Age as a predictor of sentinel node metastasis among patients with localized melanoma: an inverse correlation of melanoma mortality and incidence of sentinel node metastasis among young and old patients.

PURPOSE: We have previously reported that older patients with clinical stage I and II primary cutaneous. Melanoma had lower survival rates compared to younger patients. We postulated that the incidence of nodal metastasis would therefore be higher among older melanoma patients. METHODS: The expanded American Joint Committee on Cancer melanoma staging database contains a cohort of 7,756 melanoma patients who presented without clinical evidence of regional lymph node or distant metastasis and who underwent a sentinel node biopsy procedure as a component of their staging assessment. RESULTS: Although older patients had primary melanoma features associated with more aggressive biology, we paradoxically observed a significant decrease in the incidence of sentinel node metastasis as patient age increased. Overall, the highest incidence of sentinel node metastasis was 25.8 % in patients under 20 years of age, compared to 15.5 % in patients 80 years and older (p < 0.001). In contrast, 5-year mortality rates for clinical stage II patients ranged from a low of 20 % for those 20-40 years of age up to 38 % for those over 70 years of age. Patient age was an independent predictor of sentinel node metastasis in a multifactorial analysis (p < 0.001). CONCLUSIONS: Patients with clinical stage I and II melanoma under 20 years of age had a higher incidence of sentinel lymph node metastasis but, paradoxically, a more favorable survival outcome compared to all other age groups. In contrast, patients >70 years had the most aggressive primary melanoma features and a higher mortality rate compared to all other age groups but a lower incidence of sentinel lymph node metastasis.

Age as a prognostic factor in patients with localized melanoma and regional metastases.

BACKGROUND: We postulated that the worse prognosis of melanoma with advancing age reflected more aggressive tumor biology and that in younger patients the prognosis would be more favorable. MATERIALS AND METHODS: The expanded AJCC melanoma staging database contained 11,088 patients with complete data for analysis, including mitotic rate. RESULTS: With increasing age by decade, primary melanomas were thicker, exhibited higher mitotic rates, and were more likely to be ulcerated. In a multivariate analysis of patients with localized melanoma, thickness and ulceration were highly significant predictors of outcome at all decades of life (except for patients younger than 20 years). Mitotic rate was significantly predictive in all age groups except patients <20 and >80 years. For patients with stage III melanoma, there were four independent variables associated with patient survival: number of nodal metastases, patient age, ulceration, and mitotic rate. Patients younger than 20 years of age had primary tumors with slightly more aggressive features, a higher incidence of sentinel lymph node metastasis, but, paradoxically, more favorable survival than all other age groups. In contrast, patients >70 years old had primary melanomas with the most aggressive prognostic features, were more likely to be head and neck primaries, and were associated with a higher mortality rate than the other age groups. Surprisingly, however, these patients had a lower rate of sentinel lymph node metastasis per T stage. Among patients between the two age extremes, clinicopathologic features and survival tended to be more homogeneous. CONCLUSIONS: Melanomas in patients at the extremes of age have a distinct natural history.

A chain reaction approach to modelling gene pathways.

BACKGROUND: Of great interest in cancer prevention is how nutrient components affect gene pathways associated with the physiological events of puberty. Nutrient-gene interactions may cause changes in breast or prostate cells and, therefore, may result in cancer risk later in life. Analysis of gene pathways can lead to insights about nutrient-gene interactions and the development of more effective prevention approaches to reduce cancer risk. To date, researchers have relied heavily upon experimental assays (such as microarray analysis, etc.) to identify genes and their associated pathways that are affected by nutrient and diets. However, the vast number of genes and combinations of gene pathways, coupled with the expense of the experimental analyses, has delayed the progress of gene-pathway research. The development of an analytical approach based on available test data could greatly benefit the evaluation of gene pathways, and thus advance the study of nutrient-gene interactions in cancer prevention. In the present study, we have proposed a chain reaction model to simulate gene pathways, in which the gene expression changes through the pathway are represented by the species undergoing a set of chemical reactions. We have also developed a numerical tool to solve for the species changes due to the chain reactions over time. Through this approach we can examine the impact of nutrient-containing diets on the gene pathway; moreover, transformation of genes over time with a nutrient treatment can be observed numerically, which is very difficult to achieve experimentally. We apply this approach to microarray analysis data from an experiment which involved the effects of three polyphenols (nutrient treatments), epigallo-catechin-3-O-gallate (EGCG), genistein, and resveratrol, in a study of nutrient-gene interaction in the estrogen synthesis pathway during puberty. RESULTS: In this preliminary study, the estrogen synthesis pathway was simulated by a chain reaction model. By applying it to microarray data, the chain reaction model computed a set of reaction rates to examine the effects of three polyphenols (EGCG, genistein, and resveratrol) on gene expression in this pathway during puberty. We first performed statistical analysis to test the time factor on the estrogen synthesis pathway. Global tests were used to evaluate an overall gene expression change during puberty for each experimental group. Then, a chain reaction model was employed to simulate the estrogen synthesis pathway. Specifically, the model computed the reaction rates in a set of ordinary differential equations to describe interactions between genes in the pathway (A reaction rate K of A to B represents gene A will induce gene B per unit at a rate of K; we give details in the "method" section). Since disparate changes of gene expression may cause numerical error problems in solving these differential equations, we used an implicit scheme to address this issue. We first applied the chain reaction model to obtain the reaction rates for the control group. A sensitivity study was conducted to evaluate how well the model fits to the control group data at Day 50. Results showed a small bias and mean square error. These observations indicated the model is robust to low random noises and has a good fit for the control group. Then the chain reaction model derived from the control group data was used to predict gene expression at Day 50 for the three polyphenol groups. If these nutrients affect the estrogen synthesis pathways during puberty, we expect discrepancy between observed and expected expressions. Results indicated some genes had large differences in the EGCG (e.g., Hsd3b and Sts) and the resveratrol (e.g., Hsd3b and Hrmt12) groups. CONCLUSIONS: In the present study, we have presented (I) experimental studies of the effect of nutrient diets on the gene expression changes in a selected estrogen synthesis pathway. This experiment is valuable because it allows us to examine how the nutrient-containing diets regulate gene expression in the estrogen synthesis pathway during puberty; (II) global tests to assess an overall association of this particular pathway with time factor by utilizing generalized linear models to analyze microarray data; and (III) a chain reaction model to simulate the pathway. This is a novel application because we are able to translate the gene pathway into the chemical reactions in which each reaction channel describes gene-gene relationship in the pathway. In the chain reaction model, the implicit scheme is employed to efficiently solve the differential equations. Data analysis results show the proposed model is capable of predicting gene expression changes and demonstrating the effect of nutrient-containing diets on gene expression changes in the pathway. One of the objectives of this study is to explore and develop a numerical approach for simulating the gene expression change so that it can be applied and calibrated when the data of more time slices are available, and thus can be used to interpolate the expression change at a desired time point without conducting expensive experiments for a large amount of time points. Hence, we are not claiming this is either essential or the most efficient way for simulating this problem, rather a mathematical/numerical approach that can model the expression change of a large set of genes of a complex pathway. In addition, we understand the limitation of this experiment and realize that it is still far from being a complete model of predicting nutrient-gene interactions. The reason is that in the present model, the reaction rates were estimated based on available data at two time points; hence, the gene expression change is dependent upon the reaction rates and a linear function of the gene expressions. More data sets containing gene expression at various time slices are needed in order to improve the present model so that a non-linear variation of gene expression changes at different time can be predicted.

Update on the melanoma staging system: the importance of sentinel node staging and primary tumor mitotic rate.

The 7(th) Edition of the AJCC Staging Manual includes a detailed summary of melanoma staging and prognosis. The revisions are summarized in this article, along with details on two key aspects of melanoma staging: the incorporation of mitotic rate of the primary melanoma and the key role of the sentinel lymph node biopsy (SLNB) in determining accurate staging for clinically occult nodal metastases. Primary tumor mitotic rate was introduced as a major criterion for melanoma staging and prognosis that replaces the Clark's level of invasion, and is now proven to be an important independent adverse predictor of survival. Analysis of the AJCC melanoma staging database demonstrated a significant inverse correlation between primary tumor mitotic rate (histologically defined as mitoses/mm(2) ) and survival. The use of SLNB reliably identifies melanoma patients with nodal micrometastases, enabling clinicians to identify patients with occult nodal metastases that would otherwise take months or years to become clinically palpable The number of nodal metastases was the most significant independent predictor of survival among all patients with stage III disease, including among patients with nodal micrometastases, and continues to be a primary criterion for defining Stage III melanoma. A clinical scoring system model and multivariate predictive tool under the auspices of the AJCC has led to a first-generation web-based predictive tool (www.melanomaprognosis.org).

Factors predictive of the status of sentinel lymph nodes in melanoma patients from a large multicenter database.

BACKGROUND: Numerous predictive factors for cutaneous melanoma metastases to sentinel lymph nodes have been identified; however, few have been found to be reproducibly significant. This study investigated the significance of factors for predicting regional nodal disease in cutaneous melanoma using a large multicenter database. METHODS: Seventeen institutions submitted retrospective and prospective data on 3463 patients undergoing sentinel lymph node (SLN) biopsy for primary melanoma. Multiple demographic and tumor factors were analyzed for correlation with a positive SLN. Univariate and multivariate statistical analyses were performed. RESULTS: Of 3445 analyzable patients, 561 (16.3%) had a positive SLN biopsy. In multivariate analysis of 1526 patients with complete records for 10 variables, increasing Breslow thickness, lymphovascular invasion, ulceration, younger age, the absence of regression, and tumor location on the trunk were statistically significant predictors of a positive SLN. CONCLUSIONS: These results confirm the predictive significance of the well-established variables of Breslow thickness, ulceration, age, and location, as well as consistently reported but less well-established variables such as lymphovascular invasion. In addition, the presence of regression was associated with a lower likelihood of a positive SLN. Consideration of multiple tumor parameters should influence the decision for SLN biopsy and the estimation of nodal metastatic disease risk.

Prognostic significance of mitotic rate in localized primary cutaneous melanoma: an analysis of patients in the multi-institutional American Joint Committee on Cancer melanoma staging database.

PURPOSE: The aim of this study was to assess the independent prognostic value of primary tumor mitotic rate compared with other clinical and pathologic features of stages I and II melanoma. METHODS: From the American Joint Committee on Cancer (AJCC) melanoma staging database, information was extracted for 13,296 patients with stages I and II disease who had mitotic rate data available. RESULTS: Survival times declined as mitotic rate increased. Ten-year survival ranged from 93% for patients whose tumors had 0 mitosis/mm(2) to 48% for those with ≥ 20/mm(2) (P < .001). Mean number of mitoses/mm(2) increased as the primary melanomas became thicker (1.0 for melanomas ≤ 1 mm, 3.5 for 1.01 to 2.0 mm, 7.3 for 3.01 to 4.0 mm, and 9.6 for > 8 mm). Ulceration was also associated with a higher mitotic rate; 59% of ulcerated melanomas had ≥ 5 mitoses/mm(2) compared with 16% of nonulcerated melanomas (P < .001). In a multivariate analysis of 10,233 patients, the independent predictive factors for survival in order of statistical significance were as follows: tumor thickness (χ(2) = 104.9; P < .001), mitotic rate (χ(2) = 67.0; P < .001), patient age (χ(2) = 48.2; P < .001), ulceration (χ(2) = 46.4; P < .001), anatomic site (χ(2) = 34.6; P < .001), and patient sex (χ(2) = 33.9; P < .001). Clark level of invasion was not an independent predictor of survival (χ(2) = 3.2; P = .37). CONCLUSION: A high mitotic rate in a primary melanoma is associated with a lower survival probability. Among the independent predictors of melanoma-specific survival, mitotic rate was the strongest prognostic factor after tumor thickness.

Cutaneous melanoma: a model to study cancer metastasis.

Nodal status in melanoma is a critically important prognostic factor for patient outcome. The survival rate drops to <10% when melanoma has spread beyond the regional lymph nodes and includes visceral involvement. In general, the process of melanoma metastasis is progressive in that dissemination of melanoma from the primary site to the regional lymph nodes occurs prior to systemic disease. The goal of this review article is to describe melanoma as a clinical model to study cancer metastasis. A future challenge is to develop a molecular taxonomy to subgroup melanoma patients at various stages of tumor progression for more accurate targeted treatment.

Sentinel node positive melanoma patients: prediction and prognostic significance of nonsentinel node metastases and development of a survival tree model.

BACKGROUND: Completion lymph node dissection (CLND) following positive sentinel node biopsy (SNB) for melanoma detects additional nonsentinel node (NSN) metastases in approximately 20% of cases. This study aimed to establish whether NSN status can be predicted, to determine its effect on survival, and to develop survival tree models for the sentinel node (SN) positive population. MATERIALS AND METHODS: Sydney Melanoma Unit (SMU) patients with at least 1 positive SN, meeting inclusion criteria and treated between October 1992 and June 2005, were identified from the Unit database. Survival characteristics, potential predictors of survival, and NSN status were assessed using the Kaplan-Meier method, Cox regression model, and logistic regression analyses, respectively. Classification tree analysis was performed to identify groups with distinctly different survival characteristics. RESULTS: A total of 323 SN-positive melanoma patients met the inclusion criteria. On multivariate analysis, age, gender, primary tumor thickness, mitotic rate, number of positive NSNs, or total number of positive nodes were statistically significant predictors of survival. NSN metastasis, found at CLND in 19% of patients, was only predicted to a statistically significant degree by ulceration. Multivariate analyses demonstrated that survival was more closely related to number of positive NSNs than total number of positive nodes. Classification tree analysis revealed 4 prognostically distinct survival groups. CONCLUSIONS: Patients with NSN metastases could not be reliably identified prior to CLND. Prognosis following CLND was more closely related to number of positive NSNs than total number of positive nodes. Classification tree analysis defined distinctly different survival groups more accurately than use of single-factor analysis.

Predicting survival outcome of localized melanoma: an electronic prediction tool based on the AJCC Melanoma Database.

BACKGROUND: We sought to develop a reliable and reproducible statistical model to predict the survival outcome of patients with localized melanoma. METHODS: A total of 25,734 patients with localized melanoma from the 2008 American Joint Committee on Cancer (AJCC) Melanoma Database were used for the model development and validation. The predictive model was developed from the model development data set (n = 14,760) contributed by nine major institutions and study groups and was validated on an independent model validation data set (n = 10,974) consisting of patients from a separate melanoma center. Multivariate analyses based on the Cox model were performed for the model development, and the concordance correlation coefficients were calculated to assess the adequacy of the predictive model. RESULTS: Patient characteristics in both data sets were virtually identical, and tumor thickness was the single most important prognostic factor. Other key prognostic factors identified by stratified analyses included ulceration, lesion site, and patient age. Direct comparisons of the predicted 5- and 10-year survival rates calculated from the predictive model and the observed Kaplan-Meier 5- and 10-year survival rates estimated from the validation data set yielded high concordance correlation coefficients of 0.90 and 0.93, respectively. A Web-based electronic prediction tool was also developed ( http://www.melanomaprognosis.org/ ). CONCLUSIONS: This is the first predictive model for localized melanoma that was developed based on a very large data set and was successfully validated on an independent data set. The high concordance correlation coefficients demonstrated the accuracy of the predicted model. This predictive model provides a clinically useful tool for making treatment decisions, for assessing patient risk, and for planning and analyzing clinical trials.

Multivariate analysis of prognostic factors among 2,313 patients with stage III melanoma: comparison of nodal micrometastases versus macrometastases.

PURPOSE: To determine the survival rates and independent predictors of survival using a contemporary international cohort of patients with stage III melanoma. PATIENTS AND METHODS: Complete clinicopathologic and follow-up data were available for 2,313 patients with stage III disease in an updated and expanded American Joint Committee on Cancer (AJCC) melanoma staging database. Kaplan-Meier and Cox multivariate survival analyses were performed. RESULTS: Among all 2,313 patients with stage III disease, 81% had micrometastases, and 19% had clinically detectable macrometastases. The 5-year overall survival was 63%; it was 67% for patients with nodal micrometastases, and it was 43% for those with nodal macrometastases (P < .001). Tremendous heterogeneity in survival was observed, particularly in the microscopically detected nodal metastasis subset (from 23% to 87% for 5-year survival). Multivariate analysis demonstrated that in patients with nodal micrometastases, number of tumor-containing lymph nodes, primary tumor thickness, patient age, ulceration, and anatomic site of the primary independently predicted survival (all P < .01). When added to the model, primary tumor mitotic rate was the second-most powerful predictor of survival after the number of tumor-containing nodes. In contrast, for patients with nodal macrometastases, the number of tumor-containing nodes, primary ulceration, and patient age independently predicted survival (P < .01). CONCLUSION: In this multi-institutional analysis, we demonstrated remarkable heterogeneity of prognosis among patients with stage III melanoma, especially among those with nodal micrometastases. These results should be incorporated into the design and interpretation of future clinical trials involving patients with stage III melanoma.

Optimal designs for two-arm, phase II clinical trial design with multiple constraints.

Multi-stage Phase II trials are often employed in practice but may not be the best approach when the endpoint of interest is not obtained soon after enrollment and/or when a control arm is desired. We present a new design in which sample size determination includes a control arm and allows for the estimation of response for each treatment as well as estimation of the difference in the response rates. We evaluate this design under varying allocation schemes to treatment arms and response rates for each treatment.

Final version of 2009 AJCC melanoma staging and classification.

PURPOSE: To revise the staging system for cutaneous melanoma on the basis of data from an expanded American Joint Committee on Cancer (AJCC) Melanoma Staging Database. METHODS: The melanoma staging recommendations were made on the basis of a multivariate analysis of 30,946 patients with stages I, II, and III melanoma and 7,972 patients with stage IV melanoma to revise and clarify TNM classifications and stage grouping criteria. RESULTS: Findings and new definitions include the following: (1) in patients with localized melanoma, tumor thickness, mitotic rate (histologically defined as mitoses/mm(2)), and ulceration were the most dominant prognostic factors. (2) Mitotic rate replaces level of invasion as a primary criterion for defining T1b melanomas. (3) Among the 3,307 patients with regional metastases, components that defined the N category were the number of metastatic nodes, tumor burden, and ulceration of the primary melanoma. (4) For staging purposes, all patients with microscopic nodal metastases, regardless of extent of tumor burden, are classified as stage III. Micrometastases detected by immunohistochemistry are specifically included. (5) On the basis of a multivariate analysis of patients with distant metastases, the two dominant components in defining the M category continue to be the site of distant metastases (nonvisceral v lung v all other visceral metastatic sites) and an elevated serum lactate dehydrogenase level. CONCLUSION: Using an evidence-based approach, revisions to the AJCC melanoma staging system have been made that reflect our improved understanding of this disease. These revisions will be formally incorporated into the seventh edition (2009) of the AJCC Cancer Staging Manual and implemented by early 2010.

Neurodevelopmental outcomes following ganciclovir therapy in symptomatic congenital cytomegalovirus infections involving the central nervous system.

BACKGROUND: Ganciclovir protects against hearing deterioration in infants with symptomatic congenital cytomegalovirus (CMV) disease involving the central nervous system (CNS). OBJECTIVES: To assess the neurodevelopmental impact of ganciclovir therapy in this population. STUDY DESIGN: 100 neonates were enrolled into a controlled Phase III study of symptomatic congenital CMV involving the CNS, and were randomized to either 6 weeks of intravenous ganciclovir or no treatment. Denver developmental tests were performed at 6 weeks, 6 months, and 12 months. For each age, developmental milestones that > or =90% of normal children would be expected to have achieved were identified. The numbers of milestones not met ("delays") were determined for each subject. The average number of delays per subject was compared for each treatment group. RESULTS: At 6 months, the average number of delays was 4.46 and 7.51, respectively, for ganciclovir recipients and "no treatment" subjects (p=0.02). At 12 months, the average number of delays was 10.06 and 17.14, respectively (p=0.007). In a multivariate regression model, the effect of ganciclovir therapy remained statistically significant at 12 months (p=0.007). CONCLUSIONS: Infants with symptomatic congenital CMV involving the CNS receiving intravenous ganciclovir therapy have fewer developmental delays at 6 and 12 months compared with untreated infants. Based on these data as well as the previously published data regarding ganciclovir treatment and hearing outcomes, 6 weeks of intravenous ganciclovir therapy can be considered in the management of babies with symptomatic congenital CMV disease involving the CNS. If treatment is initiated, it should be started within the first month of life and patients should be monitored closely for toxicity, especially neutropenia. Since existing data only address the treatment of symptomatic congenital CMV disease involving the CNS, these data cannot be extrapolated to neonates with other manifestations of CMV disease, including asymptomatic babies and symptomatic babies who do not have CNS involvement.

Turning Access into a web-enabled secure information system for clinical trials.

BACKGROUND: Organizations that have limited resources need to conduct clinical studies in a cost-effective, but secure way. Clinical data residing in various individual databases need to be easily accessed and secured. Although widely available, digital certification, encryption, and secure web server, have not been implemented as widely, partly due to a lack of understanding of needs and concerns over issues such as cost and difficulty in implementation. PURPOSE: The objective of this study was to test the possibility of centralizing various databases and to demonstrate ways of offering an alternative to a large-scale comprehensive and costly commercial product, especially for simple phase I and II trials, with reasonable convenience and security. METHODS: We report a working procedure to transform and develop a standalone Access database into a secure Web-based secure information system. RESULTS: For data collection and reporting purposes, we centralized several individual databases; developed, and tested a web-based secure server using self-issued digital certificates. LIMITATIONS: The system lacks audit trails. The cost of development and maintenance may hinder its wide application. CONCLUSIONS: The clinical trial databases scattered in various departments of an institution could be centralized into a web-enabled secure information system. The limitations such as the lack of a calendar and audit trail can be partially addressed with additional programming. The centralized Web system may provide an alternative to a comprehensive clinical trial management system.

Recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF, sargramostim) administered for 3 years as adjuvant therapy of stages II(T4), III, and IV melanoma.

A hypothesis generating study was conducted to evaluate the safety and efficacy of prolonged (3 y) administration of granulocyte-macrophage colony-stimulating factor (GM-CSF, sargramostim) as surgical adjuvant therapy in patients with melanoma at high risk of recurrence. Ninety-eight evaluable patients with stages II(T4), III, or IV melanoma were given prolonged treatment with GM-CSF after surgical resection of disease. The GM-CSF was administered subcutaneously in 28-day cycles, such that a dose of 125 microg/m2 was delivered daily for 14 days followed by 14 days rest. Treatment cycles continued for 3 years or until disease recurrence, which could not be surgically excised. Patients were evaluated for toxicity, disease-free survival, and melanoma-specific survival. Prolonged administration of GM-CSF was well tolerated; grade 1 or 2 side effects occurred in 82% of the patients. There were no grade 3 or 4 treatment-related side effects. Two patients developed acute myelogenous leukemia after completion of 3 years of GM-CSF administration. With a median follow-up of 5.3 years, the median melanoma-specific survival has not yet been reached. The 5-year melanoma-specific survival rate was 60%. The current study has expanded the preliminary evidence on GM-CSF as adjuvant therapy of patients with melanoma who are at high risk for recurrence.

Parametric modeling of localized melanoma prognosis and outcome.

This investigation explored the most suitable parametric model for melanoma prognosis and compared it with the Cox model. Cox-Snell residuals and survival function plots were applied to assess whether the generalized gamma (GG) model was the best-fit parametric model for the data. The GG model is a powerful alternative to the Cox model in prognostic modeling. The GG model offers an advantage of explicit and flexible individualized hazard functions over the Cox model and provides a clinically useful risk assessment over time to aid clinicians in formulating patient treatment, follow-up plans, and clinical trial design and analysis.

Comparison of multivariate adaptive regression splines and logistic regression in detecting SNP-SNP interactions and their application in prostate cancer.

Single nucleotide polymorphism (SNP) interaction plays a critical role for complex diseases. The primary limitation of logistic regressions (LR) in testing SNP-SNP interactions is that coefficient estimates may not be valid because of numerous terms in a model. Multivariate adaptive regression splines (MARS) have useful features to effectively reduce the number of terms in a model. To study how MARS can address these drawbacks possibly better than LR, the power of MARS and LR with SNPs using the reference-coding and additive-mode scheme was compared using simulated data of ten SNPs for 400 subjects based on 1,000 replications for five interaction models. In overall scenarios, MARS performed better than LR. In the model with a dominant two-way interaction, the power range was 76-96% for MARS and 1-8% for LR in both coding schemes. In the dominant three-way interaction model, the power was 57-85% for MARS and less than 4% for LR. In the prostate cancer example, we evaluated the association between ten SNPs and prostate cancer risk in 649 Caucasians. The best model with one two-way and one three-way interaction was selected using MARS. The findings supported that MARS may provide a useful tool for exploring SNP-SNP interactions.

FCRL2 expression predicts IGHV mutation status and clinical progression in chronic lymphocytic leukemia.

CD38 and ZAP-70 are both useful prognostic markers for B-cell chronic lymphocytic leukemia (CLL), but are variably discordant with IGHV mutation status. A total of 5 human Fc receptor-like molecules (FCRL1-5) have tyrosine-based immunoregulatory potential and are expressed by B-lineage subpopulations. To determine their prognostic potential in CLL, FCRL expression was compared with IGHV mutation status, CD38 and ZAP-70 expression, and clinical features from 107 patients. FCRL1, FCRL2, FCRL3, and FCRL5 were found at markedly higher levels on CLL cells bearing mutated IGHV genes than on unmutated CLL cells or CD19(+) polyclonal B lymphocytes. Univariate comparisons found that similar to CD38 and ZAP-70, FCRL expression was strongly associated with IGHV mutation status; however, only FCRL2 maintained independent predictive value by multivariate logistic analysis. Strikingly, FCRL2 demonstrated 94.4% concordance with IGHV mutation compared with 76.6% for CD38 and 80.4% for ZAP-70. Compared with other indicators, FCRL2 was also superior at predicting the time to first therapy; the median treatment-free interval was 15.5 years for patients with high FCRL2 expression compared with 3.75 years for FCRL2-low patients. Our studies indicate that FCRL2 has robust predictive value for determining IGHV gene mutation status and clinical progression and thus may further improve prognostic definition in CLL.