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Dermatopathology: Practical & Conceptual October - December 2007
6. Leukemia cutis: Clinicopathologic study of 34 patients
Sushil Pande, M.D.
Bettina Werner, M.D.
Almut Böer, M.D.
Materials and methods
myelogenous leukemia cutis
Skin lesions are said to occur in up to 50% of patients with leukemia and have been classified conventionally as either specific (leukemia cutis) or nonspecific (leukemids). Leukemids are claimed to be more common than leukemia cutis, they being reported on in 30% of patients with leukemia. But the word leukemid has not been defined in a consistent, comprehensible way and, therefore, the term should be replaced by a specific diagnosis based on a combination of clinical features and histopathologic findings. Some leukemic cells appear inevitably in lesions of all kinds in the skin of persons with overt leukemia. For example, blasts may be encountered in lesions of psoriasis, insect bite reactions, or in a drug eruption in a patient who has acute myelogenous leukemia and in the latter circumstance those abnormal cells disappear from the skin when the drug eruption wanes. Abnormal lymphocytes also appear in infiltrates in and around malignant neoplasms such as basal-cell carcinoma or squamous-cell carcinoma, and in patients with chronic lymphocytic leukemia.
Leukemia cutis (syn. specific infiltration of the skin in leukemia) is defined as the presence of cells of leukemia in the skin. The term "leukemia" designates a malignant neoplasm of hematopoietic cells in the bone marrow, which usually manifests itself with increase in number of such neoplastic cells in the peripheral blood. When cells of leukemia find their way into the skin, the leukemia is, in most instances, already manifest in the peripheral blood. Sometimes, however, lesions in the skin precede overt manifestation of a leukemia in the peripheral blood, so-called "aleukemic leukemia cutis."[
] A variety of names have been given to leukemia cutis of myelogenous origin, among them being granulocytic sarcoma, myelosarcoma, choloroma, and extramedullary myeloid tumors (EMT), or extramedullary myeloid leukemia (EML).[
] Authentic leukemia cutis consists almost entirely of leukemic cells.
All types of leukemia may present themselves, at times, with lesions in the skin, but the most common by far are rather mature types of acute myelogenous leukemia, those classified as M4 and M5 subtypes respectively according to French-American and British classification (FAB) (incidence10%--50%).[
] In our own collection of patients, the vast majority of patients had myelogenous types of leukemias, namely, 21 of 31. In lymphocytic leukemias, involvement of the skin is rather uncommon, it being extremely rare in acute types (incidence 1.3% to 3%) and a little more common in chronic forms.[
] Clinically, lesions of leukemia cutis are said to have no distinctive appearance. Moreover, other skin diseases appear in patients with leukemia, e.g., drug eruptions, viral exanthems, Sweet syndrome, erythema nodosum, extramedullary hematopoiesis, [
] etc., are more common are reported to occur in 30% of patients with leukemia, and leukemia cutis may be confused at first with one of these conditions.
Clinically, lesions of leukemia cutis are said to have no appearance distinctive, but in most instances they are red or livid plaques and nodules devoid of any symptoms. They may present themselves as single lesion or as an exanthem, with predilection usually for the trunk. According to our own experience, cutaneous involvement in myelogenous leukemias presents more commonly in the form of an exanthem, whereas lymphocytic leukemias preferentially present with individual lesions. Lesions of leukemia cutis may resemble inflammatory skin conditions. Clinical differential diagnoses and criteria for differentiation are given in
. In this context it is noteworthy that sometimes leukemic infiltrates may be itchy, as was the case in two patients studied by us.
Histopathologically, leukemia cutis presents itself stereotypically with superficial and deep dense, diffuse, and/or nodular infiltrates. In specimens studied by us, infiltrates were moderately dense in 51% and dense in 32% of the specimens. In moderately dense and dense infiltrate, the pattern was nodular in a quarter of the specimens and diffuse in about half of the specimens. Cells of leukemia are often centered around blood vessels, hair follicles, eccrine glands, muscles, and nerves, and they also are found splayed in between collagen bundles in an "Indian file" pattern. Complete replacement of collagen fibres by leukemic cells is not uncommon. Concentric layering of neoplastic cells around blood vessels in figurate pattern has been described by Kaddu et al.[
] in myelogenous leukemia cutis, but similar figurate pattern can also be found in lymphocytic leukemia cutis around eccrine glands and hair follicles. Often, the papillary dermis is spared in the form of a so-called
(61% of our own cases), for reasons unknown.
Early in the course, however, infiltrates may be sparse and positioned mostly perivascular and periadnexal, as was seen in 17% of the cases studied by us. Whereas, in most instances the epidermis is not involved, leukemic cells may occasionally be encountered in the epidermis, accompanied by spongiosis and edema of the papillary dermis (9 cases of our own). Such manifestations are at risk to be interpreted as inflammatory infiltrates.
Involvement of the subcutaneous fat is quite typical for leukemia cutis (63% of the cases), it taking most often the form of a lobular infiltrate, and of a septal one in some cases. Subcutaneous involvement is almost always associated with extremely dense infiltrates throughout the dermis. Purely subcutaneous infiltrates, however, are a rarity. When infiltrates were dense they often gave the biopsy a rectangular shape similar to what has been described for biopsies of scleroderma adultorum Buschke. Squeeze artefacts, which are often mentioned to be a clue to malignant neoplastic infiltrates, were encountered in 17% of the specimens and made it difficult to assess cytopathologic details. Such squeeze artifacts indicate immature and therefore friable cells of leukemia cutis
Cytopathologically, cells in chronic lymphocytic leukemia tended to be small, whereas they were larger in acute lymphocytic leukemia and in myelogenous leukemias. In myelogenous leukemias, cells may take lymphocytic, plasmacytoid, or histiocytic cytomorphology. In such cases, immunohistochemistry may be of help, myeloblasts being positive for myeloperoxidase consistently. Identification of subtypes of acute myelogenous leukemia was not possible based solely on infiltrates in the skin. Usually, leukemic infiltrates are monomorphous. Pleomorphism is usually moderate it being more marked in acute lymphocytic leukemias than in acute or chronic myelogenous and chronic lymphocytic forms. Mitotic figures and necrotic cells are a common finding but more consistently present in myelogenous variants and they were also more numerous.
Rarely, specimens showed signs of acuteness of a disease process such as edema of the papillary dermis, it being present in just four specimens. Extravasation of erythrocytes was seen in four specimens; in two of them, hemorrhage was accompanied by fibrin deposits in vessel walls and around them.
Diseases to be considered in the differential diagnosis of leukemia cutis as well as criteria for differentiation are shown in
. Clues to the diagnosis of leukemia cutis are presented in
Unfortunately, follow-up information of the patients studied by us was not available to us. Leukemia cutis has been said to indicate poor prognosis of a patient, but, exceptionally, spontaneous remission of skin lesions has been observed, as was seen in one of our patients diagnosed with myelodysplastic syndrome. It must be taken into account that, in a leukemic patient, cells of leukemia may also be found in skin diseases that are not directly a manifestation of the hematologic malignancy. For example, blastic cells may be encountered in lesions of psoriasis[
] or in a drug eruption in a patient with acute myelogenous leukemia and those cells will disappear from the skin when the drug eruption wanes. It is a matter of controversy whether or not Sweet's syndrome in patients with acute myelogenous leukemia should be regarded as leukemia cutis or not.[
] Another example is the presence of atypical lymphocytes in infiltrates in and around epithelial neoplasms such as basal cell carcinoma or squamous cell carcinoma in patients with chronic lymphocytic leukemia. A very special instance is the manifestation of specific infiltrations of the skin at the site of a previous infection with herpes viruses, usually zoster infections. In all those instances, the presence of leukemic cells in the skin is not indicative of a poor prognosis.
leukemic infiltrates in the skin encompass a broad spectrum of clinical and histopathological manifestations that may at times be difficult to tell apart from inflammatory diseases of the skin. Clues to the correct diagnosis include the well known free
below the epidermis, infiltrates in arrector pili muscles, Indian file arrangement of cells, replacement of collagen bundles by cells of an infiltrate, rectangular shape of a biopsy filled with a diffuse infiltrate, squeeze artefact of cells of an infiltrate, concentric layering of cells around preexisting structures, and mitotic figures and individual necrotic cells in a monomorphous infiltrate. The best clue to the correct diagnosis, however, is proper clinicopathological correlation.
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