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Early Detection of Cutaneous Lymphoma

Early Detection of Cutaneous Lymphoma

ABSTRACT: Cutaneous lymphomas comprise a spectrum of diseases characterized by infiltration of the skin by malignant lymphocytes. The clinical manifestations of cutaneous lymphomas vary, and they can mimic benign dermatoses, as well as nodal or visceral malignancies with cutaneous spread. Cutaneous lymphomas are divided into T-cell lymphomas and B-cell lymphomas. Cutaneous T-cell lymphomas include mycosis fungoides, Szary syndrome, lymphomatoid papulosis, CD30+ large cell lymphoma, and adult T-cell leukemia/lymphoma. The extent and severity of skin manifestations in cutaneous T-cell lymphomas are prognostic indicators of extracutaneous involvement. Primary cutaneous B-cell lymphomas comprise 10% to 25% of all primary cutaneous non-Hodgkin's lymphomas and are classified according to their cell of origin. Most cutaneous B-cell lymphomas have an indolent course and excellent prognosis when compared to their nodal counterparts. Many factors have been implicated in the etiology of cutaneous lymphomas, including chemical and drug exposures, as well as microbial agents, such as the Epstein-Barr virus (EBV), human T-lymphocyte virus-1 (HTLV-1), and Borrelia burgdorferi. Immunohistochemistry and lymphocyte-receptor gene rearrangement studies are useful in distinguishing malignant from benign conditions. [ONCOLOGY 12(10):1521-1530, 1998]

Introduction

Primary cutaneous lymphomas encompass a wide spectrum of both T- and B-cell lymphomas. They are the second most common group of extranodal non-Hodgkin’s lymphomas after primary gastrointestinal lymphomas.[1] Primary cutaneous lymphomas have characteristic clinical behavior and histologic features, and their prognosis differs from that of primary nodal lymphomas of the same histologic subtype. Each case of cutaneous lymphoma must be assessed to determine whether it is of primary cutaneous origin or secondary to nodal and/or systemic disease.

Both cutaneous T-cell and B-cell lymphomas are further subdivided into different clinical entities. Within the spectrum of cutaneous T-cell lymphomas, mycosis fungoides is the most common subtype, comprising 50% of cases. Other less common clinical variants are the mycosis fungoides d’emblee variant, Woringer-Kolopp disease, Szary syndrome, alopecia mucinosa, poikiloderma vasculare atrophicans, lymphomatoid papulosis, CD30+ large cell lymphoma, and human T-lymphocyte virus type 1 (HTLV-1)-associated adult T-cell leukemia/lymphoma.

Cutaneous B-cell lymphomas are less common than cutaneous T-cell lymphomas and account for less than 20% of all primary cutaneous lymphomas.[2] Unlike the cutaneous T-cell lymphomas, the different subtypes of cutaneous B-cell lymphoma may appear similar clinically, but they are distinguishable at the histopathologic and molecular level.

Epidemiology and Causation

Cutaneous T-cell lymphoma is observed worldwide and affects both genders. Approximately 1,000 incident cases of cutaneous T-cell lymphoma occur annually in the United States. African-Americans experience the highest incidence rates, followed by Caucasians and Asian-Americans. Both incidence and mortality are higher in men than in women.[3,4]

Environmental Factors: Mycosis fungoides may be causally linked to chemical and nuclear exposures. A recent case-control study was conducted to determine whether exposure to chemicals in the workplace is related to an excess incidence of hematopoietic and lymphoid neoplasms. A positive association was found between exposure to chemicals and death due to non-Hodgkin’s lymphoma, multiple myeloma, and lymphoid leukemia at < 65 years of age.[5]

On the other hand, Whittemore et al found no consistent relationship between occupational or chemical exposure and risk for mycosis fungoides.[6] Another study conducted in Scotland showed no increased risk of childhood leukemia and non-Hodgkin’s lymphoma in cohorts of patients living near a nuclear site, but this study did not specifically mention cutaneous lymphoma.[7]

Infectious Pathogens: Evidence implicating viral infections as possible etiologic or contributing factors has been sought since the isolation of HTLV-1, a type-C retrovirus, from the lymphocytes of a patient with cutaneous T-cell lymphoma[8]. However, the restricted epidemiologic patterns (southwestern Japan, the West Indies, and southeastern United States) of HTLV-1 do not match the patterns of mycosis fungoides/Szary syndrome. In addition, serologic tests for HTLV-1 are negative in the majority of patients with mycosis fungoides/Szary syndrome.

The Epstein-Barr virus (EBV) genome has been found in B-cell lymphoma cells in persons with congenital or acquired immunodeficiency.[9] Chronic infection with Borrelia burgdorferi has also been associated with low-grade B-cell lymphoma,[10,11] while some cases of gastric B-cell lymphoma have regressed after eradication of Helicobacter pylori.[12]

Immunosuppression: Second malignancies occur with greater frequency in patients with cutaneous T-cell lymphoma, perhaps due to the immunosuppressive effect of the disease itself.[13] On the other hand, immunosuppression may be a risk factor for cutaneous T-cell lymphoma. Human immunodefic-iency virus type 1 (HIV-1) infection is associated predominantly with aggres-sive B-cell lymphomas, but mycosis fungoides has now been reported among HIV-1-positive individuals.[14]

Clinical Manifestations

FIGURE 1A

Patch-stage mycosis fungoides on the arm
FIGURE 1B

Tumor-stage mycosis fungoides
FIGURE 2

Parapsoriasis en Plaques—Ill-defined, orange-brown patch of parapsoriasis on the flank

Mycosis fungoides is a low-grade lymphoma of mature CD4+ cells. It is characterized by three phases of evolution: patch, plaque, and tumor. Patients may have lesions from the three different phases simultaneously.

Initially, mycosis fungoides consists of single or multiple, erythematous, scaly patches, occurring mainly over the trunk and extremities (Figure 1A). These patches are often associated with severe pruritus. The patch stage may last from months to years before progressing to the plaque stage.

Plaques are elevated, well-demarcated lesions that are oval or circular in shape. They may regress spontaneously or coalesce to form larger plaques.

In the tumor stage, the neoplastic cells enter a vertical growth phase, leading to the clinical appearance of an expanding nodule (Figure 1B).Tumors of mycosis fungoides have a predilection for the face and skin folds (eg, axillae, groin, and inframammary areas in women). Central necrosis with ulceration can occur, resulting in secondary bacterial infections.

Parapsoriasis en plaques is clinically and histologically indistinguishable from early patch-stage mycosis fungoides. Cutaneous manifestations of the former include red-brown, atrophic, scaly patches with a wrinkled cigarette paper-like surface (Figure 2). The size of these plaques varies from 1 to > 6 cm in diameter, and they typically occur on the trunk. Some authors regard parapsoriasis as a latent prelymphoma with the potential to transform into mycosis fungoides, whereas others believe it is simply an early form of mycosis fungoides.[15]

The d’emblee variant of mycosis fungoides is a rare presentation in which tumors develop de novo without the long progression through patch and plaque stages. Affected patients tend to have an aggressive form of the disease and a poor prognosis.[16]

Woringer-Kolopp disease, also known as pagetoid reticulosis, presents as a single, erythematous, scaly plaque, usually on the extremities. Extracutaneous spread has not been reported.[17]

Szary syndrome, the leukemic variant of mycosis fungoides, constitutes approximately 5% of all newly reported cases of cutaneous T-cell lymphomas. It can arise de novo or as a progression from preexisting mycosis fungoides.

FIGURE 3

Szare Syndrome—Erythroderma with infiltration of the skin by malignant lymphocytes

The malignant CD4+ cells circulate in the peripheral blood and populate the skin, creating diffuse erythroderma (Figure 3). Involvement of the face may lead to marked accentuation of facial folds, referred to as "leonine facies." There may be scaling and fissuring of the palms and soles, alopecia, ectro-pion, loss of nails, and ankle edema. The patient may complain of weight loss and malaise and may also experience fever and chills secondary to poor thermoregulation.

Examination of a peripheral blood smear shows hyperconvoluted lymphocytes with cerebriform nuclei, which, on immunophenotypic analysis, demonstrate a CD4+ CD7- phenotype. Investigators disagree as to how many circulating Szary cells are required to define the syndrome, but most agree that the consistent presence of more than 11% CD4+, CD7- lymphocytes, along with the appropriate clinical findings, can identify the disease.[18] Occasionally, Szary cells are encountered in patients with benign dermatoses, such as psoriasis and atopic dermatitis, and even in healthy individuals.[19]

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