Imiquimod and the Treatment of Cutaneous T-Cell Proliferative Diseases: At the Threshold

Every medical student knows, as does most of the lay public, that cancer is treated best by eliminating the diseased tissue as early as possible, yet the recommended management schemes for cutaneous T-cell lymphoma (CTCL) rely heavily on suppression, rather than elimination, of the disease. Topical treatment regimens such as mechlorethamine or psoralen plus ultraviolet A radiation are raised in intensity to levels at which the clinical signs and symptoms of the disease are no longer evident. They are then maintained at this level, rather than raising them to the level of maximum tolerated toxicity with the goal of eliminating every cancer cell, as would be done for other regimens for other types of cancer.

The reasons for this discrepancy are rooted in the nature of CTCL itself. Even if one considers only the myriad diagnostic titles within this category, one finds many different diseases, including some entities that are not always included in the various classifications of lymphomas.^[1] Even well defined entities, such as mycosis fungoides, may overlap or coexist with other entities within the group.^[2] More importantly, mycosis fungoides, which is by far the most common of these diseases, is itself heterogeneous, as any physician with experience seeing these cases is well aware. Thus, attempting to accumulate data regarding these entities or their response to any treatment is very challenging. Even if some of them, or some subsets of them, respond to more aggressive treatment early in their course, this may be difficult to prove. It may also be difficult to identify cases in the responsive subsets.

In addition, it is not clear whether some of these diseases are even cancers, at least early in their course. For example, it has been proposed that mycosis fungoides is a disease of "antigen persistence,"^[3] or is a viral infection,^[4] especially one involving epidermal Langerhans cells^[5] in which the proliferating T-cells are responding to an antigenic signal rather than multiplying independently as is characteristic of cancer cells. Some years ago I proposed a model, the "Thymus Bypass Model," in which bone marrow-derived cells destined to migrate to the thymus migrate instead to the skin, which, like the thymus, has a cornified epithelium.^[6] The normal process in the thymus is for these cells to proliferate rapidly while undergoing gene rearrangements, following which most of the cells, including those that recognize self antigens, undergo apoptosis while others become T-cells. According to this model, the T-cell precursor cells that migrate from the bone marrow to the skin do not develop normally there but give rise to abnormal clones that eventually may become malignant. Relevant to some of these models is the observation that T-cells in at least some cases of CTCL are markedly unstable cytogenetically, giving rise to large numbers of cells with different clonal chromosomal anomalies.^[7] These cells are referred to as "geno-traumatic" T-cells. This finding has been confirmed in subsequent investigations.^[8]

While it was once thought that the demonstration of clonality of T-cells within lesions would identify them as cancers and distinguish them from inflammatory conditions, more sensitive techniques have identified T-cell clones within numerous lesions of nonmalignant diseases, including, for example, pityriasis lichenoides.^[9] Moreover, demonstration of clonality within cases of mycosis fungoides using the older, less sensitive technique of Southern blotting has not been associated with a worse prognosis. Thus, demonstration of clonality, while sometimes useful diagnostically in combination with other factors, does not prove that a lesion is malignant or even potentially malignant, although it may suggest that some of the alternate models proposed to account for mycosis fungoides may also apply to some of these other diseases.

Whatever the nature and classifications of the diseases encompassed within CTCL, the introduction of imiquimod into the therapeutic arsenal is most welcome. Although many patients with these diseases do very well with existing treatments, some do not, and others experience complications of treatment. The paper by Gaspari in this issue of SKINmed^[10] reporting a good result treating Stage IB disease with imiquimod represents a significant advance in the treatment of CTCL. It also confirms a previous report of successfully treating Stage IA dis-ease with this agent. The mechanism is unclear, and given the heterogeneity of CTCL, it may be that this immunomodulator acts by more than one mechanism and/or by different ones in different patients. It may also be effective against other diseases that have been shown to be associated with T-cell clonal activity. We are at the threshold of potentially revolutionary new therapeutic advances as well as basic science discoveries based on studies that are either investigating this exciting new agent or using it as an experimental tool. If you are an interested investigator, the time to climb on board is now; if you are a clinician, stay tuned.

Skinmed. 2003;2(5) © 2003 Le Jacq Communications, Inc.

Cite this: Imiquimod and the Treatment of Cutaneous T-Cell Proliferative Diseases: At the Threshold - Medscape - Sep 01, 2003.