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The oncofetal protein IMP3: a novel molecular marker to predict aggressive meningioma.

Meningioma is the second most common primary tumor of the central nervous system. It accounts for 13% to 26% of all primary intracranial tumors in adults.1 Meningioma is generally considered to be a benign neoplasm and usually treated by surgical resection with a good clinical outcome. However, a small group of meningiomas have more aggressive behavior with a greater probability for recurrence and overall poorer survival. These patients need much closer clinical surveillance and follow-up and may require additional therapies including radiation. For this reason, it is crucial to be able to distinguish meningiomas that will behave more aggressively from those that behave in a benign manner. The World Health Organization (WHO) classification of brain tumors (1) has assigned 3 histologic grades to meningioma: grade I, grade II (atypical meningioma), and grade III (anaplastic or malignant meningioma). WHO grade I meningiomas tend to have a low recurrence rate while grade II and III meningiomas have higher recurrence rates. (2-7) This grading system, however, is based primarily on histologic appearance and/or mitotic index and often cannot accurately predict recurrence and aggressive behavior, particularly for the higher grade (II and III) meningiomas. (2-7)

Prognostic biomarkers for meningioma have been studied. (8-23) Among them, Ki-67 (MIB-1), a tumor proliferation antigen, appears to be the best and is widely accepted as a biomarker for meningioma prognosis. As a general rule, the Ki-67 proliferation index correlates well with WHO tumor grade for meningioma. (1) However, differences in interpretation methodology among individual laboratories have prevented the adoption of standard cut-off levels for the Ki-67 proliferation index. In addition, there are no conclusive results to show that Ki-67 is an independent prognostic marker for meningioma. (8,9,11,16-18) Therefore, there is a great need for biomarkers that can more accurately distinguish aggressive from indolent meningiomas.

Recently, we identified IMP3 as an independent prognostic biomarker whose expression predicts the aggressive behavior of renal cell carcinomas and urothelial carcinomas. (24-27) IMP3 is a member of the insulin-like growth factor II mRNA binding protein (IMP) family that consists of IMP1, IMP2, and IMP3. (28) IMP family members play an important role in RNA trafficking and stabilization, cell growth, and cell migration during the early stages of embryogenesis. (29) The IMP3 gene is located on chromosome 7p11.2 (30) and is identical to the KH domain containing protein overexpressed in cancer protein that was originally cloned from a pancreatic tumor complementary DNA screen. (31) IMP3 is expressed in developing epithelium, muscle, and placenta during early stages of human and mouse embryogenesis, but it is expressed at low or undetectable levels in adult tissues. (28,29) The expression of IMP3/KH domain containing protein overexpressed in cancer is also found in malignant tumors including pancreas, lung, stomach, and colon cancers and soft tissue sarcomas, but it is not detected in adjacent benign tissues. (28,31-33) Moreover, recent studies have demonstrated that IMP3 promotes tumor cell proliferation and invasion. (28,34) These findings indicate that IMP3 is an oncofetal protein that may have a critical role in the regulation of cell proliferation and invasion.

In this study, we investigate the expression of IMP3 in primary meningiomas and whether its expression correlates with tumor recurrence and overall survival.

MATERIALS AND METHODS

Patients

One hundred seven patients with meningiomas of the central nervous system (brain meningiomas, n = 94; spinal cord meningiomas, n = 11; auditory canal meningiomas, n = 2) were included in our study. Formalin-fixed, paraffin-embedded samples of the tumors were collected from the archival files at the University of Massachusetts Medical Center, Worcester, Massachusetts, and City of Hope National Medical Center, Duarte, California, between 1999 and 2007. All meningiomas in this study were completely removed during the surgery. Patients' medical records and imaging study reports were evaluated for clinical information and follow-up data. The presence of tumor recurrence was obtained from clinical, radiologic, and/or pathologic data on each patient. The number of tumor recurrences varied from 1 to 5.

All histologic slides of the tumors were evaluated independently by pathologists (S.H., T.W.S., or P.G.C.) and without knowledge of clinical outcome. Each meningioma was assigned a histologic grade using the parameters described in the most recent WHO classification. (1) Among 15 grade II meningiomas, 2 were diagnosed based on brain invasion alone and 13 were diagnosed based on the presence of 3 of the 5 atypical features described in the WHO 2007 classification. One of the grade II meningiomas showed increased mitotic activity. Two of the grade III meningiomas were diagnosed based on high-grade morphology (rhabdoid). The other two grade III cases were diagnosed based on high mitotic activity and anaplastic histology. No other variants (clear cell, chordoid, or papillary) were identified in the high-grade meningiomas. All grade II and grade III tumors were from brain.

Immunohistochemistry

Immunohistochemical studies were performed on 5-[micro]m sections of formalin-fixed, paraffin-embedded tissue from meningioma resection specimens. Antigen retrieval was carried out with 0.01 mol/L citrate buffer at pH 6.0, in an 800-W microwave oven for 15 minutes before immunostaining. The slides were stained on the DAKO Autostainer (Dako, Carpinteria, California) using the EnVision (Dako) staining reagents. The sections were first blocked for endogenous protein binding and peroxidase activity with an application of Dual Endogenous Block (Dako) for 10 minutes, followed by a buffer wash. The sections were then incubated with a mouse monoclonal antibody specific for IMP3 (L523S, Dako) at a 2.0 mg/mL concentration and a mouse monoclonal antibody specific for Ki-67 (clone Ki88, BioGenex, San Ramon, California) for 30 minutes, followed again by a buffer wash. Sections were then incubated with the EnVision+ Dual Link reagent (a polymer conjugated with goat anti-mouse immunoglobulin, and horseradish peroxidase; Dako) for 30 minutes. The sections were then washed and treated with diaminobenzidine and hydrogen peroxide to produce the visible brown pigment. A toning solution (DAB Enhancer, Dako) was used to enrich the final color. The sections were counterstained with hematoxylin, dehydrated, and coverslipped with permanent media. Sections with known positivity of IMP3 and Ki-67 were used as positive controls for IMP3 and Ki-67 staining. Negative controls were performed by replacing the primary antibody with nonimmune immunoglobulin G.

Morphologic Evaluation

Positive staining of IMP3 was defined as dark brown cytoplasmic staining pattern in tumor cells that can be easily observed at low-power magnification (<X40). Scant fine granular background staining of cells, which cannot be seen at low-power magnification (<X 40), or no staining at all was considered negative. The status of IMP3 was assessed by researchers (S.H. and Z.J.) without knowledge of the clinical and pathologic features of the cases or the clinical outcome.

To evaluate the proliferation activity of meningiomas, Ki-67 immunohistochemical staining was performed on all cases using similar methods as described previously. For each tumor, the percentage of tumor cells immunoreactive for Ki-67 was determined at the time of the initial diagnosis. Immunostaining was considered positive if there was distinct nuclear staining. The fields chosen for evaluation consisted of regions of the tumor having the greatest number of immunoreactive cells as assessed qualitatively at low-power (X100) magnification. Cell counts were performed in these areas at high-power (X 400) magnification using a standard 10 X 10 ocular grid. The total number of cells within the area defined by the grid was determined by the method of Going. The number of positive-staining cells within the grid was then divided by the total cell count and expressed as a percentage (labeling index [LI]). For each tumor, a total of 5 to 10 contiguous fields (total cell number >2000) were counted. The -proliferation index for each tumor was determined as the numerical average of the Ki-67 LI in all fields assessed. Ki-67 LI was grouped into 3 groups: less than 10%, 10% or more, and 20% or more. The status of Ki-67 LI was assessed by a researcher (T.S.) without knowledge of the clinical and pathologic features of the cases or the clinical outcome.

Statistical Analysis

Recurrence-free survival was measured from the date of first surgery to the date of first clinical evidence of recurrence and was censored at the date of recurrence or the date of the last follow-up visit for nonrecurrent patients. The median follow-up was 23 months (range, 1-144 months). Overall survival was measured from the date of surgery to the date of death or was censored as of the date of the last follow-up for survivors. The median follow-up was 53 months (range, 2-105 months). Age, sex, tumor grade, Ki-67 LI, and IMP3 status were collected as baseline variables. The distribution of each baseline variable was compared for IMP3-positive and IMP3-negative subgroups with the Wilcoxon rank sum test for continuous variables and the Fisher exact test for categorical variables. Overall survival and recurrence-free survival of 107 patients were estimated by the Kaplan-Meier method. The Cox proportional hazard model was used to assess the simultaneous contribution of the following baseline covariates of age, sex, Ki-67 LI, tumor grade, and IMP3 status. A 2-sided P value of less than .05 was considered to indicate statistical significance.

RESULTS

The relevant clinical characteristics of these 107 patients are summarized in Table 1. IMP3 protein was observed in the cytoplasm of tumor cells (Figure 1, A and B) in 7 of 107 cases (6.5%) and most meningiomas were negative for IMP3 staining (Figure 1, C). The IMP3 staining pattern in the meningiomas is heterogeneous. In the positive cases, IMP3 expression was not found in all meningioma cells. There were some areas of the tumors with diffuse IMP3 staining (Figure 1, A), while other areas of the tumors revealed the patchy staining pattern (Figure 1, B). All IMP3-positive meningiomas were intracranial in location. The normal brain tissue adjacent to tumors was negative for IMP3. IMP3 expression was much more common in high-grade tumors than in low-grade tumors (P < .001, Table 1) and correlated with the higher Ki-67 LIs in these tumors (Table 1). One of these high-grade meningiomas with rhabdoid appearance also expressed IMP3 (Figure 1, B). Although IMP3 expression was more common in tumors of older age patients, this was not statistically significant (P 5 .08, Table 1). Meningiomas from men and women expressed IMP3 equally (Table 1). Tumor recurrence was found in 13 of 107 patients (5 in grade 1 [5%], 5 in grade 2 [33%], and 3 in grade 3 [75%] patients). The recurrent rates in different grades of tumors in our study were similar to those in the previous studies. (2-7) All of the primary meningiomas that recurred arose from brain. Six of 7 patients (86%) with IMP3 positivity in their initial meningiomas developed recurrence, whereas only 7% (7 of 100 patients) without expression of IMP3 in their primary tumors developed recurrence.

Kaplan-Meier plots and log-rank tests in these 107 patients with follow-up information were done and showed that patients without IMP3 expression in their meningiomas had significantly longer recurrence-free and overall survival rates than patients with IMP3 expression. Figure 2, A, shows that the median recurrence-free survival rate was 109 months in patients with IMP3-negative tumors versus 23 months in patients with IMP3-positive tumors. In patients whose initial meningiomas were positive for IMP3 versus those with IMP3-negative meningiomas, the 5-year recurrence-free survival was 0% versus 89%. The 5-year overall survival rate was 94% in patients without expression of IMP3 versus 36% in patients with IMP3 expression (Figure 2, B).

[FIGURE 1 OMITTED]

[FIGURE 2 OMITTED]

Because most IMP3-positive tumors were WHO grade II or III tumors, we also analyzed the recurrence-free survival difference in patients with grade II and grade III tumors only. Figure 3 shows that grade II or III patients with IMP3 expression had much higher risk of developing recurrent tumors compared with those patients without IMP3 expression. The median recurrence-free survival rate was 17.5 months in patients with IMP3-positive tumors versus 109 months in patients with IMP3-negative tumors.

The results of the multivariable Cox proportional hazards regression analysis for recurrence-free and overall survival in the 107 patients with primary brain meningiomas are presented in Table 2. For these analyses, age, sex, Ki-67 LI, and WHO tumor grades (Table 1) were initially contained as covariates in the model and none of these covariates were tested as a significant factor. The final multivariable analysis showed that the expression of IMP3 in meningiomas was a strong independent predictor of tumor recurrence. The hazard ratio was 17.89 (for recurrence-free survival; 95% confidence interval, 1.98-161.32; P 5 .01), which was much higher than the hazard ratios associated with tumor grades and Ki-67 LI (Table 2). The hazard ratio was 10.34 (for overall survival; 95% confidence interval, 1.00-106.75; P = .05; Table 2).

[FIGURE 3 OMITTED]

COMMENT

In this study, we investigated the role of IMP3 expression in predicting the future recurrence of meningiomas. Our data showed that the expression of IMP3 in meningiomas is strongly associated with tumor recurrence and poor patient survival.

IMP3 displays several features that make it an attractive prognostic marker for meningioma. First, the expression of IMP3 is correlated with other pathologic indicators of aggressive behavior in meningiomas and in particular is strongly related to higher WHO tumor grade and higher Ki-67 LI.

Second, the expression of IMP3 in meningiomas is a potential independent predictor for tumor recurrence. Recurrence-free survival of patients with IMP3-positive meningiomas was extremely poor as compared with that of patients without IMP3 expression in meningiomas and this was independent of tumor grade. We found that 86% (6 of 7) of patients with IMP3 positivity in their initial meningiomas developed recurrence, whereas only 7% (7 of 100) of patients without expression of IMP3 in their primary tumors developed recurrence. In the multivariable Cox analysis, patients with IMP3 expression in meningiomas developed recurrences at a rate that is 17 times greater than patients without expression of IMP3 after adjusting for age, sex, tumor grade, and Ki-67 LI.

Third, IMP3 immunohistochemical staining is a simple, inexpensive, and reliable assay. As meningiomas are treated primarily by surgical resection, tumor tissue should be routinely available in pathology departments for immunohistochemical staining. The IMP3 monoclonal antibody specifically binds its target with very low or no background in immunohistochemical staining.

Our findings raise the possibility that IMP3 may play a direct role in the recurrence of meningioma. Interestingly, Yaniv et al (35) found that IMP3 in Xenopus laevis is required for the migration of cells forming the roof plate of the neural tube and subsequently for neural crest migration, which suggested that IMP3 may play an important role in promoting cell migration. Recent studies have demonstrated that IMP3 promotes tumor cell proliferation and invasion. (28,34) These findings indicate that IMP3 is an oncofetal protein that may have a critical role in the regulation of cell proliferation and invasion. Further study is required to investigate whether IMP3 plays a direct role in the biological behavior of meningioma.

Although our data have shown that IMP3 is a potential biomarker to predict aggressive meningiomas, the restriction of the current study is a limited number of aggressive meningiomas cases. Therefore, additional validation studies are needed to confirm our results.

In summary, IMP3 expression in the initial diagnostic sample can be used to predict whether a meningioma is likely to recur and can provide important prognostic information in patients undergoing meningioma resection. IMP3 is a potential independent prognostic marker for aggressive meningiomas and may identify a subgroup of patients who have a high potential to develop recurrence and have a poor overall survival rate after surgery.

References

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Suyang Hao, MD; Thomas W. Smith, MD; Peigou G. Chu, MD, PhD; Qin Liu, PhD; Chi Young Ok, MD; Bruce A. Woda, MD; Di Lu, MD; Pei Lin, MD; Sa A. Wang, MD; Karen Dresser, BS; Kenneth L. Rock, MD; Zhong Jiang, MD

Accepted for publication October 11, 2010.

From the Departments of Pathology (Drs Hao, Smith, Ok, Woda, Lu, Rock, and Jiang and Ms Dresser) and Medicine (Dr Liu), University of Massachusetts Medical Center, Worcester; the Division of Pathology, City of Hope National Medical Center, Los Angeles, California (Dr Chu); and the Department of Hematopathology, The University of Texas, M. D. Anderson Cancer Center, Houston (Drs Lin and Wang).

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Zhong Jiang, MD, Department of Pathology, Umass Memorial Medical Center, 3 Biotech, 1 Innovation Drive, Worcester, MA 01605 (e-mail: jiangz@ummhc.org).
Table 1. Clinicopathologic Characteristics of Patients
With Meningiomas

 IMP-Positive IMP-Negative
 Tumors (n = 7) Tumors (n = 100)
 No. (%) No. (%)

Sex
 Male 2 (7) 27 (93)
 Female 5 (6) 73 (94)

Age, y,
 mean (SD) 59.8 (14.4) 49.6 (23.1)

Tumor grade
 Grade 1 1 (1) 87 (99)
 Grade 2 4 (27) 11 (73)
 Grade 3 2 (50) 2 (50)

Ki-67
 <10 5 (5) 93 (95)
 [greater than or equal to] 10 0 (0) 7 (100)
 [greater than or equal to] 20 2 (100) 0 (0)
Atypia
 Present 6 (35) 11 (65)
 Absent 1 (1) 89 (99)
Loss of architecture
 Yes 6 (67) 3 (33)
 No 1 (1) 97 (99)
Brain invasion
 Present 3 (43) 4 (57)
 Absent 4 (4) 96 (96)
Necrosis
 Present 6 (38) 10 (62)
 Absent 1 (1) 90 (99)

 P Value

Sex
 Male >.99
 Female

Age, y,
 mean (SD) .09

Tumor grade
 Grade 1 <.001
 Grade 2
 Grade 3

Ki-67
 <10 <.001
 [greater than or equal to] 10
 [greater than or equal to] 20
Atypia
 Present <.001
 Absent
Loss of architecture
 Yes <.001
 No
Brain invasion
 Present .006
 Absent
Necrosis
 Present <.001
 Absent

Table 2. Multivariate Analyses for Recurrence-Free and Overall Survival

Variable Recurrence-Free Survival
 Hazard Ratio (95% P Value
 Confidence Interval)

IMP3 status, positive versus 17.89 (1.98-161.32) .01
 negative
 Age 0.97 (0.94-1.00) .08
 Sex 0.95 (0.19-4.81) .95
 Ki-67 0.97 (0.83-1.12) .65

Tumor grade
 II versus I 3.12 (0.38-25.61) .29
 III versus I 3.40 (0.31-37.59) .32

Variable Overall Survival
 Hazard Ratio (95% P Value
 Confidence Interval)

IMP3 status, positive versus 10.34 (1.00-106.75) .05
 negative
 Age 1.01 (0.97-1.05) .68
 Sex 1.30 (0.17-9.78) .80
 Ki-67 0.89 (0.69-1.14) .36

Tumor grade
 II versus I 2.86 (0.24-33.47) .40
 III versus I 8.32 (0.53-129.86) .80
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Author:Hao, Suyang; Smith, Thomas W.; Chu, Peigou G.; Liu, Qin; Ok, Chi Young; Woda, Bruce A.; Lu, Di; Lin,
Publication:Archives of Pathology & Laboratory Medicine
Date:Aug 1, 2011
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