Leukemia Cutis 

Updated: Feb 12, 2019
Author: Thomas N Helm, MD; Chief Editor: Dirk M Elston, MD 

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.

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]

Etiology

Both a genetic component and an environmental component appear to be involved in the pathogenesis of many types of leukemia. A variety of well-characterized chromosomal translocations result in specific leukemic syndromes.

Patients with Down syndrome have an increased risk for both megakaryoblastic leukemia and pre–B-cell leukemia.

Other genetic syndromes, including Bloom syndrome, Klinefelter syndrome, Wiskott-Aldrich syndrome, and Fanconi syndrome, have shown an increased incidence of leukemia.

CLL shows some familial tendency in approximately 20% of CLL cases.

Several genetic mutations lead to an asymmetric maturation of stem cells and result in a single clonal expansion of a severely defective stem cell. The specific mutations and phenotypic changes resulting from genetic aberration determine the subtype of leukemia. After the development of the leukemic clones, a tissue-selective homing process that leads to the infiltration of malignant cells into the epidermis, the dermis, the subcutaneous fat, and the mucosa occurs.

The molecular basis responsible for the development of leukemia cutis is not yet defined. However, initial cytogenetic studies are starting to provide insightful information that would lead to a better understanding in the pathophysiology of leukemia cutis. Prior studies have demonstrated that as many as 50% of patients with AML-M4 or AML-M5 develop leukemia cutis and other forms of EML. Karyotypic studies of leukemic cells have demonstrated the translocation of chromosomes 8 and 21 t(8;21) in these subtypes of AML. A strong association exists between aneuploidy of chromosome 8 and leukemia cutis. Other cytogenetic abnormalities noted in leukemia cutis are chromosome 3 translocations and t(6;9)(p23;q34). Chloromas, primary EMLs are associated with t(8;21), t(9;11) and inv(16) translocations. Identification of proteins coded by specific genes located in those chromosomes would assist in defining factors responsible for the development of leukemia cutis.

Environmental exposures may increase the risk of leukemia. Benzene exposure increases one's risk for AML. Ionizing radiation exposure may increase the risk of leukemia as well, particularly AML, CML, and ALL. Alkylating agents used in chemotherapy cause an increased risk of subsequent AML. The use of all trans retinoic acid to treat APL may predispose a patient to increased risk of extramedullary involvement, including leukemia cutis, which is otherwise rare in APL. Other leukemias may be caused by viral infection. These include ATLL, caused by HTLV-I and acute B-cell leukemia and large granular lymphocytic leukemia, which may be the result of Epstein-Barr virus infection.

Secondary leukemias are associated with prior hematologic disorders such as myelodysplastic syndrome or myeloproliferative disease. Therapy-related acute leukemia results from genetic damage sustained from prior radiation therapy or chemotherapy for malignancies. These are associated with the use of alkylating agents and type II topoisomerase inhibitors, and they differ from primary leukemias clinically and cytogenetically and carry a poor prognostic outcome. Therapy-related secondary leukemia with leukemia cutis as a result of chemotherapy has rarely been reported.[13]

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.[14]

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.[15]

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%.

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.

Prognosis

The prognosis is poor, with many patients having other extramedullary disease and poor survival rates.  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. Even patients with aleukemic leukemia cutis or granulocytic sarcoma progress to systemic disease and should be treated systemically from the time of diagnosis.

A study by Kaddu et al showed an average survival time in AML to be 7.5 months and in CML, 9.4 months.[16] 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.[17] 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.[18]

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.[19] 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.[20] 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.[21, 22]

Patient Education

Patients should notify their physician if any fevers, skin eruptions or suspicious lumps occur.

For patient education resources, see the patient education articles Leukemia and Skin Biopsy.

 

Presentation

History

Patients present complaining of the appearance of single or multiple skin lesions. Lesions may be localized or generalized. Color may range from violaceous or brick-red to skin colored. The appearance of skin lesions in leukemia cutis is further described in the Physical section. A current or past history of leukemia is present in most patients. In patients with no history of leukemia, eliciting symptoms of systemic disease is particularly important to reach the correct diagnosis. Because of the nonspecific appearance of the skin lesions in leukemia cutis, skin biopsy with follow-up bone marrow biopsy is necessary to confirm the diagnosis.

The lesions of leukemia cutis are most often asymptomatic. In chronic lymphocytic leukemia (CLL) and human T-lymphotropic virus type I (HTLV-1)–induced ATLL, significant pruritus may be present. A typical presentation of acute adult T-cell leukemia/lymphoma (ATLL) includes a history of fever, chills, and lethargy. Many cases of associated dermatitis, which may be extremely pruritic, have been described. Other symptoms that may be reported include abdominal pain, cough, and diarrhea. Patients may report abdominal fullness due to the hepatosplenomegaly or ascites. Patients may also report swollen lymph nodes.

The pancytopenia caused by leukemia results in a variety of manifestations. Symptoms of anemia, including pallor, lethargy, and dyspnea may be prominent. A recent history of easy bleeding and bruising is suggestive of thrombocytopenia.

Neutropenia predisposes one to bacterial, viral, or fungal infections. These infections may present in the skin, the gingiva, the urinary tract, or the lungs. Any of these infections may be accompanied by fevers. Aspergillus and Fusarium organisms may appear at sites of trauma, such as central lines or intravenous insertion sites, or as disseminated nodules and ulcerations. Atypical mycobacterium type IV also cause infections in these patients.

In a patient with a previous diagnosis of leukemia and possible leukemia cutis, the history is important to attempt to identify other potential sites of extramedullary involvement. As many as 90% of patients with leukemia cutis also have other extramedullary involvement, and as many as 40% of patients have meningeal involvement. In patients with possible leukemia cutis as the presenting sign of systemic leukemia, the history may be essential to narrowing the differential diagnosis.

Infiltration of leukemic cells into a variety of organs produces different symptoms in each organ system. Nausea, abdominal fullness, early satiety, and constipation are several symptoms that can occur as a result of hepatomegaly or splenomegaly, which are common in leukemia.

CNS involvement by leukemic cells may be associated with cranial nerve palsies, seizures, altered mental status, or headache with nausea due to increased intracranial pressure. An unusual presentation of leptomeningeal infiltration by leukemic cells is the numb chin syndrome. Patients complain of loss of sensation or altered sensation in the chin area, without any evidence of a primary dermatosis or a history of preceding trauma.

Patients may report bone and joint pain. Infiltration of the periosteum/bone results in painful lesions and, in certain cases, pathologic fractures. Joint swelling and arthritis may be secondary to gouty arthritis from hyperuricemia.

Leukostasis can occur in patients with a significant amount of circulating leukemia cells. Clinical manifestations vary from CNS symptoms, respiratory distress from lung involvement, or priapism. Rare reports describe leukemic vasculitis in which leukemic cells actually infiltrate the blood vessel walls.[23, 24, 25]

Clinicians should be aware that CLL is associated with aggressive squamous cell carcinomas and that unusually prominent infiltrates around epithelial neoplasms may be an important clue to underlying CLL. Occasionally, the brisk infiltrate of lymphocytes around an epithelial neoplasm may be the first clue to underlying disease.[26, 27] Immunohistochemistry as well as gene rearrangement studies can be helpful is establishing a diagnosis in such situations. The infiltrate of CLL exhibits a CD20+, CD3-, CD5+, CD23+ phenotype, whereas reactive infiltrates of the skin typically exhibit a CD20-, CD3+, CD5-, CD23- phenotype.

 

Physical Examination

Leukemia cutis displays a variety of clinical appearances. Classically, lesions are described as papules, plaques, or nodules ranging from violaceous to red-brown in color.[2] Skin involvement may be general or localized to one region. Others have reported flesh-colored nodules, occasionally with central ulceration.[3] Indurated plaques, hemorrhagic plaques, perifollicular acneiform papules, macules, ulcers, bullae, and palpable purpura are less frequent.

In myeloid leukemias, extramedullary collections of malignant cells called granulocytic sarcomas may form. When these involve the skin, they often appear as skin-colored or violaceous nodules with or without central ulceration. These tumors may appear as green masses at sites of ulceration. The green pigmentation is due to the presence of myeloperoxidase in tumor cells.

As mentioned briefly in History, systemic findings related to the underlying leukemic process may be present. These include pallor secondary to anemia; purpura, petechiae, or ecchymosis secondary to thrombocytopenia; and hepatosplenomegaly. Opportunistic infections may occur in any type of leukemia. Lymphadenopathy may be present. Drug reactions, including leukocytoclastic vasculitis, and opportunistic infections, particularly thrush, disseminated zoster, or severe and atypical presentations of herpes simplex, may be present.

Patients undergoing chemotherapy for leukemia or other malignancy may present with cutaneous manifestations related to therapy. These findings may complicate the clinical picture and make diagnosis more difficult. Some of the most common cutaneous manifestations of chemotherapeutic agents include alopecia, stomatitis, acral erythema, and hyperpigmentation of the nails or the mucous membranes. Other less common chemotherapy reactions include neutrophilic eccrine hidradenitis and eccrine squamous syringometaplasia. These present as localized or generalized erythematous macules, papules, or plaques.

Some inflammatory cutaneous reactions may occur in patients with leukemia, but they are not a direct result of infiltration of leukemic cells into the skin. These include acute febrile neutrophilic dermatosis (secondary to AML or granulocyte colony-stimulating factor [GCSF]), graft versus host disease, and persistent arthropod bite–like reaction (most commonly seen in CLL). These lesions are included in the differential diagnosis of leukemia cutis.

Note the images below.

Involvement of the face in a patient with acute my 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. T 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 Amer Papules and nodules on the face of an African American patient with acute myelogenous leukemia (AML). Courtesy of Mona Mofid, MD.
Diffuse macules and papules on the scalp of a pati Diffuse macules and papules on the scalp of a patient with chronic myelogenous leukemia.
Diffuse truncal eruption of infiltrated papules an Diffuse truncal eruption of infiltrated papules and plaques in chronic lymphocytic leukemia.
Close-up photo of diffuse truncal eruption of infi Close-up photo of diffuse truncal eruption of infiltrated papules and plaques in chronic lymphocytic leukemia.

Atypical presentations of leukemia cutis have been noted with specific underlying leukemic processes.

AML-M4 and AML-M5 have characteristic gingival hypertrophy as a result of leukemic infiltration. This may be present in as many as 50% of patients with these subtypes of leukemia. See the image below.

Gingival infiltration in a patient with acute myel Gingival infiltration in a patient with acute myelogenous leukemia.

In acute myelomonocytic leukemia, leukemia cutis may manifest as leonine facies.[28]

Juvenile CML may show figurate or arciform lesions.[29]

Two reports describe leukemia cutis as the presenting sign of a transformation of myelodysplastic syndrome into AML. One described leukemic infiltrates on the hands, the other described stasis dermatitis, which was, in fact, leukemia cutis.[30]

One case report of hairy cell leukemia with leukemic macrocheilitis and Melkersson-Rosenthal syndrome has been reported.[31]

Fingertip hypertrophy consisting of leukemic infiltrates of CLL has also been described.[32] B-cell CLL has manifested as symmetrical eyelid leukemia cutis.[33] A case series of 6 patients with B-cell CLL demonstrated leukemia cutis in areas typical of Borrelia burgdorferi –induced pseudolymphomas, namely earlobes, nipples, and scrotum. These cells showed aberrant CD20+/CD43+ phenotype, and 4 of the 6 tumors demonstrated B burgdorferi DNA by polymerase chain reaction.[19] CLL also may manifest as erythroderma or bullous lesions.

Other unusual manifestations include erythema nodosum, erythema annulare centrifugum, pyoderma gangrenosum, lesions mimicking urticaria, urticaria pigmentosum, guttate psoriasis,[34] chronic paronychia,[35] subungual leukemia cutis,[36] and macular erythema.

The first case of leukemia cutis manifesting as a Sister Mary Joseph's nodule was reported in a case of acute promyelocytic leukemia (APL).[37] Leukemia cutis in APL is rare; however, the patient was previously treated with all trans retinoic acid, a factor that increases the chance of extramedullary involvement with relapse.

Leukemia cutis may occur within established scars and within recent areas of trauma, including Hickman catheter sites, sites of burns, decubitus ulcers,[38] herpes simplex virus (HSV) scars, or zoster scars. Plasma cell leukemia cutis has been reported to occur in recent puncture sites. Leukemia cutis at a site of trauma has been reported in one case of Burkitt-type ALL (L3ALL).[39]

In ATLL, 60% of patients have peripheral lymph node enlargement, 26% have hepatomegaly, 22% have splenomegaly, and 39% have skin lesions.

 

DDx

 

Workup

Laboratory Studies

A complete blood count is performed to assess the degree of anemia, thrombocytopenia, and neutropenia or leukocytosis. If these measurements are low, supportive treatments may be given or precautionary measures may be initiated. A peripheral blood smear to look for circulating leukemic cells and to assess for disseminated intravascular coagulation should be performed.

Chemistry profile is necessary to assess baseline levels for BUN and creatinine prior to initiation of chemotherapy and to monitor these levels during chemotherapy as a reflection of renal function. Most patients with leukemia have an elevated lactate dehydrogenase (LDH) level and an elevated uric acid level. Elevation of LDH is often a poor prognostic sign.

Liver function tests and BUN and creatinine determinations are necessary prior to the initiation of therapy because many chemotherapeutic agents may adversely affect either renal function or hepatic function. Additionally, some agents, such as methotrexate, may be contraindicated in individuals with hepatic dysfunction.

Some leukemias may have other electrolyte abnormalities, including hypokalemia, hypocalcemia, and/or hypomagnesemia. In adult T-cell leukemia/lymphoma (ATLL), hypercalcemia occurs in approximately one third of all patients.

Appropriate cultures should be obtained in patients with fever or signs of infection.

Imaging Studies

Imaging studies should be obtained based on the patient's symptoms to determine the extent of extramedullary involvement of leukemia or potential sites of infection. Some imaging studies may be needed to assess the baseline status prior to chemotherapy administration; for example, echocardiography may be performed prior to the initiation of chemotherapy.

In all the leukemias, chest radiography may show evidence of an infection, such as pneumonia. In some cases of T-cell acute lymphocytic leukemia (ALL), mediastinal lymphadenopathy may be present.

Typical hepatomegaly and splenomegaly may be imaged by using a liver/spleen scan. Most often, these findings are so obvious in cases of chronic lymphocytic leukemia (CLL), hairy cell leukemia, and ATLL that imaging is unnecessary because the organs are easily palpable. In milder cases, liver or spleen scan or ultrasonography may reveal more subtle organomegaly.

Computed tomography of the chest, the abdomen, or the pelvis is generally not required for staging purposes. However, be careful not to miss lesions, such as obstructive uropathy or airway obstruction, that are caused by lymph node compression on organs or internal structures.

Other Tests

Modern leukemia classification is based on immunophenotyping via multicolor flow cytometry to clarify cell lineage. Older schemes used cytochemistry, which is no longer required for diagnosis of many types of leukemia. However, it may useful in some settings. For example, it may aid the identification of monocytic differentiation in AML, which is associated with cutaneous involvement.[5]

In cases of ATLL, studies to assess monoclonal integration of the human T-lymphotropic virus type I (HTLV-1) genome into genomic DNA are helpful.

Procedures

Skin biopsy

Skin biopsy with appropriate immunohistochemical staining is the key to diagnosing aleukemic leukemia cutis or identifying leukemia cutis, a sign of extramedullary extension of the leukemia, and a poor prognosis. This diagnosis will likely influence the course of treatment.

Bone marrow aspiration and biopsy are the definitive diagnostic tests for the diagnosis of systemic leukemia. Wright or Giemsa staining may be used in morphological analysis. In addition, immunocytochemistry should be used to determine cell lineage. Bone marrow samples should be sent for cytogenetic and flow cytometric studies. The presence of blast cells should be quantified as the percentage of nucleated cells in both peripheral blood and bone marrow. Although blast cell proliferation is not a component of mature cell leukemias (eg, hairy cell leukemia, ATLL), the degree of blast proliferation has prognostic significance in blastic leukemias such as AML.[5]

Diagnostic precautions with biopsy

If clinicians fail to consider the possibility of leukemia cutis, a delay in diagnosis may result. The judicious use of immunohistochemical marker studies can greatly facilitate accurate and efficient diagnosis. Clinical correlation is important. An important pitfall to keep in mind when evaluating atypical infiltrates is the so-called “granulocytic sarcoma” presentation of leukemia cutis, which can be mistaken for lymphoma. Accurate diagnosis leads to efficient management and treatment. If a patient has a known diagnosis of leukemia, a delay in diagnosis is less likely because the skin often shows the same markers as the bone marrow.

A biopsy should be performed on a patient with an established diagnosis of leukemia with a suspected case of leukemia cutis because a concurrent different leukemia could be present or transformation of the original leukemia may have occurred. In either case, a skin biopsy may be the first and least invasive test to reveal this. If there is a delay in the diagnosis of extramedullary leukemia with a resultant delay in leukemia-specific therapy, the patient’s outcome may suffer.

Experienced dermatopathologists sometimes receive biopsy samples from patients with known leukemia and a concurrent widespread dermatosis. Clinicopathological correlation and experience are important in arriving at an accurate and useful diagnosis. In a recent case encountered by one of the authors, a patient with known leukemia had a clinical diagnosis of folliculitis. A diagnosis of leukemia cutis was rendered at an outside institution, but further review of the skin biopsy revealed changes of both folliculitis and leukemia. Pathologists must take care to recognize the presence of concurrent processes and understand that patients with active leukemia have atypical cells within the infiltrate of any associated dermatosis.

Immunophenotyping

Immunophenotyping of infiltrates with specific markers is a valuable adjunct in confirming the diagnosis of leukemia cutis and in differentiating specific from nonspecific cutaneous infiltrates. Specific markers include the following: CD3 (T cells), CD45RO (mature T cells), CD45/LCA (leukocyte common antigen) (lymphocytes, monocytes), CD43 (T cells, monocytes, and granulocytes), CD20 (B cells), CD30 (activated T cells), CD68 (monocytes), and lysozyme (granulocytes, monocytes) (see Table 2 below).

Table 2. Recommended Immunohistochemical Stains For Leukemia Cutis (Open Table in a new window)

Cell Lineage

CD Antigen Marker

T cell

CD45 (LCA) strongly positive

CD45RO usually strongly positive

CD3 positive but only scattered

B cell

CD20 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

Granulocytes

Lysozyme strongly positive in well and poorly differentiated granulocytes

Chloroacetate esterase positive in well-differentiated granulocytes

CD68 usually negative in all granulocytes

CD43 positive, MPO sometimes positive

Monocytes

Lysozyme strongly positive in well and poorly differentiated monocytes

Chloroacetate esterase usually negative

CD68 positive in well-differentiated monocytes

CD163 less sensitive but more specific than CD68

CD117

Chloroacetate esterase stains CML and most subtypes of AML but not AML-M4. However, lysozyme should stain all forms of AML and CML.

AML-M4 types express CD43 and CD68 as well. CD43, CD45, and CD15 are positive in almost all types of AML-M5 and AML-M4.

B-cell CLL cells express B-cell markers, including dimCD20. They may also express both T- and B-cell markers, often co-expressing CD5 and CD23.[3] In T-cell CLL, CD45RO and CD3 are either negative or only weakly positive. ATLL cells stain with CD3, CD4, and CD25. CD8 is most often negative.

Hairy cell leukemia cells, which are of the B-cell lineage, stain strongly with tartrate-resistant acid phosphatase. Hairy cells have a mature B-cell phenotype and express immunoglobulin light chains and B-cell antigens, such as CD19, CD20, and CD22, but not CD21. Monoclonal Bly-7 has a high sensitivity and specificity for hairy cell leukemia. CD22 stains hairy cell leukemia more prominently than normal B cells.

Some studies have noted differences in phenotypic expression between leukemic cells in bone marrow and the infiltrates of myeloid leukemia cutis. CD34 and CD117, commonly used to identify blast cells, show decreased expression in leukemia cutis when compared with concurrent bone marrow samples. Increased expression of MPO and CD56 have also been noted in leukemia cutis. These findings may indicate a shift in phenotype occurring in extramedullary cell populations.[2]

Histologic Findings

The histologic findings in leukemia cutis vary depending on the subtype of leukemia. Typically, a nodular and diffuse infiltrate of leukemic cells is seen in the dermis. Perivascular and periadnexal accentuation may be present. Epidermal involvement is absent or limited, with an underlying Grenz zone. Leukemic cells often infiltrate between collagen bundles in the reticular dermis. The leukemic cells may also infiltrate along the fibrous septae of the subcutaneous fat. The cells may be seen in the lumina of the blood vessels as well as infiltrating the walls, producing a leukemic vasculitis.

Cells in AML are large with an oval, vesicular nucleus and basophilic cytoplasm. Note the images below.

Low-power view of leukemia cutis acute myeloblasti 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 acut 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.

In CML, a variety of cells at varying degrees of maturation are present. Eosinophils may be present. Note the image below.

Leukemia cutis of acute monocytic leukemia. Periva 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.

ALL shows medium-to-large blast cells, with a high nuclear-to-cytoplasmic ratio.

CLL shows small, more uniform, mature lymphocytes. These have dense nuclear chromatin. T-cell CLL may show epidermotropism, as do other T-cell leukemias.

Monocytic leukemia may be confused with large cell lymphoma because of the large nucleus with fine chromatin and prominent nucleoli. The nuclei are often indented or kidney shaped and slightly basophilic in appearance. Monocytic leukemia often involves the entire dermis and the superficial panniculus.

ATLL cells show an indented to lobulated nucleus, which has led to the term flower cells to describe the morphology. ATLL unlike many of the other leukemic infiltrates often shows epidermotropism. Pautrier microabscesses, as can be seen in mycosis fungoides, may be present.

Hairy cell leukemia, like many other forms of leukemia cutis, infiltrates the dermis and the subcutaneous fat. It too shows prominent periadnexal and perivascular infiltration. The infiltrate consists of monomorphous mononuclear cells. A grenz zone is typically present.[40] Note the images below.

Low-power view of acute promyelocytic leukemia cut 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.
Photo illustrates leukocyte esterase staining of t Photo illustrates leukocyte esterase staining of the cytoplasm of the leukemic cells in acute promyelocytic leukemia. Courtesy of Kim Hiatt, MD.
Photo illustrates leukocyte esterase staining of t 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 Leukemia cutis at low power demonstrating a Grenz zone and intercalation of leukemic cells between collagen bundles. Courtesy of Keliegh Culpepper, MD.
Infiltration of leukemic cells between collagen bu Infiltration of leukemic cells between collagen bundles.

It is often difficult to distinguish between the subtypes of leukemia based on histologic appearance. In addition, leukemia cutis can be confused with other inflammatory conditions involving a reactive infiltrate of leukocytes. For these reasons, a high degree of suspicion should used when examining dermal infiltrates from a patient with a history of leukemia. Immunohistochemistry should be used to further characterize infiltrates, and results should be correlated with bone marrow biopsy when available.

Cutaneous lymphomas can also resemble leukemia cutis both clinically and histologically. In some of these cases, malignant cells may disseminate into circulation. When leukemic involvement occurs, the associated skin lesions may be called leukemia cutis. Immunophenotyping is important in determining the correct diagnosis in these cases, as treatment and prognosis may vary depending on the tumor cell type. For example, mycosis fungoides is a proliferation of clonal T cells in the skin. Sézary syndrome represents leukemic extension of mycosis fungoides. Patients presenting with primary Sézary syndrome have a poor prognosis compared with patients with primary mycosis fungoides.[1] Note the image below.

Infiltration of dermoepidermal junction by clonal Infiltration of dermoepidermal junction by clonal T cells in Sézary syndrome.

Patients with CLL are at increased risk of nonmelanoma skin cancer. In these patients, leukemia cells may infiltrate the skin at areas of tumor involvement. Dense peritumoral leukemic infiltrates present a diagnostic challenge because they are difficult to differentiate from reactive inflammatory infiltrates based on histology alone.

Immunohistochemistry is a useful diagnostic aid in these cases. Reactive peritumoral inflammatory infiltrates commonly consist of CD3+/CD43+/CD5+/CD20- T cells. Leukemic infiltrates of CLL are often made up of B cells that stain positively for B-cell markers CD20 and CD23, as well as T-cell markers CD5 and CD43. However, they are often negative for CD3 expression. Correct diagnosis is important to identify systemic disease and to ensure resolution of skin cancer. Squamous and basal cell carcinomas are more likely to recur following surgical excision in patients with CLL.[26]

Staging

Staging is extensively discussed in the following articles about each of the subtypes of leukemia:

  • Acute Lymphoblastic Leukemia Staging

  • Acute Myeloid Leukemia Staging

  • Chronic Lymphocytic Leukemia Staging

  • Chronic Myelogenous Leukemia Staging

 

Treatment

Medical Care

Leukemia cutis is a local manifestation of an underlying systemic disease; therefore, it should be managed with systemic chemotherapy. Literature on aleukemic leukemia cutis is limited, but because diagnosis of leukemia cutis portends poor prognosis in acute leukemia, the treatment should be directed at eradicating the leukemic clone by using aggressive systemic chemotherapy and stem cell transplant possibly in first remission.

The treatment of leukemia should be determined by the subtype of leukemia and by the patient's ability to tolerate a treatment regimen. This is primarily dependent on the overall medical condition of the patient, including any comorbid conditions that may exist. Under certain circumstances, such as resistant or recurrent skin disease, local treatment in the form of electron beam therapy can be used. However, in most of these cases, reinduction systemic chemotherapy must be added unless medically contraindicated by the patient's comorbidity.

In general, most patients on chemotherapy should receive prophylaxis for common infectious agents, including herpes simplex virus (HSV), Candida species, and P carinii. They should also receive symptomatic treatment for mucocutaneous complications of chemotherapy. These treatments include ketoconazole troches (for thrush) and viscous lidocaine alone or a compound containing lidocaine solution, diphenhydramine hydrochloride, and aluminum hydroxide suspension, ie, "magic mouthwash," (for stomatitis) or chlorhexidine and may relieve symptoms. Symptomatic treatment, including topical steroids, mentholated lotions, or topical lidocaine preparations (Lida-Mantle), for medication- or radiation-induced skin eruptions is often helpful. Preparations containing hyaluronic acid or a medication containing emollients called Biafine can speed the healing of skin with radiation damage.

Patients are usually best managed by a team that includes dermatologists and hematologist and oncologist input.

Refer to Acute Myelogenous Leukemia and Acute Lymphoblastic Leukemia.

Radiation therapy

Radiation therapy can be used to palliate symptoms of pain and pruritus in patients with leukemia cutis who are not candidates for systemic chemotherapy. Addition of radiation therapy to skin lesions after complete response to systemic chemotherapy provides no additional benefit. In a rare instance, radiation may be used to treat isolated skin relapse when bone marrow shows complete remission and no other site of extramedullary relapse is evident. If these patients are subsequently treated with chemotherapy, reports detail severe radiation recall phenomenon occurring with chemotherapy drugs like cytarabine and clofarabine.[41] Treatment options for leukemia cutis are expanding rapidly. Helical irradiation of the total skin (HITS) therapy has been modified as simultaneous integrated boost (SIB)–helical arc radiotherapy of total skin (HEARTS) and used to treat acute myeloid leukemia in someone with disseminated leukemia cutis.[42]

Surgical Care

Most patients require central venous catheter placement for chemotherapy delivery, if they do not have one.

Consultations

Consult a hematologist and an oncologist if the patient presents with aleukemic leukemia cutis. Consult with a bone marrow transplantation physician if the patient is a candidate for such intensive therapy. Consider a consultation with a radiation oncologist for skin-directed therapy, if appropriate.

Diet

Neutropenic patients may be placed on diet of well-cooked foods with avoidance of deli meats, fresh fruits, and fresh vegetables to avoid associated risk of infection.

Activity

Patients may be cautioned to avoid strenuous activity.

Complications

Complications include the following:

  • Infection: As previously mentioned, patients are at risk for a variety of opportunistic infections.
  • Bleeding: Bleeding as a result of thrombocytopenia is common.
  • Reactions to chemotherapy
  • Graft versus host disease: Graft versus host disease following bone marrow transplantation is common.

Prevention

Patients should avoid crowded public places because of the risk of infection. Patients should avoid contact with others who are ill.

Patients should avoid receiving live vaccines. However, this may not apply under certain circumstances. Patients should avoid contact with persons who have been recently vaccinated with live vaccines.

Long-Term Monitoring

Further biopsies may be performed as required to rule out recurrences, graft versus host disease after bone marrow transplantation (BMT), or unusual infections resulting from immunosuppression. Appropriate prophylactic antifungal, antiviral, and Pneumocystis carinii pneumonia (PCP) agents and supportive growth factor treatment are needed.

 

Methotrexate (Folex PFS, Rheumatrex)

Methotrexate is an antimetabolite that inhibits dihydrofolate reductase, thereby hindering DNA synthesis and cell reproduction in malignant cells. It is administered as combination salvage therapy for relapse.

Sargramostim (Leukine)

Sargramostim is a GM-CSF that stimulates division and maturation of earlier myeloid and macrophage precursor cells.

Allopurinol (Zyloprim)

Allopurinol inhibits xanthine oxidase, the enzyme that synthesizes uric acid from hypoxanthine. It reduces the synthesis of uric acid without disrupting the biosynthesis of vital purines.