifestations presented by patients with leukemia are skin manifestations. In the literature there are few clinical studies on the most common skin manifestations in patients with leukemia, the majority being case reports. Pearson et al.3 determined the prevalence and type of skin lesions in patients with onco-hematological diseases, which were: acute and chronic leukemia, and multiple myeloma. Skin lesions were identified in 88% of 200 episodes in 84 patients.
The most common skin manifestations were reactions to medications, infections, and other reactional dermatoses.
The authors Frias and Iron,4 in 2007, conducted a study on 233 patients, which included patients with any diagnosis of hematopathy (leukemia 82%, multiple myeloma 4%, other 14%). Skin lesions were found in 42% of cases, with skin reactions to drugs, infectious processes, and skin infiltration being the most common. In this latest study dermatological manifestations in patients with hematological disorders were classified into four groups: nonspecific, specific, skin reactions to drugs, and preexisting with some modification. Since in our area leukemias are some of the most prevalent diseases, we decided to conduct this study to describe the frequency and type of cutaneous manifestations in these patients.
An observational, prospective, descriptive study was done. It included patients over age 16 who were IMSS clients and who agreed to participate in the study with a confirmed diagnosis of leukemia, from the Servicio de Hematología of the Hospital de Especialidades of the Centro Médico Nacional La Raza in the period from August 2009 to January 2010, who were hospitalized in the hematology area, as well as from hematology and dermatology outpatient areas. Bone marrow transplant patients were excluded. Patients were revisited once, except for four patients who presented another dermatological manifestation during the study period and were referred again to the dermatology department. After written consent, they underwent a full dermatological assessment, which consisted of a detailed examination of the skin and annexes in its entirety. A dermatological clinical history was made that included the development time of dermatosis, accompanying symptoms, topography, and morphology. Clinical findings were documented by clinical iconography, and in some cases skin biopsy was necessary as part of patient study. In the cases where clinical diagnosis suggested it, samples were sent for culture. In each case reviewed, general, demographic, and clinical data were taken and each case was classified according to its etiological factor: manifestations secondary to infectious diseases, drugs, leukemic infiltration, dermatosis associated with leukemia, and nonspecific lesions.
The data analysis included descriptive statistics with quantification of mean and standard deviation for continuous variables. Prevalence and frequencies were expressed in percentages.
A total of 142 patients were included with the following diagnoses: acute myeloid leukemia (n = 36), acute lymphoblastic leukemia (n = 52), chronic myeloid leukemia (n = 21 patients), chronic lymphocytic leukemia (n = 30), and hairy cell leukemia (n = 3).
In leukemia, in general, 42% of patients (n = 60) had positive findings for some skin diseases and 58% (n = 82) did not present any. The dermatoses present were classified as: infiltrative, drug-related, infectious, associated, and nonspecific. Overall we found 36 nonspecific dermatitis, 21 drug-related, 20 infectious, 3 infiltrative, and no associated.
Acute myelogenous leukemia
20 of these dermatoses were found, predominantly nonspecific dermatoses of which there were 9 (45%), and which clinically corresponded to soft fibroids, acne, keratosis pilaris, psoriasis, and Nevus of Ota. Drug-related dermatoses were second (7 dermatoses, 35%), with one case of skin reaction to drugs, and several patients with nail changes from chemotherapy (such as Beau's lines, Mees’ lines, and hyperpigmentation from chemotherapy). Infectious manifestations occupied 15% with three cases of onychomycosis. There was one case of infiltration which represented 5% of dermatoses.
Acute lymphoblastic leukemia
28 dermatoses were found, with 11 non-specific (39%) followed by 10 drug-related (36%) and 7 infectious (25%). Among the nonspecific manifestations we found: seborrheic dermatitis, nummular eczema, pityriasis alba, seborrheic keratosis, solar lentigo, tophi, tattooing, and even a patient with marfanoid habitus. Regarding infectious manifestations, we predominantly found onychomycosis and only one case each of the following entities: molluscum contagiosum, verruca vulgaris, and cellulite. Within drug-related manifestations, in addition to hyperpigmentation from chemotherapy, there were found: Beau's lines and Mees’ lines, plus two acneiform reactions.
Chronic myeloid leukemia
16 dermatoses were found. The most frequent manifestations were nonspecific with 7 dermatoses (43.75%) including xerosis, rosacea, and seborrheic dermatitis. Other less precise histopathologic diagnoses were included such as panniculitis, and 2 reports of superficial perivascular dermatitis, which were obtained from patients with high suspicion of infiltration and whose study was inconclusive. Regarding infectious manifestations, we had 5 cases of onychomycosis, which accounted for 32% of dermatoses. Those drug-related (3 dermatosis) accounted for 19%, where in addition to chemotherapy hyperpigmentation (Figure 1) we found a case of drug-related erythroderma and hypopigmentation from imatinib (Figures 2 and 3). Finally, we documented one case of infiltration in the face which represented 6.25% of the dermatoses (Figure 4).
Figure 1 Patient with chronic myeloid leukemia and hyperpigmentation from hydroxyurea
Figure 2 Patient with chronic myeloid leukemia and erythroderma from imatinib
Figure 3 Patient with chronic myeloid leukemia and hypopigmentation from imatinib
Figure 4 Patient with chronic myeloid leukemia and infiltration to the face
Chronic lymphocytic leukemia
A total of 15 dermatoses were registered, most were nonspecific (8 dermatoses, 53%) with the following findings: seborrheic dermatitis, prurigo from insects, seborrheic and actinic keratosis, one dermatofibroma, one patient with Dupuytren's contracture, and one case of epidermoid carcinoma of the lower lip. Within the infectious dermatoses (5 dermatoses, 33.3%) 4 cases of onychomycosis and one of mucormycosis (Figure 5) were presented. Drug-related dermatosis found one case of leukocytoclastic vasculitis representing 6.6% of dermatoses, and finally one case of infiltration (6.6%) (Figure 6).
Figure 5 Patient with chronic lymphocytic leukemia and mucormycosis
Figure 6 Patient with chronic lymphocytic leukemia and infiltration to the abdomen
Hairy Cell Leukemia
Only one patient had erythroderma, whose etiology could not be determined.
No cases of associated dermatosis were registered, as defined by the presence of clinical and histopathologic criteria for pyoderma gangrenosum and Sweet's syndrome.
In this study we found that the cutaneous manifestations of leukemia are diverse, non-specific (defined as those who did not meet criteria for classification in the rest, being infiltrative, drug-related, infectious, and associated) being the most common in all leukemias. Arbitrarily, the last four can be classified as directly related to leukemia. Nonspecific dermatitis were for the most part merely dermatological disorders (acne, nummular eczema, keratosis pilaris, seborrheic dermatitis, psoriasis, squamous cell carcinoma, prurigo from insects, tophi). Drug-related and infectious manifestations were second and third respectively, with little difference.
In the study by Pearson et al.,3 acral erythema, dermatitis of the folds, and allergic reactions (associated with antibiotics) were the predominant dermatologic manifestations. However, in our study, although the hospitalized patients were exposed to a large number of drugs, particularly chemotherapeutics and antibiotics, the frequency of skin reactions from drugs was low. We found one case erythroderma and hypopigmentation from imatinib, and the rest of the dermatoses corresponded to side effects of systemic drugs or chemotherapy, such as acneiform reactions, hyperpigmentation of the skin and annexes, Beau’s lines, and Mees’ lines. In contrast, in a study of dermatoses in patients with myeloid and acute lymphoid leukemia, dermatoses secondary to chemotherapy and other drugs were the dermatoses most often seen.5
Imatinib, a tyrosine kinase inhibitor, causes adverse skin-level events; eyelid edema, hypopigmentation of the skin, and reactivation of porphyria cutanea tarda have all been reported with all adverse events reversible.6-8 Other cutaneous manifestations vary from maculopapular rash, rash of various types (lichenoid, or psoriasiform lesions, acute generalized exanthematous pustulosis, Stevens Johnson syndrome), but usually they are mild to moderate adverse events.9 In our study one case presented with erythroderma related to imatinib. This manifestation is rare, because there is only one case reported in the literature in a patient with chronic myeloid leukemia with onset of erythroderma after therapy with imatinib, which once suspended, led to the quick disappearance of erythroderma. Restarting the imatinib at half the dose, skin lesions reappeared again, so the drug was permanently suspended.10 Few studies present adverse skin reactions to imatinib, another injury described is hypopigmented macules. Llamas-Velasco et al.11 reported in a study of patients with chronic myeloid leukemia treated with imatinib, the presence of hypopigmented spots, which upon histopathological examination, showed a significant decrease in the number of melanocytes, unlike vitiligo in which they are absent. In our study, patients with chronic myeloid leukemia and erythroderma from imatinib also presented hypopigmentation spots, although in this case no skin biopsy was performed.
In this study alopecia was not recorded, being very frequent, nor were other nonspecific manifestations such as dermatosis associated with patient care as hematomas, infections of puncture sites, or pallor of integuments, not being directly related to the base condition.
Among infectious manifestations, Frias and Hierro,4 in the case review conducted at the Hospital 20 de noviembre, found the following dermatological conditions: 8 cases of common warts, 6 of herpes zoster, 4 of herpes simplex, 1 of chickenpox, 4 cases of tinea corporis, and 6 of candidiasis. In our study we found one case of oral mucormycosis.
Mucormycosis, also known as zygomycosis, is an opportunistic fungal infection caused by a series of fungi in the Mucorales family that develops in immunocompromised patients. Usually it has a poor prognosis, often being fatal. There are reports in the literature of patients with oral mucormycosis and acute leukemia who were receiving chemotherapy and had febrile neutropenia.12,13
Other infectious manifestations in our study were dermatosis of viral origin (viral warts, molluscum contagiosum) and cellulitis, and the other infectious skin diseases were onychomycosis. The low frequency of infections in the skin is probably attributed to preventive care and comprehensive information provided to patients and families, who pay attention to any skin changes and immediately request consultations from specialized services such as infectious disease and dermatology. The high frequency in onychomycosis probably reflects the high incidence in our population, which is independent of the base condition. The study by Sánchez-Hernández et al. found labial and genital herpes as the most common infectious dermatosis after administration of chemotherapy. Similar to our study (except in the case of mucormycosis) no serious infections were reported due to close monitoring and timely treatment.5
Rodríguez García and Juárez Navarrete14 report that skin leukemia appears after hematological diagnosis in 55% of patients, and in 38% it is presented simultaneously. In our study we found infiltration in three cases, two in chronic leukemia and one in acute leukemia, the first being a woman with CML and panniculitis, and another in a patient with chronic lymphocytic leukemia, whose dermatosis clinically corresponded with nodular prurigo. Both already had the diagnosis of established leukemia.
It has been reported that skin infiltration occurs in about 10 to 15% of patients with acute myeloid leukemia presenting as raised plates or painless violet nodules, and biopsy finds infiltrated leukemia myeloblasts.15 Leukemia cutis is a localized or disseminated infiltration of the skin by malignant leukemia cells that can involve all layers of the skin. The clinical appearance of cutaneous leukemia is variable and can range from bumps and nodules to a generalized rash and erythroderma. Usually these lesions are seen in patients with aggressive clinical course and are associated with a poor prognosis.16,17 In our patients, for the third case of leukemia cutis, only one case found it as the initial manifestation in a patient with AML M5, which was initially measured by the presence of neoplasms of papular appearance and in skin-colored plates that were the reason for admission to hematology and that biopsy confirmed as skin infiltration by leukemia. Lesions were presented in the form of papules and nodules without widespread lesions.
In a cohort study it was found that all patients with acute leukemia develop some dermatoses throughout their illness. These dermatoses were expressions of the leukemia or the effects of chemotherapy or other drugs, with frequent presentation of dermatoses associated with hospital care.5 The latter were not taken into account in our study.
The study of dermatoses in patients with acute leukemia is complex, with a very wide diversity of dermatoses that can be observed. For the diagnostic approach it is essential to review the clinical profile and histological examination in cases that need it. The omission of prophylaxis, diagnosis, or treatment leads to the appearance of complications, demonstrating the importance of dermatological follow-up in such patients.18
The limitations of this study include the fact that it did not include the entire universe of patients (total number unknown), the short study period in which only consecutive cases found during that period were included, and the cross-sectional study design.
The findings of this study suggest that cutaneous manifestations directly related to leukemia are frequent, with the nonspecific being the most commonly observed. However, dermatological evaluation should be conducted intentionally in order to detect them early, as part of the comprehensive study of these patients who are particularly vulnerable because their pathology background.
Conflict of interest statement: The authors have completed and submitted the form translated into Spanish for the declaration of potential conflicts of interest of the International Committee of Medical Journal Editors, and none were reported in relation to this article.