Leukemia Cutis Workup

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 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.

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.

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)

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]

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.

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

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. ^[42] Note the images below.

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.

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 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