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-cell and NK-cell 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, including lung, testis, oral mucosa, and the CNS, is common; the lymph nodes are usually spared. The histologic appearance, although quite variable, includes proliferation of epidermotropic CD8+ cytotoxic malignant clonal T-cells. Invasion and destruction of adnexal skin structures and angiocentricity are 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.

Cutaneous B-Cell Lymphomas

Primary cutaneous B-cell lymphomas (CBCLs) are rare entities. They constitute up to 25% of all cutaneous lymphomas. However, the incidence of CBCLs has been underestimated because of the absence of immunologic and molecular markers. In addition, their terminology and classification remain controversial, with, until recently, separate and distinct terminology promoted by WHO and EORTC. Primary CBCLs are distinct from nodal lymphomas, and the majority of them have an excellent prognosis. Several types are recognized, with the most common types being follicular center lymphoma and marginal zone lymphoma.

Primary cutaneous follicular center lymphoma

Primary cutaneous follicular center lymphoma (PCFCL) is defined as a proliferation of centrocytes (small to large cleaved cells) and centroblasts (large round cells with prominent nuclei) that show a nodular or diffuse infiltrate in the majority of cases and presenting only rarely a true follicular pattern. PCFCL is the most common subtype of CBCLs, accounting for 40% of CBCLs. PCFCL shows a predilection for the head, neck, and trunk in elderly patients, with a median age of 60 years and a male predominance of approximately 1.5:1. The clinical course is usually indolent, with an excellent overall survival of up to 97%. However, relapses occur frequently. The large round cell morphology might be associated with a higher rate of disease progression and poorer prognosis.

Small centrocytes predominate in low-grade PCFCL, whereas an increased number of large cells occurs in high-grade PCFCL; however, lesions with pure high-grade disease may behave indolently and should not by themselves drive the treatment administered. In contrast to their nodal counterpart, BCL2 is usually not expressed in neoplastic cells, and the t(14;18) translocation is rarely detected. More recently, low rates of BCL2 expression have been reported. In addition to CD10+ and BCL6+ expression, PCFCL also has an aberrant expression of CD45 RA and CD43 and thus provides a helpful clue to distinguish it from pseudolymphomas. Radiation therapy (24-30 Gy) is often the preferred therapy for solitary or localized group lesions. Surgical excision can be considered for small lesions. Chemotherapy, although effective, rarely results in cure. Rituximab has proved to be effective for palliation. Observation is a reasonable alternative in many instances.

Primary cutaneous marginal zone lymphoma

Primary cutaneous marginal zone lymphoma (PCMZL) is a recently recognized low-grade lymphoma and represents the second most common subtype of CBCLs. It predominantly occurs on the upper and lower extremities. The median age at presentation is 55 years, and females are affected more often than males. The reported survival rates are 97% to 100%, although relapses commonly occur. Histologically, PCMZL has features of MALT lymphomas and shows a nodular or diffuse dermal infiltrate with a heterogeneous cellular infiltrate of small lymphocytes, lymphoplasmacytoid cells, plasma cells, intranuclear inclusions (Dutcher bodies), and reactive germinal centers that may be infiltrated by neoplastic cells. Diagnosis can be difficult, because of the variable composition of the infiltrate that may be interpreted as a reactive process or as PCFCL. In contrast to PCFCL, marginal zone lymphoma is negative for BCL6 and CD10. In 50% of cases, CD43 is highly expressed. Large-cell transformation and a head and neck presentation may be associated with a worse prognosis. Therapeutic alternatives are similar to those described for PCFCL.

Primary cutaneous diffuse large B-cell lymphoma, leg type

EORTC and the International Society for Cutaneous Lymphomas consensus recommendations for the management of CBCLs have been published by Senff and coworkers. Primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL, LT) forms a separate category in the WHO-EORTC classification, as a more aggressive type seen in elderly patients, with a median age of 76 years at diagnosis and a female predominance of 7:2. Most cases have a follicle center cell origin, and histologic evaluation shows a diffuse dermal infiltrate with predominance in large B cells with multilobulated nuclei, consisting of centroblasts and immunoblasts, with the presence of small, cleaved cells and a minor admixed infiltrate component. Eosinophilic intranuclear (Dutcher body) or intracytoplasmic (Russell body) inclusions of immunoglobulin are common. Unlike PCFCL, PCLBCL, LT consistently expresses BCL2, although it is not associated with the t(14;18) translocation.

The prognosis is less favorable for PCLBCL, LT than for other CBCLs, with a 5-year survival rate of 50% to 60%. Prognostic factors identified with a poor outcome include the predominance of round cells (centroblasts/immunoblasts) over cleaved cells (centrocytes) in the tumor infiltrate, MUM1 expression, and multiple lesions at presentation. The use of an IPI-based model is required to investigate whether PCLBCL, LT is associated with a poorer prognosis. These lymphomas should be treated as systemic DLBCLs with anthracycline-based chemotherapy. In patients who present with a single, small skin tumor, radiotherapy is a consideration. Rituximab has also been incorporated into combination regimens.

Intravascular large B-cell lymphoma

WHO and EORTC have proposed intravascular large B-cell lymphoma (IVLBCL), or angiotropic B-cell lymphoma, as a provisional entity. This subtype is rare and corresponds to the proliferation of malignant lymphocytes within lumina of small vessels, involving most frequently the skin and CNS. It was previously considered a vascular tumor and referred to as malignant angioendotheliomatosis. Although the majority of cases are of B-cell origin, a few cases of T-cell lineage have been reported. The reason for intravascular localization is not clear, but association with an unknown surface receptor or dysfunction of lymphocyte-endothelial interaction affecting adhesion molecules has been suspected.

IVLBCL is clinically characterized by tender erythematous, purpuric, indurated patches and plaques located on the trunk and thighs, where it can resemble panniculitis. Cases of generalized telangiectasia over normal skin have been reported. Cytomorphology reveals intravascular occlusion of small vessels, filled with large atypical centroblast-like B lymphocytes. IHC shows CD19, CD20, CD45, and CD79a expression. Genotypic analysis has demonstrated clonality, although it may not be positive in every case. Generally, the prognosis of this aggressive type of lymphoma is poor despite the use of combination chemotherapy, because of the initial or secondary CNS involvement. However, rituximab appears to have had a significantly favorable impact on the outcome of patients with IVLBCL.

CD4+/CD56+ Hematodermic Neoplasm

The CD4+/CD56+ hematodermic neoplasm (blastic NK-cell lymphoma) commonly presents in the skin, with nodular and extracutaneous systemic involvement. This rare disorder appears to be derived from a plasmacytoid dendritic cell precursor. T-cell receptor genes are in germline configuration. This entity causes a dismal prognosis (median survival, 14 months) despite intensive chemotherapy. For this reason, this disease is often treated as an acute leukemia. The novel IL-3 (CD123) receptor-directed recombinant diphtheria toxin protein, SL-401, has received orphan drug designation from the FDA.

Plasmacytoma

Primary cutaneous involvement of plasmacytoma is uncommon and generally develops as a consequence of direct spread from an underlying multiple myeloma. It represents 4% of extramedullary plasmacytomas and affects predominantly elderly men, with a median age of 60 years at diagnosis. It is characterized by a monoclonal proliferation of mature plasma cells. Cutaneous plasmacytomas are potentially curable, with a 5-year survival rate of more than 90%. However, the presentation of multiple lesions is an important adverse prognostic factor. Histopathology shows a dense monomorphous dermal infiltrate of plasma cells with a varying degree of maturation and atypia, admixed with few lymphocytes and histiocytes. Neoplastic plasma cells express clonal immunoglobulin, CD38, and CD79a but are negative for CD20. Rarely, amyloid deposition within the tumor is demonstrated, which is more common in secondary cutaneous involvement of plasmacytoma. A recent organized workshop on plasma cell dyscrasias questioned whether these cases are true cutaneous plasmacytomas, represent reactive B-cell infiltrates associated with an infectious etiology, or represent a variant of marginal zone lymphoma with a predominant population of plasma cells. Diagnosis may rely on demonstration of monoclonality by restriction of immunoglobulin light-chain expression. Excision or radiation treatment is most commonly used.