Non-Hodgkin Lymphoma

Cutaneous T-cell lymphomas

Cutaneous T-cell lymphomas (CTCLs) constitute a group of cutaneous NHLs with clonal expansion of T lymphocytes into the skin. Several entities are recognized by the combined EORTC and WHO classification, which is based on morphologic, histopathologic, and molecular features (Table 15). The frequency and disease-specific survival rates differ for each entity.

Mycosis fungoides/Sézary syndrome

Mycosis fungoides and its variants represent the most common type of CTCL, comprising 50% of CTCLs, with a male predominance of approximately 2:1 and a predominance of African-American patients of 1.6:1. It has a yearly incidence of 0.36 cases per 100,000 population that has remained constant over the past decade. Clinical and histologic diagnosis of mycosis fungoides has proved to be difficult, because in early stages, it may resemble other dermatoses such as eczematous dermatitis, psoriasis, and parapsoriasis.

Clinically, mycosis fungoides is characterized by erythematous patches, evolving into plaques or tumors; however, the progress is variable. It is classified as an indolent lymphoma by the EORTC. The neoplastic cells have a mature CD3+, CD4+, CD45RO+, CD8– memory T-cell phenotype. Sézary syndrome is the aggressive, leukemic, and erythrodermic form of CTCL, which is characterized by circulating, atypical, malignant T lymphocytes with cerebriform nuclei (Sézary cells), and lymphadenopathy. Circulating Sézary cells also have a mature memory T-cell phenotype with loss of CD7 and CD26. For staging purposes, the tumor node metastasis (TNM) system is most commonly used (Table 16).

Investigative and recently approved options that have shown activity against mycosis fungoides/Sézary syndrome include the histone deacetylase inhibitors vorinostat (Zolinza, FDA approved), romedepsin (Istodax, FDA approved), and panobinostat; the novel antifolate pralatrexate; the proteasome inhibitor bortezomib(Drug information on bortezomib); and monoclonal antibodies targeting CD4 (zanolimumab), CD2 (siplizumab), and CD30 (SGN-30).

Treatment of early-stage disease At present, CTCLs are regarded as incurable. In early CTCL, the cell-mediated immune response is usually normal. Therefore, the majority of these cases can be treated successfully with topical modalities. Early aggressive therapy does not improve the prognosis of patients with CTCL. The skin-targeted modalities include psoralen plus ultraviolet A (PUVA); narrow-band ultraviolet B (NB-UVB); skin electron-beam radiation therapy; spot radiation therapy; as well as topical preparations of steroids, retinoids, carmustine, or nitrogen mustard (Table 17). Radiation therapy prescriptions may be similar to those for other lymphomas or may be delivered at high doses in limited fractions.

Treatment of advanced-stage disease A limited number of patients progress to more aggressive and advanced disease with either cutaneous or extracutaneous tumor manifestations. Treatment goals in advanced stages should be to reduce the tumor burden, relieve symptoms, and decrease the risk of transformation into aggressive lymphoma. Established treatment options include mono- or polychemotherapy including CVP, CHOP or ESHAP regimens, extracorporeal photopheresis, interferons, retinoids and rexinoids (bexarotene [Targretin] capsules), histone deacetylase inhibitors (vorinostat and romidepsin), novel antifolates (pralatrexate), monoclonal antibodies (alemtuzumab), and recombinant toxins (denileukin diftitox). Combinations are frequently used (Table 17). Select patients with progressive and recalcitrant disease have been cured with an allogeneic SCT.

TABLE 15
The WHO–EORTC consensus classification for primary cutaneous lymphomas with relative frequency and 5-year survival

Primary cutaneous CD30+ lymphoproliferative disorders

Primary cutaneous CD30+ lymphoproliferative disorders are the second most common group of CTCL, representing approximately 30% of CTCLs. This spectrum of diseases includes lymphomatoid papulosis, ALCL CD30+ cutaneous type, and borderline cases. The distinction between these entities can be challenging and is often made based on clinical behavior.

Lymphomatoid papulosis

TABLE 16
Stage classification for mycosis fungoides and Sézary syndrome

Lymphomatoid papulosis is most commonly associated with mycosis fungoides, CD30+ large T-cell lymphoma, and Hodgkin lymphoma. Three histologic types have been identified, characterized as types A, B, C, and D. Types A and C consist of large lymphocytes resembling Reed-Sternberg cells. Type A cells are embedded in a dense inflammatory background, whereas type C cells form large sheets imitating CD30+ large T-cell lymphoma. Type B simulates classic features of mycosis fungoides, with epidermotropism and a dermal band-like infiltrate composed of small to medium cells. Type D is CD8+. Lymphomatoid papulosis lesions occasionally exhibit clonal gene rearrangements.

Lymphomatoid papulosis represents a benign, chronic recurrent, self-healing, papulonodular, and papulonecrotic CD30+ skin eruption. However, 10% to 20% of patients may develop a lymphoid malignancy, but the prognosis for patients with lymphomatoid papulosis is otherwise excellent, with a 5-year survival of 100%. There is no curative treatment available. Lymphomatoid papulosis is managed by observation, intralesional steroid injection, topical bexarotene, ultraviolet light therapy, or low-dose methotrexate.

Anaplastic large cell lymphoma, CD30+ cutaneous type

TABLE 17
Treatment options for cutaneous T-cell lymphoma by stage

Primary systemic CD30+ ALCL and primary cutaneous CD30+ ALCL represent identical morphologic entities, but they are clinically distinct diseases.

The neoplastic cells of primary cutaneous CD30+ ALCL are of the CD4+ helper T-cell phenotype with CD30 expression. It represents 9% of CTCLs and typically presents with solitary or localized nodules. This tumor has an excellent prognosis, as confirmed in several studies, in contrast to the transformation of mycosis lymphoma to a CD30– large cell variant. It shows histologic and immunophenotypic overlap with lymphomatoid papulosis. In most cases, tumor cells show anaplastic features, less commonly a pleomorphic or immunoblastic appearance. However, there is no difference in the prognosis and survival rate. Primary CD30+ ALCL rarely carries the t(2;5) translocation and is usually ALK-negative. These lesions may undergo spontaneous regression, as do the lesions of lymphomatoid papulosis. The mechanism of tumor regression remains unknown.

Local radiation therapy or surgical excision is the preferred treatment, with systemic chemotherapy reserved for cases with large tumor burden and extracutaneous involvement. More recently, there has been reported efficacy of recombinant IFN-γ-1b (Actimmune) and combined treatment with bexarotene and IFN-α-2a (Roferon-A). Naked anti-CD30 monoclonal antibodies (SGN-30) and immunoconjugates (SGN-35–targeting tubulin) have shown promising activity against this lymphoma. Durable responses have also been witnessed after Doxil treatment.

Subcutaneous panniculitis-like T-cell lymphoma

Subcutaneous panniculitis-like T-cell lymphoma (SCPTCL) is a rare T-cell lymphoma that infiltrates the subcutaneous fat without dermal and epidermal involvement, causing erythematous to violaceous nodules and/or plaques. Approximately 20% of patients have an associated autoimmune disease, most commonly systemic lupus erythematosus. Systemic symptoms are frequent and include weight loss, fever, and fatigue. The disease may be complicated by the hemophagocytic syndrome. SCPTCL may be preceded by a benign-appearing panniculitis for years. The infiltrate is pleomorphic and associated with inflammation and necrosis. The T-cell phenotype is α/ß+ with CD4(+/–), CD8+, and CD56(–/+). Standard treatment has historically included CHOP-like chemotherapy. However, recent data suggest patients can be controlled for long periods with local radiation treatment and/or steroids. Five-year survival rates exceed 80%.

Cutaneous γ/δ T-cell lymphoma

Cutaneous γ/δ T-cell lymphoma is a rare panniculitis presenting with disseminated (ulcerated) plaques, nodules, or tumors. Involvement of mucosal or extranodal sites is common. Systemic symptoms, including weight loss, fever, and fatigue, are almost always present. The hemophagocytic syndrome is often noted. The γ/δ+ T cells are characteristically CD2+, CD3+, CD4–, CD5–, CD7(–/+), CD8(–/+), and CD56+. Aggressive chemotherapy is indicated, with consideration of autologous or allogeneic SCT incorporated into the initial treatment schema. The median survival is less than 2 years.

Pleomorphic T-cell lymphomas with small/medium cells

The small/medium pleomorphic CTCL type appears clinically with single erythematous to violaceous nodules or tumors and accounts for less than 3% of CTCL cases. Most cases have an unfavorable prognosis, with a median survival of ≤ 24 months; however, the CD3+, CD4+, CD8–, CD30– subtype with limited lesions might be associated with a better prognosis, with a reported 45% 5-year survival rate.

The optimal therapy for pleomorphic T-cell lymphomas with small/medium cells has not been defined. Localized lesions have been treated with radiation therapy or surgical excision. Only short-term outcome has been reported. Patients with generalized skin disease or progression have been treated effectively with systemic treatments, including multiagent chemotherapy, retinoids, interferons, and monoclonal antibodies.

Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma

Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma is currently a provisional entity in the WHO classification of mature T and NK neoplasms. It is a rare disease accounting for less than 1% of CTCL. Most patients are adults and present with generalized papules, nodules, hyperkeratotic patches, and/or plaques. Central ulceration and necrosis is common. Dissemination to other visceral sites is common including lung, testis, oral mucosa, and the CNS, usually sparing the lymph nodes. The histologic appearance though quite variable includes proliferation of epidermotropic CD8+ cytotoxic malignant clonal T-cells. Invasion and destruction of adnexal skin structures and angiocentricity is common.

An aggressive clinical course is typical with a median survival of less than 3 years. Combination chemotherapy rarely provides a sustained remission. Antifolates can be effective in some patients. Allogeneic SCT should be a consideration in medically fit patients.