Primary cutaneous FL and MZL are cutaneous lymphomas with an indolent course despite the high rates of recurrence. It is therefore important to highlight that treatment should not be aggressive in most cases. The recommendations for management of LF and MZL include withholding treatment (watchful waiting), RT, surgery, or intralesional interferon alfa.3 Sometimes, however, large, painful, disfiguring, or itchy multiple lesions may be present; watchful waiting is not an option and treatment should be administered. Moreover, in these situations, local skin interventions, such as surgery or RT, are not appropriate, particularly in the case of multiple lesions or lesions on sites such as the face or neck where the interventions might leave substantial esthetic sequelae. In these circumstances, other treatment alternatives, among them systemic or intralesional rituximab, have been used.

Tables 2 and 3 summarize the published cases of FL and MZL, respectively, treated with systemic rituximab. Table 4 summarizes the cases of FL and MZL treated with intralesional administration of rituximab.

In total, 44 cases have been published of cutaneous FL treated with intravenous rituximab (Table 2).13–24 Regimens have ranged from the usual 4 infusions, once a week, with standard doses of 375mg/m2 to courses of up to 10 infusions. The complete response rate for all the published cases is approximately 77%, with a response duration ranging from 6 to 57 months. For MZL, 16 cases of systemic rituximab treatment have been published (Table 3),14,18,21,25,26 with an overall complete response rate of 43% and a duration of response of between 6 and 75 months.

This apparently worse response to rituximab in patients with MZL is pending confirmation in the future in large prospective studies; if real, the difference could be due to several mechanisms that confer resistance to rituximab. A study has been published describing the lack of efficacy of rituximab in patients with noncutaneous MZL who also received chemoimmunotherapy.27 One of the hypotheses is that malignant B cells acquire new mutations that confer resistance to rituximab-induced apoptosis. Thus, in a study of 4 patients with recurrent disease, an increase in bcl-2 activity was observed after rituximab treatment.28 Variations in the site of B-cell binding to rituximab have also been seen. Patients with certain genotypes at the antibody binding site appear to respond better to treatment with rituximab and disease-free periods are longer. This polymorphism in the expression of the CD20 antigen in malignant B cells may define a subgroup of patients with innate resistance to rituximab.29

Recurrences after treatment with intravenous rituximab, in both patients with FL and with MZL, are frequent (20% and 50%, respectively). However, recurrences of CBCL are frequent with all treatment types except surgery and RT.3 Thus, authors such as Gellrich et al.18 propose more prolonged treatments of 8 cycles instead of 4, as better response rates (90%) and remission rates are obtained; however, the benefits of prolonging treatment are not clearly demonstrated due to the small number of patients studied. In a subsequent study of 16 patients, Valencak et al.23 reported complete response in 62% of indolent CBCL treated with intravenous rituximab and proposed that 4 cycles would be sufficient. The authors highlighted the lack of studies that support the need to extend treatment. Likewise, the published studies do not provide clear indications as to whether re-treatment with rituximab after recurrence might be beneficial, as has been demonstrated in systemic FL.30,31

Most studies define complete response as disappearance of all cutaneous lesions, which are assessed clinically with regular follow-up of the patients. Some studies have, however, also evaluated histologic response of the lesions14,18,25 by means of a skin biopsy after treatment. These studies report the presence of an infiltrate of CD8-positive T cells,14 with decreased CD20 expression.25 Gellrich et al.18 took biopsies from 8 of the treated patients with complete response and found that despite a complete clinical response, only 6 had complete histologic response.

Intravenous treatment with rituximab is safe and generally well tolerated, particularly in comparison with other traditional chemotherapeutic agents. The adverse effects are summarized in Table 5.32 The most frequently reported cutaneous effects are mild, usually in the form of rash or urticaria, which occur in approximately 15% of patients. Serious side effects such as paraneoplastic pemphigus or Steven-Johnson syndrome appear in fewer than 2%. Of interest is the occurrence of wheals around the skin lesions in FL treated with systemic rituximab; this is thought to be due to the release of inflammatory cytokines.13,19 The risk of reactivation of hepatitis B virus is also of particular interest in patients with chronic infection as the event can potentially be fatal.26,33 The American Hepatology Guidelines recommend the use of lamivudine as prophylaxis for up to 6 months after finishing treatment with intravenous rituximab in carriers of HbsAg.34 Some authors suggest this prophylactic period should be extended to up to 2 years after finishing treatment, given that late reactivation of hepatitis B has been reported.26

In most studies, intravenous rituximab is considered the treatment of choice for multifocal lesions and also for lesions on the face and scalp, as RT may cause alopecia and irreversible cutaneous effects, such as poichyloderma or atrophy.19,26

In recent years, the use of intralesional rituximab has become widespread for FL and MZL. The aim is to make treatment more comfortable and accessible while minimizing side effects (Figs. 1 and 2). The published cases of treatment of FL and MZL with intralesional rituximab are summarized in Table 6.17,21,35–40 The complete response rates with this treatment in indolent B-cell lymphomas are somewhat greater than those achieved with intravenous administration. Response rates range from 83% to 89%, but the recurrence rate after treatment remains high (40% to 62%).3 In most studies, regimens of between 10 and 30mg per lesion (diluted to 10mg/mL) are used, up to 3 times a week and in cycles of up to 12 weeks, according to response. The most frequently reported side effect is injection-site pain.17,21,35–39 Of particular note given the large number of patients included is a recent study published by the Spanish Cutaneous Lymphoma Group, who retrospectively analyzed the outcomes of intralesional rituximab treatment of indolent cutaneous B-cell lymphoma in several hospitals.40 A total of 35 patients were included, 17 with MZL and 18 with FL. A mean of 2 lesions were treated per patient. Most patients were treated with 3 injections per week for 1 week in every month. A complete response rate of 74% was found—slightly below that reported in previous studies.3 Mean disease-free survival was 114 weeks. Side effects were detected in 54% of the patients, with the most common being injection-site pain. A small number of patients had fever presenting between 6 and 12 hours after the injection, although the effect was transient and observed most often in the first injections. Some of the most important findings in this study are that there were no apparent factors predictive of response or differences in responses according to underlying disease (MZL or FL), in contrast to the case when the drug is administered systemically.

Figure 1.

Image of a patient with marginal zone lymphoma in the leg.

(0.1MB).

Figure 2.

Resolution after 3 injections, each a week apart, of intralesional rituximab (10mg/mL).

(0.08MB).

The conclusion from these studies is that intralesional use of rituximab is becoming more widespread in selected patients with low-grade CBCL in view of the convenience, lower dose, and fewer side effects.

CDLBCL-LT occurs less frequently than the other 2 types of CBCL discussed above. This type accounts for approximately 1% to 3% of all primary cutaneous lymphomas and, unlike FL and MZL, follows a more aggressive course with frequent extracutaneous spread and recurrence after treatment. Prognosis is intermediate with a 5-year survival rate of approximately 50%.3 Factors indicative of poor prognosis in cutaneous large B-cell lymphomas include onset at an early age, ulceration, and positive staining for multiple myeloma oncogene (MUM) 1 and bcl-2, while expression of bcl-6 is associated with good prognosis.41 However, these findings are open to debate because the series of cutaneous large B-cell lymphomas include some forms of FL, which is typically bcl-6 positive and has a better prognosis. In contrast, CDLBCL-LT is typically MUM-1 positive and has a worse prognosis. The expression of one of these proteins may not therefore be a prognostic factor in itself, but rather related to diagnosis of 2 different lymphomas with different prognoses.

The guidelines for management of CBCL, issued by the EORTC, recommend treatment of CDLBCL-LT with polychemotherapy with or without rituximab (cyclophosphamide, hydroxydaunorubicin, Oncovin, prednisone [CHOP]-like or R-CHOP regimens). In localized disease, the recommended treatment is RT, which shows good response rates.3 There are 25 cases in the literature of CDLBCL-LT treated with rituximab in monotherapy (summarized in Table 6).13,16,42–50 Regimens of 4 to 8 infusions were used with or without local RT in the tumors. The complete response rate of the published cases is 48%, but this response is only maintained for more than 6 months in 4 of the patients, that is, 18%, and so recurrences after treatment are frequent (82%). In all cases, treatment was well tolerated, without significant side effects.

The role of rituximab as monotherapy in CDLBCL-LT is not well defined; the results reported in the literature suggest that there is a marked initial response but recurrences and disease progression are frequent.

The recommended treatment with CHOP or CHOP-like polychemotherapy in CDLBCL-LT obtains complete response rates of 81%, but once again recurrence rates are high at 54%.3 Some authors therefore recommend the use of intravenous rituximab as a less aggressive option that is better adapted to older patients.16,43,45,49 Despite the recommendations of the WHO-EORTC, some authors have wondered whether intensified treatments with greater toxicity really improve prognosis in these patients. Most suggest that the treatment of choice should be tailored and adapted to the age of the patient, with rituximab considered as a palliative measure.

There has been a report of a case of cutaneous intravascular large B-cell lymphoma treated with R-CHOP with complete clinical and histologic response maintained for 6 months. These results appear promising, as this is a very aggressive lymphoma. However, given the rarity of the condition, it is difficult to establish treatment protocols.51

There is also a published case of pseudo-B-cell lymphoma refractory to conventional therapies that responded well to intralesional rituximab.52

The authors declare that no experiments were performed on humans or animals for this investigation.

The authors declare that they have followed their hospital's protocol on the publication of data concerning patients and that all patients included in the study have received sufficient information and have given their written informed consent to participate in the study.

The authors declare that patient data do not appear in this article.