Leukemia Cutis

Leukemia cutis (LC) is a nonspecific term used for cutaneous manifestations of any type of leukemia. LC has a wide range of cutaneous manifestations, which can make it difficult to clinically distinguish LC from other skin lesions. Patients with LC usually have concomitant systemic leukemia, but occasionally skin involvement precedes the involvement of the bone marrow or peripheral blood. Thus, a skin biopsy can be the first indication of the presence of leukemia in a subset of patients. The immunophenotyping of routinely processed skin biopsy specimens is very useful in establishing the diagnosis of LC. Although the molecular mechanisms explaining the pathogenesis of LC are not well defined, chemokine receptors and adhesion molecules may have an important role in skin tropism. We review the literature and recent advances pertaining to LC, with special emphasis on the immunohistochemical assessment and possible mechanisms involved in skin tropism by leukemic cells.


Leukemia cutis (LC) is a nonspecific term used for cutaneous manifestations of any type of leukemia. LC
has a wide range of cutaneous manifestations, which can make it difficult to clinically distinguish LC from other skin lesions. Patients with LC usually have concomitant systemic leukemia, but occasionally skin involvement precedes the involvement of the bone marrow or peripheral blood. Thus, a skin biopsy can be the first indication of the presence of leukemia in a subset of patients. The immunophenotyping of routinely processed skin biopsy specimens is very useful in establishing the diagnosis of LC. Although the molecular mechanisms explaining the pathogenesis of LC are not well defined, chemokine receptors and adhesion molecules may have an important role in skin tropism. We review the literature and recent advances pertaining to LC, with special emphasis on the immunohistochemical assessment and possible mechanisms involved in skin tropism by leukemic cells.
Leukemia cutis is defined as cutaneous infiltration by neoplastic leukocytes (myeloid or lymphoid), resulting in clinically identifiable cutaneous lesions. 1 When composed of neoplastic granulocytic precursors, leukemia cutis has been designated as myeloid sarcoma, granulocytic sarcoma, primary extramedullary leukemia, or chloroma. 2 When composed of neoplastic monocytic precursors (monoblasts and promonocytes), leukemia cutis also has been designated as monoblastic sarcoma. 2 The terms myeloid sarcoma and extramedullary myeloid cell tumor have also been used to include both granulocytic and monocytic tumors. 3,4 Leukemia cutis has been described in patients with acute myeloid leukemia, chronic myeloproliferative disease, including chronic myelogenous leukemia (CML), myelodysplastic syndromes, and myelodysplastic/lymphoproliferative diseases ❚Table 1❚. 2 In patients with chronic diseases, skin involvement is associated with transformation into a blastic phase and suggests disease progression. Leukemia cutis is used as the term for lymphocytic leukemias involving skin that are also designated by their specific diagnosis, such as precursor B-or T-cell lymphoblastic leukemia/lymphoma and chronic lymphocytic leukemia.
In this review article, we discuss the various types of leukemia most frequently represented in leukemia cutis as defined by the World Health Organization classification. 4 We focus on the immunophenotypic features of leukemia cutis and will discuss the possible molecular mechanisms responsible for the migration of leukemic cells to the skin. chronic myeloproliferative diseases. 5 The frequency of leukemia cutis differs widely for the various types of AML. Skin involvement can be seen up to 50% of patients with acute myelomonocytic (AMMoL) and monocytic (AMoL) types. 6,7 Skin involvement can also be seen in patients with chronic myelomonocytic leukemia, [8][9][10][11] while skin involvement in acute erythroid leukemia and erythroleukemia is exceptional. [12][13][14] Regarding lymphocytic leukemias, skin involvement has been described in 4% to 20% of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) cases and in 20% to 70% of mature T-cell leukemias, including adult Tcell leukemia, [15][16][17] T-cell prolymphocytic leukemia (T-PLL), [18][19][20] and Sézary syndrome (SS). In contrast, leukemia cutis is unusual in patients with precursor B-or T-cell lymphoblastic leukemia/lymphomas (1%) [21][22][23] and plasma cell myeloma. [24][25][26] The frequency of leukemia cutis seems to be higher among children than adults; as many as 25% to 30% of infants with congenital leukemia develop skin involvement. 27,28 Such cases of congenital acute leukemia are most frequently AML (two thirds of cases). Acute lymphoblastic leukemia (ALL) is less frequent.

Clinical Presentation
Patients with leukemia cutis may have single or multiple skin lesions. 29 The lesions are usually described as violaceous, red-brown, or hemorrhagic papules, nodules, and plaques of varying sizes. 30 Erythematous papules and nodules are reported as the most common clinical presentation ❚Image 1A❚. 29 Legs are involved most commonly, followed by arms, back, chest, scalp, and face. 31 Leukemic infiltration tends to preferentially occur at sites of previous or concomitant inflammation ❚Image 1B❚. 31,32 A particular type of leukemia can produce different skin lesions during the course of the disease, even in the same patient. 29 Most cases of leukemia cutis occur after a diagnosis of systemic leukemia has been established. Concomitant involvement of skin and systemic leukemia have been observed in up to one third of the cases, and, occasionally (<10% of cases), skin infiltration can occur before bone marrow or peripheral blood involvement and in the absence of systemic symptoms. 33 The term "aleukemic leukemia cutis" or "primary extramedullary leukemia" has been used for this uncommon event, which occurs predominantly in patients with AML. 33,34 Aleukemia cutis lesions are usually widespread and papulonodular. 35 There are no consistent demographic and/or clinical differences between patients with leukemia with or without leukemia cutis regarding sex, age, WBC count, hemoglobin concentration, platelet count, and fibrinogen level. Higher serum levels of lactate dehydrogenase and/or β 2 -microglobulin have been reported in patients with leukemia cutis than in patients without leukemia cutis. 36,37 Up to 30% of children with congenital leukemia have skin infiltration, 28 and this is one of the causes of the "blueberry muffin" appearance. 28 Most pediatric patients with leukemia cutis have high leukemic tumor load and hepatosplenomegaly. 38,39 Unusual clinical presentations of leukemia include marked thickening of the gums and oral petechiae in AMoL, 30 leonine faces in AMMoL, eczematous lesions, 40 penile or scrotal ulcers, 41 and panniculitis resembling erythema nodosum. 42 As many as 90% of patients with leukemia cutis also have involvement of other extramedullary sites, with involvement of the meninges particularly frequent (40% of the cases). 34 Nonleukemic cutaneous manifestations of leukemia (also knows as leukemids) are more common than leukemia cutis; they occur in 40% or more of patients with leukemia. 43 These cutaneous lesions are mostly a manifestation of cytopenias and drug reactions. These include petechiae, purpura, ecchymoses, leukocytoclastic vasculitis, neutrophilic dermatoses (Sweet syndrome and pyoderma gangrenosum), and opportunistic infections, particularly thrush, disseminated herpes zoster, or severe and atypical presentations of herpes simplex. 43

Histopathologic Findings
The diagnosis of leukemia cutis is based on the morphologic pattern of skin infiltration, cytologic features, and, most important, the immunophenotype of the tumor cells. Correlation with clinical data and bone marrow and peripheral blood findings is often helpful to confirm the diagnosis.  In general, at low-power magnification, most types of leukemic skin infiltrates show a perivascular and/or periadnexal pattern of involvement ❚Image 1C❚ and ❚Image 1E❚ or a dense diffuse/interstitial ❚Image 1D❚ or nodular infiltrate involving the dermis and subcutis (Image 1D, inset) with sparing of the upper papillary dermis (Grenz zone) (Image 1E, arrow). Rare cases present as a subtle superficial interstitial infiltrate ❚Image 1F❚. Stromal fibrosis is often seen and is associated with any type of leukemic infiltrates. Based on histologic findings alone, it is often impossible to assign lineage, which is essential for classification (myeloid, monocytic, or precursor B-or T-cell).

Myeloid (Granulocytic) Sarcoma
The infiltrate is nodular with a perivascular-periadnexal distribution or interstitial and diffuse ❚Image 2A❚ and ❚Image 2B❚. Epidermotropism is unusual. Myeloblasts and granulocytic precursors are the predominant cell components. The neoplastic cells are usually large, with relatively abundant eosinophilic cytoplasm and large nuclei with blastic (finely dispersed) chromatin and occasional small nucleoli. Mitotic figures are usually prominent. Scattered macrophages and mature granulocytes can be frequently seen. Focal involvement with destruction of nerves, sebaceous glands, and muscle bundles is not unusual. 44

Myeloid (Monoblastic) Sarcoma
The infiltrate can be nodular with a perivascular or periadnexal distribution or interstitial and/or diffuse. Involvement of the subcutaneous tissue can be seen. Epidermotropism is rarely seen. The skin infiltrates in AMoL ❚Image 2C❚ or AMMoL ❚Image 2D❚ cases are composed of cells with blastic chromatin and promonocytic features (large cleaved nuclei, small nucleoli, and amphophilic cytoplasm). Skin involvement of chronic myelomonocytic leukemia is common and shows histologic features similar to those found in AMMoL.

Precursor B-or T-Cell Acute Lymphoblastic Leukemia/ Lymphoma
The most common clinical presentation is one or multiple cutaneous nodules. The cytomorphologic features of precursor B-and T-cell lymphoblastic leukemia/lymphoma are virtually identical. Typically, the infiltrates are deep seated and lack epidermotropism. The pattern of infiltration can be perivascular and/or diffuse ❚Image 2E❚. Morphologically, the cells have usually a monomorphous appearance, being intermediate in size with round nuclear contours and blastic chromatin (Image 2E, inset). Frequently, numerous mitotic and apoptotic figures are present. 23 Stromal fibrosis is frequently seen.

Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia
Leukemia cutis has been reported in 4% to 20% of patients with CLL/SLL. Three main architectural patterns are recognized: (1) perivascular and periadnexal, (2) nodular and diffuse ❚Image 2F❚, and (3) band-like. 45 Cytologically, the infiltrates are characterized by a relatively monotonous population of small lymphoid cells with round nuclear contours (Image 2F, inset). A distinctive characteristic feature of CLL/SLL, if the biopsy specimen size and degree of infiltration are large enough, is the presence of proliferation centers (aggregates of prolymphocytes and paraimmunoblasts). In some cases, the lesions are confined to sites affected by previous inflammatory or infectious conditions such as Borrelia burgdorferi, herpes zoster (Image 1B), and herpes simplex. 32,46 In other cases, leukemic infiltrates are seen associated with primary cutaneous epithelial neoplasms. 47,48 Compared with CLL/SLL, other mature B-cell lymphoid neoplasms rarely involve skin, often at the time of end-stage disease.

T-Cell Lymphoproliferative Diseases
Adult T-cell leukemia/lymphoma (ATLL) is a neoplasm of CD4+ mature T lymphocytes for which human T-cell lymphotropic virus type I (HTLV-1) is the proven etiologic agent. ATLL commonly involves the skin, peripheral blood, and lymph nodes. Cutaneous lesions of ATLL are polymorphous in appearance; skin lesions are frequently observed in all clinical subtypes (acute, chronic, lymphoma, and smoldering), and their incidence is reported to vary from 43% to 72%. 49 A primarily cutaneous subtype of ALL has also been proposed.
It is often difficult to distinguish cutaneous lesions of ATLL from those of mycosis fungoides (MF) because one third of cutaneous lesions of ATLL show a superficial bandlike infiltrate with epidermotropism and Pautrier-like microabscesses. Unlike MF, epithelial necrosis and a deepseated perivascular infiltrate ❚Image 2G❚, sometimes accompanied by angioinvasion, can be seen in ATLL. 50,51 The skin infiltrates can be heterogeneous with small, medium, large, mixed, or pleomorphic T cells (Image 2G, inset). Some cases have shown prominent granulomatous inflammation. 52 In suspected cases of ATLL, serologic confirmation of HTLV-1 infection is essential but circumstantial evidence of the role of virus in pathogenesis; confirmation of monoclonal integration of the HTLV-1 proviral genome is definitive proof of causation.
T-PLL is the most common type of mature T-cell leukemia and is characterized, in most cases, by a rapidly rising peripheral blood lymphocyte count, bone marrow involvement, and splenomegaly. Skin involvement and serous effusions, especially pleural, are encountered fairly often in these cases. 19 The reported incidence of skin involvement ranges from 25% to 30%. 53 The face is frequently involved, with or without associated swelling and relative infrequency of an erythrodermic cutaneous presentation, compared with other forms of primary cutaneous T-cell lymphomas. 18 Also characteristic is the petechial and/or purpuric quality of the lesions due to RBC extravasation.
The skin infiltrate usually involves the upper dermis with a perivascular and periadnexal distribution ❚Image 2H❚ and less frequently has a diffuse pattern. 19,53 Other histologic features include variable degree of stromal edema surrounding blood vessels, minimal endothelial damage (without fibrin deposition), RBC extravasation and hemosiderin deposition, and foci of epidermotropism. Rarely, the tumor forms a subcutaneous mass. The cytologic features of T-PLL in routinely stained tissue sections are heterogeneous. T-PLL cells are slightly larger than normal lymphocytes, frequently having relatively round nuclear contours (Image 2H, inset). Prominent nucleoli are characteristic but not always present; their presence is best detected under oil. Some cases demonstrate highly irregular nuclei (Sézary-like cells) without prominent nucleoli. 54 SS is a clonal T-cell lymphoproliferative disorder involving the blood, skin, and lymph nodes that manifests with erythroderma and circulating cerebriform lymphocytes. By convention, SS is regarded as a variant of MF because the cytologic and immunophenotypic features of the neoplastic cells are identical to those described in MF. In addition, patients with longstanding patches and plaques from MF may subsequently exhibit circulating neoplastic cells indistinguishable from primary SS. However, differences in clinical outcomes have been noted in that patients with primary SS typically experience a more aggressive disease course. 55 Skin biopsy specimens show a perivascular dermal infiltrate and/or interstitial dermal infiltration. In most skin biopsy specimens, the infiltrate is located in upper and mid dermis. Lichenoid infiltrates are present to some degree in 15% of the cases, and a dense band-like infiltrate is present in 5% ❚Image 2I❚. 56 Although epidermotropism is part of the classical definition of SS (Image 2I, arrow), a significant proportion of patients with SS lack epidermotropism. 56 The infiltrates are usually composed of small or medium lymphoid cells, with variable numbers of morphologically atypical hyperchromatic lymphocytes with irregular nuclear contours (Image 2I, inset). The presence of atypical, larger perivascular lymphocytes is a useful diagnostic key to recognizing primary SS. Parakeratosis, acanthosis, and spongiosis can be seen in most cases.

Immunophenotypic Findings
The diagnosis of leukemia cutis alone is nonspecific, and immunophenotyping is very important for generating a specific, clinically useful diagnosis. Most skin biopsy specimens involved by leukemia cutis are usually small punch biopsy specimens that are routinely fixed and processed. Fortunately, many T-cell, B-cell, and myeloid markers can be used in the assessment of formalin-fixed sections, especially when antigen-retrieval techniques are used. 57 Touch imprints of the biopsy specimen for cytochemistry can also be very helpful for diagnosis.
A summary of the immunophenotypic profile of the different types of leukemia cutis is shown in ❚Table 2❚. In addition, a systematic approach useful for immunophenotypic characterization of leukemic infiltrates is given in ❚Figure 1❚.

Myeloid Sarcoma
Myeloperoxidase (MPO) and lysozyme are helpful in discriminating between myeloid and nonmyeloid cells. MPO is strongly positive in most neoplasms of granulocytic lineage, and it can be weakly positive in a subset of monocytic neoplasms ❚Image 3A❚. Rarely, precursor B-cell lymphoblastic leukemia/lymphoma is MPO+. Lysozyme is a marker for granulocytes, monocytes, and macrophages and is positive in myeloid and monocytic neoplasms but negative in lymphoid

H G
neoplasms ❚Image 3B❚. CD56 is a neural cell adhesion molecule expressed by natural killer cells and a subset of T cells and monocytes. Its expression is well recognized in a number of neoplasms, including AML, especially with monocytic differentiation. In 1 study, however, CD56 expression was not associated with the presence of leukemia cutis in patients with AML. 58 CD68/KP-1 produces a cytoplasmic granular positivity in most of the AMLs. However, the KP-1 antibody reacts with a lysosomal antigen and is less specific than the PG-M1 antibody, which is more restricted to monocytic neoplasms ❚Image 3C❚. CD117, a c-kit product, is positive in AML, including the myeloblastic component of AMMoL ❚Image 3D❚. However, the majority of AMoL cases are negative. CD117 is not specific, however, and other hematopoietic tumors expressing CD117 include mast cell proliferations, plasma cell neoplasms, a subset of precursor T-lymphoblastic leukemia/lymphoma, and rare T-cell lymphomas.

Precursor B-Cell Lymphoblastic Leukemia/Lymphoma
Pax-5/BSAP is a B cell-specific transcription factor that is detectable at the pro-B-cell stage and subsequently in all further stages of B-cell development until the plasma cell stage, when it is down-regulated. 59 The combination Pax-5/BSAP and terminal deoxynucleotidyl transferase (TdT) is very useful to identify precursor B-cell lymphoblastic leukemia/lymphoma ❚Image 3E❚ and ❚Image 3F❚. However, Pax-5/BSAP is also expressed by AML associated with t(8;21). 60 CD10, CD19, and CD79a are positive in most cases. CD45 expression may be absent.

Mature B-Cell Neoplasms
In CLL/SLL, the neoplastic lymphocytes are positive for CD5, CD20, CD23, and CD43 and negative for CD10.

Precursor T-Cell Lymphoblastic Leukemia/Lymphoma
These neoplasms are positive for CD1a, CD3, CD10, and TdT. CD3 in combination with TdT and/or CD1a is the most specific marker for the identification of precursor T-cell lymphoblastic leukemia/lymphoma. Other useful T cell-associated markers are CD2, CD4, CD5, and CD8. A subset of cases expresses CD4 and CD8. CD99 is usually positive. It is also important to remember that CD99 can be expressed in nonhematopoietic tumors and should not be considered a marker of lymphoblastic leukemia/lymphoma.

Adult T-Cell Leukemia/Lymphoma
The neoplastic cells express CD2, CD3, CD4 ❚Image 3G❚, and CD5; a decrease in the expression of CD7 is often noted. There is increased expression of the interleukin-2α receptor, best evaluated by an antibody against CD25. 61 There is no expression of cytotoxic proteins TIA-1 and granzyme B. CD1a and TdT are negative.

T-Cell Prolymphocytic Leukemia
Most cases are positive for CD3, CD4, CD45RO, and Tcell leukemia-1 (TCL-1) and negative for CD1a, CD34, and TdT. 20 CD4 and CD8 are coexpressed in 25% of the cases; rarely, CD4 and CD8 are both absent. 62 The majority of T-PLL tumors show chromosomal rearrangement involving chromosome 14 that transcriptionally activates the TCL-1 gene at 14q32 through juxtaposition of the T-cell receptor enhancer/ promoter sequence.

Sézary Syndrome
The immunophenotype of tumor cells in primary and secondary SS is similar. 56 Most cases are positive for CD3, CD4 ❚Image 3H❚, CD25, and CD45RO. 20,56 Diminished or loss of expression of CD7 and CD26 is usually seen. The larger atypical cells may be CD5-and can express CD30.

Molecular Findings and Pathogenesis
A variety of chromosomal abnormalities have been reported in patients with AML with leukemia cutis. 5,34 It seems likely reasonable to conclude that most of the molecular abnormalities closely mirror those shown for AML in bone marrow. Relatively few molecular data have been generated from the assessment of leukemia cutis specimens directly. It seems that abnormalities of chromosome 8 are significantly more common in patients with AML with leukemia cutis than in patients with AML without leukemia cutis. 5 The underlying molecular basis responsible for the migration of leukemic cells to the skin is not defined. Homing to specific tissues is controlled by the combined expression of different chemokine receptors and specific adhesion molecule receptors. For example, homing to the skin of memory T cells is regulated by coexpression of cutaneous lymphocyte antigen (CLA) with specific chemokine receptors. 70 CLA on the T cells interacts with E-selectin on the dermal postcapillary venules and initiates rolling and tethering of T cells on the endothelial cells. Chemokine binding to T-cell receptors activates lymphocyte function-associated antigen-1 (LFA-1), which will then interact with the intercellular adhesion molecule (ICAM)-1 on endothelial cells. The interaction with integrins and endothelial-bound chemokines could then lead to the arrest of the T cells and transmigration into the dermis. One study showed that most CLA-expressing T cells are CC chemokine receptor 4 (CCR4)+. 71 The CCR4 ligand TARC (thymus and activation regulated chemokine, or CCL17) is capable of inducing integrindependent adhesion of CLA+ T cells to ICAM-1 in vitro. 72 Therefore, homing of T cells into skin is thought to be mediated via the sequential interactions of CLA with E-selectin, CCR4 with TARC/CCL17, and LFA-1 with ICAM-1. 72 The mechanism of skin homing of B cells is not also defined. The expression of CLA on circulating immunoglobulin-secreting B cells may relate, at least in part, to skin homing of some of these cells after antigen stimulation. 73 A significant fraction of malignant lymphocytes in cutaneous T-cell lymphoma express CLA and CCR4, 72,74 explaining, in part, the affinity of these neoplastic T cells for the skin. Regarding these molecules in leukemia cutis, a recent small study of 18 cases of leukemia cutis in patients with AMMoL demonstrated CLA expression in 14 (78%) of 18 cases. 75 In most ATLL cases, CCR4 expression has been demonstrated in circulating ATLL cells from peripheral blood. 76,77 Furthermore, high expression of CCR4, TARC, and macrophage-derived chemokine/CCL22 also was detected by reverse transcription-polymerase chain reaction in skin lesions of patients with ATLL. Therefore, the presence of similar chemokine receptors and adhesion molecules in leukemic cells and normal memory T cells may explain the tropism of some of these leukemias to the skin ❚Figure 2❚. 78 Avigdor et al 79 reported 2 cases of plasma cell myeloma with extramedullary progression (1 case with skin involvement) despite a good response to thalidomide in bone marrow. Various cell adhesion molecules expressed by plasma cell myeloma cells also mediate homing of those cells to bone marrow and disease progression. 79,80 It has been suggested that thalidomide, by altering cell adhesion molecules involved in the homing of plasma cells into the bone marrow, may facilitate plasma cell mobilization from the bone marrow into the circulation and toward extramedullary sites. A similar hypothesis has been mentioned in patients with AML treated with all-trans-retinoic acid in whom isolated extramedullary relapse developed. 81

Treatment and Prognosis
Leukemia cutis is a local manifestation of an underlying systemic disease; therefore, the treatment should be aimed at eradicating the systemic disease by using systemic chemotherapy, as well as local therapy.
In general, the development of leukemia cutis portends a poor prognosis. Several studies indicate that, in the presence of leukemia cutis in patients with AML or CML, the disease will follow a aggressive course and the survival is short. 6 Su 33 reported that 88% of patients with leukemia cutis die within 1 year of the diagnosis. Patients with congenital leukemia seem to be an exception because leukemia cutis does not confer a worse prognosis in this clinical setting. 27