Immunohistochemical characterization of anaplastic large cell lymphoma using tissue microarray.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 8048-8048
Author(s):  
Poorvi Kirit Desai ◽  
Ling Zhang ◽  
Qianxing Mo ◽  
Lubomir Sokol
Keyword(s):  
Protein Expression ◽  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Rank Test ◽  
Time To Event ◽  
Expression Levels ◽  
Favorable Prognosis ◽  
Log Rank Test ◽  
Large Cell Lymphoma

8048 Background: Anaplastic Large Cell Lymphoma (ALCL) is a subtype of mature T-cell lymphoma comprised of systemic (ALK+ or ALK-) and primary cutaneous (PCALCL) forms. ALK+, usually associated with NPM1-ALK gene, has a favorable prognosis. PCALCL is usually indolent. Despite worse prognosis for ALK-, pts with DUSP22 rearrangement have favorable outcomes similar to ALK+ while those with p63 aberration have poor outcomes. We hypothesize that other genetic alterations in ALCL could aid in diagnosis and prognosis. We compared protein expression levels of selected signaling molecules (JAK1, STAT3, DUSP22, ERBB4/HER4, PRDM1/BLIMP1 and SOCS3) among the subtypes and correlated to outcomes. Methods: Of 50 pts with ALCL at Moffitt (MCC) from 2000-2019, 27 tissue samples (6 ALK+, 10 ALK-, 8 PCALCL, 3 controls) met eligibility criteria. Tissue microarrays (TMAs) were constructed from formalin-fixed, paraffin-embedded lymph node biopsies. Up to 3 replicate cores were taken from each block. Immunohistochemistry was performed with antibodies to the selected proteins. Stained TMA slides were scanned using the Aperio™ ScanScope XT2 to determine % positive biomarker stain within each core per established algorithm. Statistics: ANOVA was used to compared protein expression levels, with pairwise tests when significant. T-test compared PCALCL to systemic ALCL. Boxplots were created for differences in protein expression levels and time to event outcomes (OS and RFS) using Log rank test and Cox proportional hazards models. Kaplan-Meier curves were used for clinical time-to-event outcomes and quartiles of the protein expression levels. Results: The 3 subgroups had a significant difference in SOCS3 expression with mean and std respectively: 42.4% (0.153), 17.4% (0.089), and 21.0% (0.155), p = 0.008. Among all pairs, ALK+ and PCALCL groups were statistically different (P = 0.011). Patients with high BLIMP1 (≥28.5%) across 3 ALCL subgroups were associated with better median OS (not reached) in comparison to pts with lower expression (27.3 mos) (Log rank test p = 0.014, HR = 0.17, 95% CI 0.034-0.829). The same was seen for median RFS (81.1 vs. 12.5 mos). (Log rank test p = 0.009, HR 0.23, 95% CI 0.069-0.755). Conclusions: High BLIMP1 suggests favorable prognosis in ALCL and could potentially be a positive prognostic marker. High SOCS3 appears more prevalent in PCALCL than systemic and could aid in differential. Larger samples should be used to validate results. Secondary markers like Bcl-2 can be considered in the future to correlate expression levels to targeted treatments like venetoclax.

Survivin Expression Predicts Poorer Prognosis in Anaplastic Large-Cell Lymphoma

2004 ◽  
Vol 22 (9) ◽  
pp. 1682-1688 ◽  
Author(s):  
Ellen J. Schlette ◽  
L. Jeffrey Medeiros ◽  
Andre Goy ◽  
Raymond Lai ◽  
George Z. Rassidakis
Keyword(s):  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Prognostic Significance ◽  
Survivin Expression ◽  
Large Cell ◽  
Rank Test ◽  
Anaplastic Lymphoma ◽  
Log Rank Test ◽  
Large Cell Lymphoma ◽  
Alk Positive

Purpose Survivin, a member of the inhibitor of apoptosis (IAP) family, is not detected in normal adult tissues but is overexpressed in various cancers, including some types of lymphoma. The frequency and prognostic significance of survivin expression in anaplastic large-cell lymphoma (ALCL) is unknown. Materials and Methods We assessed for survivin expression in 62 ALCL tumors (30 anaplastic lymphoma kinase [ALK]-positive and 32 ALK-negative) obtained before doxorubicin-based chemotherapy. Given that survivin is a target of the STAT3 signaling pathway and STAT3 is activated in ALCL, survivin expression was also correlated with STAT3 activation. Results Survivin was expressed in 34 tumors (55%) and did not correlate with ALK. A significant association between survivin expression and STAT3 activation was observed (P = .007, Fisher's exact test). For the ALK-positive group, the 5-year failure-free survival (FFS) was 34% for patients with survivin-positive ALCL compared with 100% for patients with survivin-negative ALCL (P = .009, log-rank test). For the ALK-negative group, the 5-year FFS was 46% for patients with survivin-positive tumors compared with 89% for patients with survivin-negative tumors (P = .03, log-rank test). Overall survival was similarly worse for patients with survivin-positive tumors in both the ALK-positive and ALK-negative groups. Furthermore, multivariate analysis confirmed the independent prognostic value of survivin expression, along with age older than 60 years and Ann Arbor stage III or IV. Conclusion Survivin is expressed in approximately half of ALCL tumors and independently predicts unfavorable clinical outcome. Modulation of survivin expression or function may provide a novel target for experimental therapy in patients with ALCL.

Methylation of SHP1 gene and loss of SHP1 protein expression are frequent in systemic anaplastic large cell lymphoma

Blood ◽  
2004 ◽  
Vol 104 (5) ◽  
pp. 1580-1581 ◽  
Author(s):  
Joseph D. Khoury ◽  
George Z. Rassidakis ◽  
L. Jeffrey Medeiros ◽  
Hesham M. Amin ◽  
Raymond Lai
Keyword(s):  
Protein Expression ◽  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Large Cell Lymphoma

NPM-ALK expression levels identify two distinct subtypes of paediatric anaplastic large cell lymphoma

Leukemia ◽  
2016 ◽  
Vol 31 (2) ◽  
pp. 498-501 ◽  
Author(s):  
E Pomari ◽  
G Basso ◽  
S Bresolin ◽  
M Pillon ◽  
E Carraro ◽  
...  
Keyword(s):  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Expression Levels ◽  
Large Cell Lymphoma

Prognostic Significance of Anaplastic Lymphoma Kinase (ALK) Protein Expression in Adults With Anaplastic Large Cell Lymphoma

Blood ◽  
1999 ◽  
Vol 93 (11) ◽  
pp. 3913-3921 ◽  
Author(s):  
Randy D. Gascoyne ◽  
Patricia Aoun ◽  
Daniel Wu ◽  
Mukesh Chhanabhai ◽  
Brian F. Skinnider ◽  
...  
Keyword(s):  
T Cell ◽  
Protein Expression ◽  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Normal Serum ◽  
Cell Phenotype ◽  
Anaplastic Lymphoma ◽  
Large Cell Lymphoma ◽  
Alk Protein

Anaplastic large cell lymphoma (ALCL) is an aggressive lymphoma that is frequently associated with the t(2;5)(p23;q35), resulting in expression of a fusion protein, nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), which can be detected by either monoclonal or polyclonal antibodies to the ALK protein. The clinical features of adults with ALCL are incompletely described, and the prognostic factors that are useful for predicting survival remain unclear. This report describes the clinical and laboratory findings in 70 adults with systemic ALCL who were treated with curative intent. We attempted to identify the clinical and pathological factors of prognostic importance, including the International Prognostic Index (IPI), immunophenotype, and expression of the ALK protein. The median age of the patients was 49 years (range, 15 to 75). There were 26 women and 44 men with a median follow-up of 50 months for living patients. Advanced stage was present in 56% and B symptoms were noted in 70% of the patients. Immunostains showed that 46% of the cases had a T-cell phenotype, 36% a null phenotype, and 18% a B-cell phenotype. The expression of ALK protein was found in 51% of the cases. The IPI factors were evenly distributed between the ALK+ and ALK− groups, except that the ALK+ patients were younger (median age, 30 v 61 years; P < .002). The ALK+ cohort included cases with null (44%), T-cell (42%), and B-cell (14%) phenotypes. All 10 cases with cytogenetic or molecular evidence of a t(2;5) were ALK+. The 5-year overall survival (OS) of the entire cohort was 65%. The 5-year OS of the ALK+ and ALK− cases was 79% and 46%, respectively (P < .0003). Analysis of only the T-cell/null cases (n = 57) showed a 5-year OS of 93% for the ALK+ cases and only 37% for the ALK− cases (P < .00001). Univariate analysis of the clinical features showed that age ≤60 years (P < .007), a normal serum lactate dehydrogenase (LDH) (P < .00001), a good performance status (Eastern Cooperative Oncology Group [ECOG] <2) (P< .03), ≤1 extranodal site of disease (P < .012), and an IPI score ≤3 (P < .00001) were associated with improved OS. Although a younger age correlated with ALK positivity, multivariate analysis showed that only a normal serum LDH (P < .00001), an IPI score of ≤3 (P < .0005), and ALK protein expression (P < .005) predicted independently for an improved OS. We conclude that ALCL is a heterogeneous disorder. However, ALK protein expression is an independent predictor of survival and serves as a useful biologic marker of a specific disease entity within the spectrum of ALCL.

Expression levels of apoptosis-related proteins predict clinical outcome in anaplastic large cell lymphoma

Blood ◽  
2002 ◽  
Vol 99 (12) ◽  
pp. 4540-4546 ◽  
Author(s):  
Rosita L. ten Berge ◽  
Chris J. L. M. Meijer ◽  
Danny F. Dukers ◽  
J. Alain Kummer ◽  
Bellinda A. Bladergroen ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Tumor Cells ◽  
Anaplastic Large Cell Lymphoma ◽  
Caspase 3 ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Favorable Prognosis ◽  
Large Cell Lymphoma ◽  
Alk Positive ◽  
Active Caspase

In vitro studies suggest that resistance to chemotherapy-induced apoptosis might explain poor response to therapy in fatal cases. Actual execution of apoptosis depends on proper functioning of effector caspases, particularly caspase 3, and on the expression levels of apoptosis-regulating proteins, including Bcl-2 and the recently identified granzyme B– specific protease inhibitor 9 (PI9). Thus, high levels of caspase 3 activation should reflect proper functioning of the apoptosis pathways, resulting in chemotherapy-sensitive neoplastic cells and a favorable prognosis. We tested this hypothesis by quantifying numbers of tumor cells positive for active caspase 3, Bcl-2, and PI9, respectively, in pretreatment biopsies of systemic anaplastic large cell lymphoma (ALCL) patients and by comparing these numbers with clinical outcome. Activation of caspase 3 in more than 5% of the tumor cells was strongly correlated with a highly favorable outcome. High numbers of Bcl-2– and PI9-positive tumor cells were found to predict unfavorable prognosis. This prognostic effect was strongly related to anaplastic lymphoma kinase (ALK) status: ALK-positive ALCL had significantly higher levels of active caspase 3, while high expression of the antiapoptotic proteins Bcl-2 and PI9 was almost completely restricted to ALK-negative cases. In conclusion, high numbers of active caspase 3–positive tumor cells predict a highly favorable prognosis in systemic ALCL patients. Poor prognosis is strongly related to high numbers of Bcl-2– and PI9-positive neoplastic cells. These data support the notion that a favorable response to chemotherapy depends on an intact apoptosis cascade. Moreover, these data indicate that differences in prognosis between ALK-positive and ALK-negative ALCL might be explained by differences in expression of apoptosis-inhibiting proteins.

Prognostic Significance of Anaplastic Lymphoma Kinase (ALK) Protein Expression in Adults With Anaplastic Large Cell Lymphoma

Blood ◽  
1999 ◽  
Vol 93 (11) ◽  
pp. 3913-3921 ◽  
Author(s):  
Randy D. Gascoyne ◽  
Patricia Aoun ◽  
Daniel Wu ◽  
Mukesh Chhanabhai ◽  
Brian F. Skinnider ◽  
...  
Keyword(s):  
T Cell ◽  
Protein Expression ◽  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Normal Serum ◽  
Cell Phenotype ◽  
Anaplastic Lymphoma ◽  
Large Cell Lymphoma ◽  
Alk Protein

Abstract Anaplastic large cell lymphoma (ALCL) is an aggressive lymphoma that is frequently associated with the t(2;5)(p23;q35), resulting in expression of a fusion protein, nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), which can be detected by either monoclonal or polyclonal antibodies to the ALK protein. The clinical features of adults with ALCL are incompletely described, and the prognostic factors that are useful for predicting survival remain unclear. This report describes the clinical and laboratory findings in 70 adults with systemic ALCL who were treated with curative intent. We attempted to identify the clinical and pathological factors of prognostic importance, including the International Prognostic Index (IPI), immunophenotype, and expression of the ALK protein. The median age of the patients was 49 years (range, 15 to 75). There were 26 women and 44 men with a median follow-up of 50 months for living patients. Advanced stage was present in 56% and B symptoms were noted in 70% of the patients. Immunostains showed that 46% of the cases had a T-cell phenotype, 36% a null phenotype, and 18% a B-cell phenotype. The expression of ALK protein was found in 51% of the cases. The IPI factors were evenly distributed between the ALK+ and ALK− groups, except that the ALK+ patients were younger (median age, 30 v 61 years; P &lt; .002). The ALK+ cohort included cases with null (44%), T-cell (42%), and B-cell (14%) phenotypes. All 10 cases with cytogenetic or molecular evidence of a t(2;5) were ALK+. The 5-year overall survival (OS) of the entire cohort was 65%. The 5-year OS of the ALK+ and ALK− cases was 79% and 46%, respectively (P &lt; .0003). Analysis of only the T-cell/null cases (n = 57) showed a 5-year OS of 93% for the ALK+ cases and only 37% for the ALK− cases (P &lt; .00001). Univariate analysis of the clinical features showed that age ≤60 years (P &lt; .007), a normal serum lactate dehydrogenase (LDH) (P &lt; .00001), a good performance status (Eastern Cooperative Oncology Group [ECOG] &lt;2) (P&lt; .03), ≤1 extranodal site of disease (P &lt; .012), and an IPI score ≤3 (P &lt; .00001) were associated with improved OS. Although a younger age correlated with ALK positivity, multivariate analysis showed that only a normal serum LDH (P &lt; .00001), an IPI score of ≤3 (P &lt; .0005), and ALK protein expression (P &lt; .005) predicted independently for an improved OS. We conclude that ALCL is a heterogeneous disorder. However, ALK protein expression is an independent predictor of survival and serves as a useful biologic marker of a specific disease entity within the spectrum of ALCL.

scholarly journals Genetic Polymorphisms in the Tumor Necrosis Factor Locus Influence Non-Hodgkin's Lymphoma Outcome

Blood ◽  
1998 ◽  
Vol 91 (10) ◽  
pp. 3574-3581 ◽  
Author(s):  
Krzysztof Warzocha ◽  
Patricia Ribeiro ◽  
Jacques Bienvenu ◽  
Pascal Roy ◽  
Carole Charlot ◽  
...  
Keyword(s):  
Overall Survival ◽  
Tumor Necrosis ◽  
Cell Lymphoma ◽  
Progression Free Survival ◽  
Large Cell ◽  
Rank Test ◽  
Free Survival ◽  
Log Rank Test ◽  
Large Cell Lymphoma ◽  
Necrosis Factor

Systemic release of tumor necrosis factor (TNF) and lymphotoxin-α (LTα) has been found to contribute to the severity of non-Hodgkin's lymphoma (NHL). We investigated whether genetic polymorphisms in the TNF locus, previously shown to influence TNF and LTα genes expression, might contribute to these cytokines production and to the clinical course of NHL. Genomic DNA from 273 lymphoma patients was typed for TNF (−308) polymorphism using an allele-specific polymerase chain reaction (PCR) and for LTα (+252) polymorphism with a PCR-based restriction fragment length polymorphism. The presence of the TNF allele involved in increased TNF gene transcription was associated with higher plasma levels of this cytokine at the time of lymphoma diagnosis (χ2 test, P = .013). An extended haplotype analysis showed that the presence of at least two TNF or LTα high-producer alleles constituted a risk factor for first-line treatment failure (χ2 test, P = .021), shorter progression-free survival (log-rank test, P = .0007), and overall survival (log-rank test, P = .012). In the subgroup of 126 patients with diffuse large-cell lymphoma, the presence of two or more TNF/LTα high producing alleles contributed significantly to a higher rate of relapse and progression (log-rank test, P = .045 and P = .027). In multivariate Cox regression models including the variables of the International Prognostic Index, the TNF/LTα haplotype status was found to be an independent risk factor for progression-free survival (relative risk 2.33, 95% confidence interval [1.17 to 4.64], P = .0053) and overall survival (relative risk 1.92, 95% confidence interval [0.63 to 5.80],P = .081) of large-cell lymphoma patients. These results indicate that genetic polymorphism leading to increased TNF production influences the outcome of NHL and suggest a pathophysiological role for the genetic control of the immune response in lymphoid malignancies.

scholarly journals Genetic Polymorphisms in the Tumor Necrosis Factor Locus Influence Non-Hodgkin's Lymphoma Outcome

Blood ◽  
1998 ◽  
Vol 91 (10) ◽  
pp. 3574-3581 ◽  
Author(s):  
Krzysztof Warzocha ◽  
Patricia Ribeiro ◽  
Jacques Bienvenu ◽  
Pascal Roy ◽  
Carole Charlot ◽  
...  
Keyword(s):  
Overall Survival ◽  
Tumor Necrosis ◽  
Cell Lymphoma ◽  
Progression Free Survival ◽  
Large Cell ◽  
Rank Test ◽  
Free Survival ◽  
Log Rank Test ◽  
Large Cell Lymphoma ◽  
Necrosis Factor

Abstract Systemic release of tumor necrosis factor (TNF) and lymphotoxin-α (LTα) has been found to contribute to the severity of non-Hodgkin's lymphoma (NHL). We investigated whether genetic polymorphisms in the TNF locus, previously shown to influence TNF and LTα genes expression, might contribute to these cytokines production and to the clinical course of NHL. Genomic DNA from 273 lymphoma patients was typed for TNF (−308) polymorphism using an allele-specific polymerase chain reaction (PCR) and for LTα (+252) polymorphism with a PCR-based restriction fragment length polymorphism. The presence of the TNF allele involved in increased TNF gene transcription was associated with higher plasma levels of this cytokine at the time of lymphoma diagnosis (χ2 test, P = .013). An extended haplotype analysis showed that the presence of at least two TNF or LTα high-producer alleles constituted a risk factor for first-line treatment failure (χ2 test, P = .021), shorter progression-free survival (log-rank test, P = .0007), and overall survival (log-rank test, P = .012). In the subgroup of 126 patients with diffuse large-cell lymphoma, the presence of two or more TNF/LTα high producing alleles contributed significantly to a higher rate of relapse and progression (log-rank test, P = .045 and P = .027). In multivariate Cox regression models including the variables of the International Prognostic Index, the TNF/LTα haplotype status was found to be an independent risk factor for progression-free survival (relative risk 2.33, 95% confidence interval [1.17 to 4.64], P = .0053) and overall survival (relative risk 1.92, 95% confidence interval [0.63 to 5.80],P = .081) of large-cell lymphoma patients. These results indicate that genetic polymorphism leading to increased TNF production influences the outcome of NHL and suggest a pathophysiological role for the genetic control of the immune response in lymphoid malignancies.

scholarly journals The biology and management of systemic anaplastic large cell lymphoma

Blood ◽  
2015 ◽  
Vol 126 (1) ◽  
pp. 17-25 ◽  
Author(s):  
Greg Hapgood ◽  
Kerry J. Savage
Keyword(s):  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Survival Rates ◽  
Large Cell ◽  
High Response Rate ◽  
First Line ◽  
Antibody Drug Conjugate ◽  
Anaplastic Lymphoma ◽  
Favorable Prognosis ◽  
Large Cell Lymphoma

Abstract Systemic anaplastic large cell lymphoma (ALCL) is an aggressive CD30+ non-Hodgkin lymphoma. Anaplastic lymphoma kinase–positive (ALK+) ALCL is associated with the NPM-ALK t(2;5) translocation, which is highly correlated with the identification of the ALK protein by immunohistochemistry. ALK+ ALCL typically occurs in younger patients and has a more favorable prognosis with 5-year survival rates of 70% to 90% in comparison with 40% to 60% for ALK-negative (ALK−) ALCL. Studies support young age as a strong component of the favorable prognosis of ALK+ ALCL. Until recently, no recurrent translocations were identified in ALK− ALCL. However, emerging data now highlight that ALK− ALCL is genetically and clinically heterogeneous with a subset having either a DUSP22 translocation and a survival rate similar to ALK+ ALCL or a less common P63 translocation, the latter associated with an aggressive course. Anthracycline-based regimens such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) remain the standard first-line treatment choice for systemic ALCL, but in many patients with ALK− ALCL, it is ineffective, and thus it is often followed by consolidative autologous stem cell transplantation. However, selection of appropriate patients for intensified therapy remains challenging, particularly in light of genetic and clinical heterogeneity in addition to the emergence of new, effective therapies. The antibody drug conjugate brentuximab vedotin is associated with a high response rate (86%) and durable remissions in relapsed/refractory ALCL and is under investigation in the first-line setting. In the future, combining clinical and genetic biomarkers may aid in risk stratification and help guide initial patient management.

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