The clinicopathological characteristics and prognosis of patients with gallbladder SRC remain unclear, possibly because of its rarity. Current knowledge about gallbladder SRC is mainly extrapolated from anecdotal case reports, with limited statistical power [6–17]. It is therefore necessary to undertake an analysis on gallbladder SRC based on large databases such as SEER that can provide a more comprehensive and larger sample size cohort of patients. To the best of our knowledge, this is the first population-based analysis to describe the clinicopathological characteristics, prognosis and treatment strategies specific to gallbladder SRC.
In this large population-based study, 22,781 patients with gallbladder adenocarcinomas (SRC and non-SRC) were identified from the SEER database, of whom 1.7% patients were diagnosed with gallbladder SRC. The mean age of the SRC patients was 69.0 years in our cohort, similar to the mean age of 61.3 (range 22–86) years reported in the previous articles [6–17]. Contrary to the finding of male predilection for primary SRC in other sites, such as the pancreas and colon, our study showed that the male-female ratio was 0.30 for gallbladder SRC, presenting a female predilection [18–21]. This difference may be caused by the female-predilection nature of gallbladder carcinoma itself . Among this cohort, we found that patients with gallbladder SRC were more significantly associated with older age, female gender, poor differentiation, advanced tumor stage, lymph node metastasis, distant metastasis, and advanced AJCC stage than those with non-SRC. When adjusting for other clinical and demographical features that were available, SRC was identified as an independent negative prognostic factor in patients with gallbladder adenocarcinomas. Although SRC exhibits dedifferentiated, highly malignant and aggressive properties, its mechanism remains unclear. Previous articles have reported that the abnormal activation of ErbB2/ErbB3 or loss of E-cadherin and MUC4 may deprive signet ring cells of the ability to maintain cell-to-cell contact, thereby promoting invasion and metastasis [23–26]. This mechanism may partly explain the high metastasis rate and poor prognosis of SRC, as derived from our analyses.
Given the poor prognosis of gallbladder SRC, it is necessary to find an optimal treatment strategy. Total tumor excision with adjuvant chemoradiotherapy is the mainstay of treatment for gallbladder adenocarcinomas at present [27, 28]. However, no standardized protocol and guideline for the treatment of gallbladder SRC are available at present because of the limited number of cases and studies. In the previous 12 cases reported, five patients underwent surgery with chemotherapy [6, 8, 10, 13, 17], three underwent surgery alone [7, 9, 12], one underwent surgery with chemoradiotherapy , two received no treatment[11, 15], and one had no detail information . In our analysis, we found that patients who underwent surgery, with or without chemotherapy or radiotherapy, had better survival than those who received chemotherapy alone (Table 3). When compared with surgery alone, we found an interesting trend, showing that patients who underwent surgery with chemotherapy had significantly improved OS (P = 0.036), whereas no difference in OS was shown in patients who underwent surgery with radiotherapy (P = 0.467), suggesting that surgery with chemotherapy may be the optimal treatment for gallbladder SRC, which is consistent with the traditional management strategy of SRC in other sites [29–31]. As for adjuvant radiotherapy, no benefit was obtained in our study, and a similar result was also reported in a study involving 51 patients with stage II rectal SRC . In addition, previous studies have reported that SRC histology seems associated with resistance to radiotherapy in patients with cervical and esophageal adenocarcinoma [33, 34]. Therefore, adjuvant radiotherapy is not recommended for routine treatment of SRC.
The present study represents the first and largest study on gallbladder SRC to date, but several limitations remain. Firstly, selection bias could not be ignored due to the retrospective nature of the study. In addition, some important information about therapies was not recorded in the SEER database, such as the radiation dosage and chemotherapy regimens. Meanwhile, some important variables associated with survival, including co-morbidities and the resection margin status, were also not accessible. Finally, we did not study the effect of radiotherapy alone on survival, for no patient in our cohort received radiotherapy alone. Despite these limitations, the results of this study can still provide clinicians with deeper insights into this rare tumor.