Anaplastic large cell lymphoma (ALCL) is a type of non-Hodgkin lymphoma that features in the World Health Organisation (WHO) classification of lymphomas. Defining features consist of a proliferation of predominantly large lymphoid cells with strong expression of the cytokine receptor CD30 and a characteristic growth pattern. ALCL can be classified in three distinct forms:
- Systemic ALCL, ALK positive, which affects children or young people
- Systemic ALCL, ALK negative, which affects older people
- Primary cutaneous ALCL
Primary systemic ALCL is the most frequent subform, accounting for 2% to 8% of non-Hodgkin lymphomas in adults and approximately 20%-30% of large cell lymphomas in children.
ALK+ ALCL mostly occurs in the first 3 decades of life with male predominance being particularly striking in the second and third decades of life (male/female ratio 6.5). This lymphoma frequently presents as an aggressive stage III to IV disease, usually associated with systemic symptoms (75%), especially high fever. Extranodal involvement is frequent (60%), with approximately 40% of patients showing 2 or more extranodal sites of the disease.
ALK- systemic ALCL occurs in older individuals and is associated with a lower male/female ratio (0.9), as well as a lower incidence of stage III to IV disease. It showed a poorer prognosis than ALK+ ALCL.
Primary cutaneous ALCL arises de novo in the skin and affects older patients with a median age of approximately 60 years. It accounts for approximately 9% of cutaneous lymphomas.
The first sign of systemic ALCL is often a painless swelling in the neck, armpit or groin, caused by enlarged lymph nodes. Often, more than one group of nodes is affected. This lymphoma may also occur in skin and sometimes in other organs such as the lungs, liver, bone marrow or bones. Some people experience a loss of appetite and tiredness.
Other symptoms, known as B symptoms, typical for aggressive lymphomas, include weight loss, significant sweats at nighttime and unexplained fevers.
Disease limited to the skin is quite slow growing (indolent). ALCL primary cutaneous type, manifests as a solitary nodule or ulcerating tumor in patients without a history of or concurrent Mycosis Fungoides (MF) or lymphomatoid papulosis (LyP) and no evidence of disease outside the skin. The appearance of the tumor varies among patients from a small raised discolored papule to a larger tumor. Lymph nodes in the same region are involved 25% of the time.
The diagnosis can be made with certainty by a biopsy of an involved lymph node or another involved organ.
In common variant of systemic ALCL,tumor cells have a distinctive morphology that includes large cells with eccentric, horseshoe, or kidney-shaped nuclei. Cells with these cytologic features have been called hallmark cells because they are encountered in all ALCL variants, including the small cell and lymphohistiocytic variants. Invagination of cytoplasm into the nucleus of tumor cells creates the en face appearance of doughnut cells. Other distinctive cell types are multinucleated cells with a wreath-like arrangement of nuclei and cells with huge nucleoli resembling Reed-Sternberg cells of Hodgkin’s lymphoma.
A common variant with a diffuse monomorphic pattern lacking giant cells had been associated with a poorer prognosis, older age, and frequent bone marrow involvement in a clinicopathologic study preceding identification of the ALK protein.
We recognize also:
• A small cell Variant, which is characterized by a mixture of small, medium-sized, and large lymphoid cells. The nuclei of the small and medium-sized cell population are often irregular. Large cells surrounding small vessels are a frequent and characteristic finding. This is particularly evident following immunostaining for CD30, which highlights the large anaplastic cells. In contrast, heterogeneity is seen in CD30 expression in the smaller cell population, with many small cells being CD30- (more commonly) or weakly positive
• A lymphohistiocytic Variant, in which there is a large number of histiocytes, that may mask the anaplastic tumor cell population; the latter can be highlighted by CD30 immunostaining
• An Hodgkin’s-Like ALCL, characterized by collagen bands surrounding lymphoid nodules containing Reed-Sternberg or Reed-Sternberg like cells.
Tumor cells of all ALCL cases show a strong expression of CD30 on the cell membrane and in the Golgi region. The analysis of conventional T- and B-cell markers revealed 3 immunophenotypes, with the T-cell type being the most frequent.
ALCL is immunophenotypically characterized by the sustained expression of CD30 and in ALK+ ALCL the transcription of CD30 is upregulated by ALK through the ERK1 and ERK2 pathway, which induces the expression of JUN-B, and by phosphorylated STAT3. It is possible to found the breakpoint in the ALK gene at 2p23 by FISH. Systemic ALCL is also characterized by the expression of EMA (DAKO) and LCA (CD45), but is CD15 negative.
ALCL node staining for CD30+ (ALCL.com)
It can be useful to find extranodal sites of involvment, which can cause osteolytic lesions in ALK+ ALCL.
While the pathogenesis of ALK- ALCL and cutaneous ALCL is still unknown, the ALK+ ALCL pathogenesis is relatively well comprised.
In the late 1980s, it was found that a proportion of ALCLs were associated with a 2;5 chromosomal translocation.
The 2;5 translocation juxtaposes the portion of the nucleophosmin (NPM) gene encoding the N-terminal domain of NPM (amino acids 1-117) to the part of the ALK gene that codes for the entire cytoplasmic region of the ALK protein. As a consequence, the ALK gene comes under the control of the NPM promoter, which induces a permanent and ubiqitous transcription of the NPM-ALK hybrid gene, resulting in the production of an 80-kd chimeric protein termed NPM-ALK or p80.
This NPM-ALK protein contains the NPM oligomerization domain and the intracytoplasmic region of ALK. The C-terminal NPM domain carrying the nuclear localization signals and the extracellular and transmembrane region of the ALK are absent. The NPM-ALK protein can form homodimers (by cross-linking with other NPM-ALK molecules) or heterodimers (by cross-linking with wild-type NPM). The formation of homodimers results in the constitutive activation of the catalytic ALK domain contained in the NPM-ALK fusion protein. The activated ALK domain has been shown to bind GRB2 and the SH2 domains of phospholipase C-gamma,interactions that have been demonstrated to induce mitogenic activity and are likely to be involved in neoplastic ransformation.
Transfection of murine hematopoietic cells with the NPM-ALK fusion gene induces transplantable lymphoid tumors. NPM-ALK was also found to transform rat fibroblasts in vitro. Both of these latter findings further support the oncogenic property of this fusion protein.
“Genetic and Molecular Genetic Studies in the Diagnosis of T-Cell Malignancies”, Marshall E. Kadin, MD; 2003 Elsevier Inc.
“CD30+ anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features”, Stein H. et al.; 2000 Blood
“The anaplastic lymphoma kinase in the pathogenesis of cancer”, Chiarle R. et al.; 2008 Nature Reviews
“Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma”, Morris SW et al.; Science. 1994;263:1281
“Role of the nucleophosmin (NPM) portion of the non-Hodgkin’s lymphoma-associated NPM-anaplastic lymphoma kinase fusion protein in oncogenesis.” Bischof D, et al.; Mol Cell Biol. 1997;17:2312.
“The NPM/ALK gene fusion in the pathogenesis of anaplastic large cell lymphoma.” Ladanyi M. et al.; Cancer Surv. 1997;30:59.
“Characterization of the transforming activity of p80, a hyperphosphorylated protein in a Ki-1 lymphoma cell line with chromosomal translocation t(2;5).” Fujimoto J et al.; Proc Natl Acad Sci U S A. 1996;93:4181.
“NPM-ALK transgenic mice spontaneously develop T-cell lymphomas and plasma cell tumors.” Chiarle R., Inghirami G. et al.; Blood. 2003 Mar
Lymphoma Information Network
Lymphoma Research Foundation; Lymphoma Today newsletter article Fall 2007, Q & A with Andrei Shustov, M.D., by Jo Cavallo.