Anaplastic large cell lymphoma (T- and null cell) (ALCL)

ANAPLASTIC LARGE CELL LYMPHOMA (T- AND NULL CELL) (ALCL)

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It was originally described in 1985 by Stein et al as a pleomorphic large cell lymphoma with strong membrane and Golgi associated CD30 expression in virtually every cell and prominent involvement of nodal sinuses^ref1,
ref2. The first clinical description was in a series by Kadin et al in 6 children, all of whom had skin lesions^ref. Subsequent studies including adults recognized a disease with a wide morphologic spectrum, young median age, frequent extranodal involvement, and a good prognosis^ref1,
ref2.Prior to that time many cases of ALCL were misdiagnosed as metastatic carcinoma, melanoma, or malignant histiocytosis due to the anaplastic appearance and sinus pattern of infiltration. In the years that followed the initial description of ALCL it became apparent that the clinical and pathologic features of ALCL were heterogeneous (Kinney MC, Kadin ME. The pathologic and clinical spectrum of anaplastic large cell lymphoma and correlation with ALK gene dysregulation. Am J Clin Pathol.1999;111(Suppl.1):S56-S67)^ref.
Epidemiology : the age distribution is bimodal with young and old patients^ref. The different age distribution (years) of ALK⁺ anaplastic large cell lymphoma (ALCL) and ALK^- ALCL^ref

Aetiology : ?
Laboratory examinations : the histology varies from pleomorphic to monomorphic^ref1,
ref2; small cell predominant^ref, lymphohistiocytic^ref; Hodgkin's-like (HD-related)^ref or rarely sarcomatoid (Chan JKC, Buchanan R, Fletcher CDM: Sarcomatoid variant of anaplastic large cell Ki-1 lymphoma. Am J Surg Pathol.190;14:383-390) or neutrophil-rich^ref. Approximately 70-80% of cases had a T or null cell phenotype and 60-70% were epithelial membrane antigen (EMA)⁺, but approximately 20% of CD30⁺ lymphomas were B cell. This heterogeneity in ALCL and the nonspecificity of CD30 expression led to controversy as to whether ALCL was a specific entity. In 1989, a proportion of ALCLs were associated with t(2;5)(p23;q35) chromosomal translocation (Rimokh R, Margaud JP, Berger F, et al. A translocation involving a specific breakpoint (q35) on chromosome 5 is characteristic of anaplastic large cell lymphoma (‘Ki-1 lymphoma’). Br J Haematol. 1989:7:31–36)^ref1,
ref2. Morris et al in 1994 identified the genes involved in the t(2;5), a nucleophosmin (NPM) gene at 5q35 fuses with a gene at 2p23 encoding the receptor tyrosine kinase anaplastic lymphoma kinase (ALK)^ref,
ref2. As a result of the t(2;5) ALK on 2p23 is fused to the strong nucleophosmin (NPM) promoter on 5q35 and the ALK protein, not normally expressed in lymphoid tissue, is present. The NPM-ALK fusion protein can be detected immunohistochemically using antibodies (ALK1 and p80^NPM/ALK) against the ALK protein^ref1,
ref2, and further subdivides ALCL into at least 2 clinical subtypes of ALCL :

ALK⁺ systemic ALCL (30-60% of cases overall (range 13-92%)^ref1,
ref2 (Kinney MC, Kadin ME. The pathologic and clinical spectrum of anaplastic large cell lymphoma and correlation with ALK gene dysregulation. Am J Clin Pathol.1999;111(Suppl.1):S56-S67)). Because the variants are of T or null cell origin and occur in a similar age group as the t(2;5), Falini et al. have proposed the term "ALKoma" for all patients expressing the ALK protein^ref

Epidemiology

Pathogenesis

Stat3

in vitro

in vivo

^ref

IL-9

Jak3

⁺

^ref

Symptoms & signs

^ref

Laboratory examinations

^ref1,
ref2

cytomorphology : morphologic spectrum varying from small (small cell and lymphohistiocytic variants) to large cell predominant (pleomorphic and monomophic) (approximately 80% of monomorphic, 75-100% of small cell, and 30% of pleomorphic histologies are ALK⁺)
immunophenotype : CD3^+/-15^+/-25^+/-30 / Ki-1 Ag⁺43^+/-45^+/-227 / EMA⁺T or null cell, and cytolytic proteins

Therapy

ALK⁺ ALCL tends to respond better to chemotherapy than ALK^- systemic ALCL
allogeneic HSCT in relapsed or chemotherapy-refractory ALCL^ref

ALK^- group : heterogeneous group of lymphomas more similar to PTCLUS in terms of clinical behavior and inferior survival^ref

ALK^- systemic ALCL

Hodgkin's lymphoma related ALCL
secondary ALCL in patients with lymphomatoid papulosis (LyP), mycosis fungoides (MF), rarely Hodgkin's disease (HD)
CD30⁺ large B-cell lymphomas
CD30⁺ ALCL in HIV⁺ patients

primary cutaneous ALCL

features	ALK⁺ systemic ALCL	ALK^- systemic ALCL	primary cutaneous ALCL
T-cell phenotype (occasional cases ALCL CD8⁺/CD4^–)	CD4⁺	CD4⁺	CD4⁺
ALK protein	+	–	–
CD30 / Ki-1 Ag	+	+	+
clusterin	+	+	–
CD227 / epithelial membrane antigen (EMA)	+	–/+	–
cytotoxic proteins: granzyme B, perforin, TIA-1 (T-cell intracytoplasmic antigen)	+ (80%)	+ (50%)	+ (70%)
median age	< 30	> 50	> 50
sex	M > F	M = F	M > F
5-year OS	65–90%	30–40%	> 90%

Prognosis : there has been approximately a 2 fold or higher increase in survival in ALK⁺ ALCL compared to ALK^- ALCL in 3 series^{ref1,
ref2,
ref3}. Other series, however, have not confirmed an improved survival for ALK⁺ ALCL (Greer JP, Flexner JM, Kallianpur AR, et al. Ki-1 anaplastic large cell lymphoma (ALCL): correlation of clinical features with p80NPM/ALK expression and histology (abstract). Blood. 1996:224a). Differences among studies could be due to variable percentages in adverse prognostic factors between groups and due to the younger age of ALK⁺ ALCL; however, an improved survival has been reported for ALK⁺ ALCL over ALK^- ALCL in patients < 30 years of age^ref. Several investigators have since demonstrated that those cases with ALK expression (~60%, ALK-positive) have a 5-year survival that is superior (93%) to those who lack expression (ALK-negative) (37%)^ref. The difference in overall survival between ALK⁺ ALCL and ALK^- ALCL^ref :

Unlike most NHL, no significant differences were observed between ALCL patients with a low or high International Prognostic Index (IPI) in a report of the Non-Hodgkin's Lymphoma Classification Project^ref. These data were based on a small number of patients and did not have information on ALK expression. Subsequent studies have identified a worse prognosis for ALCL patients with an age-adjusted intermediate/high IPI (> 2) compared to the low/intermediate risk group (IPI 0-1)^ref1,
ref2. While therapy for adults has not been consistently stratified according to prognostic features, pediatric groups have based therapy according to risk factors. Therapy for pediatric ALCL has varied from prolonged therapy for ALL to short course combination chemotherapy. Both German and French groups have studies supporting the use of short course therapy developed for B NHL in pediatric ALCL^ref (Bruegieres L, Deley MC, Pacquement H, et al. CD30(+) anaplastic large-cell lymphoma in children: analysis of 82 patients enrolled in two consecutive studies of the French Society of Pediatric Oncology. Blood. 1998;92:35921–3598). After a brief cytoreduction phase, the German group stratified therapy according to stage: 3 5-day courses for St. Jude's stage I and II resected, 6 courses for stage II non-resected and stage III, and six intensified courses, including high dose methotrexate, cytarabine, and etoposide, for stage IV or multifocal bone disease. The 5-year event free survival (EFS) was 76% + 5% for all patients and 100%, 73% + 6%, and 79% + 11% for the three groups, respectively^ref. The French reported a similar EFS of 66% + 12%, but identified visceral involvement, mediastinal disease, and an elevated lactate dehydrogense as adverse prognostic factors (Bruegieres L, Deley MC, Pacquement H, et al. CD30(+) anaplastic large-cell lymphoma in children: analysis of 82 patients enrolled in two consecutive studies of the French Society of Pediatric Oncology. Blood. 1998;92:35921–3598).

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