Leukemia Cutis (Leukemia specific skin lesions, myelosarcoma, granulocytic sarcoma, monoblastic sarcoma, chloroma, primary extramedullary leukemia, aleukemic leukemia cutis)

Are You Confident of the Diagnosis?

The term leukemia cutis (LC) describes the skin changes caused by infiltration of extramedullary leukemic cells. Leukemia can be myeloid or lymphoid and acute or chronic. Acute leukemias are due to malignant transformation of leukocytes early in development while chronic leukemias arise from more differentiated malignant leukocytes. Most pateints with LC will have concomitant leukemia; rarely do skin manifestations precede the development of leukemia.

Chloroma is a term used to describe single or multiple areas of skin involvement by chronic or acute myelogenous leukemia (Figure 1). The term was coined due to the greenish hue of the skin from the myeloperoxidases made by the granulocytes. Granulocytic sarcoma, myelosarcoma and the other synonyms above describe both the location of the cells in the soft tissues (sarcoma) and the differentiation of the cells (white blood cells).

Characteristic findings on physical examination

The skin is the most common site of leukemic involvement outside the blood stream and bone marrow. The skin is involved in 22% to 41% of those with extramedullary (leukemic deposits outside the bone marrow) leukemia. Typical cutaneous lesions are erythematous, violaceus, or hemorrhagic papules and/or nodules. The extremities are the most common site of involvement, followed by the trunk and head. Rare findings include erythroderma as well as hand and nail involvement. Lymphadenopathy and hepatosplenomegaly may also be found, especially in patients with acute myelogenous leukemia (AML).

Expected results of diagnostic studies

Biopsy findings will vary with the type of leukemia. Most infiltrates will be nodular with perivascular and periadnexal infiltrates. Poorly differentiated cells may be few to numerous (Figure 2, hematoxylin and eosin stains). The origin of the cells (myeloid, lymphoid or others) and type of leukemia can be determined by histopathologic appearance and immunophenotypic studies. Ancillary stains that are positive in AML-derived leukemia cutis include antimyeloperoxidase (MPO), lysozyme, CD43, and CD45; CD7 is variably expressed by these cells. The M4 and M5 subtypes of AML will also demonstrate CD4, CD56, and CD68.

Leukemia cutis. Atypical leukocytes throughout the dermis. H&E stain. (Courtesy of Bryan E Anderson, MD)

Patients with LC but without concomitant leukemia may have biopsies that are misinterpreted as lymphoma. Misdiagnosis as cutaneous lymphoma has been reported to occur in up to 47% of patients with aleukemic LC.

The laboratory work-up should begin with a complete blood count (CBC) with differential. Patients with an underlying leukemia will often have anemia, thrombocytopenia, and leukocytosis. A small percentage (2% to 10%) will have a normal CBC. These patients should still have a bone marrow biopsy to assess for low levels of malignant leukocytes. In some patients with LC, bone marrow involvement may be below the threshold to diagnose leukemia; however, even a lower percentage of blasts should prompt aggressive treatment.

Who is at Risk for Developing this Disease?

LC occurs in 10% to 15% of those with AML. About 70% of those with LC have either myelomonocytic (M4) or monoblastic (M5) AML. Abnormalities in chromosome 8 have been detected more frequently in patients with LC than those without LC. The significance of this is unknown. LC is less common with lymphoid leukemias (4% to 20% prevalence). LC has been reported rarely in patients with myelodysplastic syndrome and myeloma.

Rates of leukemia cutis are similar between men and women. Infants have higher rates of LC than adults; 25% to 30% of infants with congenital leukemia will develop LC.

What is the Cause of the Disease?

The cause of leukemia cutis is unknown. Theories to explain the affinity of the malignant leukocytes for extramedullary tissues (eg, the skin) include a local transformation of leukocytes into malignant cells or a tissue homing mechanism developed by a subset of the malignant cells.

Systemic Implications and Complications

Leukemic involvement of the skin may indicate the skin is a site of sanctuary for the malignant cells. Traditional therapy for leukemia may result in normalization of the bone marrow and lymph nodes, but with persistent or rapidly recurrent disease in the skin. Relapse of leukemia is more common for patients with leukemia cutis. Overall survival may be shorter for patients with LC versus those without (6% vs 30%, respectively).

Patients with LC are more likely to have involvement of other extramedullary sites. The central nervous system (CNS) is particularly at risk and rates of concomitant CNS involvement are higher than those without LC. A lumbar puncture along with prophylactic intrathecal methotrexate should be considered.

Treatment Options

Table I. Therapeutic Ladder for the Treatment of Leukemia Cutis

Table 1.

Medical Therapies	Surgical Therapies	Physical Modalities
Multiagent chemotherapy		Adjunctive cutaneous radiation therapy
Autogenic or allogeneic transplant		Adjunctive total skin electron beam therapy

Optimal Therapeutic Approach for this Disease

Nearly all untreated patients will go on to develop overt leukemia within 1 year (median = 7 months) of the diagnosis of LC; hence localized therapy such as surgery and radiation rather than systemic chemotherapy is not recommended. Chemotherapy with the consideration of adjunctive radiation or electron beam should be considered in cooperation with a hematologist-oncologist. Treatment options for LC are summarized in the Table I. Radiation or total electron beam in addition to standard chemotherapy regimens should be considered to specifically address this portion of disease in the skin.

Patient Management

After definitive therapy, patients should be closely monitored for relapse of their leukemia at any site. The optimal method for monitoring these patients is not well defined. A reasonable approach is to monitor a CBC with differential every 3 to 4 months and perform a bone marrow biopsy if significant abnormalities develop. Relapse of leukemia cutis is often a sign of impending relapse in the bone marrow. Median time to relapse in the bone marrow, following cutaneous relapse was 7 months.

Unusual Clinical Scenarios to Consider in Patient Management

Pateints with aleukemic LC lack evidence of leukemia in the bone marrow and peripheral blood before and up to 1 month after the diagnosis of LC. Caution is advised since nearly all of the patients will develop leukemia within 1 year. Patients lacking definitive evidence of leukemia on a bone marow biopsy may have a low percentage of blasts or lymphadenopathy that will support aggressive therapy with standard chemotherapeutic regimens.

LC may localize to sites of previous injury such as catheter insertion sites, scars, sites of minor trauma, or striae distensae. It is theorized that malignant cells can better penetrate previously injured tissues due to altered vessels, nerves or local immmunity.

Patients with leukemia who were misdiagnosed as having lymphoma and hence received anthracycline-based chemotherapeutic regimens are likely to relapse with either extramedullary or medullary leukemia. For those cases, repeat chemotherapy. Transplantation should be strongly considered.

What is the Evidence?

Byrd, JC, Edenfield, WJ, Shields, DJ, Dawson, NA. ” Extramedullary myeloid cell tumors in acute nonlymphocytic leukemia: a clinical review”. J Clin Oncol . vol. 13. 1995. pp. 1800-16. (An older but extensive review of leukemia cutis.)

Chang, H, Shih, LY, Kuo, TT. “Primary aleukemic myeloid leukemia cutis treated successfully with combination chemotherapy: report of a case and review of the literature”. Ann Hematol. vol. 82. 2003. pp. 435-9. (This report describes a case of aleukemic LC and reviews 31 prior cases from the literature in a concise tabular format. The authors found only 5 of the 31 patients did not go on to develop evidence of leukemia in the bone marrow.)

Cho-Vega, JH, Mediros, LJ, Pietro, VG, Vega, F. ” Leukemia cutis”. Anat Pathol . vol. 129. 2008. pp. 130-42. (This is an excellent recent review of the clinical manifestations, epidemiology, and histopathology. It discusses and compares the histopathology and immunophenotypes of several types of LC. There are several clinical and histologic photographs.)

Lee, JI, Park, HJ, Oh, ST, Lee, JY, Co, BK. ” A case of leukemia cutis at the site of a prior catheter insertation”. Ann Dermatol. vol. 21. 2009. pp. 193-6. (This is a short and illustrative case of leukemia cutis exhibiting an “isotopic” response, which is supported by multiple similar reports of LC arising at sites of previous trauma or inflammations (eg, herpes simplex infection, vaccination sites, Lyme disease and others).

Reinhardt, D, Pekrun, A, Lakomek, M, Zimmerman, M, Ritter, J, Creutzig, U. “Primary myelosarcomas are associated with a high rate of relapse: report on 34 children from the acute myeloid leukaemia-Berlin-Frankfurt-Münster studies”. Br J Haematol . vol. 110. 2000. pp. 863-6. (This is a case series of 34 children with LC and AML in Germany. Fourteen of the children had sub-leukemic amounts of bone marrow blasts. The report summarizes the details of the patients, laboratory findings, treatment and outcomes.)

Zweegman, S, Vermeer, MH, Bekkink, MW, van der Valk, P, Nanayakkara, P, Ossenkoppele, GJ. “Leukaemia cutis: clinical features and treatment strategies”. Haematologica. vol. 87. 2002. pp. ECR13(This is a brief case report with tables comparing patient and disease characteristics of those with and without LC. It also discusses the risk of decreased overall survival and the role of adjuvant radiation or electron beam.)

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