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Cutaneous T-Cell Lymphoma - 10/18/2012

posted Oct 18, 2012, 6:35 AM by Rohit Das   [ updated Dec 27, 2012, 6:42 AM by Purnema Madahar ]
Cutaneous T-Cell Lymphoma at the Weiler Division, by Rohit Das

At resident report yesterday, the residents went through a case of a woman presenting with insidious onset of a nodular plaque-like, ulcerating rash, diffusely present throughout her body. On biopsy, the lesions were most likely due to Cutaneous T-Cell Lymphoma (CTCL). An interesting diagnosis worth reviewing. Today, I’d like to talk about the epidemiology, pathophysiology, clinical presentation and prognosis of this disorder…and leave the management to the cancer docs.

What is the epidemiology and pathophysiology of CTCL?

·         There are several subtypes of CTCL, but the most common, by far, are Mycosis Fungoides (MF) and Sezary Syndrome (SS). Both are very uncommon malignancies. In the most recent population registries, the case rate in Europe and the U.S. seems to be about 6 cases per million per year, representing 2-4% of all non-Hodgkin’s lymphomas. For unclear reasons, the incidence seems to have increased by 2-3-fold from the 1970s. The peak age of incidence is 55-65 years old. MF is male predominant (about 2:1), and more common in the African-American population.

·         SS is much less common, with registries reporting an incidence of about 0.9 cases per million per year. Though also more common in males, incidence is slightly higher in whites than in blacks, at least in the U.S.

·         The pathophysiology of both MF and SS are not clear. There is conflicting evidence that MF is associated with HTLV-1, with equal studies for and against the concept. Studies have also looked at the role of environmental antigen exposure, bacterial colonization of the skin, and cytokines…though nothing has really panned out definitively. Central to the dermal presentation is the migration of neoplastic T-Cells to the dermis, which is thought to be mediated via T-cell skin-homing receptors (not normally produced) and their interaction with endothelial adhesion molecules.

What are the clinical manifestation of MF and SS? How do they differ?

·         Basically, SS is a much more symptomatic, generalized presentation of MF. Additionally, the diagnosis requires a leukemic involvement of malignant T-cells that clonally match those in the skin. It is thought that SS can either evolve from MF, but also can present de novo with full blown symptomology at presentation.

·         MF if often characterized by a “premycotic period,” where patients can have nonspecific, waxing-waning scaly, diffuse skin lesions for months to decades…some patients may or may not progress to full-blown MF, and skin biopsies of the rash during this period are often negative. The rate to progression to MF is not well defined.

·         MF can have a heterogeneous presentation, which is often characterized by three different types (which are respectively representative of more severe disease) – patch, plaque and tumor subtypes. In regard to distribution, MF can affect any part of the body, but most often presents with a truncal distribution. Patches are usually larger than 5 cm and can vary in shape and color. Plaques represent more infiltrative disease, are more erythematous, have well-demarcated margins, and generally in areas of previous patches. Tumors represent extension into the deep dermis, and are defined as dome-shaped solid masses greater than 1cm in size; ulceration of tumors leads to significant morbidity. A nice pictorial overview is provided on the attached review article.

·         In contrast to these different stages, patients with SS, by definition, have a more generalized erythroderma presentation (>80% involvement of the body surface area) and usually also have peripheral lymphadenopathy. The gestalt is that it is basically on the more severe end of the CTCL spectrum, and seemingly represents a more advanced version of MF.

·         The majority of patients (66%) with MF/SS have pruritis, the severity of which correlates with the extent of skin involvement. Pruritis in these patients can be very disabling, leading to significant morbidity. Extracutaneous disease does occur (around 30% of patients, and much more common in SS) in the lymph nodes, lungs, spleen/liver, and GI tract, and also correlates with the extent of skin involvement. Patients with MF/SS are also relatively immunosuppressed, and have an increased incidence of second cancers, particularly lymphoma.

How is MF/SS staged, and what is the prognosis?

·         Diagnosis is based on skin biopsy usually, though lymph node biopsy or examination of peripheral blood cells can also make the diagnosis in more advanced disease. Staging for MF/SS is the same, and an overview is provided on Table 2 and 3 of the attached review article.

·         Studies have shown that patients with stage 1A MF (<10% patch/plaque involvement withtou extracutaneous disease) have an excellent prognosis and do not have an altered survival as compared to age-matched controls. After 30 years, only 10% of patients progress to more advanced cutaneous disease, and only 1-2% die of their disease. At further stages…more details:

o   Stage IB and IIA – median survival of 15-20 years, with disease progression of 40% at 20 years. Death due to MF occurs in 20% of cases.

o   Stage IIB and III – median survival of 4-6 years, with the majority dying of MF.

o   Stage IVA and IVB – median survival <4 years

·         SS has a worse prognosis, with an overall 5-year survival of around 40%. Studies have identified three adverse indicators, including PAS-positive inclusions in Sezary cells, CD7-negative phenotype, and the presence of large circulating Sezary cells (see the pictorial overview). With 0-1 adverse factors, 5 year survival is 60%; with more, 5 year survival is 5%.

·         Quick word on treatment – stage IA to IIA disease is treated with skin-directed therapy (topical steroids/chemotherapy, UV light, or radiation), while later stage is treated with various systemic agents.

In summary, CTCL exists along a spectrum of disease, with early stage MF at one end, and SS/late-stage MF at the other. Extent and type of skin involvement correlate with prognosis. Patients having early stage disease have an excellent prognosis. Not such a sad diagnosis…If caught/presenting early enough…

Primary Cutaneous T-Cell Lymphoma: Review and Current Concepts
Siegel et. al., J Clin Onc 2000, Volume 18: 2908-2925