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From the Division of Gastrointestinal/Liver Pathology,*
Department of Pathology; Division of Thoracic
Surgery,
Department of Surgery; Division of
Oncology Biostatistics,
Oncology Center; and
Medical Oncology,§
Oncology Center, The
Johns Hopkins University School of Medicine, Baltimore, Maryland
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Studies of genetic abnormalities in esophageal adenocarcinoma and its precursor have shown alterations in the p53 tumor suppressor gene, an important regulatory gene in cell cycle control and apoptosis, and the p53-regulated cyclin-dependent kinase inhibitor p21WAF1/CIP1.7-14 Allelic losses in multiple chromosomal loci of known tumor suppressor genes have also been reported.15-19 These include chromosome 17p (p53 gene), 18q (DCC, DPC4, and JV18-1), 5q (APC), and 9p (p16). In contrast to colorectal adenocarcinomas, allelic losses in esophageal adenocarcinomas are rarely associated with mutations in the corresponding tumor suppressor genes except for 17p allelic loss and p53 gene mutation.20-22 DNA replication errors (RERs) manifested as microsatellite instability due to defective repair of nucleotide mismatches have been reported infrequently in esophageal adenocarcinomas.23-25
Clinical associations with these molecular genetic alterations have not been investigated extensively. Overexpression of p53 suppressor gene product and expression of p21WAF1/CIP1 were found to have no prognostic value in patients with surgically resected esophageal adenocarcinomas in our previous study.10 The roles of RER status and multiple chromosomal allelic losses in the development of esophageal adenocarcinomas remain unclear, and their prognostic implications have not been studied. We therefore evaluated RER; loss of 17p, 18q, and 5q; and overexpression of p53 gene product in resected adenocarcinomas of the distal esophagus and EGJ region and compared the findings with clinical and pathological features, including patient survival.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Ninety-two patients (82 men and 10 women) with adenocarcinoma of the distal esophagus or EGJ region in an esophagectomy specimen and 11 patients (9 men and 2 women) with Barrett esophagus and columnar epithelial dysplasia in a prophylactic esophagectomy specimen were identified from the computerized surgical pathology files of The Johns Hopkins Hospital from 1988 to 1996 and had specimens available for study. Among the 92 patients with adenocarcinoma, 56 (61%) had Barrett mucosa, 11 (12%) had undergone preoperative chemotherapy or irradiation, and 24 (26%) were treated with postoperative chemotherapy or irradiation. Follow-up information was obtained from The Johns Hopkins Hospital Tumor Registry and chart review.
Pathological Evaluation
Routine hematoxylin and eosin-stained slides from the resection specimens were evaluated for the presence of Barrett mucosa, columnar epithelial dysplasia (low-grade or high-grade),3 grade of tumor differentiation (well, moderate, and poor), depth of tumor invasion, and lymph node metastasis.26 The nondysplastic Barrett mucosa included Barrett mucosa negative for dysplasia and indefinite for dysplasia. Paraffin blocks of adenocarcinoma (n = 92), Barrett mucosa with high-grade dysplasia (HGD; n = 33, including 24 accompanied by adenocarcinoma and 9 from prophylactic esophagectomy specimens), Barrett mucosa with low-grade dysplasia (LGD; n = 19, including 14 accompanied by adenocarcinoma and 5 from prophylactic esophagectomy specimens), nondysplastic Barrett mucosa (n = 22, including 19 accompanied by adenocarcinoma and 3 from prophylactic esophagectomy specimens), and squamous-lined esophageal mucosa (n = 92) were selected for immunohistochemical study and microdissection for DNA extraction. In 51 of 56 adenocarcinomas with Barrett esophagus, specimens of Barrett mucosa were satisfactory for immunohistochemistry and allelic loss analysis; 24 (47%) had HGD, 11 (22%) had LGD, and 16 (31%) were negative or indefinite for dysplasia.
The adenocarcinomas were staged according to the Union Internationale Contre le Cancer TNM system.27 Tumors arising at the EGJ without evidence of Barrett mucosa were staged as esophageal cancer if more than 50% of the tumor was above the EGJ and as gastric cancer if more than 50% of the tumor was in the stomach.28
RER and Allelic Loss of Chromosomes 17p, 18q, and 5q
Histopathological sections from H&E-stained slides were
microdissected for DNA extraction. Genomic DNA was extracted as
described previously.29
Loss of heterozygosity (LOH) on the
short arm of chromosome 17 (17p) was assessed by microsatellite assays
using polymerase chain amplifications of three microsatellite markers
(TP53, D17S520, and D17S1176) and one tandem sequence repeat marker
(VNTR, Figure 1
), LOH on the long arm of
chromosome 18 (18q) by eight microsatellite markers (D18S57, D18S65,
D18S69, D18S64, D18S55, D18S61, D18S58, and D18S70, Figure 2
), and LOH on the long arm of chromosome
5 (5q) by three microsatellite markers (D5S299, D5S82 and D5S346). In
brief, polymerase chain reaction-based microsatellite assays were
performed in 96-well plates with 38 cycles (95°C for 30 seconds,
55°C for 30 seconds, and 72°C for 1 minute) using PCR Master
(Boehringer Mannheim, Mannheim, Germany) in a 10-µl volume and 10 ng
of both 5' and 3' oligonucleotides. The 5' oligonucleotide was end
labeled with [
32P]ATP (NEN DuPont, Boston, MA) using
T4 polynucleotide kinase (New England Biolabs, Beverly, MA). The
polymerase chain reaction products were analyzed on 6% polyacrylamide
gel containing 7 mol/L urea.
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. A specimen was considered as
RER+ when allelic shifts were present in at least 4 of the 14
dinucleotide microsatellite markers.
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Immunohistochemistry for p53 Gene Product
Immunoperoxidase staining using diaminobenzidine as chromogen was performed on histopathological sections from formalin-fixed paraffin-embedded tissue. p53 tumor suppressor gene product (mouse monoclonal antibody DO7 (DAKO, Nutley, NJ) at a dilution of 1:100) was stained in deparaffinized sections after antigen retrieval using a heat-induced epitope retrieval method.30 The TechMate 1000 automatic staining system (BioTek Solutions, Tucson, AZ) was used. Percentage of nuclei with staining in adenocarcinomas and Barrett mucosa was estimated. p53 overexpression was defined by staining of more than 50% of the nuclei.31 The results of p53 immunohistochemistry for 76 of the patients with adenocarcinoma and 6 of the patients with Barrett mucosa were published previously.10
Statistical Analysis
Associations of molecular markers with clinical and pathological features were evaluated by Fisher's exact test. Factors tested for prognostic value included the presence of Barrett mucosa; stage of disease; preoperative or postoperative chemoradiation; grade of tumor differentiation; overexpression of p53 tumor suppressor gene product; and allelic loss of 17p, 18q, and 5q. The major statistical endpoint of survival analysis was the duration of survival after surgical resection of tumor. The event-time distributions for this endpoint were estimated by the method of Kaplan and Meier32 and compared using log-rank statistics33 or the proportional hazards regression model.34 The simultaneous effect of two or more factors was studied using the Cox multivariate proportional hazards model. Covariates marginally significant (P < 0.19) in the univariate analysis were entered into the multivariate regression model, and nonsignificant effects were removed in a stepwise fashion. All P values reported were two sided. Computations were performed using the Statistical Analysis System (SAS Institute Inc, Cary, NC) or EGRET (Statistics and Epidemiological Research Corp., Seattle, WA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Among the 92 adenocarcinomas, 56 (61%) were accompanied by
Barrett mucosa. There was a male predominance in patients who had
adenocarcinoma with and without Barrett mucosa (88% and 92%,
respectively) and in patients with prophylactic esophagectomy for
dysplasia in Barrett esophagus (82%). The demographic and pathological
findings are summarized in Table 1
. There
were no significant differences in the grade of differentiation or
pathological stage between adenocarcinomas with and without Barrett
mucosa.
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RER was rare, present in only 3.6% (2 of 56) of adenocarcinomas
with Barrett mucosa (Figure 3)
and 8.3% (3 of 36) of adenocarcinomas
without Barrett mucosa. The number of markers shifted ranged from 4 of
14 to 13 of 14. Histopathologically, 4 RER+ adenocarcinomas showed poor
differentiation, and the other one had moderate differentiation. Among
the 4 poorly differentiated adenocarcinomas, 3 had features of
medullary carcinoma with lymphoid infiltrate.35
No RER was seen in any HGD, LGD, or nondysplastic Barrett mucosa; in the two RER+ adenocarcinomas with Barrett mucosa, allelic shift was seen in only 1 of 14 microsatellite markers in the accompanying nondysplastic Barrett mucosa as contrasted with 4 of 14 and 9 of 14 in the adenocarcinomas.
Allelic Loss of Chromosomes 17p, 18q, and 5q
As shown in Figure 4
, accumulation
of chromosomal losses occurred in the neoplastic sequence from
nondysplastic Barrett mucosa to LGD, HGD, and adenocarcinoma; loss of
17p as compared with squamous-lined mucosa was present in 14% of
Barrett mucosa, 42% of LGD, 79% of HGD, and 75% of adenocarcinomas,
respectively (P < 0.00001 for adenocarcinoma
versus Barrett mucosa, Figure 1
); loss of 18q in 32%, 42%,
73%, and 69%, respectively (P = 0.003 for
adenocarcinoma versus Barrett mucosa, Figure 2
); and loss of
5q in 10%, 21%, 27%, and 46%, respectively
(P = 0.001 for adenocarcinoma versus
Barrett mucosa). The majority (64%) of nondysplastic Barrett mucosa
had no allelic loss.
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Multiple chromosomal allelic losses of 17p, 18q, and 5q were seen in
30% of adenocarcinomas either with or without Barrett mucosa, but
rarely in nondysplastic Barrett mucosa (4%, P = 0.02;
Figure 5
). The allelic losses of
chromosomes 17p, 18q, and 5q in cancers were not associated with
clinical stage, tumor differentiation, patient age, or presence of
Barrett mucosa. HGD of prophylactic esophagectomy specimens and stage
I adenocarcinomas had no significant differences in frequency
of 17p loss (78%, 7 of 9, and 64%, 7 of 11, respectively), 18q loss
(89%, 8 of 9, and 55%, 6 of 11, respectively), and 5q loss (44%, 4
of 9, and 18%, 2 of 11, respectively).
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Overexpression of p53 gene product was seen more frequently in
adenocarcinomas and HGD (54% and 71%, respectively) than in LGD
(31%) and nondysplastic Barrett mucosa (5%) (P
= 0.00007 for adenocarcinoma versus Barrett mucosa, Figure 4
). Overexpression of p53 gene product was not seen in nonneoplastic
squamous-lined mucosa. Furthermore, there were no significant
differences in frequency of p53 overexpression between HGD in
prophylactic esophagectomy specimens and stage I adenocarcinomas (67%
and 55%, respectively). Similarly, there were no significant
differences in p53 overexpression between adenocarcinomas with or
without Barrett mucosa (49% and 58%, respectively). Overexpression of
p53 gene product was present in 60% (3 of 5) of RER+ esophageal
adenocarcinomas.
p53 Overexpression and 17p Allelic Loss
p53 overexpression and 17p allelic loss were concordant in 63% (57 of 90) of adenocarcinomas and in 71% (49 of 69) of Barrett mucosa with or without dysplasia. p53 overexpression was seen in 64% (42 of 66) of adenocarcinomas with 17p allelic loss but in 37% (9 of 24) of adenocarcinomas without 17p allelic loss (P = 0.048); it was also seen in 62% (21 of 34) of Barrett mucosa with 17p allelic loss but in 20% (7 of 35) of Barrett mucosa without 17p allelic loss (P = 0.0006).
Prognosis of Adenocarcinomas
The overall median survival for patients with resected
adenocarcinomas in the distal esophagus and EGJ region was 16.3 months.
The Kaplan-Meier survival curves by stage are shown in Figure 6
. Clinical stage of disease was a very
strong prognostic factor for survival (Table 2)
. The median survival times for stages
I–IV were 66, 22, 11, and 9 months, respectively, and the hazards
ratios (HRs) for stages II-IV as compared with stage I were 7.6
(P = 0.007), 12.2 (P <
0.001), and 20.4 (P < 0.001).
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Allelic loss of chromosome 18q was a significant prognostic indicator
(HR = 1.8, P = 0.04), and allelic loss of 17p
(HR = 1.8, P = 0.06) and 5q (HR = 1.5,
P = 0.08) was marginally associated with survival in a
Cox proportional hazards model. As shown in Table 2
, preoperative or
postoperative chemoradiation, presence of Barrett mucosa, and p53
overexpression were not prognostic indicators. When the allelic losses
of 17p, 18q, and 5q were adjusted for stage of disease in a
multivariate regression model, only allelic loss of 17p (HR = 1.8,
P = 0.06) and 18q (HR = 1.7, P =
0.08) remained marginally predictive of survival (Table 3)
. Statistically significantly worse
survival was noted in patients with adenocarcinomas that had allelic
losses of both 17p and 18q as compared with no allelic loss or a single
allelic loss (HR = 1.9, P = 0.002; Figure 6
). By
contrast, patients with adenocarcinomas that had both p53
overexpression and allelic loss of 18q did not have a statistically
significant worse survival as compared with no p53 overexpression
and/or no allelic loss of 18q (P = 0.12).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In this study, we clearly demonstrated accumulation of genetic alterations in the morphological Barrett mucosa–columnar epithelial dysplasia–adenocarcinoma sequence.6,38 Allelic losses of 17p and 5q have been reported in premalignant Barrett lesions.12,39-41 In contrast to colorectal carcinoma, allelic loss of 17p (p53) appeared to precede allelic loss of 5q (APC) during neoplastic progression of esophageal adenocarcinoma.39 The presence of allelic losses in nondysplastic Barrett mucosa may be due to allelic losses occurring before the development of recognizable morphological changes. 18q loss has been shown previously to occur frequently in esophageal adenocarcinomas.15,19,42 In our study, there was a higher percentage of allelic loss of both 18q and 17p as compared with 5q in Barrett mucosa and LGD. These findings suggest that 18q as well as 17p allelic losses may provide selective advantage to the dysplastic columnar epithelial cell population in the Barrett mucosa–dysplasia–adenocarcinoma sequence. Therefore, alteration of tumor suppressor gene(s) on the long arm of chromosome 18 as well as the p53 tumor suppressor gene on 17p may play an important early role in the development of esophageal adenocarcinoma.
As in colorectal tumorigenesis,43 allelic losses of chromosomes in multiple foci of known tumor suppressor genes, including 17p (p53 gene), 18q (DCC, DPC4, and JV18-1), 5q (APC), and 9p (p16), have been reported in esophageal adenocarcinomas.15-19 The high frequency of 18q allelic loss has not been associated with mutations in the DPC4 tumor suppressor gene in esophageal adenocarcinoma,22 but the possible roles of DCC and JV18-1 are not clear. The importance of p53 is supported by the high frequency of overexpression of p53 gene product in dysplastic Barrett mucosa7-8,10 and the strong association between 17p allelic loss and p53 gene mutation in esophageal adenocarcinoma and Barrett mucosa in this and a previous study.44 In addition, mutation of the APC gene on 5q has been identified in only 6% (1 of 18) of esophageal adenocarcinomas.21
Interestingly, allelic loss of 17p (2 cases), 18q (2 cases), or 5q (1 case) was occasionally present in dysplastic Barrett mucosa but not in associated adenocarcinoma, similar to p53 overexpression in our previous study.10 These findings suggest that in some patients, adenocarcinoma develops from subclones in Barrett mucosa without these genetic alterations that appear to be important in the molecular pathogenesis of most esophageal adenocarcinomas. The discordance between dysplastic Barrett mucosa and adenocarcinoma cannot be explained by technical errors introduced by microdissection, because allelic loss of the other chromosomal arms was present in the adenocarcinoma in all five cases.
We found 5.4% (5 of 92) of adenocarcinomas in the distal esophagus and
EGJ region were RER+, but RER was not found in Barrett mucosa either
with or without dysplasia. The differing criteria used to define RER+
in this study (
4 of 14 markers) and in the literature (more than one
locus) can explain the lower rate of RER+ esophageal adenocarcinomas in
this study.24-25
The lower frequency in Barrett mucosa
than in adenocarcinoma in our study and the literature shows that when
RER does develop, it occurs late in the dysplasia–adenocarcinoma
sequence.24
p53 overexpression was found in 3 of 5 RER+
esophageal adenocarcinomas, in marked contrast with RER+ colorectal
carcinoma, which rarely has overexpression of p53
gene.45
RER+ esophageal adenocarcinomas tended to have poor
differentiation (80%, 4 of 5), as previously described in RER+
sporadic colorectal carcinomas (53%, 9 of 17).45
RER+
cancers have been associated with a better prognosis in hereditary
nonpolyposis colorectal carcinoma, sporadic colon
carcinoma,46
and gastric carcinoma.47
We found
a trend toward longer median survival for the 5 RER+ esophageal
adenocarcinomas in this series. Future study of a larger number of
patients is needed to clarify further the molecular features and
survival in the subset of patients with RER+ esophageal adenocarcinoma.
The management of patients with high-grade columnar epithelial dysplasia in Barrett esophagus is controversial. The premalignant nature of HGD and the difficulty in detection of invasive carcinoma by endoscopy make prophylactic esophagectomy and ablative therapy considerations,48-51 whereas some investigators recommend treatment when cancer is diagnosed.52 We found similar genetic alterations in HGD from prophylactic esophagectomy specimens and stage I adenocarcinomas. This finding further supports the premalignant nature of HGD and its utility as an indication for prophylactic therapy.
Survival after surgical resection in patients with symptomatic adenocarcinoma in the distal esophagus and EGJ region is poor. Early clinical stage is the most important prognostic factor in resected esophageal adenocarcinoma, as shown in this and previous studies,10,53 but molecular markers may also be helpful. Allelic loss of chromosome 17p (P = 0.06) and 18q (P = 0.08) each appeared to be marginally predictive of patient survival when adjusted for clinical stage, and there was no association of allelic loss of 17p or 18q with clinical stage or tumor differentiation. However, patients with adenocarcinoma characterized by allelic losses of both 17p and 18q had worse survival, with an HR of nearly 2 as compared with those with no or single allelic loss (P = 0.002). Therefore, evaluation of these allelic losses may be useful as an additional prognostic indicator. However, patients with adenocarcinomas that had both p53 overexpression and allelic loss of 18q did not have a statistically significantly worse survival. We evaluated the status of the p53 gene by both immunohistochemistry and 17p allelic loss, but not by DNA sequencing of all of the exons of the p53 gene due to the large number of cases studied. There is recognized discordance between p53 overexpression by immunohistochemistry and presence of p53 mutation,9,54 and allelic loss of 17p is more frequent than p53 overexpression and mutation.7,11 Overexpression of p53 tumor suppressor gene product was not a prognostic indicator in our previous study.10 Therefore, study of p53 gene mutation by DNA sequencing is needed to further clarify the prognostic implication of p53 gene mutations.
In conclusion, we have provided additional evidence that genetic alterations accumulate in the morphological dysplasia–adenocarcinoma sequence during esophageal carcinogenesis. RER was uncommon, but allelic loss of chromosome 18q as well as 17p occurred early, and these losses may play important roles in neoplastic progression. Furthermore, high-grade columnar epithelial dysplasia had a genetic profile similar to that of adenocarcinoma, supporting its importance as a premalignant lesion. Clinical stage was the most important prognostic indicator for patient survival after esophagectomy, but concomitant allelic losses of chromosomes 17p and 18q appear to predict a worse prognosis.
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Acknowledgements |
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Footnotes |
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Accepted for publication April 10, 1998.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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