Cutaneous T-Cell Lymphoma in Sub-Saharan Africa (2024)

Diagnosis

Diagnosis of CTCLs is difficult even in resource-abundant regions of the world. A long follow-up and evaluation of multiple biopsies are often necessary to confirm the diagnosis. If a tumor-stage lesion is present, a biopsy is typically performed to evaluate for large-cell transformation. Otherwise, the most indurated lesion is usually selected. Before a biopsy is performed on an involved early-stage skin lesion, therapy is typically held for 2 to 4 weeks because the treatment effect can obscure the characteristic histologic features, including epidermotropism and the cerebriform nuclear appearance. To facilitate the diagnosis in resource-rich settings, clinicopathologic criteria were proposed by Pimpinelli et al.⁷ Although these criteria can support a diagnosis of MF with clinical and histopathologic findings alone, most cases require adjunctive polymerase chain reaction and/or immunohistochemistry testing, including staining for CD2, CD3, CD4, CD5, CD7, and CD8.⁷

Because cost constraints preclude assessment of multiple immunophenotypic markers in SSA, a consensus was reached that, in resource-limited settings, the combination of characteristic clinical findings, morphologic appearance on hematoxylin-eosin staining, and a positive CD3 or CD4 immunohistochemical result is sufficient to diagnose MF (Table 1). Clearly, new approaches are needed to develop cost-effective methods to increase the diagnostic capacity in SSA.

In addition to overcoming these challenges associated with diagnosing CTCL, an additional potential neoplasm, adult T-cell leukemia/lymphoma (ATLL), should be considered when diagnosing MF in Africa. Human T-cell lymphotropic virus 1 (HTLV-1) is endemic in parts of Africa, Japan, and the Caribbean (Figure 2) and was first identified in cells from a patient diagnosed with CTCL.⁸ Since this discovery, a smoldering clinical subtype of ATLL was described that can mimic CTCL clinically and pathologically.^9-11 According to the Shimoyama classification, these patients may have progressive skin lesions that develop over many years, a normal serum calcium concentration and lactate dehydrogenase level, no visceral organ involvement, and a skin biopsy with small T lymphocytes and even Pautrier microabscesses, just as in CTCL. A diagnosis of smoldering ATLL requires either the presence of greater than 5% abnormal circulating T lymphocytes in the peripheral blood or the histologic confirmation of typical “flower cells” in a T-cell infiltrate (not present in this case).¹² Although the rare patient carries HTLV-1 but has a negative serum antibody test to the virus, this serologic test for HTLV-1 can help differentiate smoldering ATLL of the skin from CTCL. Immunohistochemistry for CD25 may also be helpful, because it is expressed strongly in almost all cases of ATLL. Because HTLV-1 is not endemic in Uganda, these tests were not necessary in the described case.

Treatment

Patients with CTCL are typically divided into early-stage (IA, IB, IIA) and advanced-stage (IIB, III, IV), because the first group should be treated with skin-directed therapy, whereas the latter is treated predominately with systemic therapy (Table 2).

Early-Stage Disease: Early-stage (IA, IB, IIA) CTCL (65%-85% of all patients) is not associated with a change in overall survival when compared with an age-matched population, and early therapy has not been shown to impact the rate of progression. Therefore, the goal of treatment in this setting is to improve symptoms with minimal associated toxicity.¹³ In the absence of significant symptoms, patients with early-stage CTCL can be expectantly managed without additional therapy.

The main therapeutic options for early-stage CTCL in resource-limited settings include topical corticosteroids, radiation therapy, and heliotherapy; heliotherapy generally takes the place of controlled phototherapy, which is usually not available. Topical corticosteroids lead to a complete response (CR) in approximately 60% of patients with T1 disease, with an additional 30% experiencing a partial response (PR). Patients with T2 disease also fare well, with 25% CR and 50% PR rates, respectively.¹⁴

In the setting of diffuse lesions or inadequate response to corticosteroids, heliotherapy should be considered. The optimal dose of heliotherapy, although never specifically studied in CTCL, can be estimated with data from a South African study that measured the natural ultraviolet B (UVB) exposure at meteorologic centers in Cape Town, Durban, and Pretoria throughout an entire year. In patients with Fitzpatrick skin type VI, 0.08 J/cm² is the initial recommended daily treatment dose (0.03 J/cm² in type III skin) for CTCL. Previous studies show that 70% of the minimal erythema dose is effective in treating MF, with the daily dose increased by 15% every 3 days until the maximum tolerated dose (MTD) is reached.¹⁵ This MTD is then maintained throughout the treatment course. To reach these UVB targets with heliotherapy, a patient in Pretoria at 10 am with type VI skin, for example, requires 77 minutes of sun exposure to all affected areas in December, 113 minutes in March, and 228 minutes in June¹⁶ (one-third of this time is required for type III skin in each instance). Because an equatorial country such as Uganda has less seasonal variation and more intense UVB exposure, these durations are likely overestimates for that region, although a significant amount of time is still required to achieve therapeutic UVB doses using natural sunlight, especially in dark-skinned individuals.

Although the availability of radiation therapy is limited in SSA, some centers such as the UCI do have access to this modality, usually with a cobalt-60 source. Prior studies support the efficacy of cobalt-60 radiation for the treatment of CTCL, with the most durable responses reported for lesions treated with at least 3000 cGy at 200 cGy per fraction.¹⁷ Because more recent reports suggest that acceptable disease control (94% CR) is possible with lower doses (400-900 cGy) of radiation delivered in a single fraction,¹⁸ consideration should be given to this approach in SSA to optimize the use of radiation therapy and associated costs.

Second-line options for patients with early-stage CTCL in resource-limited settings include topical chemotherapeutics, such as mechlorethamine or carmustine, and low-dose oral methotrexate (MTX). Although no prospective studies have investigated weekly oral MTX, Zackheim et al¹⁹ described 69 previously treated patients (60 with T2 disease) who received weekly oral MTX, and reported a CR rate of 12% and a 22% PR rate in patients with T2 disease, with a median time to treatment failure of 15 months. Notably, almost half of these patients received another concurrent therapy at the same time as MTX. The median weekly dose was 25 mg with a maximum dose of 75 mg. In patients who did not experience an initial response, the dose was increased until response occurred or dose-limiting toxicity was noted. Seven patients with tumor-stage disease were described in this retrospective analysis, with only 1 PR described, suggesting that this strategy is of limited value in advanced-stage disease.

Advanced-Stage Disease: In contrast to patients with early-stage disease, advanced-stage disease impacts overall survival. Optimal skin care is crucial in these patients because a common cause of death in patients with CTCL is infection originating from the skin. Because therapy is not expected to be curative, optimal control of symptoms while minimizing the risk of infection is the goal of treatment. Because of cost constraints, many agents are not yet available in resource-limited settings (eg, vorinostat, bexarotene, romidepsin, pralatrexate), and therefore this discussion of advanced-stage disease focuses on the use of traditional cytotoxic chemotherapy, such as gemcitabine and doxorubicin.

Duvic et al²⁰ reported an overall response rate of 68% (8% CR; n=25) to gemcitabine at a dose of 1000 mg/m² given on days 1, 8, and 15 every 28 days in patients treated previously with a median of 5 prior regimens. In the front-line setting, Marchi et al²¹ reported a 75% overall response rate (22% CR; n=32) at a dose of 1200 mg/m² given on days 1, 8, and 15 every 28 days for 6 cycles. Toxicities included mild cytopenias, but it was otherwise well tolerated. The median duration of response in those that experienced a CR was 10 months.

Most of the literature on anthracycline monotherapy in CTCL reports on the use of liposomal doxorubicin, with an overall response rate of 56% (20% CR) reported in a prospective study of advanced-stage CTCL.²² Notably, no reports have been published on the response rate to doxorubicin monotherapy in CTCL, because prior studies used this agent in combination regimens.²³ Evaluating the activity of doxorubicin monotherapy could contribute to more cost-effective treatment of CTCL and help lessen the impact of any future shortages of the liposomal variant.

In the setting of refractory or transformed disease with an aggressive growth rate, combination chemotherapy can be considered, as detailed in Table 2. However, extrapolation of the experience with aggressive regimens developed in resource-abundant settings can lead to significant toxicity in SSA. For example, treatment of endemic Burkitt lymphoma in Malawi with a dose-reduced version of the LMB 89 Group B protocol led to a 33% treatment-related mortality compared with less than 1% reported in the original European cohort.^24,25 Therefore, combination regimens should be delivered with caution, and only in centers able to provide adequate supportive care.

Based on the consensus reached at the conference, this patient was treated with gemcitabine at 1000 mg/m² on days 1, 8, and 15 every 28 days, and showed a significant response after 2 cycles with minimal toxicities to date.

The authors have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors.