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Clinical Cancer Research Vol. 10, 2824-2831, April 15, 2004
© 2004 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Prognostic Value of CD40 in Adult Soft Tissue Sarcomas

Alessandro Ottaiano1, Anna De Chiara2, Francesco Perrone3, Gerardo Botti2, Flavio Fazioli4, Vincenzo De Rosa5, Nicola Mozzillo6, Vincenzo Ravo7, Brunello Morrica7, Ciro Gallo9, Carmela Pisano1, Maria Napolitano8, Paolo Antonio Ascierto8, Rosario Vincenzo Iaffaioli1 and Gaetano Apice1

1 Medical Oncology B, 2 Surgical Pathology, 3 Clinical Trials Unit, 4 Department of Orthopedics, 5 Department of Radiology, 6 Surgical Oncology B, 7 Department of Radiotherapy, 8 Clinical Immunology, National Cancer Institute, and 9 Medical Statistics, Second University, Naples, Italy


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: The purpose is to evaluate the expression of CD40, a membrane protein predominantly expressed on B cells, dendritic cells, and macrophages, in a series of adult soft tissue sarcomas and to test its possible prognostic value.

Experimental Design: CD40 expression was studied by immunohistochemistry. Correlations with other baseline characteristics of patients and tumors were analyzed with {chi}2 test. The prognostic value was studied with univariable and multivariable analysis adjusted by age, sex, tumor size, grade, location, and distant metastases.

Results: Eighty-two patients, between January 1994 and May 2001, were analyzed. Membrane or cytoplasmic staining for CD40 protein was absent in 30% of the tumors but present in <10% of cells in 22 (27%), in 10% to 50% in 23 (28%), and in >50% of cells in 12 (15%) tumors. There was no correlation between CD40 expression and age, sex, size, grade, and location of the primary tumor and distant metastases. With 61 patients (74.4%) progressed and 31 (37.8%) dead, CD40 expression was a significant prognostic factor for disease-free and overall survival at univariable and multivariable analysis. Patients with tumors expressing CD40 in >50% of cells had a dramatically unfavorable prognosis with median disease-free and overall survival of 7 and 17 months, respectively, and hazard ratios of relapse and death as compared with patients with CD40-negative tumors of 2.89 (95% confidence interval: 1.26–6.60) and 6.92 (95% confidence interval: 2.18–22.0), respectively.

Conclusions: These data suggest that expression of CD40 protein in >50% of cells might indicate an unfavorable prognosis in adult soft tissue sarcomas.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Soft tissue tumors are a highly heterogeneous group of neoplasms classified on a histogenetic basis according to the adult tissue they resemble. Three groups may be identified on morphological basis: round-cell sarcoma; spindle-cell sarcoma; and pleomorphic sarcoma. Adult no-round-cell soft tissue sarcomas include tumors arising in different tissues and are characterized by cells that can range from spindled to fusiform in shape; they are locally aggressive and capable of produce recurrence and distant metastasis. The most common metastatic site is the lung. Standard treatment is surgery in low-grade/superficial lesions or surgery plus radiotherapy in high-grade/deep lesions; in case of insufficient excision margins, surgery is followed by radiotherapy. In the metastatic disease, chemotherapy is the gold standard. In general, prognosis in intermediate/high-grade sarcomas is poor (1) . The only well-recognized prognostic factor is the stage of disease that includes grading, extension, and volume of the lesions (American Joint Committee on Cancer/Union International Contre Cancer staging system). Additional prognostic factors could be useful to improve the therapeutic decision-making process.

CD40 belongs to the tumor necrosis factor receptor family and is expressed on B cells, dendritic cells, and macrophages (2) . It is also expressed on keratinocytes, the basal layer of the nasopharynx, gastrointestinal and bronchial mucosa, and several exocrine glands such as the salivary glands, sweat glands, mammary glands, and pancreas (3) . Its receptor, CD40L, is a type II membrane protein belonging to the tumor necrosis factor family and is predominantly expressed on CD4+ CD3+ T cells, CD56+ CD3– natural killer cells and platelets (4) . The CD40-CD40L interaction has been primarily implicated in B cells proliferation, growth, and differentiation and in the T-dependent humoral immune responses (4) , but recent studies have highlighted its role in other immunity functions such as the stimulation of production of proinflammatory cytokines (tumor necrosis factor {alpha}, interleukin 8, and interleukin 12) from macrophages and dendritic cells (3) . It also strongly augments the antigen-presenting activity of B cells, macrophages, and dendritic cells by up-regulating the expression of B7 and other costimulatory molecules (3 , 5) . Recent studies demonstrated critical involvement of the CD40-CD40L interaction in induction of apoptosis in tumors and of antitumor immunity by vaccination with irradiated tumor cells (6) . In addition, it has also recently been demonstrated that transgenic expression of CD40L in some tumor cell lines reduced their tumorigenicity and elicited protective immunity, but the mechanism by which CD40L exerted the antitumor effect in vivo has not yet been elucidated (7 , 8) .

Recently, it has been demonstrated that stimulation of CD40 is associated with matrix metalloproteinase 9 induction and secretion (9 , 10) and with angiogenesis (11, 12, 13, 14) . These phenomena are known to be involved in invasion and metastases establishment of tumor cells. The molecule is expressed in several tumors of different origin, including bladder, lung, prostate, breast, and colon (15, 16, 17) . The expression of functioning CD40 in sarcomas has been demonstrated in vitro in established sarcoma cell lines (18) . Little is known about its expression and its role in human sarcomas.

The present study was undertaken to describe the expression of CD40 and of its ligand in adult soft-tissue sarcomas and to test its possible prognostic value.


   PATIENTS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients were seen at the Division of Medical Oncology B of the National Cancer Institute of Naples from 1994 to 2001. The histological section was reviewed by an expert pathologist (A. De Chiara) to verify the histological diagnosis of adult soft-tissue sarcomas (excluding Ewing sarcoma and primitive neuroectodermal tumors) before performing immunohistochemistry. Standard therapeutic strategies were applied for these patients, according to stage of disease and presumed risk of relapse; patients with high-grade or large tumor size or deep location or inadequate resection margins were considered at high risk. Patients with local disease were treated with surgery alone if considered at low risk or with surgery followed by radiotherapy in case of high risk. Patients with locally advanced disease received neoadjuvant chemotherapy (ifosfamide plus epirubicin) before surgery and radiotherapy. Patients with advanced disease metastatic to lung and/or bone were mainly treated with palliative chemotherapy alone. A few selected patients underwent pulmonary metastasectomy in case of solitary lesion or single lobe involvement and adequate disease-free survival (at least 1 year). Selected patients (PS < 2, age < 75 years, normal cardiac and renal functions, and life expectancy > 6 months) were treated with second line chemotherapy. Locations of the primary tumor were grouped as extremity (upper extremity, including shoulder and axilla, or lower extremity, including groin, hip, and buttock) or nonextremity (retroperitoneal/visceral sarcoma, intra-abdominal, intrathoracic, head and neck, or body wall) according to Weiss and Goldblum (1) .

Immunohistochemistry.
In all cases, immunohistochemistry was performed on the primary tumors. Five-µm sections of formalin-fixed, paraffin-embedded tissues were immunostained using the biotin-Streptavidin-peroxidase method (YLEM). Deparaffinized sections were microwaved in 1 mM EDTA (pH 8.0) for four cycles of 5 min each to unmask epitopes. After treatment with 1% hydrogen peroxidase for 10 min to block endogenous peroxidases, the sections were subsequently incubated with monoclonal antibodies (anti-CD40, N-16, and anti-CD40L, D-19; Santa Cruz Biotechnology) for 2 h at room temperature. The sections were then incubated with biotin-labeled secondary antibody (1:30) and Streptavidin-peroxidase (1:30) for 20 min each. Slides were stained for 5 min with 0.05% 3,3'-diaminobenzidine tetrahydrochloride freshly prepared in 0.05 M Tris-HCl buffer (pH 7.6) containing 0.024% hydrogen peroxidase and then counterstained with hematoxylin, dehydrated, and mounted in Diatex. The dilutions of the monoclonal antibody, biotin-labeled secondary antibody, and streptavidin-peroxidase were made with PBS (pH 7.4) containing 5% BSA. All series included positive controls (skin sections with keratinocytes and B- and T-cell lymphomas). Negative controls were obtained by substituting the primary antibody with a mouse myeloma protein of the same subclass, at the same concentration as the monoclonal antibody. All controls gave satisfactory results. Staining was categorized into four semiquantitative classes based on the rate of stained (positive) tumor cells: absence of staining, <10% positive cells, 10–50% positive cells, and >50% positive cells. Slides were evaluated by two blinded observers (G. Botti and A. De Chiara); discordant cases were discussed, and concordance was then achieved.

Statistical Analysis.
Correlations between CD40 expression and baseline characteristics of patients and tumors were studied by contingency tables and the {chi}2 test. Disease-free survival was defined as the time elapsed from the date of the initial diagnosis (even if done outside the National Cancer Institute of Naples) to the appearance of local relapse or distant metastasis or death, whichever occurred first. Overall survival was defined as the time elapsed from the date of the initial diagnosis to death or to the date of the last available information on vital status. Kaplan-Meier product limit method was applied to draw disease-free and overall survival curves. Univariable analysis was performed with the log-rank test, and the Cox model was applied for multivariable analysis. Hazard ratios are reported with 95% confidence intervals (CIs).


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Eighty-two patients, seen between January 1994 and May 2001, were analyzed. For 5 patients referring to our division at the moment of local or distant relapse, tissue blocks of the primary tumor were recovered from outside hospitals. Characteristics of all patients are summarized in Table 1Citation . Median age was 58; 19 patients were >=70 years old. Genders were equally represented. Three-fourths of patients had tumors >5 cm; more than one-half had high-grade disease and one-fifth showed metastatic disease at presentation. Tumors located in the extremities accounted for 56% of the cases. Most common histologies were liposarcoma, leiomyosarcoma, malignant fibrous hystiocytoma, and malignant schwannoma.


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  		Table 1 Characteristics of 82 patients

 
All tumors were negative for CD40L; thus, no additional test was done for this molecule. CD40 was absent in 30% of the tumors; it was expressed in <10% of cells in 22 (27%), in 10–50% of cells in 23 (28%), and in >50% of cells in 12 (15%) tumors. Staining was observed both on membrane surfaces and in the cytoplasm of tumor cells. Fig. 1Citation shows some examples of typical positive stainings. There was no significant association between CD40 expression and age, gender, tumor size, tumor grade, distant metastases, and location of the primary tumor (Table 2)Citation .



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  		Fig. 1. Examples of CD40 expression in adult soft tissue sarcomas. Positive immunohistochemical staining in (A) high-grade leyomiosarcoma, (B) malignant schwannoma, and (C) malignant fibrous hystiocytoma. Negative immunohistochemical staining in (D) high-grade leyomiosarcoma and (E) malignant schwannoma. All magnifications are x20.

 

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  		Table 2 Correlations between CD40 expression and baseline characteristics of patients and tumors

 
As of November 2001, after a median follow-up for alive patients of 31 months, 61 patients (74.4%) had suffered tumor progression and 31 (37.8%) had died. Median disease-free and overall survival in the whole series were 14 months (95% CI: 11–19) and 80 months (95% CI: 59–not assessable), respectively.

Analysis of prognostic factors for disease-free survival is summarized in Table 3Citation . CD40 expression and distant metastases had a significant prognostic value at univariable analysis. Their predictive ability was confirmed at multivariable analysis (Table 3)Citation adjusted by age, sex, tumor size, tumor grade, and tumor location. Both hazard ratios of relapse and graphic pattern of Kaplan-Meier estimated curves (Fig. 2)Citation suggest that prognosis is particularly unfavorable for patients whose tumors expressed CD40 in >50% of cells (median disease-free survival, 7 months; hazard ratio of relapse 2.89, 95% CI: 1.26–6.60).


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  		Table 3 Analysis of disease-free survival

 


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  		Fig. 2. Kaplan-Meier progression-free survival curves for patients with soft tissue sarcomas according to CD40 expression.

 
Similar results were found in overall survival analysis (Table 4)Citation . In addition to CD40, sex, tumor grade, distant metastases, and primary tumor location showed some prognostic value at univariable analysis. Multivariable analyses confirmed the independent prognostic role of sex, tumor grade, distant metastases, tumor location, and CD40 expression. Again, patients with tumors expressing CD40 in >50% of cells had the worst prognosis with a median survival of 17 months and a 6.92 (95% CI: 2.18–22.0) hazard ratio of death (Table 4Citation and Fig. 3Citation ).


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  		Table 4 Analysis of overall survival

 


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  		Fig. 3. Kaplan-Meier survival curves for patients with soft tissue sarcomas according to CD40 expression.

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In recent years, many different biological prognostic factors have been studied in soft-tissue sarcomas; unfortunately, none of them seems to play a definitive role because of methodological limitations of retrospective studies and because of contrasting results. Analyses of the prognostic role of DNA abnormalities (e.g., aneuploidy, gene rearrangement) have produced both positive [Wijnaendts et al. (19) , Oda et al. (20) , Dreinhofer et al. (21) , Levine et al. (22) , De Zen et al. (23) , Kawai et al. (24) , Landanyi et al. (25) , and Sorensen et al. (26) ] and negative [Gustafson et al. (27) , Kuratsu et al. (28) , Huuhtanen et al. (29) , Collin et al. (30) , Plaat et al. (31) , and Huuhtanen et al. (32) ] results. The role of antioncogenes expression has been studied; p53 has been tested in four studies, two with positive [Kawai et al. (33) and Antonescu et al. (34) ] and two with negative [Heslin et al. (35) and Skytting et al. (36) ] results; nm23 [Royds et al. (37) ] and mdm2 [Heslin et al. (35) ] have shown no prognostic value. Markers of cell kinetics (S-phase fraction, KI67, and cyclin D1) have been tested with prevalently positive results [Wijnaendts et al. (19) , Levine et al. (22) , Collin et al. (30) , Gustafson et al. (38) , Heslin et al. (35) , Huuhtanen et al. (32) , Skytting et al. (36) , Hoos et al. (39) , and Kim et al. (40) ] and one study only reporting no prognostic value for S-phase fraction [Huuhtanen et al. (29) ]. Other isolated studies have proposed prognostic value for vascular endothelial growth factor [Yudoh et al. (41) ], TERT, and survivin [Wurl et al. (42) ], and E-cadherin and A-catenin expression [Saito et al. (43) ].

The present study was planned with an explorative aim, considering that there were only few background data on the prognostic ability of CD40; surprisingly, we found that the expression of CD40 in adult sarcomas is able to predict prognosis, independently of many established or potential prognostic factors. This ability holds true both for disease-free and overall survival and seems particularly evident for patients whose tumors were positively stained in more than half of cells, who had a really unfavorable prognosis. To the best of our knowledge this is the first report on CD40 expression in soft tissue sarcomas and the first evidence of its possible clinical relevance in these tumors. We think that our results need to be confirmed in larger series because of the relatively small size of our sample, particularly evident for the subgroup of patients with highly positive tumors, i.e., those with a dramatically worse prognosis.

CD40 signal is important for B-cell proliferation, growth, and differentiation, but more recently, several studies have showed that it mediates a diverse array of biological process. CD40 engagement may have opposite effects on tumor cell survival and malignancy, increasing the level of apoptotic cells, and stimulating the angiogenesis and the transcription/secretion of matrix metalloproteinase 9. It is also well known that CD40 mediated up-regulation of ICAM-1, a cell-adhesion molecule important for cell-cell interactions (44) . These processes are involved in tumor cell migration and invasion. Up-regulation of CD40 was observed in the tumor vessels of renal carcinomas (11) and Kaposi’s sarcoma (12) , suggesting a possible role of CD40 protein in inducing the tumor angiogenesis. On the other hand, it has been shown that the activation of CD40 on endothelial cells induces the tubule formation and the expression/secretion of matrix metalloproteinases (9 , 10) and vascular endothelial growth factor (13 , 14) .

Stimulation of CD40 on tumor cells may induce conflicting phenomena. In fact, it has suppressive or apoptotic effects on some CD40-expressing neoplasms (45) , but it may also prevent apoptosis (46) and augment tumor cell growth (47) . Furthermore, it has been demonstrated that activation of CD40 in renal cell carcinoma stimulated cell proliferation, motility, and production of platelet-activating factor, a phospholipid mediator of inflammation with angiogenic properties, thus suggesting a role for CD40 in promoting disease progression (48) .

Interestingly, many receptors belonging to the tumor necrosis factor receptor superfamily (CD40, p55, p70, and FAS) may have dual functions in transducing signals of cell growth or apoptosis (49) . In fact, CD40 has no kinase activity, but it activates signaling pathways by recruiting many different proteins. This molecular adaptation may influence specific cellular triggers (50) . Thus, the conflicting effects of CD40 stimulation on tumor cells may depend on cell-type specific signaling. As a consequence of the conflicting evidences coming from basic studies, some neoplasms such as the renal carcinomas and Kaposi’s sarcomas may rather benefit of CD40 inhibition.

Interestingly, immunohistochemical studies have revealed that detection of CD40 in primary cutaneous melanoma have negative prognostic value (51) , and some data suggest that CD40 expression on lung cancer cells may play a role in metastatic spread (52) .

Our results are consistent with the hypothesis of Lollini et al. (18) that CD40 might have opposite functions at different stages of sarcomas pathogenesis and progression. CD40 could protect from the onset of the disease thanks to its proapoptotic activity and its ability of inducing immunological response. Later, with established cancer and failure of immune protection, CD40 might promote genes involved in tumor invasion and metastasis and, thus, worsen patients outcome. On the basis of this hypothesis, the perspective of using CD40 as a target for therapeutic approach is intriguing but difficult. On one hand, our data seem to support the hypothesis that counteracting the activation of CD40 in advanced tumors could be of therapeutic value, considering that the higher the expression of CD40 the worst the prognosis of patients. It is also reasonable to test the opposite hypothesis that activating CD40 could produce benefit thanks to the induction of apoptosis and the activation of the immune system. According to the latter strategy, a Phase I study has been recently reported on treatment with recombinant human CD40 ligand, which is able to activate CD40 (53) . In this study, 32 patients with advanced solid tumors or high-grade non-Hodgkin’s lymphomas were treated at three different dose levels. Transaminase increase was dose limiting and the maximum-tolerated dose was reached at 0.1 mg/kg/day for 5 consecutive days. Two patients had a partial response: 1 with cancer of the larynx and 1 with a lymphoma. Of course, Phase II studies are required for a correct estimation of activity; hopefully, CD40 expression in tumor cells should be studied in such trials before enrollment to correlate activity with the target expression that was not tested in the Phase I study.


   ACKNOWLEDGMENTS
 
We thank Antonio Barbato and Fernando Caccavello for their technical assistance in the Laboratory of Pathology.


   FOOTNOTES
 
Grant support: The Clinical Trials Unit is partially supported by Associazione Italiana per la Ricerca sul Cancro and Clinical Trials Promoting Group.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Requests for reprints: Alessandro Ottaiano, Division of Medical Oncology B, National Cancer Institute, "G. Pascale" Foundation, via M. Semmola, 80131 Naples, Italy. Phone: 39-081-5903269, ext. 283; Fax: 39-081-5903820; E-mail: ale.otto{at}libero.it

Received 1/29/03; revised 12/ 9/03; accepted 12/18/03.


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Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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L. Shorts, J. M. Weiss, J.-K. Lee, L. A. Welniak, J. Subleski, T. Back, W. J. Murphy, and R. H. Wiltrout
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