Leukemia cutis occurs in 10% to 15% of patients with AML and less frequently in chronic MPDs.⁷ Of note, the frequency of leukemia cutis varies on the basis of subtype of AML, and can be seen in up to 50% of patients with acute monocytic and myelomonocytic types.^8,9 Cutaneous infiltrates can also be seen in patients with chronic myelomonocytic leukemia (CMML),^10,11,12,13 but is exceedingly rare in acute erythroid leukemia.^14,15 In lymphocytic leukemias, skin involvement has been reported in 4% to 20% of chronic lymphocytic leukemia/chronic lymphocytic lymphoma (CLL/SLL).¹⁶ In mature T-cell leukemia, the rate can range from 20% to 70%.¹⁶ The frequency of disease is higher in children than in adults. Remarkably, 25% to 30% of infants with congenital leukemia subsequently develop skin involvement, usually related to a diagnosis of AML, but acute lymphoblastic leukemia (ALL) has also been implicated.^17,18

Etiology is the same as for acute and chronic leukemias as well as MDS and MPD.²

Most patients present with single or multiple erythematous papules or nodules¹⁹; however, lesions can be violaceous, red–brown, or hemorrhagic and vary from papules to nodules to plaques.^19,20 The lesions of patients with an aleukemic presentation most frequently have a myeloid immunophenotype and are widespread in distribution with a papulonodular clinical appearance.^21,22,23 Children with congenital leukemia can also have cutaneous presentation, resulting in a “blueberry muffin” appearance (Fig. 53-1).¹⁸ Most of these children have high leukemic tumor burden and concurrent hepatosplenomegaly.¹⁸

Other more unusual presentations of leukemia include oral petechiae or thickened gums, leonine faces, eczematous lesions, genital ulcers, and panniculitis.^20,24,25,26 A significant proportion of patients with leukemia cutis (90%) can also have involvement of other extramedullary sites, most commonly the meninges.²²

In most cases, leukemia cutis is a local manifestation of an underlying systemic disease, and treatment is aimed at eradicating the systemic disease usually via chemotherapy combined with local therapy. In general, the diagnosis of leukemia cutis portends a poorer prognosis, with many studies showing an aggressive course.¹ It has been reported that 88% of patients with leukemia cutis die within 1 year of the diagnosis.²¹

Diagnosis is based on the morphologic pattern of skin infiltration, cytologic features, and immunophenotype of the malignant cells. Correlation with clinical history, especially bone marrow and peripheral blood findings, is imperative. Typically, leukemia cutis shows a perivascular and/or periadnexal pattern of involvement at low-power magnification.² It can also have a dense diffuse/interstitial or nodular deep infiltrate involving the dermis and subcutis with sparing of the papillary dermis (grenz zone; Fig. 53-2).¹ Stromal fibrosis is common, and when tumor cells invade between collagen bundles, the cells can resemble an “Indian file” pattern similar to that seen in lobular carcinoma of the breast (Fig. 53-3).² Rarely, sparse interstitial infiltrates can also be the first presentation of disease, and care should be taken to recognize these subtle findings.

Numerous subtypes of leukemia can infiltrate the skin (Table 53-1). In acute myeloblastic leukemia (FAB-M1 and FAB-M2), the cells are predominately myeloblasts and myelocytes, characterized as medium-to-large mononuclear cells with scant cytoplasm and slightly basophilic, eccentrically placed nucleus with central prominent nucleolus (Fig. 53-4).² Acute myelomonocytic and monoblastic/monocytic leukemias (FAB-M4 and FAB-M5) are characterized by medium-sized atypical oval monocytoid cells with kidney-shaped nuclei.² Conversely, the infiltrate of chronic myeloid leukemia is more pleomorphic with both immature and mature granulocytes (myelocytes, metamyelocytes, segmented neutrophils).²⁷ Tumor cells with large eosinophilic granules are a helpful clue that the cutaneous infiltrate is of myeloid origin (Fig. 53-5).² Mitoses and apoptotic bodies are often present.

A diagnosis of leukemia cutis alone is nonspecific. Thus, elucidation of an immunophenotype is critical in providing clinically useful information. For myeloid infiltrates, CD68 and lysozyme are the most sensitive markers, but are not lineage-specific.² Myeloperoxidase, CD45, HLA-DR, and CD43 are also useful markers.²⁷ Other markers that may be present are CD34, CD56, and CD117 (Fig. 53-6).²

In mature B-cell neoplasms, such as CLL/SLL, the neoplastic lymphocytes will show positive immunoreactivity for CD5, CD20, CD23, and CD43, but will be negative for CD10.¹ The combination of PAX-5 and TdT positivity are useful in the identification of precursor B-cell acute lymphoblastic leukemia/lymphoma (Pre-B-ALL).¹ CD10, CD19, and CD79a are also positive in most cases of Pre-B-ALL, although CD45 expression may be absent.^1,27

The tumor cells in adult T-cell leukemia/lymphoma will be positive for CD2, CD3, CD4, and CD5, but often show decreased CD7 expression; there is lack of expression of TIA-1, granzyme B, CD1a, and TdT.^1,27 Combined immunopositivity for CD3 with TdT and/or CD1a is the most specific indicator of precursor T-cell acute lymphoblastic leukemia/lymphoma (P-T-ALL).¹ Other T-cell markers, CD2, CD3, CD4, CD5, and CD8, are also useful in the diagnosis of T-cell leukemia.^2,27

Most cases of T-cell prolymphocytic leukemia are positive for CD3, CD4, CD45RO, and T-cell leukemia 1 (TCL1) and negative for CD1a, CD34, and TdT.¹ Finally, Sézary syndrome will be positive for CD3, CD4, CD25, and CD45RO, typically with diminished or absent expression of CD7 and CD26.^28,29

Patients with leukemia of ambiguous lineage (including biphenotypic acute leukemia) may also present with cutaneous involvement. Identification of some combination of B-cell-, T-cell-, and myeloid-associated antigens is necessary (Fig. 53-7).