Leukemia Cutis 

  • Author: Jeyanthi Ramanarayanan, MD; Chief Editor: Dirk M Elston, MD   more...
 
Updated: Jun 22, 2010
 

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 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 called aleukemic leukemia cutis. A diagnosis of leukemia cutis generally portends a poor prognosis and strongly correlates with additional sites of extramedullary involvement. This can alter the appropriate treatment regimen for a patient.[1] Note the image below.

A patient with typical plum-colored lesions seen iA 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 leukemias result from the abnormal development of leukocytes in the bone marrow. Maturational arrest occurs, and a proliferative, clonal population of cells result. A variety of defects promote the clonal expansion of leukemic cells. These defects include an abnormal proliferative potential, defects in terminal differentiation, and defective apoptosis. The increased proliferative potential is caused by the activation of oncogenes or the inactivation of tumor suppressor genes. Leukemia cutis is thought to result from a local proliferation of the leukemic cells within 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, prolymphocytic leukemia, and myelodysplastic syndromes. In patients with chronic diseases, skin involvement may be associated with transformation into aggressive histology and disease progression.

The pathophysiology underlying the specific migration of leukemic cells to the skin is not clear. It has been speculated that the chemokine, integrin and other adhesion molecules may play a role in skin specific homing of T and B leukemic cells. In the case of human T-cell leukemia virus type I (HTLV-I)–induced leukemia, it may be due to 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.

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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 the table 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%.

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, localized disease occurs prior to bone marrow infiltration and systemic symptoms (aleukemia cutis or primary extramedullary leukemia [EML]).

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

Type of LeukemiaIncidence in the United StatesPercentage of Patients with Leukemia Cutis (%)
AML2.5 cases per 100,000 population13
Acute lymphocytic leukemia1.3 cases per 100,000 population3
Chronic myelogenous leukemia (CML)1-2 cases per 100,000 population2-8
Chronic lymphocytic leukemia (CLL)2.3 cases per 100,000 population8
Hairy cell leukemia0.6-2.9 cases per 1,000,000 population8
Adult T-cell leukemiaExtremely low40-70

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.[2]

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.[3] Another study by Baer et al showed 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.[4] 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.[5]

Skin infiltration in CLL is rare. In a study by Cerroni et al, CLL was associated with advanced stage and a poor prognosis.[6] One series by Su et al of 16 patients with CLL showed a mean survival of 16 months, with 88% of the patients dying within 1 year.[7]

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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Contributor Information and Disclosures
Author

Jeyanthi Ramanarayanan, MD  Assistant Professor, Department of Medicine, Division of Medical Oncology, Roswell Park Cancer Institute

Jeyanthi Ramanarayanan, MD is a member of the following medical societies: American Association of Physicians of Indian Origin and American Society of Hematology

Disclosure: Nothing to disclose.

Coauthor(s)

Shweta Singhal, MD  Resident Physician, Department of Internal Medicine, Rochester General Hospital

Shweta Singhal, MD is a member of the following medical societies: American College of Physicians

Disclosure: Hematology-Oncology None None

Specialty Editor Board

Noah S Scheinfeld, MD, JD, FAAD  Assistant Clinical Professor, Department of Dermatology, Columbia University; Consulting Staff, Department of Dermatology, St Luke's Roosevelt Hospital Center, Beth Israel Medical Center, New York Eye and Ear Infirmary; Private Practice

Noah S Scheinfeld, MD, JD, FAAD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Optigenex Consulting fee Independent contractor

David F Butler, MD  Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic

David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Jeffrey J Miller, MD  Associate Professor of Dermatology, Penn State University College of Medicine; Staff Dermatologist, Penn State Milton S Hershey Medical Center

Jeffrey J Miller, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, Association of Professors of Dermatology, North American Hair Research Society, and Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Joel M Gelfand, MD, MSCE  Medical Director, Clinical Studies Unit, Assistant Professor, Department of Dermatology, Associate Scholar, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania

Joel M Gelfand, MD, MSCE is a member of the following medical societies: Society for Investigative Dermatology

Disclosure: AMGEN Consulting fee Consulting; AMGEN Grant/research funds Investigator; Genentech Grant/research funds investigator; Centocor Consulting fee Consulting; Abbott Grant/research funds investigator; Abbott Consulting fee Consulting; Novartis investigator; Pfizer Grant/research funds investigator; Celgene Consulting fee DMC Chair; NIAMS and NHLBI Grant/research funds investigator

Chief Editor

Dirk M Elston, MD  Director, Department of Dermatology, Geisinger Medical Center

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

References

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  2. Agis H, Weltermann A, Fonatsch C, et al. A comparative study on demographic, hematological, and cytogenetic findings and prognosis in acute myeloid leukemia with and without leukemia cutis. Ann Hematol. Feb 2002;81(2):90-5. [Medline].

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  14. Connelly TJ, Kauh YC, Luscombe HA, Becker G. Leukemic macrocheilitis associated with hairy-cell leukemia and the Melkersson-Rosenthal syndrome. J Am Acad Dermatol. Feb 1986;14(2 Pt 2):353-8. [Medline].

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  16. Ikeda T, Sakurane M, Uede K, Furukawa F. A case of symmetrical leukemia cutis on the eyelids complicated by B-cell chronic lymphocytic lymphoma. J Dermatol. Jul 2004;31(7):560-3. [Medline].

  17. Ferreira M, Caetano M, Amorim I, Selores M. Leukemia cutis resembling a flare-up of psoriasis. Dermatol Online J. Mar 30 2006;12(3):13. [Medline].

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  28. Schwonzen M, Kuehn N, Vetten B, Diehl V, Pfreundschuh M. Phenotyping of acute myelomonocytic (AMMOL) and monocytic leukemia (AMOL): association of T-cell-related antigens and skin-infiltration in AMOL. Leuk Res. 1989;13(10):893-8. [Medline].

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Involvement of the face in a patient with acute myelogenous leukemia. Courtesy of Grant Anhalt, MD.
Red-brown papules can be seen in leukemia cutis. They are confluent in this patient. Courtesy of Nevena Damjanov, MD, and Elizabeth Prechtel.
Papules and nodules on the face of an African American patient with acute myelogenous leukemia (AML). Courtesy of Mona Mofid, MD.
A patient with typical plum-colored lesions seen in leukemia cutis. This patient had acute myelogenous leukemia. Courtesy of Grant Anhalt, MD.
This photograph shows linear areas, which are more violaceous in color, likely due to trauma to the area, such as excoriation, which results in hemorrhage into the skin. Frequent hemorrhage into the skin can make any inflammatory skin lesion appear more violaceous in patients with leukemia. Courtesy of Nevena Damjanov, MD, and Elizabeth Prechtel.
Low-power view of leukemia cutis acute myeloblastic leukemia (AML-M1). Note the perivascular and periadnexal infiltrate with relative epidermal sparing. Courtesy of Kim Hiatt, MD.
This is a higher power view of leukemia cutis acute myeloblastic leukemia (AML-M1). This photo illustrates a perivascular infiltrate of leukemic cells. The nuclei are round to oval with little cytoplasm. Courtesy of Kim Hiatt, MD.
Leukemia cutis of acute monocytic leukemia. Perivascular and periadnexal infiltration is also present, but the cell morphology is distinct. Many of the nuclei are folded or indented. The cytoplasm of the leukemic cells is gray-blue and more abundant than in the M1 subtype. Courtesy of Kim Hiatt, MD.
Low-power view of acute promyelocytic leukemia cutis with a perivascular and periadnexal but also interstitial infiltrate, with epidermal sparing but significant upper dermal edema, which could be confused with Sweet syndrome at a low-power view. Courtesy of Kim Hiatt, MD.
Acute promyelocytic leukemia cutis at high power. The round-to-indented nuclei with prominent cytoplasmic granules are evident. Courtesy of Kim Hiatt, MD.
Photo illustrates leukocyte esterase staining of the cytoplasm of the leukemic cells in acute promyelocytic leukemia. Courtesy of Kim Hiatt, MD.
Leukemia cutis at low power demonstrating a Grenz zone and intercalation of leukemic cells between collagen bundles. Courtesy of Keliegh Culpepper, MD.
A higher-power view of intercalation of leukemic cells between collagen bundles. Courtesy of Keliegh Culpepper, MD.
Table 1. Incidences of Types of Leukemia
Type of LeukemiaIncidence in the United StatesPercentage of Patients with Leukemia Cutis (%)
AML2.5 cases per 100,000 population13
Acute lymphocytic leukemia1.3 cases per 100,000 population3
Chronic myelogenous leukemia (CML)1-2 cases per 100,000 population2-8
Chronic lymphocytic leukemia (CLL)2.3 cases per 100,000 population8
Hairy cell leukemia0.6-2.9 cases per 1,000,000 population8
Adult T-cell leukemiaExtremely low40-70
Table 2. Recommended Immunohistochemical Stains For Leukemia Cutis
Cell LineageCD Antigen Marker
T cellCD45 (LCA) strongly positive



CD45RO usually strongly positive



CD3 positive but only scattered



B cellCD20 strongly positive but scattered in normal B cells, weakly positive or negative in abnormal small B cells, positive in abnormal large B cells



CD43 usually negative



GranulocytesLysozyme strongly positive in well and poorly differentiated granulocytes



Chloroacetate esterase positive in well-differentiated granulocytes



CD68 usually negative in all granulocytes



MonocytesLysozyme strongly positive in well and poorly differentiated monocytes



Chloroacetate esterase usually negative



CD68 positive in well-differentiated monocytes



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