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Journal of Clinical Oncology, Vol 19, Issue 4 (February), 2001: 1008-1014
© 2001 American Society for Clinical Oncology

Microsatellite Instability Is an Independent Indicator of Recurrence in Sporadic Stage I-II Endometrial Adenocarcinoma

By Silvia Fiumicino, Alfredo Ercoli, Gabriella Ferrandina, Patricia Hess, Giuseppina Raspaglio, Maurizio Genuardi, Valentina Rovella, Alfonso Bellacosa, Lucia Cicchillitti, Salvatore Mancuso, Margherita Bignami, Giovanni Scambia

From the Laboratory of Comparative Toxicology and Ecotoxicology, Istituto Superiore di Sanità, and Department of Gynecology and Medical Genetics, Catholic University, Rome, Italy.

Address reprint requests to G. Scambia, MD, Department of Gynecology, Catholic University of the Sacred Heart, L.go A. Gemelli, 8-00168, Rome, Italy; email: giovanni.scambia{at}agora.it


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: The aim of this study was to define the prognostic role of microsatellite status in 65 stage I-II primary sporadic endometrioid endometrial adenocarcinoma (EEA) patients.

PATIENTS AND METHODS: Familiarity for neoplasia was ascertained in all patients on the basis of a questionnaire. Microsatellite status was assessed by matching normal and tumoral DNA probed for five dinucleotide repeats and one mononucleotide repeat marker. Microsatellite status was analyzed in relation to clinicopathologic characteristics of the patients and length of disease-free survival (DFS).

RESULTS: Eleven tumors (17%) of 65 had instability at two or more loci and were considered as unstable or microsatellite instability (MI). Tumors with no instability or instability at one locus were classified as microsatellite stable (MS). The percentage of MI was significantly higher in poorly than in well to moderately differentiated tumors (50% v 9%; P = .003). The 5-year DFS rate of MI patients was 63% (95% confidence interval [CI], 35% to 91%) versus 96% (95% CI, 91% to 101%) of MS patients (P = .0004). In multivariate analysis, only the presence of MI, stage II of disease, and depth of myometrial invasion greater than 50% retained independent prognostic roles.

CONCLUSION: The assessment of microsatellite status may provide useful information for preoperative prognostic characterization of stage I-II primary sporadic EEA patients in which more individualized treatment options can be attempted.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
ADENOCARCINOMA of the endometrium is currently the most frequent malignancy of the female genital tract in developed countries. At present, International Federation of Gynecology and Obstetrics stage, depth of myometrial invasion, and grade of differentiation are commonly used to predict clinical outcome and plan treatment modalities in these patients. However, none of these parameters can be considered as accurate. As a consequence, different parameter associations have been proposed to provide patients with prognostic information and especially to determine the need for postoperative adjuvant therapy in early-stage tumors,1,2 which account for approximately 85% of newly diagnosed endometrial carcinomas.3 Although early-stage endometrial cancer often follows a favorable course, 10% of stage I and 17% of stage II patients experience recurrence4 and eventually die of the disease. In this context, the identification of biologic factors correlating with tumor aggressiveness would be of utmost importance in the selection of individualized primary and adjuvant therapy according to the relative risk of recurrence of each patient.

Microsatellites are widely distributed repetitive DNA sequences composed of short repeated nucleotide motifs. Alterations in these simple repeat DNA sequences represent a novel marker of genetic instability known as microsatellite instability (MI). MI was first discovered in patients affected by hereditary nonpolyposis colorectal cancer.5,6 In this setting, the presence of MI reflects germline mutations in the mismatch repair genes, especially hMSH2 and hMLH1,7-10 and correlates with particular clinicopathologic features and better prognosis.5,11 Interestingly, MI has been also detected in a significant fraction of sporadic human tumors, including colorectal, endometrial, gastric, breast, and non–small-cell lung cancer.12 Although the biologic significance of MSI in sporadic tumors has yet to be fully established, it has been demonstrated that this type of genetic instability can be used as a marker of disease prognosis.13-15

MI has been detected in approximately 20% of sporadic endometrial cancers and seems to be restricted to the endometrioid endometrial adenocarcinoma (EEA),16-19 which accounts for 60% of all endometrial neoplasia.3 In this tumor much of the efforts up to date have been aimed at investigating the prevalence and the biologic relevance of MI, while its possible prognostic role is far from being clarified. Risinger et al16 and Duggan et al17 reported that MI seemed to occur in endometrial cancer patients characterized by a favorable prognosis, while Caduff et al18 demonstrated a direct association between MI and a higher recurrence rate.

However, none of these studies can be considered conclusive, because the survival data were not analyzed by means of survival curves and the impact of MI and clinicopathologic factors were not investigated in the multivariate setting.

The aim of this study was to investigate the clinical significance of microsatellite status in a large homogeneous group of stage I-II primary sporadic EEA patients. To this purpose, the relationship of MI with clinicopathologic features and clinical outcome has been assessed in the multivariate analysis.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
This study was conducted on 65 primary untreated EEA patients with stage I-II disease who were admitted, treated, and followed-up at the Gynecologic Oncology Department of the Catholic University of Rome. All cases were considered as sporadic on the basis of a questionnaire targeted to establish the presence of tumors in first- and second-degree relatives revealing the absence of a familial history of cancer.20 The median age of the patients was 62 years (range, 30 to 84 years). All patients were treated by total extrafascial abdominal hysterectomy plus bilateral salpingo-oophorectomy. In 31 patients (48%), systematic pelvic and aortic lymphadenectomy was performed according to a national randomized clinical protocol undergoing in our department. All patients were staged according to International Federation of Gynecology and Obstetrics classification and their tumors graded as well (G1), moderately (G2) or poorly (G3) differentiated. The characteristics of the patients are listed in Table 1. After completing treatment, patients were seen every 4 months for the first 2 years, every 6 months from the third up to the fifth year, and yearly thereafter. Recurrence was considered as any documented relapse of the tumor, either locally in the pelvis or systemic dissemination. Disease-free survival (DFS) was calculated from the day of surgery until the day of clinical recurrence (uncensored) or the date last seen (censored). Patients who died as a result of any cause other than endometrial cancer were also considered as censored at the time of death. The median follow-up time was 76 months (range, 12 to 139 months).


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  		Table 1. Patient Characteristics and Distribution of MI
 
DNA Preparation
Formalin-fixed, paraffin-embedded specimens were used for DNA analysis. Tumor and normal tissue were microdissected, and DNA was extracted by incubating individual 5 µm histologic sections in 0.5 mL of buffer containing 10 mmol/L of Tris pH 8.3, 50 mmol/L of KCl, 1.5 mmol/L of MgCl2, 100 mg/mL-1 of BSA, 1% Tween 20, and 100 µg/mL-1 of proteinase K.21 The sections were incubated overnight at 55°C, boiled for 5 minutes, and then cooled on ice. Five-microliter aliquots were used in polymerase chain reactions (PCR).

Microsatellite Analysis
DNA from normal and tumor tissues was assayed for instability using six microsatellite markers: D2S123, D2S119, D9S171, D9S157, D10S216,22 and BAT26.23 PCR amplification (25 µL of DNA samples) was performed using the locus-specific primers (600 ng each) and dNTPs (200 mmol/L each) in a reaction buffer containing 2 mmol/L of MgCl2 and one unit of Taq polymerase (Boehringer Mannheim, Mannheim, Germany). Thirty cycles of 1 minute at 90°C, 30 seconds at 55°C, and 30 seconds at 70°C were performed on a Perkin Elmer Thermal Cycler. Amplification products were separated on a 6% denaturing polyacrylamide gel and transferred to Hybond N+ membrane (Amersham Italia, Milan, Italy). One of the PCR primer oligonucleotides radiolabeled with alpha phosphorous-32 by terminal deoxynucleotidyltransferase (GIBCO BRL, Gaithersburg, MD) was used as a hybridization probe to detect the amplification products. Hybridization was performed overnight at 42°C in 130 mmol/L of sodium phosphate pH 7.0, 250 mmol/L of NaCl, 10% polyethylene glycol (Mr 4,000; Sigma, Milan, Italy), and 7% sodium dodecyl sulfate. Hybridization products were detected by autoradiography. Tumors showing instability at two or more loci were subsequently probed for inactivating mutations in the polyadenine tract of the RII component of the transforming growth factor beta (TGF-ß) receptor using locus-specific primers.24

Immunohistochemical Analysis of hMLH1 Protein Expression
Immunohistochemical analysis of the hMLH1 protein expression was performed using the avidin-biotin-peroxidase complex method with the antihuman hMLH1 mouse monoclonal antibody (clone G168-728; Pharmingen). After routine deparaffinization and rehydration, antigen retrieval was accomplished by microwaving sections in citrate buffer. The sections were then washed in Tris-buffered saline (TBS; pH 7.6) and incubated with normal serum as the blocking reagent to minimize nonspecific binding. The primary antibody was applied overnight (dilution, 1:100) and sequentially followed by biotinylated antimouse immunoglobulin and horseradish peroxidase-conjugated streptavidin (ABC-Vector Laboratories, Burlingame, CA). Sections were then incubated in the chromogenic substrate solution (3, 31-diaminobenzidine; Sigma) for 10 minutes. Sections were lightly counterstained with Harris’s hematoxylin, dehydrated, cleared, and mounted.

The percentage of positivity of the neoplastic cells was evaluated by counting at high magnification (x1,000) at least five different areas of the sections. hMLH1 immunoreactivity was determined by two independent observers.

Statistical Analysis
Fisher’s exact test was used to analyze the relationship between MI and clinicopathologic features. All reported P values are two-sided. Statistical analysis was performed by using STATA statistical package (Release 6.0; Stata Corporation).

All medians and life tables were computed using the product-limit estimate and the curves were examined by means of the log-rank test.25 Multivariate analysis was performed by the Cox proportional hazards model.26 Survival data analysis was carried out using SOLO Statistical Software (BMDP Statistical Software Inc, Los Angeles, CA).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Microsatellite status was assessed examining six independent genomic sites, including five dinucleotide repeat microsatellites and one mononucleotide repeat microsatellite. One case showed instability at five loci, four cases at four loci, three cases at three loci, three cases at two loci, and one case at one locus. Eleven tumors (17%) of 65 had instability at two or more loci and were considered as unstable or MI (Table 1). Tumors with no instability or instability at one locus were classified as microsatellite stable (MS). Both increases and decreases in the length of microsatellite were detected. Examples of MI cases are shown in Fig 1. No inactivating mutations in the polyadenine tract of the RII component of the TGF-ß receptor were found in MI tumors (data not shown).



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  		Fig 1. Examples of different microsatellite loci from paired normal (N) and tumor (T) tissue in primary sporadic EEA. The assayed loci are indicated at the bottom of each panel. Tumors with MI are indicated by an arrow.

 
The frequency of MI was significantly higher in tumors with poor histologic grade than in well to moderately differentiated tumors (50% v 9%; P = .003), while no difference in the distribution of MI according to stage of disease, myometrial invasion, and age at diagnosis was found (Table 1).

During the follow-up period, recurrence of disease was observed in nine (14%) of the 65 patients. Figure 2 shows the DFS curves in relation to microsatellite status. A highly significant association between the presence of MI and a shorter DFS was found (P = .0004). The 5-year DFS was 63% (95% confidence interval [CI], 35% to 91%) in MI cases compared with 96% (95% CI, 91% to 101%) in MS cases. The median DFS duration was 83 months for MI patients, while in MS patients, the median DFS was not reached. There was no significant difference in the distribution of recurred MI versus MS endometrial cancer pa-tients according to age (three [60%] of five and two [50%] of four older than 60 years, respectively).



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  		Fig 2. DFS according to microsatellite status in patients with primary sporadic stage I-II EEA.

 
The relative risk of recurrence was estimated in univariate and then in multivariate analysis ( Table 2). In univariate analysis, the presence of MI, stage II of disease, grade 3 of differentiation, and depth of myometrial invasion greater than 50% were shown to be significantly associated with a higher risk of recurrence. In multivariate analysis, microsatellite status, stage, and depth of myometrial invasion retained a significant association with DFS, while grading yielded no independent prognostic information. Because it has been reported that methylation of the hMLH1 promoter invariably results in absent hMLH1 expression27,28 and is associated with the MI phenotype in 71% to 92% of all endometrial cancers,28 the association between microsatellite status and hMLH1 protein expression has been investigated in eight MI tumors and in 11 MS tumors including the only case showing instability at a single locus. Figure 3 shows a representative example of the specific immunostaining for hMLH1 in a primary MS endometrial adenocarcinoma.


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  		Table 2. Results of Univariate and Multivariate Analysis for Recurrence of Disease in 65 Primary Endometrial Carcinomas
 


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  		Fig 3. hMLH1 immunoreaction in a representative primary MS endometrial adenocarcinoma. hMLH1 staining was mostly nuclear. Magnification x200.

 
Seven (87.5%) of eight MI tumors failed to show any specific nuclear immunostaining, while all MS tumors exhibited a specific nuclear immunoreactivity in more than 80% of cancer cells (P = .0002; data not shown). The relationships between hMLH1 protein expression and clinicopathologic parameters and outcome of the patients have not been investigated because of the low number of cases analyzed.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study investigated the relationship of microsatellite status with clinicopathologic features and clinical outcome in a large group of patients with primary sporadic stage I-II EEA. The prevalence of MI described here was similar to that observed in other studies.16,17,19,27-29,30,31 A direct correlation between MI and poor grade of differentiation was found, while no differences in the distribution of MI with respect to age, stage of disease, and myometrial invasion have been observed in accordance with results from previous studies.18,19,31

The vast majority of sporadic human tumors exhibiting MI, including colorectal, endometrial, breast, and non–small-cell lung cancer, show a significantly higher frequency of poor clinicopathologic features than MS tumors.13-15,18,31 However, the clinical significance of microsatellite status seems to significantly differ according to different types of tumors. We found that MI is associated with a worse prognosis in stage I-II EEA, as also reported for breast and stage I non–small-cell lung cancer.14,15 By contrast, MI seems to characterize colorectal and gastric cancer patients with a better clinical outcome.13,32 These discrepancies could indicate the existence of a tissue specificity of MI effects in the light of possibly different patterns of mutations in cell growth-related genes. For instance, we found no inactivating mutations in the polyadenine tract of the RII component of the TGF-ß receptor in our series of MI tumors, confirming previous data indicating a low frequency of somatic mutations of this gene in MI endometrial, breast, and non–small-cell lung cancer.24,29,33 Conversely, a high mutation rate of the RII component of the TGF-ß receptor has been reported in sporadic MI colorectal and gastric cancer.24,33 Other genes that are frequently mutated in MI gastrointestinal cancers, including IGFIIR, BAX, E2F4, BRCA1, and BRCA2 are rarely mutated in endometrial cancers.29 On the other hand, PTEN tumor suppressor gene mutations seems to be specifically involved in the tumorigenesis of MI endometrial cancers29,34 but are rarely present in MI gastrointestinal cancers.35

It remains to be clarified why some MI EEA did not show recurrence of disease. Some differences in a series of biologic markers with prognostic significance, including estrogen and progesterone receptor expression, p53 status, and PTEN and c-K-ras mutations have been described for some MI endometrial cancers.17-19,34,35 Therefore, the simultaneous assessment of a panel of genetic alterations could help in defining different biochemical profiles of MI EEA patients characterized by a different clinical outcome. In our series, MI was found to be a predictor of risk of recurrence in patients with primary untreated stage I-II EEA assessed by univariate and multivariate analysis. In particular, multivariate analysis indicates that the prognostic information provided by grade is likely to be summarized in those from microsatellite status and myometrial invasion. Interestingly, these two parameters can be easily assessed in the preoperative setting due to the upcoming methodology for assessing MI36 and the high sensitivity of MNR/ultrasound imaging for detecting the depth of myometrial invasion.37,38

This observation becomes relevant considering that endometrial cancer patients often also present cardiovascular disease, diabetes mellitus, hypertension, and severe obesity,39 which are known risk factors for morbidity from abdominal surgery. In this context, to better define patient subgroups at high versus low risk of recurrence at time of diagnosis would be of utmost importance in the selection of candidates for less aggressive surgical procedures. Thus EEA patients with low risk of recurrence and high surgical risk could benefit from a vaginal approach to total hysterectomy, which can be easily and safely performed with equivalent long-term survival.40,41

Finally, it has been reported that immortalized cells carrying targeted disruptions of selected mismatch repair genes, which imply the acquisition of MI, might be more radioresistant than mismatch repair proficient cells42 and that MI cancer cell lines are resistant to some cytotoxic agents.43-45 Therefore, it is conceivable that knowledge of microsatellite status would help to select those patients who could benefit from adjuvant therapies.

A highly significant association between the absence of hMLH1 immunostaining and MI was found, suggesting a primary role of hMLH1 in the acquisition of the MI phenotype in sporadic EEA, as also suggested by Simpkins et al.27

In conclusion, we demonstrated that the assessment of microsatellite status can provide additional independent information relevant to the prognostic characterization of early stage EEA patients in which more individualized treatment options can be attempted. Future studies should be conducted to investigate the clinical and biologic role of hMLH1 protein expression in EEA.


   ACKNOWLEDGMENTS
 
This research was partially supported by a grant from the CNR (CNR-ACRO) and AIRC, Italy.

We thank L. Gargano for technical help, P. Karran for reading the manuscript, and M. Ercoli for the statistical analysis.


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 INTRODUCTION
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 RESULTS
 DISCUSSION
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Submitted August 2, 1999; accepted October 25, 2000.


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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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