Primary Cutaneous and Systemic Anaplastic Large Cell Lymphoma

Anaplastic large cell lymphoma (ALCL) is a biologic and clinically heterogenous subtype of T-cell lymphoma. Clinically, ALCL may present as localized (primary) cutaneous disease or widespread systemic disease. These two forms of ALCL are distinct entities with different clinical and biologic features. Both types share similar histology, however, with cohesive sheets of large lymphoid cells expressing the Ki-1 (CD30) molecule. Primary cutaneous ALCL (C-ALCL) is part of the spectrum of CD30+ lymphoproliferative diseases of the skin including lymphomatoid papulosis. Using conservative measures, 5-year disease-free survival rates are > 90%. The systemic ALCL type is an aggressive lymphoma that may secondarily involve the skin, in addition to other extranodal sites. Further, systemic ALCL may be divided based on the expression of anaplastic lymphoma kinase (ALK) protein, which is activated most frequently through the nonrandom t(2;5) chromosome translocation, causing the fusion of the nucleophosmin (NPM) gene located at 5q35 to 2p23 encoding the receptor tyrosine kinase ALK. Systemic ALK+ ALCLs have improved prognosis compared with ALK-negative ALCL, although both subtypes warrant treatment with polychemotherapy. Allogeneic and, to a lesser extent, autologous stem cell transplantation play a role in relapsed disease, while the benefit of upfront transplant is not clearly defined. Treatment options for relapsed patients include agents such as pralatrexate (Folotyn) and vinblastine. In addition, a multitude of novel therapeutics are being studied, including anti-CD30 antibodies, histone deacetylase inhibitors, immunomodulatory drugs, proteasome inhibitors, and inhibitors of ALK and its downstream signaling pathways. Continued clinical trial involvement by oncologists and patients is imperative to improve the outcomes for this malignancy.

T-cell non-Hodgkin lymphomas (NHLs) represent a heterogeneous spectrum of lymphoid malignancies. While this disease is more common in Asia, there is significant geographic variation in its incidence, which has been attributed in part to risk factors such as human T-cell leukemia virus-1/2 (HTLV-1/2) and Epstein-Barr virus (EBV).[1] In a recent international clinicopathologic lymphoma study from 22 institutions in North America, Europe, and Asia, T-cell and natural killer (NK)-cell lymphomas accounted for approximately 12% of all NHLs.[2] The most common subtypes were peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS; 26%), angioimmunoblastic T-cell lymphoma (AITL; 19%), NK/T-cell (10%), adult T-cell leukemia/lymphoma (ATLL; 10%), and anaplastic large cell lymphoma (ALCL, 12%: anaplastic lymphoma kinase [ALK]-positive 6.5%; ALCL, ALK-negative 5.5%).

ALCL was first described in 1985 based on the large pleomorphic cells expressing CD30, their propensity to invade sinusoids, and the cohesive appearance of the tumor.[3] ALCL occurs as two distinct entities-a widespread systemic disease or a localized (primary) cutaneous disease-with different clinical and biologic features.[4,5] However, both types share similar histology, with cohesive sheets of large lymphoid cells expressing the Ki-1 (CD30) molecule. In a subset of systemic ALCLs the t(2;5) chromosomal translocation occurs, which is known to cause the fusion of the nucleophosim (NPM) gene at 5q35 with the receptor tyrosine kinase ALK gene at 2p23 encoding the NPM-ALK fusion protein.[6-9] The updated World Health Organization (WHO) classification of hematopoietic tumors and lymphoid tissues now recognize this subclassification, dividing systemic ALCL into ALK-positive and ALK-negative disease.[4]

This article will provide a comprehensive review of the morphologic, immunologic, and molecular pathologic features of primary cutaneous-ALCL (C-ALCL) and systemic ALCL, including implications for prognosis. We will also describe standard and newer treatment approaches for patients with ALCL.

Clinical and Prognostic Features

Primary C-ALCL

Primary C-ALCL and lymphomatoid papulosis (LyP) represent a disease spectrum of CD30-positive lymphoproliferative disorders (CD30+ LPD) with many overlapping clinical, histologic, and immunophenotypical features as systemic ALCL.[4,10,11] Primary C-ALCL accounts for approximately 9% of all cutaneous T-cell lymphomas (CTCL) and affects older patients in the sixth decade with a median age of 61 years. It has rarely been described in the pediatric population.[12,13]

FIGURE 1

(A)

Cutaneous anaplastic large cell lymphoma (C-ALCL).

(B)

Pathology of C-ALCL.

(C)

Morphology.

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