Leukemia Cutis Clinical Presentation
- Author: Kyle Devins; Chief Editor: Dirk M Elston, MD more...
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.[22, 23, 24]
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. Skin involvement may be general or localized to one region. Others have reported flesh-colored nodules, occasionally with central ulceration. 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.
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.
Juvenile CML may show figurate or arciform lesions.
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.
Fingertip hypertrophy consisting of leukemic infiltrates of CLL has also been described. B-cell CLL has manifested as symmetrical eyelid leukemia cutis. 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. 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, guttate psoriasis, chronic paronychia, subungual leukemia cutis, 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). 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, 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).
In ATLL, 60% of patients have peripheral lymph node enlargement, 26% have hepatomegaly, 22% have splenomegaly, and 39% have skin lesions.
Both a genetic component and an environmental component appear to be involved in the pathogenesis of many types of leukemia. A variety of well-characterized chromosomal translocations result in specific leukemic syndromes.
Patients with Down syndrome have an increased risk for both megakaryoblastic leukemia and pre–B-cell leukemia.
Other genetic syndromes, including Bloom syndrome, Klinefelter syndrome, Wiskott-Aldrich syndrome, and Fanconi syndrome, have shown an increased incidence of leukemia.
CLL shows some familial tendency in approximately 20% of CLL cases.
Several genetic mutations lead to an asymmetric maturation of stem cells and result in a single clonal expansion of a severely defective stem cell. The specific mutations and phenotypic changes resulting from genetic aberration determine the subtype of leukemia. After the development of the leukemic clones, a tissue-selective homing process that leads to the infiltration of malignant cells into the epidermis, the dermis, the subcutaneous fat, and the mucosa occurs.
The molecular basis responsible for the development of leukemia cutis is not yet defined. However, initial cytogenetic studies are starting to provide insightful information that would lead to a better understanding in the pathophysiology of leukemia cutis. Prior studies have demonstrated that as many as 50% of patients with AML-M4 or AML-M5 develop leukemia cutis and other forms of EML. Karyotypic studies of leukemic cells have demonstrated the translocation of chromosomes 8 and 21 t(8;21) in these subtypes of AML. A strong association exists between aneuploidy of chromosome 8 and leukemia cutis. Other cytogenetic abnormalities noted in leukemia cutis are chromosome 3 translocations and t(6;9)(p23;q34). Chloromas, primary EMLs are associated with t(8;21), t(9;11) and inv(16) translocations. Identification of proteins coded by specific genes located in those chromosomes would assist in defining factors responsible for the development of leukemia cutis.
Environmental exposures may increase the risk of leukemia. Benzene exposure increases one's risk for AML. Ionizing radiation exposure may increase the risk of leukemia as well, particularly AML, CML, and ALL. Alkylating agents used in chemotherapy cause an increased risk of subsequent AML. The use of all trans retinoic acid to treat APL may predispose a patient to increased risk of extramedullary involvement, including leukemia cutis, which is otherwise rare in APL. Other leukemias may be caused by viral infection. These include ATLL, caused by HTLV-I and acute B-cell leukemia and large granular lymphocytic leukemia, which may be the result of Epstein-Barr virus infection.
Secondary leukemias are associated with prior hematologic disorders such as myelodysplastic syndrome or myeloproliferative disease. Therapy-related acute leukemia results from genetic damage sustained from prior radiation therapy or chemotherapy for malignancies. These are associated with the use of alkylating agents and type II topoisomerase inhibitors, and they differ from primary leukemias clinically and cytogenetically and carry a poor prognostic outcome. Therapy-related secondary leukemia with leukemia cutis as a result of chemotherapy has rarely been reported.
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|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