Leukemia Cutis

Updated: Feb 24, 2015
  • Author: Kyle Devins; Chief Editor: Dirk M Elston, MD  more...
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Overview

Background

Leukemia cutis is the infiltration of neoplastic leukocytes or their precursors into the epidermis, the dermis, or the subcutis, resulting in clinically identifiable cutaneous lesions. The appearance of these lesions is variable and may include flesh–colored-to-violaceous papules, plaques, or nodules. Many terms have been used to describe varying presentations of leukemia cutis. These include granulocytic sarcoma, monocytic sarcoma, primary extramedullary leukemia, and chloroma.

Leukemia cutis is a broad term used to describe any cutaneous presentation of leukemia. [1, 2, 3] Owing to the variety of hematologic malignancies or proliferative disorders that may be associated with leukemia cutis, terms such as myeloid or lymphoid leukemia cutis have been used to further classify the leukemic cells. [4]

Leukemia cutis usually occurs in the setting of a previously diagnosed systemic leukemia or lymphoproliferative disorder/myelodysplastic syndrome. In rare cases, leukemia cutis may be the first manifestation of systemic disease. [1]

The dermatologist is often instrumental in the diagnosis of leukemia cutis. Accurate diagnosis has tremendous prognostic significance and may establish a diagnosis in cases in which leukemia cutis is the harbinger of a systemic leukemic process. This is known as aleukemic leukemia cutis. Leukemia cutis can also be a manifestation of a relapse of previously treated systemic leukemia. A diagnosis of leukemia cutis in the setting of acute leukemia generally portends a poor prognosis and strongly correlates with additional sites of extramedullary involvement. In the setting of chronic leukemia, cutaneous involvement can indicate blast transformation. [1] This can significantly alter the treatment regimen for a patient. [1] Note the image below.

A patient with typical plum-colored lesions seen i A patient with typical plum-colored lesions seen in leukemia cutis. This patient had acute myelogenous leukemia. Courtesy of Grant Anhalt, MD.
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Pathophysiology

All types of leukemia result from the abnormal development of leukocytes in the bone marrow. Accumulation of genetic defects in hematopoietic precursors leads to impaired cellular differentiation, increased proliferative potential, unregulated proliferation, and defective apoptosis. Ultimately, these defects result in arrest of cell maturation and expansion of a clonal cell population. The subtype of leukemia is determined by the hematopoietic lineage of neoplastic cells and the stage at which maturational arrest occurs.

Genetic alterations predisposing to leukemia may be congenital or acquired. Advancing age, exposure to radiation, chemotherapy, and certain viral infections may promote leukemogenesis in some cases. Some antecedents are specific to a leukemia subtype, such as the association of acute T-cell leukemia-lymphoma (ATL) with human T-lymphotropic virus type I (HTLV-1). Similarly, some genetic or chromosomal abnormalities are found in specific leukemia subtypes. The association of t(15,17) with the M3 subtype of acute myeloid leukemia (acute promyelocytic leukemia) is one example.

The pathogenesis of leukemia is well-characterized in the two-hit hypothesis of acute myeloid leukemia. This model describes at least two genetic alterations required for leukemogenesis. Class II mutations cause defects in myeloid cell differentiation. These occur early and result in maturation arrest. Class I mutations promote cell survival and proliferation. These lead to progression of acute myeloid leukemia. [5]

Leukemia cutis is defined by migration of leukemic cells to the skin. Leukemia cutis has been described in patients with myeloid and lymphoid types of leukemias. Cutaneous infiltration by neoplastic lymphocytes may be seen in acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chronic lymphoid leukemia, hairy cell leukemia, prolymphocytic leukemia, chronic myelomonocytic leukemia, and myelodysplastic syndromes. In patients with chronic diseases, skin involvement may be associated with transformation into aggressive histology and disease progression.

Therapy-related leukemia cutis preceding a diagnosis of systemic acute leukemia has been reported among patients treated with chemotherapy for breast cancer. [4, 6, 7, 8, 9]

The pathophysiology underlying the specific migration of leukemic cells to the skin is not clear. While some associations can be made, no definitive phenotype has been demonstrated to consistently lead to leukemia cutis. A number of mechanisms have been proposed. It has been speculated that the chemokine, integrin and other adhesion (ICAM-1) molecules may play a role in skin specific homing of T and B leukemic cells. CD56 (blast neural cell adhesion molecule) expression on leukemic blasts has been associated with extramedullary disease in acute leukemia in patients with t(8;21). [10] This may be due to the role of this surface glycoprotein in cell-cell or cell-matrix adhesion. Its role is further supported by the prominent skin involvement in CD56+ cutaneous lymphomas. [11]

In the case of HTLV-I–induced leukemia, it may be from the abundant expression of the CC chemokine receptor 4 (CCR4) on the cell surface of the leukemic cells. The ligands thymus and activation-regulated chemokine (TARC/CCL17) and macrophage-derived chemokine (MDC/CCL22) are present in the skin and may explain the predilection of adult T-cell leukemia to involve the skin.

High expression of CCR4, TARC, and macrophage-derived chemokine/CCL22 in the skin has also been noted by reverse transcription–polymerase chain reaction studies. Evidence also suggests that the presence of T-cell–related antigens on the cell surface of leukemic cells in acute monocytic leukemia (AML-M5) in patients with leukemia cutis may promote selective homing to the skin. Additionally, one small study of 18 cases of myelomonocytic leukemia cutis patients showed cutaneous lymphocyte-associated antigen (CLA) staining in 14 (78%) of 18 cases. The presence of CLA may confer a specific tropism to the skin in these leukemic cells.

In addition, some authors have noted leukemic infiltrates in preexisting inflammatory lesions and skin malignancies, suggesting that chemotactic mechanisms may be involved. [12] Other factors associated with cutaneous involvement include aneuploidy of chromosome 8, acute myeloid leukemia with monocytic differentiation, and involvement of other extramedullary sites. [2]

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Epidemiology

Frequency

United States

Because leukemia cutis is a relatively rare condition and because it may manifest in a variety of leukemia subtypes, the exact overall incidence of leukemia cutis is unclear. For the various subtypes, the approximate incidences are listed in Table 1 below.

Although adult T-cell leukemia/lymphoma (ATLL) is exceedingly rare in the United States, a disproportionate percentage of patients develop leukemia cutis. The rate of seroprevalence of HTLV-I in volunteer blood donors in the United States is 0.02%. Of the individuals infected with HTLV-I, only 2-4% develop ATLL. Acute myelogenous leukemia (AML) shows the second highest rates of leukemia cutis. The French-American-British (FAB) classification divides AML into 8 main subtypes M0 to M7, based on the morphology and the state of differentiation of the leukemic cells. Acute myelomonocytic leukemia (AML-M4) and AML-M5 have the highest rates of skin involvement of all the subtypes and are reported to be as high as 30-50%.

The World Health Organization (WHO) has offered an updated classification of AML, which incorporates immunophenotyping and cytogenetics. The WHO method allows more accurate classification based on factors that affect prognosis. Cases of AML that do not meet WHO criteria for a specific diagnosis fall into the category of “AML not otherwise specified.” [5] In these cases, leukemic cells are further classified by morphology, similar to the older FAB classification scheme.

More information about AML classification, including a full outline of the WHO scheme, can be found in Acute Myeloid Leukemia Staging.

The FAB classification of AML, with FAB subtype and description, is as follows:

  • M0: Undifferentiated myeloblastic
  • M1: Myeloblastic with minimal maturation
  • M2: Myeloblastic with maturation
  • M3: Promyelocytic
  • M4: Myelomonocytic
  • M4eo: Myelomonocytic with eosinophils
  • M5a: Monocytic without differentiation
  • M5b: Monocytic with differentiation
  • M6: Erythroleukemic
  • M7: Megakaryoblastic

The incidence of leukemia cutis also appears to be high among children, and cases of leukemia cutis have been documented in as many as 25-30% of infants with congenital leukemia. Most of these patients have myelogenous leukemia. In congenital leukemia, leukemia cutis does not worsen the prognosis.

In most cases of leukemia cutis, systemic disease precedes the development of skin lesions. However, in as many as 7% of patients with leukemia cutis, skin disease occurs prior to bone marrow infiltration and systemic symptoms (aleukemia cutis or primary extramedullary leukemia [EML]). Aleukemic involvement may be diffuse and papulonodular and these patients eventually develop AML. [13]

Table 1. Incidences of Types of Leukemia (Open Table in a new window)

Type of Leukemia Incidence in the United States Percentage of Patients with Leukemia Cutis (%)
AML 2.5 cases per 100,000 population 13
Acute lymphocytic leukemia 1.3 cases per 100,000 population 3
Chronic myelogenous leukemia (CML) 1-2 cases per 100,000 population 2-8
Chronic lymphocytic leukemia (CLL) 2.3 cases per 100,000 population 8
Hairy cell leukemia 0.6-2.9 cases per 1,000,000 population 8
Adult T-cell leukemia Extremely low 40-70

International

In general, the international incidence of leukemia cutis is thought to be similar to that in the United States. One study by Agis et al in Vienna showed a prevalence of 2.9-3.7% for AML. This is a figure similar to the rate determined by Baer et al in the United States. [14]

The exception to this rule would be the prevalence of HTLV-I–induced ATLL, which is significantly higher in the Caribbean and Japan. In Japan, 6-37% of the population is infected with HTLV-I in endemic areas. Of these, 0.5 per 1000 women and 1.5 per 1000 men will develop ATLL. In the Caribbean, 3-6% of the population is seropositive for HTLV-I. Reportedly, the rate of cutaneous involvement in ATLL ranges from 40-70%.

Mortality/Morbidity

In general, leukemia cutis is a poor prognostic sign. Several studies indicate that, in the presence of leukemia cutis in AML or CML, the disease course is aggressive and the length of survival is short.

A study by Kaddu et al showed an average survival time in AML to be 7.5 months and in CML, 9.4 months. [15] Another study by Baer et al revealed that of 18 patients with leukemia cutis in AML, 90% had other sites of extramedullary involvement, and, in 40% of these patients, the meninges were involved. [16] In a smaller case series by Shaikh et al with only 5 patients with AML, all 5 died within 6 months of their diagnosis of leukemia cutis. [17]

The prognostic significance of leukemia cutis in CLL is less clear. In a study by Cerroni et al, CLL was associated with advanced stage and a poor prognosis. [18] One series by Su et al of 16 patients with CLL demonstrated a mean survival of 16 months, with 88% of the patients dying within 1 year. [19] Other reports suggest that finding of leukemia cutis in CLL in the absence of large cell transformation or worsening systemic disease, skin infiltration alone does not affect prognosis. [20, 21]

Race

Although specific racial, sexual, and age predilections for the subtypes of leukemia exist, no data regarding any of these factors in leukemia cutis are available.

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