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Primary Cutaneous and Systemic Anaplastic Large Cell Lymphoma

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]


(A) Cutaneous anaplastic large cell lymphoma (C-ALCL). (B) Pathology of C-ALCL. (C) Morphology.

LyP represents a benign, chronic recurrent, self-healing, papulonodular, and papulonecrotic CD30+ skin eruption.[13] Although 10% to 20% of patients with LyP may develop a lymphoid malignancy, the prognosis is otherwise excellent, showing a 100% 5-year survival. Most patients with primary C-ALCL present with solitary or localized skin tumors (see Figure 1A). Generalized or multifocal lesions are seen in about 20% of the patients.[11] Extracutaneous involvement is seen in 5% to 10% of patients at presentation and most commonly occurs with regional nodal involvement. Site of origin and ALK expression are important prognostic markers. Notably, C-ALCL lesions are known to regress spontaneously. C-ALCL patients have an excellent prognosis, with a 5-year disease-specific survival (DSS) exceeding 90%, as confirmed by several studies.[13,14] A recent report, however, describes a subset of C-ALCL patients with extensive limb disease (ELD) who have a worse treatment and survival outcome compared with patients who do not have ELD.[14] CD30/CD56 coexpression and increased fascin levels have also been associated with disease progression in selected cases.[15,16]

Systemic ALCL

ALCL, systemic type, accounts for approximately 2% to 3% of all NHLs.[17,18] Prior analyses showed that ALK+ ALCL was most frequently diagnosed in men prior to age 35 (male-to-female ratio: 3.0), while ALK-negative ALCL are usually older (median age, 61 years) with a male-to-female ratio of 0.9.[19-21] In a more recent series, Savage et al confirmed the younger median age for ALK+ vs ALK− ALCL (34 years vs 58 years, respectively, P < .001), while the male-to-female ratio was similar between ALK groups.[9] Approximately two-thirds of patients with systemic ALCL are known to have advanced-stage disease at presentation.[9,20,21] Systemic ALCL primarily involves lymph nodes, although extranodal sites may be involved. Based on ALK status, there is a similar distribution of nodal (ALK+, 54% vs ALK–, 49%) and extranodal disease (ALK+, 19% vs ALK–, 21%),[9] although other studies have shown more frequent extranodal disease in patients with ALK+ ALCL.[19-21] The most frequent extranodal sites in ALK– ALCL include bone, subcutaneous tissue, bone marrow, and spleen, whereas in ALK+ patients, the most common sites are skin, lung, liver, bone, and bone marrow.[9] There are rare reports of ALCL presenting as a leukemic disease, typically occurring in children and associated with a poor prognosis.[22] There has also been a recent association of ALCL occurring in women with breast implants. De Jong et al reported an odds ratio of 18.2 (95% confidence interval, 2.1–156.8) for ALCL associated with breast prostheses.[23]

The impact of NPM-ALK expression on patient outcome was first observed by Shiota in 1995.[24] In a series of 57 cases of adult ALCL, including T-cell and null cell phenotypes, 5-year overall survival (OS) was 67%. When stratified for expression of ALK, there was a significant favorable prognosis with ALK positivity, with a 5-year OS of 93% vs 37% (P < .00001) and 5-year FFS of 88% vs 37% (P < .0001).[25] The report by Savage et al confirmed the superior survival of systemic ALK+ ALCL compared with ALK-negative cases (5-year failure-free survival [FFS] 60% vs 36%; P = .015; and 5-year OS 70% vs 49%; P = .016); as previously discussed, however, ALK-positive patients were significantly younger than ALK-negative patients. Moreover, when they limited the survival comparison of ALK-negative and -positive cases to patients older or younger than 40 years of age, there were no differences in FFS or OS.[9]

When histologic subgroups within T-cell lymphoma are compared, most reports have shown that the survival of systemic ALCL is superior to survival of PTCL-NOS. Further, patients with systemic ALK-negative ALCL have a slightly improved survival compared with those who have PTCL-NOS,[26] although not all analyses support this.[21] Savage et al showed that, compared with patients who had PTCL-NOS, ALK-negative ALCL patients treated with curative intent had an improved 5-year FFS (39% vs 20%; P = .011) and 5-year OS (51% vs 32%; P = .028).[9]

Comparison of Clinicopathologic Features of Primary Cutaneous ALCL and Systemic ALCL

The International Prognostic Index (IPI) is an independent prognostic marker that predicts survival in multivariate analysis across all peripheral T-cell lymphomas, including ALCL.[27] It identifies high-risk groups within both the ALK+ and ALK− ALCL subgroups (Table 1).[9] Another prognostic tool known as the ‘prognosis in T-cell lymphoma’ (PIT) scoring system was originally devised for PTCL-NOS patients; it incorporates age, performance status, LDH, and bone marrow involvement.[28] The PIT has also shown to be predictive of progression-free survival (PFS) and OS in ALCL.[9] In addition, expression of CD56, a neural cell adhesion molecule, was shown in a series of 143 patients with ALCL to be a predictor of poor survival (approximate 5-year OS: 28% vs 65%, P = .002).[20] The inferior outcome associated with CD56 was seen with ALK+ and ALK− patients.


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