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 myelogenous leukemia. Courtesy of Grant Anhalt, MD.
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 American patient with acute myelogenous leukemia (AML). Courtesy of Mona Mofid, MD.
Diffuse macules and papules on the scalp of a patient with chronic myelogenous leukemia.
Diffuse truncal eruption of infiltrated papules and plaques in chronic lymphocytic leukemia.
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.
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, [34] guttate psoriasis, [35] chronic paronychia, [36] subungual leukemia cutis, [37] 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). [38] 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, [39] 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). [40]
In ATLL, 60% of patients have peripheral lymph node enlargement, 26% have hepatomegaly, 22% have splenomegaly, and 39% have skin lesions.
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Involvement of the face in a patient with acute myelogenous leukemia. Courtesy of Grant Anhalt, MD.
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Red-brown papules can be seen in leukemia cutis. They are confluent in this patient. Courtesy of Nevena Damjanov, MD, and Elizabeth Prechtel.
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Papules and nodules on the face of an African American patient with acute myelogenous leukemia (AML). Courtesy of Mona Mofid, MD.
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A patient with typical plum-colored lesions seen in leukemia cutis. This patient had acute myelogenous leukemia. Courtesy of Grant Anhalt, MD.
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This photograph shows linear areas, which are more violaceous in color, likely due to trauma to the area, such as excoriation, which results in hemorrhage into the skin. Frequent hemorrhage into the skin can make any inflammatory skin lesion appear more violaceous in patients with leukemia. Courtesy of Nevena Damjanov, MD, and Elizabeth Prechtel.
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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.
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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.
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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.
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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.
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Acute promyelocytic leukemia cutis at high power. The round-to-indented nuclei with prominent cytoplasmic granules are evident. Courtesy of Kim Hiatt, MD.
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Photo illustrates leukocyte esterase staining of the cytoplasm of the leukemic cells in acute promyelocytic leukemia. Courtesy of Kim Hiatt, MD.
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Leukemia cutis at low power demonstrating a Grenz zone and intercalation of leukemic cells between collagen bundles. Courtesy of Keliegh Culpepper, MD.
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Infiltration of leukemic cells between collagen bundles.
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Infiltration of dermoepidermal junction by clonal T cells in Sézary syndrome.
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Diffuse macules and papules on the scalp of a patient with chronic myelogenous leukemia.
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Gingival infiltration in a patient with acute myelogenous leukemia.
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Diffuse truncal eruption of infiltrated papules and plaques in chronic lymphocytic leukemia.
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Close-up photo of diffuse truncal eruption of infiltrated papules and plaques in chronic lymphocytic leukemia.
Tables
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 |
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 |
