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CEACAM1 Expression in Cutaneous Malignant Melanoma Predicts the Development of Metastatic Disease

From the Institute for Anatomy, Dermatological Hospital, Institute for Mathematics and Computer Science in Medicine, Department of Clinical Chemistry, University Hospital Hamburg-Eppendorf, Hamburg, and the Departments of Dermatology and Cancer Research, Fachklinik Hornheide, University of Münster, Münster, Germany.

Address reprint requests to Anka Thies, MD, Institute for Anatomy, University Hospital Hamburg-Eppendorf, Martinistraße 52, D-20246 Hamburg, Germany; email: thies{at}uke.uni-hamburg.de

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: The cell adhesion molecule CEACAM1 is involved in intercellular adhesion and subsequent signal transduction events in a number of epithelia. CEACAM1 downregulation has been demonstrated in colorectal and prostate carcinomas. This study sought to analyze whether its expression in malignant melanoma is associated with metastasis.

PATIENTS AND METHODS: CEACAM1 expression was immunohistochemically evaluated in 100 primary cutaneous malignant melanomas and correlated with metastasis in a 10-year follow-up. Furthermore, CEACAM1 expression was analyzed in metastatic lesions (11 distant metastases and six sentinel lymph node metastases). Univariate Kaplan-Meier analysis and multivariate Cox proportional hazard regression analysis adjusted for standard prognostic indicators were performed to assess the prognostic relevance of CEACAM1 expression.

RESULTS: A total of 28 of 40 patients with CEACAM1-positive primary melanomas developed metastatic disease, compared with only six of 60 patients with CEACAM1-negative melanomas. Often, the strongest CEACAM1 expression was observed at the invading front. In addition, CEACAM1 expression was preserved in the metastatic lesions. Kaplan-Meier analysis revealed a highly significant association between CEACAM1 expression and metastasis (P < .0001); multivariate Cox regression analysis, including CEACAM1 expression status adjusted for tumor thickness, presence of ulceration, and mitotic rate, confirmed that CEACAM1 is an independent factor for the risk of metastasis and demonstrated that the predictive value of CEACAM1 expression is superior to that of tumor thickness.

CONCLUSION: Expression of the cell adhesion molecule CEACAM1 in the primary tumors in melanoma patients is associated with the subsequent development of metastatic disease. This raises the possibility of a functional role for this cell adhesion molecule in the metastatic spread it indicates.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
METASTATIC SPREAD IN malignant melanoma is thought to occur at the onset of the vertical growth phase, and hence Breslow’s vertical tumor thickness is currently the most accepted single prognostic factor for predicting the prognosis in this tumor entity.¹ However, the underlying mechanisms of this process are complex and still not clarified; patients with thin melanomas may suffer from early metastasis and death, although there are other patients with thick melanomas at the time of surgery who survive. During metastasis development, cell-cell and cell-matrix interactions play a key functional role.² These interactions are mediated by cell adhesion molecules and modulation of the expression of a number of adhesion molecules belonging to the immunoglobulin superfamily—notably VCAM, ICAM-1, and MUC18—have been associated with metastatic spread in malignant melanoma.^3,4 A loss of melanoma cell adhesion mediated by VCAM-1 has been associated with the development of metastases.⁵ In contrast, an upregulation of the cell adhesion molecule L1, which is also a member of the immunoglobulin superfamily, has been noted in the metastatic phenotype of malignant melanoma (data not shown).

In this context, emphasis is placed on the cell adhesion molecule CEACAM1. CEACAM1, formerly known as biliary glycoprotein I or CD66a, is a member of the carcinoembryonic antigen family also belonging to the immunoglobulin superfamily (reviewed in Thompson et al⁶). CEACAM1 is known to mediate both homophilic and heterophilic adhesion⁶ and is expressed in a variety of normal human tissues, including, among others, colonic mucosa, mammary gland, prostate, and uterus.⁷ However, its expression has not been reported in normal melanocytes. In addition to its expression in normal tissues, CEACAM1 is downregulated or dysregulated in malignant tissues deriving from breast,⁸ colon,⁹ prostate,¹⁰ and endometrium.¹¹

Because no data on CEACAM1 expression in malignant melanoma and patients’ outcome have been reported, this study aimed to analyze a possible correlation between CEACAM1 expression in cutaneous malignant melanoma and metastasis formation in a 10-year follow-up study. Additionally, CEACAM1 expression was determined in metastatic lesions.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Primary Cutaneous Malignant Melanomas
Paraffin-embedded sections of primary cutaneous malignant melanoma from 100 patients who underwent surgery between 1983 and 1996 in the Dermatological Hospital, University Hospital Hamburg-Eppendorf, Germany, were investigated. Data of Breslow’s vertical tumor thickness and clinical stage, as well as date of diagnosis, surgery, occurrence of first metastasis, and death, were recorded from the original reports of 100 patients in a 10-year follow-up. Informed consent of all patients whose tumors were investigated had been obtained following institutional guidelines.

Patient Characteristics
The majority of the patients were women (60 women and 40 men), and the median age was 66.5 years (range, 19 to 97 years). All patients presented with localized cutaneous melanoma at the time of diagnosis. Forty-one patients were classified as having stage IA tumors (tumor thickness 0.75 mm), 22 as stage IB (0.76 to 1.5 mm), 32 as stage IIA (1.6 to 4.0 mm), and five as stage IIB (> 4.0 mm); staging was performed according to recommendations of the German Dermatological Society (DDG).¹²

After a median follow-up of 10 years, 34 patients demonstrated clinical signs of metastasis, and of these, 18 demonstrated hematogenous spread to lung (n = 3), liver (n = 5), brain (n = 4), and skin (n = 6); 16 demonstrated lymphatic spread as the primary manifestation of metastasis. During the observation period, 20 patients had died as a result of metastatic disease. Two patients had died as a result of disease other than metastatic melanoma.

Metastatic Lesions
To analyze CEACAM1 expression in metastatic lesions, a second series of melanomas was investigated. Primary melanomas (n = 17, stage DDG stages III/IV) and corresponding distant metastases (cutaneous/subcutaneous; n = 11) and metastasis-positive sentinel lymph nodes (n = 6) were obtained from the files of the Fachklinik Hornheide, University of Münster, Germany. Histologic proof of metastases in the sentinel lymph nodes was confirmed by immunohistochemistry in adjacent sections according to standard procedures as reported elsewhere.^13,14

Detection of CEACAM1
Details on the production and characterization of the monoclonal CEACAM1 antibody 4D1/C2 have been published previously.¹⁵ For immunohistochemistry, routinely fixed and paraffin-embedded primary melanomas were cut at 5 µm. Paraffin was removed from the sections, which were then rehydrated through a series of graded ethanols and rinsed in Tris-buffered saline (TBS; pH 7.6) with 0.1% Tween-20 added. All antibodies were diluted in antibody diluent with background reducing components (Dako, Glostrup, Denmark). The slides were microwaved at 500 W five times for 2 minutes in 10 mmol/L citrate buffer (pH 6.0). After cooling the slides for 20 minutes, they were washed three times in TBS + 0.1% Tween-20 for 5 minutes. Nonspecific binding was blocked by incubating the slides in 10% normal rabbit serum (Dako) for 30 minutes, followed by an incubation with the monoclonal CEACAM1 antibody 4D1/C2 at 8 µg/mL (in-house preparation by C.W.) in a humid chamber overnight at 4°C. The next morning, the sections were first washed three times in TBS for 5 minutes and then incubated with a 1:40 diluted biotinylated rabbit anti-mouse antibody (Dako) for 40 minutes at room temperature.

After further washes in TBS, sections were incubated with an avidin-alkaline phosphate complex (Vectastain ABC kit; Vector, Burlingame, CA) for 30 minutes. Next, additional washes in TBS were performed. Enzyme reactivity of the alkaline phosphate complex was visualized using Naphtol-AS-bisphosphate as a substrate, and hexatozized new fuchsin was used for simultaneous coupling. Slides were counterstained with Mayer’s hemalum diluted 1:1 in distilled water for 10 seconds, blued under running tap water, and mounted with Crystal Mount (Biomeda, Foster City, CA). Negative controls were treated the same way, omitting the incubation with the primary antibody.

Evaluation of Ulceration and Mitotic Rate
The presence of ulcerations in the primary melanomas was evaluated microscopically by using hematoxylin and eosin–stained slides. Mitotic rates were determined on hematoxylin and eosin–stained slides, as described by Schmoeckel and Braun-Falco.¹⁶ Mitotic rate was taken as the mean of the mitotic count in 10 high-power fields (magnification, x400).

Evaluation of Staining Pattern and Statistical Analysis
The staining of the melanoma cells was recorded by an observer who was unaware of the clinical data at the time of evaluation. Generally, the 100 cases of malignant melanoma were divided into positive and negative tumors. Samples were regarded as positive when at least 20% of the malignant cells were positively stained. Additionally, the intensity of positive staining from weak to intense staining was recorded. For documentation, the slides were examined under a Zeiss Axioplan photomicroscope (Oberkochem, Germany) and photographed with a Kodak 64T color film (Stuttgart, Germany).

The association between CEACAM1 expression in the primary lesions of malignant melanoma and patients’ disease-free survival was analyzed by univariate analysis and stratified by clinical stage (I v II) and CEACAM1 expression status as combined measures, applying the log rank test using Graph Pad Prism (Intuitive Software for Science, San Diego, CA). Multivariate Cox regression analysis was applied for CEACAM1 expression adjusted for tumor thickness (categorical < 1.5 mm, > 1.5 mm, as described by Duncan et al¹⁷), and presence of ulceration and mitotic rate (continuous) were assessed by SPSS for Windows, version 10 (SPSS, Chicago, IL), on an IBM-compatible microcomputer.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The melanocytes in the normal skin adjacent to the melanoma did not demonstrate binding of the anti-CEACAM1 antibody in all 100 cases. In general, the classification of melanomas as being positive or negative was definite. Either the majority of the tumor cells were positively stained, or no staining of any malignant cells could be detected (Fig 1).

View larger version (90K): [in this window] [in a new window]   Fig 1. Immunostaining of primary melanoma with the monoclonal 4D1/C2 antibody directed against CEACAM1. Most of the positive cases demonstrated increased immunoreactivity for the anti-CEACAM1 antibody at the invading front (A, B). Magnification, x100. CEACAM1-negative melanoma (C). Magnification, x200.

A total of 28 of these 40 CEACAM1-positive melanomas had metastasized, 15 of which demonstrated hematogenous spread to liver (n = 4), lung (n = 2), brain (n = 3), and skin (cutaneous, subcutaneous, or both; n = 6), and 13 had metastasized via the lymphatic route at primary metastasis. Of the 60 CEACAM1-negative melanomas, only six had metastasized, and 54 demonstrated no clinical signs of metastasis at 10-year follow-up. Of the six metastatic/CEACAM1-negative patients, two demonstrated hematogenous spread and four demonstrated lymphatic spread.

Ulceration was present in 13 of the 100 melanomas investigated. Of these, eight had metastasized. The mean mitotic rate was 1.094 (range, 0.0 to 6.0; SEM, 0.133; 95% confidence interval [CI], 0.831 to 1.357). For further statistical analyses, mitotic rate was taken as continuous variable.

Metastatic Lesions
In the 17 patients whose metastases were examined for CEACAM1 expression, the primary lesions were all CEACAM1 positive. In 11 patients with distant metastases, staining of metastatic deposits demonstrated homogenous and strong CEACAM1 expression in all malignant cells (Fig 2A). The melanoma cells in the six patients with irrespective metastasis in sentinel lymph nodes also expressed CEACAM1 (Fig 2B).

View larger version (123K): [in this window] [in a new window]   Fig 2. Immunostaining of melanoma metastases with the monoclonal 4D1/C2 antibody directed against the cell adhesion molecule CEACAM1. (A) CEACAM1-positive subcutaneous distant metastasis and (B) CEACAM1-positive metastases in a sentinel lymph node. Magnification, x140.

View larger version (12K): [in this window] [in a new window]   Fig 3. Kaplan-Meier analysis of disease-free survival in 100 patients with primary cutaneous melanoma stratified by CEACAM1 expression status.

View larger version (15K): [in this window] [in a new window]   Fig 4. Kaplan-Meier analysis of disease-free survival in 100 patients with primary cutaneous malignant melanoma stratified by German Dermatological Society stage and CEACAM1 expression status as combined measures.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

The considerable predictive power of CEACAM1 expression is highlighted by incorporating other known prognostic factors, including tumor thickness, presence of ulceration, and mitotic rate, into the multivariate analysis. When this tool is used, only CEACAM1 expression and ulceration remained as independent predictors for outcome in our study. In connection with CEACAM1 expression and ulceration, mitotic rate and even tumor thickness as the single most accepted dominant independent prognostic factor¹⁸ did not add statistically significant information for risk estimations in multivariate analysis; however, all four variables were significant predictors for metastasis in univariate analysis.

Until now, tumor thickness has been the gold standard for prognosis in patients with cutaneous malignant melanoma,¹ and the American Joint Committee on Cancer recommended tumor thickness and ulceration as sole criteria for the tumor classification in melanoma.¹⁸ However, patients with thin melanomas at time of surgery may experience early metastasis and death, whereas other patients with thick melanomas survive. Hence, there is a clinical need to improve the accuracy of risk estimations obtained with the accepted parameters. Thus, a variety of immunohistochemical markers have been identified as adjunct prognostic parameters in primary human melanomas, including loss of melastatin expression,¹⁷ binding of Peanut¹⁹ and Helix pomatia agglutinin,²⁰ and expression of ß3 integrin.²¹

These studies are particularly valuable because the cohorts included at least 100 patients with follow-up periods of 5 to 10 years, and multivariate analysis was used to establish the prognostic significance of these markers. In contrast, in another study that used multivariate analysis of the prognostic value of different immunohistochemical markers in primary melanoma, nine markers with established prognostic significance were not found to improve risk estimation assessed by tumor thickness, ulceration, and mitosis.²² However, the present study provides evidence that determination of CEACAM1 expression has a considerably higher predictive value than tumor thickness, ulceration, and mitotic rate.

Determination of CEACAM1 expression status is not only of prognostic interest but may also provide insight into the mechanism of tumor cell metastasis in melanoma. To our knowledge, this is the first study that demonstrates that upregulation of CEACAM1 expression in a tumor is associated with metastatic spread. In contrast, it is well established that CEACAM1 is downregulated in malignant tumors originating from glandular tissues, particularly in colorectal⁹ and prostate cancer,¹⁰ where its loss of expression is causally related to the loss of glandular differentiation.²³ This is particularly well demonstrated in prostate cancer, where a sharp decline of CEACAM1 expression is noted when glands fuse (Gleason stage III to IV transition).²⁴

The only ligands of the extracellular domain of CEACAM1 identified so far are CEACAM1 itself and CEACAM6.²⁵ Hence, both homophilic and heterophilic interactions of CEACAM1 may be relevant during glandular differentiation. The role of heterophilic interactions is emphasized in endothelial cells, where CEACAM1 expression is observed at the abluminal side of the microvessels,²⁶ suggesting a yet unidentified ligand in the surrounding basal lamina. That these interactions with the basal lamina are of physiologic relevance is indicated by the fact that the cytoplasmic domain of CEACAM1 interacts with the cytoskeleton^27,28 and may thus be an important mediator of cell-matrix interactions. The heterotypic interaction between CEACAM1 and the surrounding matrix is further highlighted by the fact that CEACAM1 expression is particularly upregulated at the invading front in our series, where cell-matrix interactions play an important role, thus implying a heterotypic interaction of CEACAM1 with matrix molecules.

This speculation is in accordance with findings that a concentrated coexpression of CEACAM1 and ß3 integrin, which has a well established role in the invasion and metastasis of malignant melanoma,^29,30 is found at the invading front.³¹ A potential function of CEACAM1 in invasion is corroborated by the findings that CEACAM1 is strongly expressed by the intermediate trophoblast at the implantation site, as well as by the extravillous trophoblast cells with an invasive phenotype in primary culture, suggesting that CEACAM1 may be functionally involved in the motility or invasiveness of cells.³² Further evidence for a possible role of CEACAM1 in cell migration and spreading is reported in migrating cells such as activated T cells and endothelial cell, where CEACAM1 enhances proliferation.^26,33 Thus, CEACAM1 may play a role in melanoma metastasis by facilitating invasion of blood vessels and lymphatics as well as migration to distant sites.

CEACAM1 has been demonstrated to be a potent angiogenic factor in tumor vascularization.²⁶ CEACAM1 is expressed in the microvessels of a variety of human tumors, such as renal cell carcinoma and carcinomas of the prostate and urinary bladder,²⁶ where its expression is restricted to small, immature blood vessels. In our series of 100 melanomas, CEACAM1 expression was only detectable in the microvessels of seven patients, and in these patients, no association between the CEACAM1 expression in the microvessels and prognosis could be demonstrated (data not shown). However, an association between the microvasculature and CEACAM1 expression within the melanomas and metastasis exists. We performed an analysis of vascular loops and networks on the same series of patients. We could demonstrate that these vascular channels were significant prognostic indicators³⁴ and thus could extend the observations on the prognostic relevance of vascular channels made by Maniotis et al³⁵ in uveal melanoma to cutaneous melanoma.

When we correlated the vascular channel data from our previous study with the CEACAM1 expression data, a close correlation between CEACAM1 expression and vascular loops and networks was observed (data not shown). This close correlation may just be a coincidence; however, it could also be functionally linked. CEACAM1 expression was observed at the abluminal site of the tumor blood vessels and thus points to the extracellular matrix. As the melanoma cells express CEACAM1 on their cell surface, which points to the extracellular matrix as well, a role of CEACAM1 in modulating angiogenesis may be postulated. Therefore, CEACAM1 would influence the extracellular matrix in a proangiogenic way, irrespective of its cellular origin.

In conclusion, this study indicates that determination of CEACAM1 expression status in primary cutaneous melanoma improves the accuracy of prognostic estimations. Furthermore, the upregulation of CEACAM1 in the metastatic phenotype including its metastatic deposits might be a tool in antimetastatic immunotherapy in malignant melanoma.

	ACKNOWLEDGMENTS

 
Supported in part by the Arbeitsgemeinschaft für Krebsbekämpfung Nordrhein-Westphalen, Bochum, Germany, and the Gustav Spierling Stiftung, Hamburg, Germany.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted May 9, 2001; accepted February 26, 2002.

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