Context.—

The clinicopathologic and prognostic significance of ARID1A mutation in esophageal adenocarcinoma (EAC) is unknown.

Objective.—

To determine the morphological correlates and prognostic significance of ARID1A-deficient EAC.

Design.—

One hundred twenty cases of primary EAC were evaluated for a predetermined set of histologic features and immunohistochemistry for ARID1A, p53, and MLH1 performed on EAC, as well as adjacent Barrett esophagus and Barrett esophagus–associated dysplasia, when feasible. Associations between categorical clinicopathologic variables were analyzed by Fisher exact test, and survival analysis was performed by a Cox proportional hazards analysis.

Results.—

The study group included 97 men and 23 women (mean age, 66 years). Loss of ARID1A expression was seen in 12 of 120 EACs (10%). ARID1A-deficient tumors showed a strong correlation with a medullary and mucinous phenotype, and 8 of 12 (67%) had at least one feature reminiscent of high microsatellite instability colon carcinomas (mucinous or medullary differentiation, marked intratumoral or peritumoral lymphoid infiltrate). A mutant p53 pattern was present in 52 of 120 EACs (43%) and showed no correlation with ARID1A deficiency (P > .05). MLH1 loss was present in only 2 of 120 EACs (2%); both of which were also deficient in ARID1A. ARID1A-deficient EACs showed a trend toward increased risk of nodal metastasis but had no effect on overall patient survival.

Conclusions.—

ARID1A-deficient EACs show a phenotype similar to colon cancer with high microsatellite instability but do not appear to have any prognostic significance. Concurrent MLH1 loss is not seen in most ARID1A-deficient tumors, suggesting that ARID1A may be a primary driver of carcinogenesis in a subset of EACs.

Esophageal adenocarcinomas (EACs) are morphologically heterogeneous tumors.13  This phenotypic diversity is reflected in the heterogeneous molecular pathways described in EACs. Mutations of tumor suppressor genes TP534 and p165; dysregulation of proto-oncogenes EGF,6  EGFR,7  TGF,8  and HER29; and loss of DNA mismatch repair function10,11  have all been described. There is also evidence of epigenetic alteration by promoter hypermethylation involving APC, CDH1, CDKN2A, MGMT, and TMEFF2/HPP1.12  Recently, whole exome analyses have revealed several novel, recurrent mutations in EACs, including loss-of-function mutations in ARID1A, with a prevalence of approximately 10%.13,14 

ARID1A (AT-rich interactive domain 1A), also known as BAF250A and SMARCF1, is a member of the switch/sucrose nonfermentable, ATP-dependent family of chromatin-restructuring genes that are involved in epigenetic regulation and are collectively mutated in approximately 20% of all malignancies.15  The chromatin-remodeling function of these switch/sucrose nonfermentable complexes is essential for the regulation of gene expression, cell proliferation, cell-fate determination, and DNA damage repair.16  The ARID-DNA interactions are essential for the tumor-suppressor function of ARID1A, and inactivation of the gene by somatic mutation or other epigenetic mechanisms leads to tumorigenesis.17 

Loss-of-function somatic mutations in ARID1A have been described in carcinomas from multiple sites, including the esophagus, stomach, colon, liver, biliary tract, endometrium, ovary, urinary bladder, and pancreas.15,18  ARID1A mutations in ovarian cancer have been described in approximately 50% of ovarian clear cell carcinomas19  and 30% of endometrioid endometrial carcinomas.20  Moreover, loss of the ARID1A protein expression in Müllerian adenocarcinomas correlates with DNA mismatch-repair enzyme deficiency4,21,22  and is mutually exclusive of TP53 mutations,23  suggesting a distinct pathway of carcinogenesis. The aims of our study were to analyze the morphological and immunophenotypic associations of ARID1A loss in EAC and to determine the prognostic significance of ARID1A-deficient EACs.

Study Group

We searched our archives for all esophagectomies and esophagogastrectomies performed between 1989 and 2011 for esophageal adenocarcinoma. Of the 863 resections, 521 (60%) had received neoadjuvant therapy and were excluded from the study. Of the remaining 342 primary resections, 164 tumors (48%) were centered in the esophagus with or without involvement of the gastroesophageal junction. Complete clinical information and archival slides and paraffin blocks were available for the final 120 tumors (73%) in the study group. Patient demographics and clinical outcome data were obtained by medical chart review, and overall survival was obtained by querying the social security death index. The study was approved by the institutional review board.

Morphological and Immunohistochemical Evaluation

All cases were evaluated for a predetermined set of parameters, including tumor location, tumor size and grade, maximum depth of invasion, lymphovascular and perineural invasion, presence of Barrett esophagus (BE), and the grade of any BE-associated dysplasia. In addition, the presence or absence of tumor-infiltrating lymphocytes and peritumoral lymphoid aggregates was noted. Tumors were classified according to the most recent World Health Organization classification1  and reviewed and restaged using the American Joint Committee on Cancer, 7th edition, staging criteria.24 

Representative tumor tissue blocks were selected from each case for immunohistochemical analysis to include EAC as well as background BE and any BE-associated dysplasia, whenever possible. Immunoperoxidase studies were performed on 5-μm sections with antigen retrieval to assess expression of p53 (mouse monoclonal 1767, 1:1200; Beckman Coulter, Atlanta, Georgia), MLH1 (mouse monoclonal, MCL-L-MLH1; 1:75, Leica, Buffalo Grove, Illinois), and ARID1A (rabbit polyclonal, HPA 005456; 1:500, Sigma-Aldrich, St. Louis, Missouri) with automated immunostainers.

ARID1A and MLH1 expression in the tumor cells was scored as deficient when complete loss of expression was present in the entire tumor with intact staining in adjacent stromal cells, or when a discrete, confluent focus of complete loss, compatible with a distinct tumor clone, was present anywhere in the tumor. Similarly, ARID1A and MLH1 were scored as deficient in background BE and any BE-associated dysplasia only when complete loss of staining involved the entire crypt from the crypt base to the surface epithelium, with retained nuclear staining in the adjacent stromal cells. P53 expression, in EAC and in BE-associated dysplasia, was scored as a wild-type pattern when only scattered nuclei were positive and as a mutant pattern when confluent, strong overexpression or complete absence of staining (null pattern) was seen in the neoplastic cells.25,26 

Data Analysis

Fisher exact test was used to compare differences in categorical variables between ARID1A-deficient and -intact EAC. Differences in overall survival were analyzed with a Kaplan Meier analysis and a Cox proportional hazards model computed with the R statistical programming language (version 2.15.1, R development core 2012; R Foundation for Statistical Computing, Wien, Austria, http://cran.r-project.org/). P < .05 was considered statistically significant.

Study Group

The final study group consisted of 97 men (81%) and 23 women (19%), with a mean age of 66 years (range, 30–87 years). The clinical and pathologic features of the study group are summarized in Table 1. Barrett esophagus, defined as columnar metaplasia in the distal esophagus with goblet cells, was seen in 77 of 120 tumors (64%) and BE-associated dysplasia adjacent to carcinoma was present in 88 of 120 cases (73%). In the tumor tissue blocks selected for immunohistochemical analysis, 43 of 120 (36%) contained adjacent, nondysplastic BE, and 17 of 120 (14%) and 47 of 120 (39%) contained foci of adjacent BE-associated low- and high-grade dysplasia, respectively.

Table 1. 

Patient Demographics and Tumor Characteristics of Study Group, n = 120

Patient Demographics and Tumor Characteristics of Study Group, n = 120
Patient Demographics and Tumor Characteristics of Study Group, n = 120

Morphological and Immunohistochemical Data

Loss of ARID1A staining was seen in 12 of 120 EACs (10%), with complete loss of staining in the entire tumor in 10 of 12 cases (83%) and in a discrete, confluent focus in 2 of 12 (17%) cases. In 1 of these latter 2 cases, loss of ARID1A staining was restricted to the poorly differentiated component, with intact staining in the conventional glandular component. Loss of ARID1A in EAC was associated with a distinctive morphology reminiscent of microsatellite instability high (MSI-H) colorectal adenocarcinomas. A medullary phenotype, with solid architecture and increased tumor-infiltrating lymphocytes; a conventional gland-forming carcinoma, with increased tumor-infiltrating lymphocytes or an exophytic, tubulovillous growth pattern with copious, extracellular mucin, consistent with mucinous adenocarcinoma; or prominent, peritumoral, lymphoid aggregates (Figure 1, A through C) were characteristic of ARID1A-deficient EAC. At least one of those features was present in 6 of 12 ARID1A-deficient tumors (50%), with loss of staining throughout the tumor, compared with only 5 of 108 of the ARID1A-intact tumors (5%; P < .001). The remaining 4 tumors with complete ARID1A loss were conventional gland-forming adenocarcinomas (Figure 1, D), with no tumor-infiltrating lymphocytes or peritumoral lymphoid aggregates.

Figure 1. 

A through C, The morphological spectrum of ARID1A-deficient esophageal adenocarcinoma is similar to microsatellite-unstable colon cancer. A, Tubulovillous precursor lesions with conventional gland-forming adenocarcinoma and prominent peritumoral lymphoid aggregates (arrowheads). B, Medullary carcinoma with solid architecture and marked intratumoral lymphoid infiltration. C, Mucinous adenocarcinoma with abundant extracellular mucin. D, A minor subset of ARID1A-deficient tumors has conventional gland-forming adenocarcinomas that do not show any of the features described above. All tumors illustrated showed diffuse loss of ARID1A staining with intact nuclear positivity in the stromal cells (hematoxylin-eosin, original magnifications ×12 [A], ×100 [B and C], and ×200 [D]).

Figure 1. 

A through C, The morphological spectrum of ARID1A-deficient esophageal adenocarcinoma is similar to microsatellite-unstable colon cancer. A, Tubulovillous precursor lesions with conventional gland-forming adenocarcinoma and prominent peritumoral lymphoid aggregates (arrowheads). B, Medullary carcinoma with solid architecture and marked intratumoral lymphoid infiltration. C, Mucinous adenocarcinoma with abundant extracellular mucin. D, A minor subset of ARID1A-deficient tumors has conventional gland-forming adenocarcinomas that do not show any of the features described above. All tumors illustrated showed diffuse loss of ARID1A staining with intact nuclear positivity in the stromal cells (hematoxylin-eosin, original magnifications ×12 [A], ×100 [B and C], and ×200 [D]).

Close modal

Loss of MLH1 expression was present in 2 of 12 cases (17%) with ARID1A loss but in none of the ARID1A-intact tumors. Interestingly, in one case, the MLH1 loss was noted in both the carcinoma and in the adjacent dysplasia, whereas the ARID1A loss was seen in the carcinoma component only (Figure 2). The other case with concordant MLH1 and ARID1A loss showed diffuse loss of MLH1 in the entire tumor and a discrete, confluent focus of ARID1A-deficient tumor cells.

Figure 2. 

In concurrent MLH1- and ARID1A-deficient tumors, the loss of MLH1 expression appears to precede the loss of ARID1A. In this example of dysplastic Barrett esophagus (left half of image) and intramucosal adenocarcinoma (right half; A), MLH1 expression is lost in both the dysplastic and carcinoma components (B), whereas ARID1A loss is limited to the carcinoma component only, with intact staining in the dysplastic epithelium (C) (hematoxylin-eosin, original magnification ×100 [A]; MLH1, original magnification ×100 [B]; ARID1A, original magnification ×100 [C]).

Figure 2. 

In concurrent MLH1- and ARID1A-deficient tumors, the loss of MLH1 expression appears to precede the loss of ARID1A. In this example of dysplastic Barrett esophagus (left half of image) and intramucosal adenocarcinoma (right half; A), MLH1 expression is lost in both the dysplastic and carcinoma components (B), whereas ARID1A loss is limited to the carcinoma component only, with intact staining in the dysplastic epithelium (C) (hematoxylin-eosin, original magnification ×100 [A]; MLH1, original magnification ×100 [B]; ARID1A, original magnification ×100 [C]).

Close modal

ARID1A and MLH1 staining was patchy in nondysplastic and dysplastic BE, and negative surface epithelial staining was quite frequently associated with intact staining in the crypt base (Figure 3, A and B). Loss of ARID1A staining was not seen in any of the 43 foci of nondysplastic BE adjacent to the carcinoma. In the 64 cases (53%) with BE-associated low- or high-grade dysplasia, loss of ARID1A was seen in only one focus (1.5%) of low-grade dysplasia (Figure 3, C and D) separate from the main tumor mass. Thus, in most cases, loss of ARID1A was restricted to the carcinoma component only.

Figure 3. 

A and B, ARID1A expression in nondysplastic Barrett esophagus is typically heterogeneous with consistent staining of the crypt bases and reduced or absent expression toward the surface epithelium. C and D, Loss of ARID1A staining was not seen in any focus of nondysplastic Barrett esophagus in our study and in only one focus of low-grade dysplasia (hematoxylin-eosin, original magnification ×100 [A and C]; ARID1A, original magnification ×100 [B and D]).

Figure 3. 

A and B, ARID1A expression in nondysplastic Barrett esophagus is typically heterogeneous with consistent staining of the crypt bases and reduced or absent expression toward the surface epithelium. C and D, Loss of ARID1A staining was not seen in any focus of nondysplastic Barrett esophagus in our study and in only one focus of low-grade dysplasia (hematoxylin-eosin, original magnification ×100 [A and C]; ARID1A, original magnification ×100 [B and D]).

Close modal

A mutant p53 staining pattern was seen in 52 of 120 EACs (43%), as well as in 3 of 17 foci (18%) of low-grade and 15 of 47 foci (32%) of high-grade dysplasia. A mutant p53 pattern of staining was not seen in any focus of nondysplastic BE. Six of 12 (50%) of the ARID1A-deficient tumors also showed a mutant staining pattern for p53 (Figure 4, A through D).

Figure 4. 

Loss of ARID1A expression is not exclusive to the p53 mutant pattern of staining in esophageal adenocarcinomas. A poorly differentiated adenocarcinoma with tumor infiltrating lymphocytes (A) shows loss of ARID1A expression (B), retained MLH1 expression (C), and diffuse, strong positivity for p53 immunohistochemistry (D) (original magnification ×40 [A through D]).

Figure 4. 

Loss of ARID1A expression is not exclusive to the p53 mutant pattern of staining in esophageal adenocarcinomas. A poorly differentiated adenocarcinoma with tumor infiltrating lymphocytes (A) shows loss of ARID1A expression (B), retained MLH1 expression (C), and diffuse, strong positivity for p53 immunohistochemistry (D) (original magnification ×40 [A through D]).

Close modal

Clinicopathologic Correlates and Prognostic Significance of ARID1A Loss in EAC

As mentioned above, loss of ARID1A expression in EAC showed a significant association with a medullary and mucinous histology. All 3 EACs with a medullary phenotype and 3 of 7 mucinous EACs (43%) were ARID1A-deficient compared with only 6 of 110 conventional gland-forming adenocarcinomas (5.4%; Table 2). A trend was noted for increased risk of nodal metastasis in ARID1A-deficient tumors but was not statistically significant (P = .06). The overall survival of patients with ARID1A-deficient EAC was similar to that of those with intact ARID1A expression on both a Kaplan Meier (Figure 5; P = .10) and Cox proportional hazards analysis (Table 3).

Table 2. 

Clinicopathologic Correlates and Prognostic Significance of ARID1A Loss in Esophageal Adenocarcinoma

Clinicopathologic Correlates and Prognostic Significance of ARID1A Loss in Esophageal Adenocarcinoma
Clinicopathologic Correlates and Prognostic Significance of ARID1A Loss in Esophageal Adenocarcinoma
Figure 5. 

Kaplan-Meier analysis of overall survival among patients with esophageal adenocarcinoma with retained or deficient ARID1A expression shows no difference in prognosis.

Figure 5. 

Kaplan-Meier analysis of overall survival among patients with esophageal adenocarcinoma with retained or deficient ARID1A expression shows no difference in prognosis.

Close modal
Table 3. 

Prognostic Significance of Clinicopathologic Features and Immunohistochemical Findings in Esophageal Adenocarcinoma, n = 120

Prognostic Significance of Clinicopathologic Features and Immunohistochemical Findings in Esophageal Adenocarcinoma, n = 120
Prognostic Significance of Clinicopathologic Features and Immunohistochemical Findings in Esophageal Adenocarcinoma, n = 120

ARID1A functions as a tumor suppressor and has an important role in carcinogenesis in many organs.27  There is a strong correlation between loss of ARID1A expression and DNA mismatch repair deficiency in carcinomas involving the stomach and colon, suggesting that ARID1A loss may be a secondary phenomenon related to impaired DNA repair and not a primary driver of carcinogenesis.22,28,29  In our study, loss of ARID1A expression was present in 10% (12 of 120) of EACs and the majority of ARID1A-deficient EACs showed morphologic features similar to microsatellite unstable colorectal adenocarcinomas. Only 2 of 12 tumors (17%) with ARID1A loss showed a concurrent loss of MLH1, whereas a mutant p53 pattern was seen in 6 of 12 (50%) of the ARID1A-deficient tumors. These findings suggest that ARID1A is a primary driver of carcinogenesis in a subset of EACs and, unlike Müllerian carcinomas, abnormal ARID1A and p53 expression are not mutually exclusive in EAC.

Loss of DNA mismatch repair proteins with MSI-H occurs in only 3% to 6% of all EACs.3  The MSI-H esophageal adenocarcinomas are morphologically heterogeneous but may show medullary or mucinous differentiation or marked tumor-infiltrating lymphocytes, similar to their colorectal counterparts. The association between ARID1A loss and DNA mismatch repair protein deficiency has been reported in gastric, colorectal, and Müllerian adenocarcinomas and shows some interesting site-specific correlations.29  ARID1A mutation or loss of protein expression in gastric cancer shows a strong correlation with Epstein-Barr virus infection and microsatellite instability.29,30  ARID1A is predominantly mutated by indels involving short mononucleotide repeats in MSI-H gastric carcinomas, but ARID1A mutations in microsatellite-stable gastric cancer seldom involve similar indels and are most often single-nucleotide variations, comprising nonsense or missense mutations.31  Similar findings have also been reported in colorectal carcinoma.22  Knockdown of ARID1A leads to inhibition of Fas-mediated apoptosis,32  and it has been speculated that selection for ARID1A mutations in MSI-H tumors may be due to its ability to inhibit apoptosis and thereby promote immune evasion from the abundant tumor-infiltrating lymphocytes that are a feature of microsatellite-unstable gastric carcinomas.31  In contrast, MSI-H endometrial carcinomas do not show indels of short repeats within ARID1A.33  The association between ARID1A and MSI is not surprising because the ARID1A coding region contains many short, 4 to 7 mononucleotide repeats. However, the mutation rate of ARID1A in MSI-H gastric cancer is 12- to 60-fold higher than the global background somatic indel rate in mononucleotide repeats of similar length in other genes.31  This finding indicates preferential selection of a driver gene in MSI-H gastric carcinomas and is similar to other genes, such as TGFBR2, which are selected in MSI-H colon cancer.34  In addition, mutations in the switch/sucrose nonfermentable family of chromatin-remodeling genes ARID1A, SMARCA4, and ARID2 also occur in about 20% of microsatellite-stable EACs, supporting the role of ARID1A as an independent tumor-suppressor pathway in esophageal carcinogenesis.13  This is further supported by the reports of ARID1A mutations not only in EACs but also in a subset of nondysplastic BE and BE-associated dysplasia.35 

Our findings support the role of switch/sucrose nonfermentable chromatin regulators as important tumor suppressor genes36  and highlight some features that distinguish ARID1A-deficient carcinomas in the esophagus from similar tumors at other sites. An inverse relationship has been reported between ARID1A and TP53 mutations in gastric and colorectal carcinomas.22,30,31  Similarly, TP53 mutations are uncommon in ovarian clear cell carcinomas and endometrioid endometrial carcinomas that carry ARID1A mutations, whereas ovarian serous carcinomas that typically harbor TP53 mutations seldom show concurrent mutations in ARID1A.23  Interestingly, there was no difference in prevalence of a mutant p53 pattern in ARID1A-proficient (52 of 108; 48%) and ARID1A-deficient (6 of 12; 50%) tumors (P = .55). Similar findings were reported in a prior small series of EACs using next-generation sequencing, in which 10 of 13 ARID1A-mutant EACs (77%) demonstrated concurrent TP53 mutations.13 

Loss of ARID1A has been shown in precursor lesions adjacent to carcinomas at various sites,37,38  suggesting that it is an early event in carcinogenesis. Similarly, loss of ARID1A expression was previously reported in 5% of nondysplastic BE, with increasing prevalence in BE with low- and high-grade dysplasia.35  However, in our study, loss of ARID1A was restricted to foci of carcinoma, and only one focus of low-grade dysplasia showed complete, confluent loss of ARID1A staining. The reason for this discrepancy may be the strict definition used in our study to define ARID1A loss in nondysplastic and dysplastic epithelium. As illustrated in Figure 4, ARID1A staining in nondysplastic and dysplastic BE consistently shows a heterogeneous pattern and a significant reduction in the intensity of staining toward the surface epithelium. The latter finding is similar to that seen in DNA mismatch repair immunohistochemistry in healthy colonic mucosa. The similarity in reported prevalence of ARID1A mutations13,14  and the loss of protein expression in our cohort suggests that the strict criteria used in our study to define ARID1A loss were appropriate. A precise correlation of ARID1A mutational status and protein expression in metaplastic and dysplastic background epithelium was beyond the scope of this study in which our primary aim was to determine the morphological correlates and prognostic significance of ARID1A loss in EAC.

There are some limitations to our study. We did not perform any mutational analysis in EAC cases that were stained for ARID1A. Although loss of protein expression certainly implies loss of function, there may be additional tumors with retained protein expression that harbor mutations or epigenetic changes with deleterious functional consequences. Secondly, we used primary resections to ensure we had adequate tissue material to evaluate ARID1A expression in EAC and in background columnar mucosa. The lack of prognostic significance for ARID1A-deficient tumors may be due to the small number of EACs with ARID1A loss in our study. Moreover, the prognostic findings may not be applicable to all patients with EAC because most cases are now treated with neoadjuvant therapy followed by surgery.

In summary, loss of ARID1A expression is seen in about 10% (12 of 120) of EACs, and most of those tumors show features similar to those described in MSI-H colorectal carcinomas. The ARID1A-deficient EACs are also more likely to show loss of MLH1 compared with ARID1A-intact tumors. The prevalence of a mutant p53 pattern is similar in EAC with and without the loss of ARID1A. Finally, in primary resections for EAC, loss of ARID1A expression carries no prognostic significance.

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Author notes

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

Competing Interests

Presented in part at the 103rd Annual Meeting of the United States and Canadian Academy of Pathology; March 1–7, 2014; San Diego, California.