INTRODUCTION
Gastric cancer is the sixth most common malignancy worldwide, with approximately 1.2 million new cases diagnosed in 20161. Despite its overall declining incidence in recent years, gastric cancer is still the second leading cause of cancer-related death worldwide,1,2 and the incidence of a specific histotype, signet ring cell carcinoma (SRC), has in fact been increasing.1 Indeed, data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program demonstrate a 10-fold increase in the incidence of SRC between 1973 and 2000.3,4 More recent SEER program data have shown that even in light of national cancer detection and prevention efforts, the incidence of SRC has not decreased.5
Despite these troubling statistics, data from the United States (US) regarding gastric SRC are particularly scarce, in part due to SRC being an uncommon malignancy. According to the World Health Organization (WHO) classification, it is a histological type of epithelial carcinoma based on more than 50% of the tumor containing intracytoplasmic mucin. This globoid, optically clear glycoprotein pushes the cells’ nuclei against the cell membrane, creating what has been classically described as a “signet ring” appearance.6 Compared to other gastric cancer types, it has been reported to have a female predominance, younger age at diagnosis, and late presentation, making treatment particularly challenging.7,8 Although there have been studies of the clinicopathological features and prognosis of gastric SRC of the stomach, results have been inconsistent, with some reports showing SRC to have a better prognosis than other gastric carcinomas,9 some showing no significant difference,10,11 and others reporting a poorer prognosis.8
At our institution, a predominantly minority county hospital in Los Angeles County, it was independently observed by both the Department of Pathology and Department of Medicine that the number of gastric SRC cases seemed surprisingly large and the presentation commonly in young patients. We therefore aimed to examine the occurrence, features, and outcomes of gastric SRC in this unique population.
METHODS
This study was approved by the Institutional Review Board of Olive View-UCLA Medical Center.
Patients and setting
We retrospectively identified all patients greater than 18 years of age with a biopsy-proven diagnosis of gastric SRC of the stomach at Olive View-UCLA Medical Center between the years of 2004 and 2017. This Los Angeles County hospital serves a population of over 2 million people within a catchment area of almost 1000 square miles and is one of five hospitals run by the Los Angeles County Department of Health Services, the second largest municipal health care system in the United States. Approximately 65% of this population identify as Hispanic, and over 50% speak a primary language other than English.
Cases of non-gastric primary origin were excluded, as well as non-Los Angeles County patients who received an outside diagnosis and referred to our healthcare system for follow-up care.
In order to compare the characteristics and outcomes of patients in this study with that of other cohorts, we abstracted data from the National Cancer Institute’s SEER program. The SEER database represents the most comprehensive cancer registry in the US, representing approximately 27.8% of the US population.13 We selected patients with gastric SRC using the International Classification of Diseases code 8490 and filtering only for cases of gastric primary. SEER data that were abstracted included gender, race, tumor location, T stage, N stage, overall cancer stage, tumor differentiation, and survival time.
Study variables and outcomes
Comprehensive demographic, clinical, endoscopic, histopathologic, imaging, and oncologic data were abstracted using a standardized data collection form, including: sex, age at diagnosis, race, tumor size, tumor location, TMN stage, differentiation, lymph node involvement, type of surgery, neoadjuvant and adjuvant chemotherapy, Helicobacter pylori (H. pylori) infection status, and time to death or hospice.
Primary outcome was survival, defined as time to death or hospice. Secondary outcomes included patient characteristics (e.g age, gender, race), presenting tumor features (e.g. stage, size, tumor location, tumor differentiation), H. pylori status, and comparison of these features to available SEER data. Age at diagnosis was determined by subtracting the year of birth from the year of diagnosis. Similarly, time to death or hospice was determined by subtracting the date of death or date of hospice initiation from the date of diagnosis. Pathological stage was classified according to the American Joint Committee on Cancer (AJCC) staging manual, 7th edition.12 H. pylori status was determined by reviewing histopathology reports (most often confirmed by Warthin-Starry silver stain), serum H. pylori IgG antibody, or stool H. pylori antigen testing. Patients were categorized as H. pylori positive if any of the three testing methods were positive and H. pylori negative if all H. pylori tests that were performed were negative. Patients without any documented H. pylori testing were categorized as unknown status.
Statistical analysis
Patient demographic and clinical characteristics were described using descriptive statistics. Means were compared with independent T-tests, and survival curves were generated using the Kaplan-Meier method and then compared with the log-rank test. Hazard analysis was performed by constructing Cox Regression models. Time to hospice or death (by any cause) was used as a proxy for approximating survival. All study data was analyzed using IBM SPSS Statistics 23 (SPSS, Inc., Chicago, IL). SEER data was analyzed using the SEER*Stat software (version 8.3.5, National Cancer Institute).
RESULTS
Clinico-demographic characteristics
A total of 63 patients with gastric SRC were identified. Of these, 81.0% were Hispanic, 7.9% White, 6.3% Other, and 4.8% Asian/Pacific Islander. Cases of gastric SRC had a female predominance (57.1%). The mean age at diagnosis was 52.6 ± 11.9 years, with no significant age difference between males and females (p=0.95). Recent or ongoing H. pylori infection was present in 75.6% of patients, of which 38.7% were diagnosed by serum antibody, 48.4% by pathology, 6.5% by stool antigen, and 6.5% by a combination of serum antibody and pathology. Median follow-up was 8.3 months (interquartile range 2.2–18.1 months). These and additional sample characteristics are summarized in Table 1.
Table 1:
Clinic-demographic characteristics
| Variables | n (%) |
|---|---|
|
| |
| Gender | |
| Male | 27 (42.9) |
| Female | 36 (57.1) |
| Age at diagnosis (in years) | 52.6±11.9 |
| Male | 52.7±9.8 |
| Female | 52.5±13.4 |
| Ethnicity | |
| Hispanic | 51 (81.0) |
| White | 5 (7.9) |
| Asian/Pacific Islander | 3 (4.8) |
| Other | 4 (6.3) |
| H pylori (n=41) | |
| Positive | 31 (75.6) |
| Serum antibody only | 12 (38.7) |
| Pathology only | 15 (48.4) |
| Stool antigen only | 2 (6.5) |
| Combination of 2 or more methods | 2 (6.5) |
| Negative | 10 (24.4) |
Tumor presentation
Mean tumor size was 6.8 ± 5.1 cm. Approximately 8.9% of cases were located at the gastroesophageal junction, 2.2% in the fundus, 37.8% in the body, 24.4% in the antrum, and 36.7% in multiple locations or diffusely. Over 75% of patients presented with tumor pathologic stages T3 or T4, and nearly 90% presented with lymph node metastases. Eighty-six percent of patients presented with cancer stage III or IV, and approximately 87% had poorly differentiated (G3) or undifferentiated (G4) histology reported. These and additional tumor presentation data are presented in Table 2.
Table 2:
Tumor characteristics
| Variables | n (%) |
|---|---|
|
| |
| Mean tumor size (cm, n=33) [1] | 6.8±5.1 |
| Median tumor size (cm) | 5.5 |
| Tumor location (n=45) | |
| Fundus | 1 (2.2) |
| GE junction | 4 (8.9) |
| Body | 17 (37.8) |
| Antrum | 11 (24.4) |
| Multisite | 12 (26.7) |
| Depth of invasion (n=30) | |
| T1 | 1 (3.3) |
| T2 | 6 (20.0) |
| T3 | 14 (46.7) |
| T4 | 9 (30.0) |
| Lymph node metastasis (n=27) | |
| N0 | 4 (14.8) |
| N1 | 4 (14.8) |
| N2 | 12 (44.4) |
| N3 | 7 (30.0) |
| Stage (n=50) | |
| Ia | 0 (0.0) |
| Ib | 3 (6.0) |
| IIa | 1 (2.0) |
| IIb | 3 (6.0) |
| IIIa | 8 (16.0) |
| IIIb | 5 (10.0) |
| IIIc | 3 (6.0) |
| IV | 27 (54.0) |
| Differentiation (n=38) | |
| Well differentiated | 0 (0.0) |
| Well-moderately differentiated | 0 (0.0) |
| Moderately differentiated | 1 (2.6) |
| Moderately-poorly differentiated | 4 (10.5) |
| Poorly differentiated | 30 (78.9) |
| Undifferentiated | 3 (7.9) |
Excludes tumors from post-adjuvant chemotherapy
Oncologic treatment
Sixty-two percent of patients with gastric SRC underwent either subtotal or total gastrectomy. Approximately 10% had neo-adjuvant chemotherapy consisting of capecitabine, an alkylating antineoplastic agent (either cisplatin or oxaliplatin), +/− epirubicin. Seventy-six percent of patients received chemotherapy (most frequently with 5-fluorouracil and radiotherapy via the Macdonald protocol) with either palliative or curative intent.
Survival outcomes
Median time between date of diagnosis and date of death or hospice initiation was 12.6 months, and 5-year survival was 14.3%. Eighty-eight percent of patients were either deceased or on hospice within 2 years of diagnosis. Kaplan-Meier curves are shown in Figure 1. Median survival in males and females was not significantly different (12.9 vs. 12.6 months, log rank, p=0.406), and there was no significant difference in survival between patients who were younger than 52 (the median age of patients in this study) and older than 52 years of age at diagnosis (15.8 vs. 11.4 months, log rank, p=0.291). Similarly, there was no statistically significant difference in median survival between patients with tumors smaller than 5.5 cm (the median tumor size in this study) and larger than 5.5 cm (20.3 vs. 12.9 months, log rank, p=0.171), though there was a trend towards shorter survival with larger tumors. Higher overall cancer stage (stage IV vs. stage I-III) was associated with poorer survival (4.2 months vs 20.4 months, log rank, p=0.001). Patients with recent or active H. pylori infection were found to have longer survival than patients who had negative H. pylori tests (17.9 vs. 5.6 months, log rank, p=0.017). Patients who underwent surgical intervention had longer survival than patients who did not undergo surgery (20.4 vs. 3.3 months, log rank, p<0.001). Survival did not appear to be associated with whether or not patients received chemotherapy (13.0 vs. 17.9 months, p=0.618). These predictors of survival are shown in Figure 2.
Figure 1:
Kaplan-Meier survival curves comparing months of survival in signet ring cell carcinoma (SRC) are shown for (A) all patients, (B) by gender (p=0.406), (C) by age (p=0.291), (D) by tumor size (p=0.171), (E) by cancer stage (p=0.004), (F) by H. pylori infection status (p=0.017), (G) by surgical intervention (p<0.001), (H) by chemotherapy (p=0.618). All comparisons performed by log-rank tests.
Figure 2:
Predictors of survival. Horizontal lines indicate 95% confidence intervals. The following variables were associated with shortened survival (as indicated by *): advanced stage (p=0.001), H. pylori negative (p=0.017), and no surgery (p<0.001).
DISCUSSION
Gastric SRC is a rare but highly lethal cancer whose incidence, based on the limited available data, does not appear to be decreasing in the US unlike gastric cancer overall. In this study, we aimed to examine and better understand the clinical epidemiology of gastric SRC in the US and specifically in the predominantly minority patient population of Los Angeles County. The major findings of this study included: i) Hispanic patients had a younger age at diagnosis, ii) females comprised a larger proportion of patients with a new diagnosis of SRC of the stomach, iii) patients in this population had more advanced TMN staging, iv) despite more advanced presentations, patients in this population had longer survival times.
We found that compared to data from SEER, the mean age of diagnosis was younger in this population, with the average age of diagnosis being 10 years earlier (52.6 vs. 63.5 years), consistent with our initial clinical observation.14 We suspect that ethnoracial factors (and possibly geographical and environmental factors) may play a role in this discrepancy, as 81% of patients were Hispanic in this study. Interestingly, when including only patients of Hispanic descent from the SEER database, we found the average age of diagnosis to be 57 years, which is more similar to our cohort and younger than SEER patients overall, thus further suggesting that Hispanic patients may represent a high-risk group.14 Indeed, the early age of diagnosis in Hispanic patients appears to be similar to and in some cases even earlier than other populations traditionally considered to be high-risk.15–17
In regards to other demographic characteristics, we also found that this population had a higher proportion of females with gastric SRC, with 57.1% of patients with a new diagnoses of SRC being female, compared to 45% in SEER14 and 33–50% in other studies of patients with SRC.10,11,15–17 While it is unclear why the proportion of females was higher in this study, numerous previous studies have found that a higher percentage of signet ring cell patients are female when compared with non-signet ring cell carcinoma patients. There are hypotheses that SRC histology may be influenced by female sex hormones, as estrogen receptors have frequently been found to be expressed in poorly differentiated gastric cancer, thus suggesting a relationship between hormone environment and gastric cancer.18
Tumor characteristics were also unique. Compared with SEER data, a higher percentage of patients presented with advanced tumor staging; 76.7% of patients presented with tumor stages of T3 or T4, compared with 60.7% in SEER. Lymph node involvement was also higher in this population (89.2% vs. 48.5%). Interestingly, the presentation of SRC has been observed to differ between studies from the West vs. the East; for example, US studies have gastric SRC to be associated with advanced TNM stage upon presentation, while many Asian studies indicate large proportions of SRC tumors being diagnosed at earlier stages.11,15,16,19 One explanation for this difference is the variations in preventative cancer screening practices throughout the world. Asian countries such as Korea and Japan have high participation rates for gastric cancer screening. For example, in 2012, the participation rate for gastric cancer screening via endoscopy or upper gastrointestinal series biennially in Korean men and women older than 40 years was 47.3%.20,21 In these Asian countries, routine gastric cancer screening is standard of care, which would likely contribute to cancers being detected in earlier stages. Conversely, in Western countries diagnostic testing is often performed only after symptom onset. In the present study, patients presented with even more advanced presentations than what has been previously reported in Western studies, potentially in part due to delays and difficulties with access to health care in this largely uninsured population.
However, even with more advanced presentations of T and N stage, survival trended higher in this population compared with SEER data. In the cases of gastric SRC in SEER with known survival data (n=14,148), the median survival was 9.8 months. Although we were not able to calculate true median survival due to limited survival data, by including time until hospice, we found the mean time to death or initiation of hospice to be 12.6 months, indicating the possible existence of protective factors in this population. From their analysis of SEER data from 2004–2007, Taghavi et al. previously indicated that age of diagnosis, Hispanic ethnicity, tumor stage, node stage, grade, and overall stage increase mortality. In this study, the majority of patients were Hispanic and had high tumor and node stage; however, the average age of diagnosis was younger and the percentage of high grade tumors was lower (poorly differentiated, 78.9% vs. 92.6%, and undifferentiated, 7.9% vs. 3.8%), thus possibly offsetting mortality and contributing to better outcomes.14
In subgroup survival analyses using log-rank tests, we found no significant difference in survival based on gender, age, tumor size, and treatment with chemotherapy. However, as expected, we did see longer survival times in patients with less advanced tumor stages. We also found improved survival with gastrectomy vs. no surgery, but subsequent review of surgery subgroups revealed that the no surgery group was biased towards more advanced tumor staging (all had T4 disease), as patients with metastatic disease were usually not surgical candidates due to metastatic disease. Lastly, we found improved survival with H. pylori positive status. Studies of H. pylori and gastric cancer have found that most patients with gastric cancer are H. pylori-positive, with reported seropositivity rates varying from 80% to 100%.22,23 For the small percentage of patients with H. pylori-negative gastric cancer, the most common subtype is SRC.24 However, the role of H. pylori in SRC is unclear, as there have been few studies on this subject. Horiuchi et al. found that the proliferative ability of cancer was higher in gastric SRC patients who were H. pylori-positive than those who were H. pylori negative, suggesting that H. pylori-positive gastric cancers of the SRC subtype progress more rapidly.24 Although our results do not seem consistent with this previous finding, a direct comparison cannot be made, as survival was not analyzed in the aforementioned study. We believe more studies will be needed to better evaluate and understand the impact of H. pylori on SRC outcomes.
There are several limitations to the present study, including the small sample size due to the relatively low incidence of this disease, as well as lack mortality data for some patients. To approximate survival, both time to death and time to hospice initiation was included, which systematically underestimated mean survival.
CONCLUSION
In this first US study to examine the occurrence, features, and outcomes of SRC at a predominately minority county hospital in Los Angeles County, we found the mean age of diagnosis was younger, the proportion of females was higher, and the severity of tumor stage and lymph node involvement was greater than what has been reported in SEER data. However, despite presenting with higher tumor stage and lymph node involvement, median survival was higher, thus suggesting possible protective factors in this study population.
Table 3:
Outcomes
| Variables | n (%) |
|---|---|
|
| |
| Surgery (n=56) | |
| Gastrectomy (subtotal) | 22 (39.3) |
| Gastrectomy (total) | 13 (23.2) |
| No surgery | 21 (37.5) |
| Neoadjuvant chemotherapy (n=51) | |
| Yes | 5 (9.8) |
| No | 46 (90.2) |
| Chemotherapy (n=51) | |
| Yes (palliative and curative) | 39 (76.5) |
| No | 12 (23.5) |
| Survival | |
| Median survival (months) | 12.6 |
| 3 months | 44/55 (80.0) |
| 6 months | 33/53 (62.3) |
| 12 months | 27/51 (52.9) |
| 24 months | 10/45 (22.2) |
| 60 months | 6/42 (14.3) |
Table 4:
Univariate analysis of prognostic characteristics for gastric SRC
| Univariate Analysis |
Multivariate Analysis [1] |
|||
|---|---|---|---|---|
| Characteristic | Hazard Ratio (95% CI) | p value | Hazard Ratio (95% CI) | p value |
|
| ||||
| Higher stage [2] | 3.172 (1.584–6.355) | 0.001 | 1.133 (0.223–5.764) | 0.881 |
| Larger size [3] | 1.130 (1.032–1.238) | 0.009 | 1.266 (0.983–1.631) | 0.067 |
| HP (+) | 0.292 (0.100–0.854) | 0.025 | 0.214 (0.023–1.967) | 0.173 |
| Female | 1.327 (0.678–2.598) | 0.408 | ||
| Older age [3] | 0.995 (0.963–1.028) | 0.757 | ||
| Chemotherapy | 0.893 (0.575–1.395) | 0.618 | ||
Multivariate analysis performed on characteristics that were significant on univariate analysis
Stage IV vs Stage I-III
These variables evaluated as a continuous variable. All others evaluated as categorical variables.
Acknowledgments
Financial disclosures, grant support, writing assistance, personal conflict of interest: none
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