Lauren histologic type is the most important factor associated with pattern of recurrence following resection of gastric adenocarcinoma

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Abstract​

Objective​

To examine sites of initial recurrence in patients after resection of gastric and gastroesophageal junction Siewert II/III adenocarcinoma (GA).

Summary Background Data​

There are few recent studies on recurrence for Western patients following potentially curative resection of GA.

Methods​

A review of a prospectively maintained, single institution database was performed. Clinicopathologic factors, site(s) of initial recurrence, disease-free survival (DFS), and overall survival (OS) were examined.

Results​

From January 2000–June 2010, 957 patients underwent potentially curative resection for GA, 435 patients (46%) had recurrent disease, and complete data on recurrence site(s) could be obtained in 386 patients. Tumors were Lauren intestinal type in 206 (53%) and diffuse or mixed-type in 180 (47%). Median time to recurrence was 12 months and 75% of recurrences occurred within 2 years. There was a significant difference in pattern of initial recurrence between the intestinal and diffuse/mixed cohorts (p = <0.001). For intestinal tumors, distant metastasis was the most common site (54%), followed by locoregional (20%), peritoneal (15%), and multifocal (11%). For diffuse/mixed tumors, peritoneal recurrence was the most common (37%), followed by distant (32%), locoregional (22%), and multifocal (9%). On multivariate analysis, Lauren histologic type was the only significant factor that was associated with both peritoneal recurrence (diffuse, HR 2.22, CI 1.38–3.94) and distant recurrence (intestinal, HR 1.888, CI 1.202–2.966). After recurrence, median OS was only 8.4 months.

Conclusion​

In GA patients who recur after resection, patterns of recurrence vary significantly based on Lauren histologic type.
For patients with gastric adenocarcinoma, an improved ability to predict sites of recurrence after surgical resection may help determine adjuvant treatment and surveillance options. In our analysis of 386 patients with recurrence after potentially curative resection at a single Western institution, Lauren histologic type (intestinal vs. diffuse/mixed) was the most important factor in the pattern of initial recurrence.

 

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INTRODUCTION​

There are about one million cases of gastric cancer worldwide per year and over 700,000 deaths per year, making gastric cancer the fifth most common cancer and the third leading cause of cancer death.1 In the United States alone, there were an estimated 24,590 new cases and 10,720 deaths related to gastric cancer in 2015.2 Except in a few Asian countries such as Japan and South Korea where there is endoscopic screening for gastric adenocarcinoma, the majority of gastric adenocarcinoma patients present with locally advanced or metastatic disease. Survival rates after potentially curative surgery vary significantly between Asian and Western countries, with 3-year overall survival rates in prospective trials with surgery alone being about 70–80% in Asian countries and 30–40% in Western countries.3–6 Adjuvant chemotherapy or chemoradiation can improve absolute overall survival by 9–15%.

In Western countries, overall survival for patients with metastatic gastric adenocarcinoma is 3–5 months with best supportive care.7 The response rate to multi-agent chemotherapy is 50% or greater, but nearly all patients develop chemotherapy resistance, and median survival is extended only to 9–11 months.8 Patients who develop recurrence after potentially curative surgery also have limited survival. In a prior study from our institution, 77% patients with recurrence after potentially curative surgery were dead within one year.9

 

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In 1965, Lauren described two distinct histological types of gastric adenocarcinomas: intestinal and diffuse.10 The intestinal type exhibits components of glandular, solid, or intestinal architecture as well as tubular structures. This type is more common in men and older patients, and is associated with environmental exposures such as Helicobacter pylori (H. pylori) infection. The diffuse type demonstrates single cells or poorly cohesive cells infiltrating the gastric wall, and progressive disease can ultimately lead to linitis plastica (a.k.a. leather bottle stomach). This type is more common in women and in younger patients and more associated with familial occurrence. Recent broad molecular analyses of gastric adenocarcinoma have discovered that intestinal and diffuse type tumors have quite different genomic profiles, with intestinal tumors often harboring chromosomal instability and diffuse tumor often being genomically stable.11

Prognostic factors for recurrence following potentially curative resection of gastric adenocarcinoma have been extensively investigated. The pattern of recurrence, especially in large series of Western patients, has been much less examined.12 Furthermore over the past 15 years, the increased use of neoadjuvant and adjuvant therapies, along with the development of higher resolution imaging technologies may have altered the site and detection of recurrences.13We sought to examine recurrence patterns in patients at our institution following surgical resection in a contemporary cohort of patients. Because of the distinct histological, clinical, and genomic differences between intestinal and diffuse type tumors, we hypothesized that patterns of recurrence following potentially curative resection of gastric adenocarcinoma would vary significantly based on Lauren histologic type.

 

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METHODS​

A retrospective review was performed of a prospectively maintained gastric cancer database at Memorial Sloan Kettering Cancer Center following Internal Review Board (IRB) approval. We initially examined 1,146 patients with gastric or gastroesophageal junction (Siewert type II or III) adenocarcinoma without metastatic disease who underwent potentially curative resection (i.e., R0 resection) between January 2000 and June 2010 (Fig. 1). Patients who underwent completion gastrectomy or wedge resection, who experienced postoperative death within 30 days, or had incomplete follow-up were also excluded. Of the remaining 957 patients, 522 (54.5%) had no recurrence and 435 (45.5%) had recurrence. The final study population included 386 patients who experienced recurrent disease and for whom the site(s) of recurrence was documented.

 

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Patients who underwent surgery at MSKCC were from around the United States and also from abroad. For those patients who received followup at MSKCC, this generally included clinic visits every 3 months for two years and then every 6 months in year 3–5. Labs were obtained at each clinic visit and a chest/abdomen/pelvis CT scan was obtained every other visit. Followup was similar in patients with intestinal and diffuse/mixed tumors. For all such patients, the timing of recurrence and site or sites of recurrence were documented. Some patients received followup outside of MSKCC. Of patients followed outside MSKCC, 150 patients were excluded because we did not have any followup information on these patients. For another 49 patients followed outside of MSKCC, we received information that they suffered recurrence but we did not receive complete information regarding the site or sites of recurrence.

Patient characteristics and clinicopathologic data​

Demographic and clinicopathologic characteristics and treatment of the study population were determined by review of the database and of the medical records. Tumor stage was determined according to the 7th edition of the International Union Against Cancer (UICC)/American Joint Committee on Cancer (AJCC) classification system.14For patients with proximal gastric or gastroesophageal junction (Siewert type II or III) tumor, the AJCC gastric adenocarcinoma staging system was used rather than the esophageal adenocarcinoma staging system given several studies suggest the gastric system is more accurate.15 In patients with multiple synchronous gastric cancers (n=23), the lesion with the deepest infiltration of the gastric wall was considered to be the index tumor. Lymph node ratio was defined as the number of positive nodes divided by the number of examined nodes.
Perioperative treatment was defined as preoperative chemotherapy, preoperative chemoradiotherapy, postoperative chemotherapy, and/or postoperative chemoradiation. For the purpose of characterizing the extent of lymphadenectomy the 1998 Japanese Gastric Cancer Association definitions of D1 and D2 lymphadenectomy were used.16
The Laurén classification separates gastric adenocarcinomas into two primary subtypes, intestinal and diffuse, and tumors exhibiting features of both the intestinal and diffuse types (>25% of either component) are designated as mixed-type adenocarcinoma. The intestinal type is characterized by the formation of glands exhibiting various degrees of differentiation either with or without extracellular mucin production. The diffuse type is composed of poorly cohesive cells without gland formation. This type of tumor often may contain cells with or without intracytoplasmic mucin, known as “signet ring cells”.

 

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Definition and categorization of recurrence​

Recurrences were categorized by the site involved: locoregional, peritoneal, distant, or multiple. The presence of recurrent disease in two or more sites was defined as multiple. Multiple recurrences in the same site were not categorized as “multiple” sites of recurrence.

Locoregional recurrence included masses in the gastric bed, D2 lymphadenectomy nodal stations, or anastomotic recurrence. Peritoneal recurrence was documented by positive cytology in ascitic fluid or by convincing presence of peritoneal nodules on cross-sectional imaging as determined by the radiology report. Distant metastases were further defined according to the specific organ involved. Disease involving the cervical lymph nodes or abdominal nodes beyond the upper retroperitoneum was considered distant metastasis. Mediastinal lymph node recurrence was considered locoregional for gastroesophageal junction tumors and distant recurrence for all other tumors. Tumors involving the ovaries were considered peritoneal recurrence and classified as Krukenberg tumors.17All recurrences were documented by pathologic diagnosis and/or radiologic imaging. Radiologic proof of recurrence was specifically reviewed in the context of the clinical situation and typically required sequential imaging demonstrating progression of metastatic lesions.

 

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Outcome data and statistical analysis​

The primary endpoint of the study was tumor recurrence pattern. Deaths from any cause and disease-related deaths (defined as death from recurrence) were analyzed. Overall survival (OS) was calculated from the date of operation to death from any cause. Disease-free survival (RFS) was calculated from the date of operation to the date of tumor recurrence or death with evidence of recurrence. For RFS, patients who died without known tumor recurrence were censored at the last documented evaluation. Patients were followed until death or the cut-off date of June 30, 2015. Patients with at least one followup visit/note and then subsequently lost to follow-up were treated as censored.

Descriptive statistical analysis was performed by IBM SPSS Statistics software, 64-bit version 22.0.0 (IBM Corp.). Continuous variables were compared using the Student’s t test, and categorical variables were analyzed using the Pearson’s chi square test. Logistic regression was used for multivariate analysis. Survival curves were generated by the Kaplan–Meier method and analyzed using the log rank test.15 Statistical significance was set at p<0.05.18

 

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RESULTS​

Clinicopathologic characteristics and treatment​

In this study, we first reviewed 957 patients with gastric or gastroesophageal junction (Siewert II or III) adenocarcinoma who underwent potentially curative resection between January 2000 and June 2010 at our institution, met our inclusion criteria, and had follow-up information (Fig. 1). Five hundred twenty two patients (54.5%) had no evidence of recurrence at last follow-up and 435 patients (45.5%) developed recurrent disease. Among the patients with recurrent disease, complete data on site(s) of recurrence could be obtained for 386 subjects (89%). Demographic and clinicopathological characteristics for these 386 patients are outlined in Table 1. Median age was 66 years (range, 24–89 years), and 267 patients (69%) were male. Tumors were located in the mid or lower third of the stomach in 149 patients (38.6%) and the proximal stomach or GE junction (Siewert II or III) in 230 patients (59.6%). Seven patients (1.8%) had tumor diffusely involving the entire stomach

 

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Of the 386 tumors, 206 (53.4%) were Lauren intestinal type and 180 (46.6%) tumors were Lauren diffuse or mixed type; clinicopathologic factors for patients with intestinal vs. diffuse/mixed tumors are shown in Table 1. Compared to the intestinal cohort, patients with diffuse/mixed-type GA were more commonly female and had tumors that were larger in size, primarily poorly differentiated or had signet ring cells, had more vascular and neural invasion, and had more advanced TNM stage. Patients with intestinal tumors also had less positive nodes and a lower lymph node ratio.

For surgical resection, patients underwent a distal gastrectomy (27.7%), total or proximal gastrectomy (26.9%), or esophagogastrectomy (45.4%) (Table 2). Ninety-three percent of patients had a D2 lymphadenectomy. About two-thirds of patients received some form of adjuvant treatment with 50.8% receiving preoperative treatment and 17.1% receiving postoperative treatment. Neoadjuvant or adjuvant therapy included chemotherapy only in 28.8% of patients and chemoradiation in 39.1% of patients. Intestinal-type tumors were more often in the GEJ, compared to diffuse/mixed-type tumors, which were more commonly gastric. As such, compared to patients with intestinal tumors, patients with diffuse/mixed tumors less commonly underwent esophagogastrectomy and more commonly received chemotherapy rather than chemoradiation.

 

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Pattern of recurrence for intestinal and diffuse type tumors​

We initially performed an initial analysis of recurrence patterns for patients with intestinal, diffuse, and mixed tumors, and found that the recurrence pattern for patients with mixed tumors was similar to that of patients with diffuse tumors. Thus patients with mixed and diffuse tumors were combined for subsequent analyses.

Figure 2A illustrates the distribution of initial recurrence sites for all patients. Most patients (89.9%) had initial recurrence involving only a single site; 38 patients (9.8%) had initial recurrence involving two sites, and one patient (0.3%) had initial recurrence involving all three sites. There was a significant difference in the pattern of recurrence between the intestinal and diffuse/mixed cohorts (Fig. 2B, C). Distant metastasis was the most common site of initial recurrence in patients with intestinal-type tumors (54.4%), followed by locoregional (19.9%) and peritoneal (14.6%). Recurrence was multifocal in 11.1%. For diffuse/mixed-type tumors, peritoneal recurrence the most common (37.2%), followed by distant recurrence (31.7%), locoregional recurrence (22.2%), and multifocal recurrence (8.9%). In patients with intestinal-type tumors, the most common distant recurrence site by far was the liver (61.0%) followed by the lung (17.9%) and distant lymph nodes (16.1%) (Fig. 2B). In contrast for diffuse/mixed-type tumors, sites of distant recurrence were more evenly distributed and included the liver (31.6%), distant lymph nodes (22.8%), and bone (21.1%) (Fig. 2C).

 

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Disease-free and overall survival​

The median duration of follow-up for the 386 patients was 23.6 months (range, 2.8–106.3 months). The median time to recurrence from the time of operation was 12 months (Fig. 3A). 74.9% of recurrence occurred by two years, 88.1% by three years, 94.3% by four years, and 96.6% by five years. Only 3.4% of recurrences occurred beyond 5 years. There was no difference in disease-free survival between intestinal and diffuse/mixed tumors (Fig. 3B).

The median overall survival of these patients from the time of operation was 24.9 months (Fig. 3C). The 2 and 5 year overall survivals were 50.1% and 7.7%, respectively. In comparing patients with intestinal-type and diffuse/mixed-type tumors, there was no difference overall survival (25.9 vs. 22.4 months, p=0.11, Fig. 3D). Among the 386 patients diagnosed with recurrence, the median post-recurrence survival was only 8.4 months; 63.5% of patients had died by 1 year, and 87.0% of patients had died by 2 years (Fig. 3E). Post-recurrence survival was significantly better for patients with intestinal-type tumors compared to diffuse type tumors (Fig. 3F).