Leukemia Cutis Clinical Presentation

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 in narrowing the differential diagnosis.

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.

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.^{[8, 9, 10]}

The specific lesions of leukemia cutis are most often asymptomatic. No pruritus, pain, or tenderness is associated. The exceptions to this are CLL and HTLV-I–induced ATLL, in which significant pruritus can occur. A typical presentation of acute 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, which may be present. Patients may also report swollen lymph nodes.

As mentioned briefly in History, pallor; hepatosplenomegaly; nonspecific findings (eg, purpura, petechiae); drug reactions, including leukocytoclastic vasculitis; and opportunistic infections, particularly thrush, disseminated zoster, or severe and atypical presentations of herpes simplex may be present.

Many cutaneous manifestations of chemotherapeutic agents may occur. Some of the most common 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.

More specific cutaneous lesions of leukemia cutis are typically papules and nodules; indurated plaques, hemorrhagic plaques, perifollicular acneiform papules, macules, ulcers, bullae, and palpable purpura are less frequent. The lesions can range from red-brown to violaceous, or plum. The lesions may be seen in any type of leukemia causing leukemia cutis.

Patients may present with single or multiple nodules in the absence of any systemic findings. The tumors are called granulocytic sarcoma or primary EML. These tumors may appear greenish. They have been aptly called chloromas because of the green pigmentation caused by myeloperoxidase within the myeloid cells.

Note the images below.

More unusual lesions vary depending on the underlying leukemia. Note the following:

• 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.
• In acute myelomonocytic leukemia, leukemia cutis may manifest as leonine facies.^[11]
• Juvenile CML may show figurate or arciform lesions.^[12]
• 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.^[13]
• One case report of hairy cell leukemia with leukemic macrocheilitis and Melkersson-Rosenthal syndrome has been reported.^[14]
• Fingertip hypertrophy consisting of leukemic infiltrates of CLL has also been described.^[15] B-cell CLL has manifested as symmetrical eyelid leukemia cutis.^[16] 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.^[6] 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,^[17] chronic paronychia,^[18] subungual leukemia cutis,^[19] 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).^[20] 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,^[21] 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).^[22]

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 many leukemias. 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.^[23]