Associated Factors in Pediatric Anaplastic Large Cell Lymphoma
Associated Factors in Pediatric Anaplastic Large Cell Lymphoma
In anaplastic large cell lymphoma (ALCL), anaplastic lymphoma kinase (ALK) activates (phosphorylates) signal transducer and activator of transcription 3 (STAT3) with subsequent cytoplasmic expression, in some cases, of survivin and tissue inhibitor of metalloprotease 1 (TIMP1). These are inhibitors of apoptosis and negative prognostic factors. CD56 is also a negative prognostic marker in ALCL. We assayed 40 cases of predominantly ALK+ pediatric ALCL for pSTAT3, survivin, TIMP1, and CD56 using immunohistochemical analysis. The patients were derived from a Pediatric Oncology Group treatment protocol that showed 72% event-free survival at 4 years for ALCL. The results show that in advanced-stage pediatric ALCL, although most tumors express ALK and a majority show activated STAT3, cytoplasmic localization of survivin and TIMP1 is not frequent, nor is expression of CD56. This may help, in part, explain the relatively good prognosis of pediatric ALCL.
Lymphoma in aggregate is the third most common childhood cancer, representing 13% of newly diagnosed malignancies in the pediatric age group. Approximately 60% of pediatric lymphomas are non-Hodgkin lymphomas, with the remainder being Hodgkin lymphomas. Anaplastic large cell lymphoma (ALCL) accounts for approximately 3% of adult and 10% of childhood non-Hodgkin lymphomas. ALCL, first described in 1985 by Stein et al, is a category of T/natural killer (NK) lymphoma with characteristic neoplastic cells that express CD30.
A large subset of ALCL is characterized by chromosomal aberrations involving the anaplastic lymphoma kinase (ALK) gene on chromosome 2p23, with t(2;5)(p23;q35) the most frequent abnormality, leading to the expression of the hybrid protein nucleophosmin-ALK (NPM-ALK). The proportion of ALCLs expressing ALK has varied dramatically among different studies, ranging from 12% to 85%. Several studies have reported that ALK+ ALCL is a distinct subtype with a much younger age distribution and favorable prognosis.
Although the precise biologic mechanisms mediating the oncogenic potential of NPM-ALK remain undetermined, there is evidence that NPM-ALK may promote tumorigenesis by constitutively activating a number of cell signaling pathways, including the signal transducer and activator of transcription 3 (STAT3) pathway. Activated STAT3 up-regulates multiple downstream targets, including survivin and tissue inhibitor of metalloprotease 1 (TIMP1), which are inhibitors of apoptosis. Previous reports of ALK+ ALCL with cytoplasmic TIMP1 or survivin, not stratified for stage, have showed a less than 50% failure-free survival or progression-free survival at 5 years. Expression of CD56, a neural cell adhesion molecule, is also a negative prognostic marker in ALK+ and ALK subgroups. Relatively little, however, is known about the frequency of expression or influence of phosphorylated STAT3 (pSTAT3), survivin, TIMP1, or CD56 in pediatric ALCL. We, therefore, assessed the expression levels of these markers in 40 uniformly treated pediatric cases of ALCL.
Abstract and Introduction
Abstract
In anaplastic large cell lymphoma (ALCL), anaplastic lymphoma kinase (ALK) activates (phosphorylates) signal transducer and activator of transcription 3 (STAT3) with subsequent cytoplasmic expression, in some cases, of survivin and tissue inhibitor of metalloprotease 1 (TIMP1). These are inhibitors of apoptosis and negative prognostic factors. CD56 is also a negative prognostic marker in ALCL. We assayed 40 cases of predominantly ALK+ pediatric ALCL for pSTAT3, survivin, TIMP1, and CD56 using immunohistochemical analysis. The patients were derived from a Pediatric Oncology Group treatment protocol that showed 72% event-free survival at 4 years for ALCL. The results show that in advanced-stage pediatric ALCL, although most tumors express ALK and a majority show activated STAT3, cytoplasmic localization of survivin and TIMP1 is not frequent, nor is expression of CD56. This may help, in part, explain the relatively good prognosis of pediatric ALCL.
Introduction
Lymphoma in aggregate is the third most common childhood cancer, representing 13% of newly diagnosed malignancies in the pediatric age group. Approximately 60% of pediatric lymphomas are non-Hodgkin lymphomas, with the remainder being Hodgkin lymphomas. Anaplastic large cell lymphoma (ALCL) accounts for approximately 3% of adult and 10% of childhood non-Hodgkin lymphomas. ALCL, first described in 1985 by Stein et al, is a category of T/natural killer (NK) lymphoma with characteristic neoplastic cells that express CD30.
A large subset of ALCL is characterized by chromosomal aberrations involving the anaplastic lymphoma kinase (ALK) gene on chromosome 2p23, with t(2;5)(p23;q35) the most frequent abnormality, leading to the expression of the hybrid protein nucleophosmin-ALK (NPM-ALK). The proportion of ALCLs expressing ALK has varied dramatically among different studies, ranging from 12% to 85%. Several studies have reported that ALK+ ALCL is a distinct subtype with a much younger age distribution and favorable prognosis.
Although the precise biologic mechanisms mediating the oncogenic potential of NPM-ALK remain undetermined, there is evidence that NPM-ALK may promote tumorigenesis by constitutively activating a number of cell signaling pathways, including the signal transducer and activator of transcription 3 (STAT3) pathway. Activated STAT3 up-regulates multiple downstream targets, including survivin and tissue inhibitor of metalloprotease 1 (TIMP1), which are inhibitors of apoptosis. Previous reports of ALK+ ALCL with cytoplasmic TIMP1 or survivin, not stratified for stage, have showed a less than 50% failure-free survival or progression-free survival at 5 years. Expression of CD56, a neural cell adhesion molecule, is also a negative prognostic marker in ALK+ and ALK subgroups. Relatively little, however, is known about the frequency of expression or influence of phosphorylated STAT3 (pSTAT3), survivin, TIMP1, or CD56 in pediatric ALCL. We, therefore, assessed the expression levels of these markers in 40 uniformly treated pediatric cases of ALCL.
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