Nuytens F, Drubay V, Eveno C, Renaud F, Piessen G. Systematic review of risk factors, prognosis, and management of colorectal signet-ring cell carcinoma. World J Gastrointest Oncol 2024; 16(5): 2141-2158 [PMID: PMC11099453 DOI: 10.4251/wjgo.v16.i5.2141]
Corresponding Author of This Article
Frederiek Nuytens, MD, Surgeon, Department of Digestive and Oncological Surgery, University Lille, Claude Huriez University Hospital, Rue Michel Polonowski, Lille 59000, France. frederiek.nuytens@gmail.com
Research Domain of This Article
Surgery
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Systematic Reviews
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This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Frederiek Nuytens, Clarisse Eveno, Guillaume Piessen, Department of Digestive and Oncological Surgery, University Lille, Claude Huriez University Hospital, Lille 59000, France
Frederiek Nuytens, Department of Digestive and Hepatobiliary/Pancreatic Surgery, AZ Groeninge, Kortrijk 8500, Belgium
Vincent Drubay, Cambrai Hospital Center and Sainte Marie, Group of Hospitals of The Catholic Institute of Lille, Cambrai 59400, France
Clarisse Eveno, Florence Renaud, Guillaume Piessen, CNRS, Inserm, UMR9020-U1277-CANTHER-Cancer, University Lille, CHU Lille, Lille 59000, France
Author contributions: Nuytens F and Drubay V were involved in analysis and interpretation of the data, and drafting and final approval of the manuscript; Eveno C and Renaud F were involved in analysis and interpretation of the data, and revision and final approval of the manuscript; Piessen G was involved in design of the study, decision of publishing the paper, analysis and interpretation of the data, and revision and final approval of the manuscript.
Conflict-of-interest statement: The authors have no potential and real conflicts of interest to disclose.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Frederiek Nuytens, MD, Surgeon, Department of Digestive and Oncological Surgery, University Lille, Claude Huriez University Hospital, Rue Michel Polonowski, Lille 59000, France. frederiek.nuytens@gmail.com
Received: December 24, 2023 Peer-review started: December 24, 2023 First decision: January 10, 2024 Revised: January 27, 2024 Accepted: March 19, 2024 Article in press: March 19, 2024 Published online: May 15, 2024 Processing time: 137 Days and 3 Hours
Abstract
BACKGROUND
Colorectal signet-ring cell carcinoma (CSRCC) is a rare clinical entity which accounts for approximately 1% of all colorectal cancers. Although multiple studies concerning this specific topic have been published in the past decades, the pathogenesis, associated risk factors, and potential implications on treatment are still poorly understood. Besides the low incidence, historically confusing histological criteria have resulted in confusing data. Nevertheless, the rising incidence of CSRCC along with relatively young age at presentation and associated dismal prognosis, highlight the actual interest to synthesize the known literature regarding CSRCC.
AIM
To provide an updated overview of risk factors, prognosis, and management of CSRCC.
METHODS
A literature search in the MEDLINE/PubMed database was conducted with the following search terms used: ‘Signet ring cell carcinoma’ and ‘colorectal’. Studies in English language, published after January 1980, were included. Studies included in the qualitative synthesis were evaluated for content concerning epidemiology, risk factors, and clinical, diagnostic, histological, and molecular features, as well as metastatic pattern and therapeutic management. If possible, presented data was extracted in order to present a more detailed overview of the literature.
RESULTS
In total, 67 articles were included for qualitative analysis, of which 54 were eligible for detailed data extraction. CSRCC has a reported incidence between 0.1%-2.4% and frequently presents with advanced disease stage at the time of diagnosis. CSRCC is associated with an impaired overall survival (5-year OS: 0%-46%) and a worse stage-corrected outcome compared to mucinous and not otherwise specified adenocarcinoma. The systematic use of exploratory laparoscopy to determine the presence of peritoneal metastases has been advised. Surgery is the mainstay of treatment, although the rates of curative resection in CSRCC (21%-82%) are lower compared to those in other histological types. In case of peritoneal metastasis, cytoreductive surgery with hyperthermic intraperitoneal chemotherapy should only be proposed in selected patients.
CONCLUSION
CSRCC is a rare clinical entity most often characterized by young age and advanced disease at presentation. As such, diagnostic modalities and therapeutic approach should be tailored accordingly.
Core Tip: Although multiple studies concerning colorectal signet-ring cell carcinoma (CSRCC) have been published in the past decades, the pathogenesis, associated risk factors, and potential implications on treatment are still poorly understood. As such, the aim of this systematic review was to provide an updated overview of CSRCC by means of a synthesis of the current literature concerning this topic with emphasis on risk factors and clinical and histopathological features of the disease along with diagnostic and therapeutic features that should be tailored to this specific clinical entity.
Citation: Nuytens F, Drubay V, Eveno C, Renaud F, Piessen G. Systematic review of risk factors, prognosis, and management of colorectal signet-ring cell carcinoma. World J Gastrointest Oncol 2024; 16(5): 2141-2158
Colorectal signet-ring cell carcinoma (CSRCC) is a rare clinical entity that accounts for approximately 1% of all colorectal cancers (CRCs)[1]. According to the latest WHO classification of digestive system tumors, a tumor is defined as signet-ring cell carcinoma (SRCC) if > 50% of the tumor cells have prominent intracytoplasmic mucin, typically with displacement and molding of the nucleus[2].
Although multiple studies concerning this specific topic have been published since it was first described by Laufman and Saphir[3] in 1951, the pathogenesis, associated risk factors, and potential implications on treatment are still poorly understood. The low incidence of this disease, with historically confusing histological criteria, renders comparison between studies difficult to make, especially in the less recent literature[4]. Nevertheless, the rising incidence of CSRCC along with the relatively young age at presentation and associated dismal prognosis, highlight the actual interest in synthesizing the known literature regarding CRSRCC. In this context, we conducted a systematic review of the literature regarding CSRCC with emphasis on risk factors and the influence of the clinical and histopathological features on the management of the disease.
MATERIALS AND METHODS
A literature search in the MEDLINE/PubMed database was conducted according to the PRISMA guidelines[5]. The following search terms were used: ‘Signet ring cell carcinoma’ and ‘colorectal’. Only studies in the English language, published after January 1980, were eligible for inclusion. Studies were screened based on the abstract. Additional studies were retrieved by screening the references of each individual article. The exclusion criteria were the following: Case reports, studies in which the full text was not available, and studies in which SRCC was not clearly defined as a histological entity according to the WHO guidelines. Additionally, studies focusing on SRCC and mucinous adenocarcinoma (MA) as a single group, were excluded. The literature search was performed by Drubay V and Nuytens F. In case of doubt, additional advice was obtained from a third party (Piessen G). A last update of the literature search was performed in November 2020. Studies included in the qualitative synthesis were evaluated for content concerning epidemiology, risk factors, and clinical, diagnostic, histological, and molecular features along with the metastatic pattern and their influence on therapeutic management. Based on these findings, a narrative synthesis was performed. If possible, data on demographic, surgical, pathological, and molecular features as well as survival outcomes were extracted to present a more detailed overview of the literature. No funding was granted for this systematic review.
RESULTS
Study selection
Overall, 476 studies were identified through the database search. An additional 9 studies were identified through other sources. An overview of the study selection using a PRISMA flow diagram is shown in Figure 1. After screening and application of the exclusion criteria, 67 articles were included for qualitative analysis and integration in the narrative review. In total, 54 articles were eligible for detailed data extraction. An overview of the methodological details concerning these articles is summarized in Table 1.
CSRCC has a reported incidence between 0.1%-2.4%[6,7]. Significantly higher incidence rates of up to 5% in Egypt and 18.5% in Jordan and Lebanon have been reported. Potential overlap in histologic diagnosis of MA with CSRCC, tertiary center referral bias, and nutritional (dietary habits) as well as hereditary factors have been suggested as potential reasons for these isolated differences in incidence rate[8]. After the stomach (63.4%), the colon is the second most affected organ by SRCC histology (18.2%), followed by the esophagus (5%) and the rectum (3.5%)[9-11]. Interestingly, in a report based on the Surveillance, Epidemiology and End Results program database (SEER), Kang et al[12] showed that the incidence of CSRCC has increased by 0.2% from 1990 till 2000. In a multivariate analysis of rectal SRCC, Tawadros et al found that especially in patients under the age of 40, the incidence has risen by 3%, entailing a 3.6-fold increased risk of CSRCC compared to the general population[13]. Higher detection rates and more widespread implementation of the histological criteria for CSRCC, along with an increased diagnostic rate of SRCC-related diseases such as inflammatory bowel disease (IBD), are likely to be responsible for this observed increase in the incidence rate[12]. Several authors have indeed identified IBD and more specifically ulcerative colitis as a potential risk factor for CSRCC[13,14]. One study mentioned that 14.3% of patients with CSRCC had a history of IBD[15]. Hartman et al[16] found that IBD-associated intestinal cancers displayed significantly more signet-ring cell (SRC) characteristics than other subtypes of adenocarcinoma (OA; 28% vs 4%, P < 0.001).
Historically, SRCC has been associated with young age at presentation, which is confirmed by more recent reports[6,8,12,17]. Several other authors, however, were unable to demonstrate any association between CSRCC and younger age[4,15,18]. Median age at presentation varies from 40 to 70 years old. Small study samples are probably accountable for this major variability. Ciarrocchi[4] showed that especially in the case of rectal SRCC, younger patients were more frequently affected. Psathakis et al[15] stated that although the proportion of CSRCC in young patients is high, the overall median age and range are similar to those of OA.
Concerning gender distribution, the literature is also characterized by major heterogeneity. Most authors mentioned a male predominance or no significant difference at all[6,17,19,20]. One report showed that in patients with rectal SRCC, the male-to-female ratio was 2:1[4]. In another study, a multivariate analysis identified female gender as an independent prognostic factor for worse OS in CSRCC compared to patients with MA[21].
Concerning racial differences, only Tawadros et al[13] found that patients with rectal SRCC were more frequently from another race than black or white. In a review comparing Asian and Western data of patients with CSRCC, however, no significant differences in demographic data could be withheld[22].
With regard to genetic predisposition, most authors found no correlation between CSRCC and a positive family cancer history[15,23,24]. Whether this is the result of small study samples or because of current clinicopathological features, remains to be determined[24]. In a study sample of 61 patients, only Song et al[25] found a positive family cancer history in 49.2% of the patients. In half of these cases, it concerned gastric cancer or CRC.
Out of all of the above-mentioned risk factors, only young age and male gender were described as negative prognostic factors[26,27]. Patients with CRSCC under the age of 35 display significantly worse cause-specific survival (CSS) as compared to older patients. More aggressive tumor biology in this specific subset of young patients, as well as a delay in diagnosis, caused by a low index of suspicion, both for patients and physicians, have been hypothesized as potential reasons for these findings[26].
Clinical and diagnostic features
Most studies including a large number of patients observed that CSRCC is predominantly located in the proximal (right) colon and rectum[4,8,17,18]. Only a few authors report a more frequent location in the left hemi-colon or rectosigmoid, mostly in studies containing smaller numbers of patients[20,28,29]. In rectal SRCC, tumors are more frequently located at the level of the lower rectum, which results in a higher rate of abdominoperineal resection[6].
Table 2 shows an overview of the literature reporting on tumor characteristics at the time of diagnosis. CSRCC is frequently characterized by the presence of advanced disease stage at the time of diagnosis, including large tumor size and high rates of lymph node- and peritoneal metastasis[6,7,15,17]. At the time of diagnosis, the mean tumor size varies from 4.6 to 8 cm, with the vast majority of patients (61%-100%) already being affected by stage III or IV disease[7,13,14,23,30]. As a consequence, patients with CSRCC more often require emergency procedures[8,15]. A change in bowel habits has been described as the most frequent presenting symptom in two small studies[31,32]. Ooi et al[23] on the other hand found that rectal bleeding and bowel obstruction were the two most common presenting symptoms, both in 33% of the cases.
Table 2 Overview of articles reporting on tumor characteristics at the time of diagnosis.
Locally advanced and metastatic disease at the time of diagnosis has been attributed to the specific clinical course and a more frequent proximal location of CSRCC, resulting in a later onset of symptoms as compared to left-sided colon cancer[8,15]. Nitsche et al[33] stated that other histological types of tumors of the right hemi-colon are not associated with such a delay in diagnosis. Because of a primarily submucosal infiltration pattern in SRCC, a fecal occult blood test is often negative[34]. Moreover, the submucosal infiltration associated with the histopathological characteristics of SRCC is translated into an endoscopic and radiographic morphology that frequently mimics that of IBD[34]. In this context, endoscopic deep-tissue biopsies or even endoscopic-ultrasound-guided biopsies have been recommended to obtain adequate histological proof[35]. Because of no adenoma-carcinoma sequence in early CRSCC, meticulous endoscopic inspection for subtle superficial lesions has been proposed[34]. Despite the importance of early diagnosis for CSRCC, Sasaki et al[14] found that the implementation of this recommendation into clinical practice appears to be difficult since the average duration between symptoms and diagnosis was only 2.8 mo.
Because of the increased risk of peritoneal carcinomatosis (PC) in the case of CSRCC, other authors have suggested the systematic use of a staging laparoscopy with peritoneal lavage and cytology to determine the presence of peritoneal (micro) metastases, especially since the sensitivity of CT scan for PC in this context tends to be low[35,36]. Few studies have evaluated the role of carcinoembryonic antigen (CEA) as a potential marker for CSRCC. Except in one small study containing 12 patients, no significant difference in CEA levels could be identified between CSRCC and OA[22,29,37].
Histologic and molecular features
According to the latest WHO classification of digestive system tumors, adenocarcinoma of the colon is defined as CSRCC if > 50% of the tumor cells have prominent intracytoplasmic mucin, typically with displacement and molding of the nucleus[2]. Carcinomas with SRCs in < 50% of the tumor are categorized as having a SRC component. SRCCs are now classified as poorly cohesive carcinomas.
The term ‘linitis plastica’ finds its origin as a macroscopic description for a sclerotic and rigid stomach wall and has little to no relevance in the context of CSRCC. However, it has often been confounded with MA and SRCC[7]. In reality, only 16%-20% of all ‘linitis plastica’ cases involve SRCC[32]. In general, CSRCC is associated with poor differentiation: 51%-90% of CSRCCs are classified as poorly differentiated or undifferentiated[12,26,38,39]. Although the cut-off for CSRCC has been set at > 50% SRCs, Ogino et al[40] have stated that tumors with a SRC component less than 50% display molecular features that are similar to those that contain more than 50% of SRCs. This similarity seems to be of clinical importance since another study found that the dismal prognosis in patients with tumors containing > 50% of SRCs did not differ from that of patients with tumors that had less than 50% of SRCs[41]. As a consequence, it has been recommended that the pathology report should mention any SRC component, even minor, as this could be relevant for the subsequent treatment and prognosis. Additionally, Hartman et al[16] suggested taking into account whether the SRCs are either mucin-rich or -poor: Although most studies have demonstrated that CSRCC, in general, is associated with a high rate of lymphovascular invasion (LVI), Hartman et al[16] found that even after adjustment for stage, especially mucin-poor CSRCC is associated with a high degree of LVI, more advanced stages, and worse OS[8,16,21,42]. An overview of studies describing the rate of LVI invasion or molecular features is listed in Table 3.
Table 3 Overview of studies describing rate of lymphovascular invasion or molecular features.
Blood vessel invasion: 7.5% vs 22.5% vs 11.9%; LVI: 42.5% vs 2.5% vs 3.5% (P < 0.001); neural invasion: 17.5% vs 7.5% control group vs 4.7% CRC (P < 0.001)
Several molecular features have been identified to be responsible for the high infiltrative potential of CSRCC, resulting in high rates of LVI and lymph node- and peritoneal metastasis: First of all, the mucopolysaccharide produced by SRCC tends to inhibit discrimination by host immunocytes, resists encapsulation, and thus favors LVI and peri-intestinal infiltration[22,31]. Second, only 26%-39% of CSRCCs retain E-cadherin expression[42,43]. As E-cadherin plays an important role in cell-to-cell adhesion, an increased potential for invasion and metastasis is observed in its absence[22,33]. A retrospective study among 59 patients with CSRCC demonstrated that loss of E-cadherin expression was associated with significantly worse survival[41]. Finally, a higher activity of acid phosphatase and β-glucuronidase in CSRCC is associated with an increased disintegration of the fibrous tissues surrounding the tumor[31].
Several studies have found a significantly higher rate of microsatellite instability (MSI; 30-43%) in CSRCC, compared to OA[29,31]. An association between MSI and the more frequent right-side location of CSRCC has previously been suggested[33]. Parallel to the characteristics of MSI in OA, an association between MSI CSRCC and a more frequent right-sided location, larger tumor size, older age, and female gender has been demonstrated[21,44]. In contrast, however, to MSI characteristics in OA, the majority of recent studies were unable to identify MSI as a favorable prognostic factor for survival in CSRCC, even when adjusted for stage[21,27,44]. A BRAF mutation is identified in 22%-30% of CSRCCs and was associated with an impaired 5-year survival in the subgroup of microsatellite stable tumors[40,45]. In a study by Kakar et al[45], a BRAF mutation was found in 43% of MSI CSRCC tumors. In the same study, the authors hypothesized that the high rate of loss of heterozygosity observed in MSI CSRCC (80%) could counterbalance the potential beneficiary effect of MSI on survival. The presence of KRAS mutations in 52% of patients was not associated with any specific clinical feature or change in oncological outcome[45]. Two other studies, on the other hand, found a lower rate of KRAS-mutations in CSRCC (11.4%-36.4%) compared to OA (60%)[14,46]. Since a lower rate of KRAS mutations is presumably associated with a non-polypoid carcinoma etiology, as frequently observed in IBD-associated tumors, Sasaki et al[14] and Kim et al[47] suggested that the carcinogenesis in CRSCC is different from that of OA. The identification of IBD as a risk factor for CSRCC, as stated above, seems to support this hypothesis. Moreover, CSRCC has more molecular features (positivity for trefoil factor and MUC2, E-cadherin negativity, and Bcl-2 amplification) in common with SRCC of, for instance, the stomach than it has with OA[33]. In an attempt to synthesize the different molecular characteristics, one study found two distinct molecular profiles of CSRCC: An MSI/CIMP (CpG Island Methylator Phenotype)/BRAF-mutated/PD-L1+ hypermethylated genotype, which accounts for most of the tumors found in the proximal colon and a hypomethylated genotype which is more often found in the distal colon[48].
Finding the primary tumor in the case of an SRCC with diffuse PC can sometimes pose a challenge, especially if endoscopy is not conclusive. Immunohistochemical markers such as CK20 or CDX2 are not reliable to differentiate whether the primary SRCC is located in the lower or upper gastrointestinal (GI) tract in addition to the fact that these markers are frequently negative for SRCC. In this context, Ma et al[49] demonstrated that the special AT-rich sequence binding protein (SATB2) alone and in combination with CDX2 is more frequently expressed in SRCC of lower GI tract origin.
Metastatic pattern and prognosis
As already mentioned, CSRCC is more frequently diagnosed at an advanced stage (61%-100% stage III or IV) compared to MA or OA[10,13,15,30]. Ciarrocchi[4] found that local invasiveness was more frequent in patients with rectal tumors, while the rate of metastatic disease was higher in colon tumors. The extended local invasion is reflected by the higher rate of circumferential resection margin positivity (19%) in rectal SRCC compared to rectal tumors involving other histological types (4%)[50]. Given its histopathological features, CSRCC predominantly metastasizes to the peritoneum rather than the liver or lung, as is the case in OA. In stage IV CSRCC, 43%-86% of patients are affected by PC while liver metastases occur only in 5%-14% of cases[22,29,51-53]. Ovarian metastases are found in 4.8%-7.2% of cases[8,15]. Table 4 shows an overview of the literature reporting on survival outcomes for CSRCC. Although more favorable in comparison to gastric or pancreatic SRCC, the overall prognosis of CSRCC is still poor, with most studies reporting a 5-year OS rate between 0%-46% and a median survival between 8 and 48 mo[4,8,10,11,54]. CSS at 5 years varies from 11% to 52%[1,22,26]. Once again, Hartman et al[16] demonstrated the importance of differentiating between mucin-rich vs -poor CSRCC since mucin-rich tumors were associated with an OS of 66% whereas this was 19% in mucin-poor tumors. Most studies found that SRCC histology has a significantly increased risk of recurrence after curative treatment, with rates varying between 33% and 79%[7,22,29,33]. Chew et al[22] were unable to demonstrate any difference in locoregional or systemic recurrence rates between CSRCC and MA or OA. In the study by Ciarrocchi, after adjustment for confounding factors, rectal SRCC was found to have a worse prognosis compared to non-rectal SRCC (hazard ratio [HR] = 0.79)[4]. These findings, however, have to be interpreted with caution, since the SEER database on which the latter study was based did not include a standardization concerning adjuvant treatment for rectal cancer.
Table 4 Overview of articles reporting on survival outcomes for colorectal signet-ring cell carcinoma.
Relative survival: Colon IIIa: 0.81 vs 0.87 MA vs 0.86 OA; IIIb: 0.49 vs 0.66 MA vs 0.65 OA; IIIc: 0.21 vs 0.42 MA vs 0.45 OA; rectum IIIa: 0.91 vs 0.82 MA vs 0.86 OA; IIIb: 0.55 vs 0.56 MA vs 0.64 OA; IIIc: 0.3 vs 0.44 MA vs 0.48 OA
26.8% vs 58.1% MA (P < 0.0001) vs 62.9% OA (P < 0.0001)
IIIa: 68.3% vs 87.3% MC vs 83.8% OA; IIIb: 46% vs 64.3% MC (P = 0.0002) vs 63.6% OA (P <0.0001); IIIc: 19% vs 29.2% MC (P <0.0001) vs 30% OA (P <0.0001)
Historically, the question has been asked whether the worse prognosis of CSRCC is related to the advanced stage at the time of diagnosis or whether the tumor biology is inherently more aggressive[7]. Several studies evaluated this topic through stage-per-stage and multivariate analysis as well as using a propensity score matching technique. Although some authors found that SRCC histology was not an independent prognostic factor for survival, most studies including a larger number of patients found that CSRCC was associated with a worse stage per stage survival compared to MA and OA, especially in stage III disease[1,8,15,17,19,36]. In a study containing 78 patients with peritoneal metastasis from colorectal origin, SRCC was found to be independently associated with worse survival[55]. Ishihara et al[56] identified a proximal colonic CSRCC location as an independent prognostic factor for increased survival. This study, however, was not included in the qualitative synthesis of this review, since in their analysis, SRCC was grouped with poorly differentiated adenocarcinoma and MA.
Implications for therapeutic management
There are no specific guidelines for the treatment of CSRCC, other than those applicable for CRC in general. Surgery is considered the mainstay of treatment, but as expected in the context of advanced disease at the time of diagnosis, the rates of curative resection in CRSCC (21%-82%) are lower compared to those of other histological types of CRC[8,15,33]. Concerning early CRC, Song et al[25] found that SRC histology in the case of a pT1 tumor was associated with a significantly higher rate of lymph node metastasis compared to OA (35.5% vs 11.6%). In light of these results, the authors do not recommend local excision as a definitive surgical treatment in the case of SRCC histology[25]. The role of (neo-)adjuvant chemo- or radiotherapy for CSRCC has not been well studied. The majority of the less recent literature including databases going several decades back in time, as well as studies based on large national databases such as the SEER database, frequently suffer from incomplete data concerning (neo)-adjuvant treatment. In the context of higher rates of stage III disease, patients with CSRCC more frequently undergo (neo-)adjuvant therapy[18,19,22]. In a small study with 22 patients diagnosed with CSRCC, (neo-)adjuvant radio- or chemotherapy was not found to result in any survival benefit[20]. Hugen et al[17] and Belli et al[20] were among the first to evaluate the role of adjuvant chemotherapy in a larger cohort of 1972 patients with CSRCC. In this study, 51.6% of stage III patients were treated with adjuvant chemotherapy, which significantly improved survival (5-year-relative survival: 52%) compared to the group of patients who did not receive adjuvant treatment (5-year-relative survival: 30%). Moreover, in a multivariate analysis, the added value of adjuvant chemotherapy in CSRCC was comparable to that of OA[17]. For rectal SRCC specifically, Jayanand et al[57] found that SRCC histology was, surprisingly, a positive predictive factor for a pathological complete response after neoadjuvant chemoradiation. Although this study contained only 6 patients with SRC histology out of 248 rectal cancer patients, their results seem to be confirmed by Tamhankar et al[51] who reported a relatively high pathological complete response rate of 21.6% after neo-adjuvant chemoradiation in a group of 37 rectal SRCC patients. Two studies evaluating the role of (preoperative) radiotherapy in rectal SRCC, found an improved CSS compared to surgery alone in stage III, but not stage II, disease[11,50].
The value of surgery in metastatic CSRCC has been investigated by Fu et al[58] who compared the surgical and oncological outcomes of 94 patients with synchronous resectable metastatic CRSCC to those of 3474 patients without SRC histology. The authors found that SRCC histology was associated with a significantly higher rate of invalid surgery (defined as disease recurrence within 6 mo after surgery) compared to non-SRC histology (24.5% vs 13%, P = 0.001). Because of a frequent peritoneal metastatic pattern associated with CSRCC, a high level of difficulty associated with curative surgery in these patients has been hypothesized as one of the reasons for the increased rate of invalid surgery. As expected, patients with CSRCC in this study were affected by a significantly poorer OS (HR = 1.445, 95% confidence interval: 1.156-1.808, P = 0.001)[58]. The authors suggested that in light of these findings, the selection of patients with resectable metastatic CSRCC for surgical therapy should be highly individualized since the added value of surgery in this context seems limited.
Because PC is frequently diagnosed early on in the process of CSRCC and is less prone to the effect of systemic chemotherapy, several studies have evaluated the value of intraperitoneal chemotherapy for PC in CSRCC[38,53,59]. Parallel to the conclusion of Fu et al[58], van Oudheusden et al[59] recommended that cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) should only be proposed to patients with CSRCC and PC if no other relative contra-indications such as extensive peritoneal disease, liver metastases, or poor general condition, are present, since it is questionable whether the limited survival benefit of CRS with HIPEC outweighs the associated reduction in quality of life. Although a peritoneal cancer index of < 20 was respected and both groups were comparable regarding the rate of neoadjuvant chemotherapy, the authors found that in patients with PC from CSRCC, the median survival after CRS and HIPEC was only 14.1 mo vs 35.1 mo in non-CSRCC patients[59]. It should be noted, however, that in the CSRCC group, a macroscopically complete cytoreduction was obtained in 87.5% of patients vs 97.2% in the non-CSRCC group (P = 0.04). Moreover, groups were not comparable regarding the rate of N2 stage disease (62.5% CSRCC vs 36.1% non-CSRCC, P = 0.04). Among 385 patients with CSRCC and peritoneal metastases, Simkens et al[38] demonstrated that CRS with HIPEC resulted in an absolute median survival benefit of 18 mo compared to supportive care only, with an additional survival benefit of supplementary systemic chemotherapy. Interestingly, the same study showed that in patients with CSRCC and PC with concomitant liver or lung metastases, systemic chemotherapy did not result in any survival benefit compared to best supportive care. Finally, in a study of 33 patients with SRCC and PC, Chua et al[53] found that CRS with HIPEC in patients with colonic SRCC resulted in a median survival of 13 mo compared to 18 mo (P = 0.75) in patients who received systemic chemotherapy only. In 18 patients with appendiceal SRCC on the other hand, CRS and HIPEC were associated with a median survival of 27 mo vs 15 mo in patients treated with systemic therapy only (P = 0.12). These findings led to the conclusion that a clear distinction between appendiceal SRCC and colorectal SRCC should be made, as this could have a significant influence on the potential benefits of CRS and HIPEC and thus on the optimal treatment strategy that should be implemented[53].
Few to no clinical studies so far have specifically focused on potential immunological, molecular, or genetic therapeutic agents for CSRCC. Based on its distinct molecular characteristics, some potential therapeutic pathways have been hypothesized[60]. Because a significant amount of CSRCC is MSI-H, the benefit of immune checkpoint inhibitors should be investigated[29,31,60]. However, since MSI in CSRCC does not appear to be associated with a similar prognostic benefit as it is in OA, the question remains how this could affect the mechanism of action and potential benefit of these checkpoint inhibitors. Since one study demonstrated a relatively high incidence of BRAF mutations in CSRCC, the use of a BRAF inhibitor could be evaluated as a potential therapeutic agent[60]. A major phase II study evaluating the interest of several combinations of BRAF, EGFR, and MEK inhibitors in the treatment of CRC (NCT01750918) reached study completion recently[48,60]. A subanalysis in function of the different histological subtypes could answer some questions concerning the role of these inhibitors in the treatment of CSRCC. Interestingly, Alvi et al[48] also found that 25% of CSRCCs are characterized by a KIT actionable mutation, which could as such potentially benefit from a KIT inhibitor (imatinib).
Regarding follow-up of patients with CSRCC, most studies agree that in light of the demographic characteristics and the aggressive biological behavior of CSRCC, a more frequent follow-up is warranted compared to OA, especially to detect recurrent peritoneal disease at an early stage[33].
DISCUSSION
The incidence of CSRCC has risen in the past decades, although it remains a rare histological subtype of CRC. Patients with CSRCC more frequently present at a younger age, with tumors predominantly located in the right colon and rectum. CSRCC is often characterized by locally advanced or even metastatic disease at the time of diagnosis. In contrast to OA, and facilitated by its biological and molecular features, CSRCC predominantly metastasizes into the peritoneal cavity. As such, oncological outcomes for CSRCC are very poor with a 5-year OS between 0% and 46%. According to the latest WHO definition, the amount of SRCs in the histological specimen should be mentioned in the pathology report since even a minor SRC component appears to entail prognostic and therapeutic implications similar to those of well-defined CSRCC. Furthermore, the pathological analysis should specify the presence of mucin-rich or -poor SRCC, as the latter is characterized by significantly worse biological behavior and survival. CSRCCs are often MSI-H, although this is not translated into improved survival as is the case in OA. As such, the role of immunological therapeutic agents in the case of MSI-H CSRCC remains unclear but will be a topic in future studies. Adjuvant chemotherapy and neo-adjuvant chemoradiation are found to offer improved long-term outcomes for CSRCC. For patients with PC, most authors suggest reserving CRS and HIPEC for well-selected patients in whom the reduction in quality of life, associated with this therapeutic option, does not outweigh the survival benefit, which was proven to be limited. In light of its aggressive biological behavior and metastatic pattern, a more frequent follow-up after surgical therapy is warranted, with the focus on early detection of peritoneal recurrent disease.
CONCLUSION
CSRCC is a rare clinical entity most often characterized by young age and advanced disease at presentation. As such, diagnostic modalities and therapeutic approach should be tailored accordingly.
ARTICLE HIGHLIGHTS
Research background
Colorectal signet-ring cell carcinoma (CSRCC) is a rare clinical entity which accounts for approximately 1% of all colorectal cancers with, however, a rising incidence with relatively young age at presentation and associated dismal prognosis.
Research motivation
Although multiple studies concerning this specific topic have been published in the past decades, the pathogenesis, associated risk factors, and potential implications on treatment are still poorly understood. Besides the low incidence, historically confusing histological criteria have resulted in confusing data. This highlights the actual interest to synthesize the known literature regarding CSRCC.
Research objectives
The aim of this systematic review was to provide an updated overview of risk factors, prognosis, and management of CSRCC.
Research methods
A literature search in the MEDLINE/PubMed database was conducted with the following search terms used: ‘Signet-ring cell carcinoma’ and ‘colorectal’. Studies in English language, published after January 1980, were included. Studies included in the qualitative synthesis were evaluated for content concerning epidemiology, risk factors, and clinical, diagnostic, histological, and molecular features, as well as metastatic pattern and therapeutic management.
Research results
In total, 67 articles were included for qualitative analysis, of which 54 were eligible for detailed data extraction. CSRCC has a reported incidence between 0.1%-2.4% and frequently presents with advanced disease stage at the time of diagnosis. CSRCC is associated with an impaired overall survival (5-year OS: 0%-46%) and a worse stage-corrected outcome compared to mucinous and not otherwise specified adenocarcinoma. Surgery is the mainstay of treatment, although the rates of curative resection in CSRCC (21%-82%) are lower compared to those of other histological types. In case of peritoneal metastasis, cytoreductive surgery with hyperthermic intraperitoneal chemotherapy should only be proposed in selected patients.
Research conclusions
The incidence of CSRCC has risen in the past decades, although it remains a rare histological subtype of CRC. Patients with CSRCC more frequently present at a younger age, with tumors predominantly located in the right colon and rectum. CSRCC is often characterized by locally advanced or even metastatic disease at the time of diagnosis. CSRCC predominantly metastasizes into the peritoneal cavity. As such, oncological outcomes for CSRCC are very poor with a 5-year OS between 0% and 46%.
Research perspectives
In light of its aggressive biological behavior and metastatic pattern, a more frequent follow-up after surgical therapy is warranted, with the focus on early detection of peritoneal recurrent disease. The role of immunological therapeutic agents in the case of MSI-H CSRCC remains unclear but will be a topic in future studies.
Footnotes
Provenance and peer review: Invited article; Externally peer reviewed.
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