Primary Signet-Ring-Cell Carcinoma in the Colorectum: A Case-Based Literature Review

Abstract

Primary colorectal signet-ring-cell carcinoma of the colon and rectum (PSRCCR) is an extremely rare subtype of mucinous adenocarcinoma with a reported rate of less than 1%. This low rate is mainly because it is generally diagnosed at advanced stages. The most common stage at which it is diagnosed for the first time is III or IV, with a lower median survival than other histological subtypes. To diagnose PSRCCR of the colon, at least half of the tumor must be consistent with a signet-ring-cell pattern. This review aims to provide a comprehensive overview of PSRCCR by synthesizing the existing literature and clinical data. Our objective was to elucidate the clinical features, diagnostic challenges, histopathological characteristics, molecular alterations, treatment modalities, and prognostic factors associated with this carcinoma. Additionally, we highlighted the significance of early detection, accurate diagnosis, and personalized therapeutic approaches in improving outcomes for patients with this challenging malignancy. By presenting a case report on the topic, we aimed to enhance understanding among clinicians, pathologists, and researchers, ultimately contributing to optimized management strategies and improved patient care for PSRCCR.

1. Introduction

Colorectal cancer (CRC) remains the third most common cancer worldwide and the fourth most common cause of death related to cancer. Even though widely accepted screening programs, including tumor markers and colonoscopy, have helped in the decline of the overall incidence of colorectal cancer over the past few years, there are still many patients diagnosed at a later stage of the disease [1].

The disease is more common in women than in men [2]. Overall, CRC has decreased by almost 3% each year. Still, the clinical data show that the incidence in patients over 50 years has increased by about 1.5–1.6% [3,4].

As the data in the literature are quite discordant about the pathological features, a study attempted to resolve the controversies by examining 34 cases of primary colorectal SRCC [5]. They found that different applied diagnostic criteria could explain the differences in the literature.

In the late 1990s, the World Health Organization developed a histological classification of colorectal cancers [6]. The following different subtypes were introduced—classical adenocarcinomas (ACs), which account for the large majority of cases; mucinous adenocarcinomas (MACs); signet-ring-cell carcinomas (SRCCs); and other less common types such as small-cell carcinoma, squamous-cell carcinoma, medullary carcinoma, undifferentiated carcinoma, and primary signet-ring-cell carcinoma of the colon and rectum (PSRCCR). The classification is presented in Figure 1.

Patients with colorectal cancer exhibit symptoms of abdominal pain, rectal bleeding, weight loss, diarrhea, constipation, blood in the stool, cramping, weakness, episodes of vomiting, etc. [7,8]. In some cases, additional symptoms are also manifested, which are not characteristic of older patients [9,10,11].

The histological classification complements the widely accepted TNM staging system, adding value to risk assessment and patient prognosis [12]. It is worth mentioning that colorectal carcinogenesis can occur via the serrated pathway and the adenoma-to-carcinoma sequence. Jass et al. [13] identified serrated carcinomas in 1992, and the underlying genetic and epigenetic changes have since been characterized. It was shown that they contain mutations in BRAF, KRAS, PIK3CA, TP53, and APC, where microsatellite instability is also considered a crucial process in cancer development [14]. In addition to the genetic factors, the other factors involved are inflammation (such as inflammatory bowel disease), young age, and male sex [15]. No data are available for the association of PSRCCR with alcohol consumption and smoking, as there is an established connection between these risk factors and CRC. However, SRCCs represent a distinct entity in CRCs, among which PSRCCR is one of the rarest.

Our literature review used various databases to identify similar cases that have been published in the last 10 years. We focused on case reports and studies on signet-ring-cell carcinomas (SRCCs) and primary sigmoid ring cell carcinoma (PSRCCR). We aimed to gather the available literature on the problem, including clinical case reports, epidemiologic data, survival analyses, experimental studies, clinical features, prognostic factors, treatment outcomes, and challenges associated with this rare and aggressive form of colorectal cancer.

In addition, we examined in detail PSRCCR of the colon, a rare and aggressive subtype of colorectal cancer. By synthesizing the existing literature and clinical data and providing our experience in the field, our objective was to elucidate the clinical features, diagnostic challenges, histopathological characteristics, molecular alterations, treatment modalities, and prognostic factors associated with this carcinoma.

2. Literature Review on Signet-Ring-Cell Carcinoma (SRCC) and Primary Colorectal Signet-Ring-Cell Carcinoma (PSRCCR)

2.1. Search Strategy

To comprehensively review the topic, we employed an extensive search strategy using various databases, including PubMed, Medline, Scopus, Web of Science, and Google Scholar. Our search strategy aimed to identify the relevant literature on primary signet-ring-cell carcinoma (PSRCCR) in the colon and rectum, focusing on case reports, survival rates, and studies related to this rare and challenging form of colorectal cancer.

We combined medical subject headings (MeSHs) and free-text keywords to enhance the search’s comprehensiveness. The key terms included the following by using Boolean operators: [“primary signet-ring cell carcinoma” OR “PSRCCR” OR “colorectal cancer” OR “colorectal neoplasms” OR “colorectal tumors”] AND [“mucinous adenocarcinoma” OR “mucin-producing adenocarcinoma” OR “case report” OR “case study” OR “survival rate” OR “prognostic factors” OR “treatment outcomes”] AND [“literature review” OR “systematic review” OR “meta-analysis” OR “clinical review].

In addition to electronic searches, we manually scanned the reference lists of the retrieved articles and relevant review papers to identify any additional studies that may contribute valuable insights to our review. We confined our search from January 1900 to March 2024. This comprehensive search strategy aimed to gather a wide range of the literature, including clinical case reports, epidemiological data, survival analyses, and experimental studies related to PSRCCR, as well as clinical characteristics, prognostic factors, treatment outcomes, and challenges associated with this rare and aggressive form of colorectal cancer.

2.2. Epidemiology of PSRCCR

The PSRCCR tumor was first described in 1951, with an estimated total incidence of 0.1–2.4% [1,16,17]. Therefore, according to the literature, colorectal signet-ring-cell carcinoma (SRCC) is uncommon. It comprises only 0.1–1% of all colorectal neoplasms, with no difference between Western and Eastern countries [11,18]. PSRCCR is a scarce variety of tumors with characteristically histologic features. The largest number of described cases of this type of neoplasia are adult patients [19,20,21], with a mean age of 54.3 years at diagnosis. According to the literature, patients with poorly differentiated adenocarcinoma with intracellular mucin production (signet-ring-cell type) and mucinous adenocarcinomas metastasize primarily to the peritoneum and ovary (75 and 56% of metastatic cases, respectively) and rarely to the liver/lung. In contrast, colorectal adenocarcinoma without mucinous or signet-ring components mainly affects the liver/lungs and rarely the peritoneum/ovaries (12.5%) [22]. These patients usually have a dismal prognosis [17,23,24], mainly because of delayed diagnosis. This is the case, particularly in our patient case described below.

Usually, the tumor is found in most patients in the right colon. At the time of primary diagnosis, the patients have already demonstrated more advanced clinical stages, lymphovascular invasion, and lymph node metastases [17,19]. Compared with signet-ring-cell carcinomas, mucinous adenocarcinomas were characterized by less frequent vascular invasion and lymph node metastasis [25].

2.3. Histopathology

PSRCCR tumor cells typically contain mucin that pushes the nucleus to the periphery, giving the distinctive signet-ring morphology. The main group of SRCCs represents a highly malignant adenocarcinoma with an aggressive course of disease. The name of SRCC is related to the resemblance to signet rings, which result from the formation of large mucin vacuoles that displace the nucleus to the cell’s periphery. SRCC is defined by the presence of >50% of signet cells [18]. Macroscopically, the SRCC most often appears as a linitis plastica—a diffuse thickening of the bowel wall.

SRCC is commonly found in the stomach (95%) but can also be seen in the colon, rectum, ovary, peritoneum, breast, and gallbladder [1,16,26]. More than 90% of colorectal carcinomas are adenocarcinomas originating from epithelial cells of the colorectal mucosa, followed by other rarer types of colorectal carcinomas, including neuroendocrine, squamous, adenosquamous, spindle cells, and undifferentiated carcinomas [27]. Classical adenocarcinoma is characterized by the formation of glands, which is the basis of the histological classification of the tumor. In well-differentiated adenocarcinoma > 90% of the tumor is composed of acinar (glandular) structures; in moderately differentiated adenocarcinoma, the acinar structures are in 50–90%, while poorly differentiated adenocarcinoma is mostly solid, and acinar structures are found <50% [17,28]. In practice, about 70% of colorectal adenocarcinomas are diagnosed primarily as moderately differentiated. Only 10 and 20% of cases are revealed to be well and poorly differentiated, respectively [28].

In addition, establishing the diagnosis does not present a particular difficulty to pathologists; however, additional immunohistological (IHC) examination is required in a small part of cases. The IHC includes a panel of several antibodies, with positive expression detected in CK20, CDX2, MUC2, and MUC5AC, and negative expression for CK7. The epithelial marker CK20 is usually positive in colon adenocarcinomas, especially at an early stage, but is less sensitive for poorly differentiated colon carcinomas. In contrast, positive expression in mucinous colon adenocarcinomas is found in about 79% of cases [29,30,31]. CDX2, also called caudal-related homeobox gene 2, caudal type homeobox transcription factor 2, is a specific marker of GI origin for adenocarcinomas and is less specific if the adenocarcinoma is poorly differentiated [32]. In line with this, MUC2 is an epithelial mucin expressed in intestinal goblet cells and airway epithelium. MUC5AC, also known as MUC5, in the majority of cases, is positive in mucinous adenocarcinomas of the ovary and diffuse-type gastric carcinomas (83%) [33].

From this perspective, it is clear that these antibodies are not highly specific for SRCC of the colon, but they are positive for ordinary adenocarcinoma of the colon. This is precisely the reason why the diagnosis is placed based on the histological characteristics of the tumor. At the same time, IHC is used only in cases of metastases with an unclear primary focus.

2.4. Genetics

SRCC may be associated with genetic mutations in the CDH 1 gene, which is responsible for maintaining E-cadherin integrity [34]. Mutations in this gene cause a loss of cohesiveness of the epithelial lining of the transformed cells, increasing the chances of early metastasis. Specific molecular characteristics of the adenocarcinoma may help to stratify and select patients who might benefit from a certain therapy. Currently, there are only three therapeutically relevant, routinely tested biomarkers in adenocarcinoma (HER 2 expression, PDL1 expression, and deficient mismatch repair) [35].

Other molecular signatures of SRCC are linked to an increased frequency of BRAF and CIMP (CpG island methylator phenotype) mutations, decreased expression of p16 and p53, and lower prevalence of KRAS and NRAS mutations [36]. However, the E-cadherin adhesion protein, which forms a compound with catenin proteins to preserve the polarity of epithelial cells, has been found to be substantially less expressed in SRCC. Because there is less expression of E-cadherin molecules, the cells have acquired motility, contributing to the invasive phenotype of SRCC [37].

In this instance, no mutations in the KRAS, NRAS, or BRAF genes were found. The molecular underpinnings of colorectal SRCC and non-signet-ring conventional colorectal adenocarcinoma differ in that the former is typically richer in SRCC-specific genes that lead to epithelial–mesenchymal transition (EMT) and stem cell upregulation, which enhances the invasiveness of such tumors, according to a recent whole-exome and RNA sequencing study [38].

Korphaisarn et al. demonstrated that SRCC contains specific molecular characteristics, including low KRAS, PIK3CA, and APC mutations [39]. However, more research into activation pathways and potential treatment targets is required, especially regarding its unique clinical features and association with early age of disease onset.

In Figure 2, we present the mechanism of cellular changes during the development of signet-ring-cell carcinoma of the stomach.

2.5. Diagnosis

The diagnostic methods for signet-ring colorectal cancer are those used for conventional adenocarcinomas, with upper or lower gastrointestinal endoscopy, barium enema, and computed tomography [40]. The above methods may be helpful in differentiating SRCC from Crohn’s disease. Texture analysis is a novel method assessing the heterogeneity in the acquired CT images and may be valuable as a new non-invasive imaging biomarker. Until now, this type of analysis has been applied in various tumors, including colorectal cancer and lung cancer, as a promising tool for tumor treatment response and disease prognosis evaluation [40]. The described method analyzes the distribution and relationship of voxel gray levels, which accounts for tumor heterogeneity. A study compared the CT imaging texture features between patients with SRCC and adenocarcinoma and found promising data that may be used as a foundation for future research [41]. Importantly, due to its advanced and aggressive course of disease, the first manifestation of SRCC may be an emergent laparotomy if the tumor obstructs the bowels and causes an acute surgical abdomen [42].

Weng et al., in their experience of 18 patients with PSRCCR identified from among 11,515 patients with CRC, revealed that most patients with non-SRCC CRC were diagnosed by colonoscopy. In contrast, over one-third of patients with PSRCCR were diagnosed with either surgery or non-colon site biopsy (p < 0.001) [43]. Furthermore, patients with PSRCCR had higher levels of CEA and lower levels of albumin than patients with non-SRCC [43].

PSRCCR is usually associated with higher lymphovascular invasion, distant metastases, and more malignant biological behavior than ordinary colorectal adenocarcinoma. Meanwhile, signet-ring-cell carcinoma strongly predicts poor overall survival. All studies reported that delayed diagnosis reflects the poor outcomes of the patients along with poor prognosis. Compared to non-SRCC colorectal cancer, signet-cell adenocarcinoma occurs at a younger age [44]. According to the literature, patients with SRCC were more frequently diagnosed at an advanced stage (75.2–91%) [45] than patients with colon adenocarcinoma (43.6–48%) and, therefore, had a poorer prognosis.

Interestingly, despite the advanced technology methods and detailed diagnostic workup, often, the primary site of origin for about 3–5% of metastatic tumors could not be determined. The most commonly reported metastasis of unknown primary origin is with characteristics of adenocarcinoma [46].

2.6. Clinical Course and Prognosis

PSRCCR has an aggressive course, and most cases are diagnosed at advanced stages. The symptoms of SRCC may include but are not limited to body weight loss, changes in the rhythm and consistency of defecation, abdominal or lower back pain, and bloody stool [47]. Unfortunately, symptoms usually appear at a late stage. This underlines the importance of the accurate diagnosis of the specific type of colorectal cancer and patients’ risk stratification.

A study assessing the long-term clinical outcomes of patients with colorectal cancer reports a worse five-year survival for SRCC (58.1%) than for mucinous or adenocarcinoma [44]. Furthermore, when evaluating outcomes based on tumor location, SRCC subtypes located in the colon had significantly better survival than those in the rectum.

In their analysis, Makino et al., who included 154 patients, revealed that the 5-year survival rate of patients with T2 disease was 75.0%. In contrast, patients with T3 or T4 had 5.1% and 0% survival rates, respectively [21]. In addition, Sung et al. reported that a higher TNM stage and the T4 stage are independent predictors of poor outcomes. Their observations strongly suggest that pathologists should document the percentage of signet-ring-cell components in colorectal mucinous adenocarcinomas. This is because of the biological behavior of signet-ring-cell adenocarcinomas, which differs from that of pure mucinous adenocarcinoma without signet-ring-cell components [25].

Weng et al. demonstrated that poor differentiation grade, lymphovascular invasion, advanced cancer stage, high CEA level, and histological SRCC subtype were all linked to higher death rates (all p < 0.05) in the univariable analysis of overall survival in all patients with CRC [43]. The results of an additional multivariate analysis using an adjusted Cox proportional hazard model showed that the histological SRCC subtype (HR, 8.333; 95% CI, 1.42–50; p = 0.005) and CEA level (HR, 1.003; 95% CI, 1.000–1.005; p = 0.03) were independent predictors of overall survival [43]. Weng et al. [43] also confirmed the poor survival rate estimated by other authors. Patients with PSRCCR had an estimated survival time of 26.9 months, significantly less than those without SRCC (162.7 months). Using the Cox proportional hazard regression model, the SRCC subtype and high CEA were found to be independent predictors of overall survival. Patients with PSRCCR were more likely to experience lymphovascular invasion, poorly differentiated carcinoma, invasion of the visceral peritoneum, lymph node, and distant metastases as compared to those without SRCC [43].

This suggested that PSRCCR was acting in a more hostile manner. The study conducted by Huang et al. [48] found that patients under the age of 35 had worse cancer-specific survival rate than those above the age of 35. The 5-year cancer-specific survival rates for these patient groups were 31.1% and 54.9%, respectively. Five of the eighteen patients in their series had an age below 35. In this cohort, the average survival duration was 20.6 months. There was no discernible difference in the survival time between these two groups. However, due to the small number of cases, care should be taken when interpreting the data [48].

2.7. Treatment Approaches

As for the therapeutic approach, surgical excision of the tumor formation is almost always recommended at different therapeutic stages. When SRCC is diagnosed, radical surgical resection and systemic preoperative radiotherapeutic treatment should be performed [49]. The most commonly used technique is right hemicolectomy, which involves resectioning the primary tumor and removing the regional lymph nodes.

Poor prognosis after radical surgery for colorectal SRCC remains a significant clinical problem when compared with the prognosis after resection for adenocarcinoma. A retrospective study of 22 patients with signet-ring colorectal carcinoma reports mean overall survival and mean progression-free survival times to be 33.3 ± 7.1 months (95% CI, 19.4–47.2 months) and 11.8 ± 3.5 months (95% CI, 4.9–18.7 months) for curative and palliative resections, respectively [23].

Even with the advances in current chemotherapy and targeted therapy, these therapies appear to have a limited effect in improving the survival of patients with PSRCCR [50].

2.8. Pharmacological Treatments

The treatment for PSRCCR mainly involves surgical resection, neoadjuvant radiotherapy, and adjuvant radio-chemotherapy [51].

Cetuximab and bevacizumab were prescribed as target therapies for PSRCCR, with bevacizumab administered to all patients with non-SRCC CRC. Patients with non-SRCC had a better outcome than patients with PSRCCR, regardless of the specific therapy chosen. However, target therapy, whether treated or untreated, did not increase the overall survival of patients with PSRCCR [43]. Therefore, for patients with PSRCCR, novel therapy, such as chemotherapy or target therapy, remains an unmet need [52].

A comprehensive table of published similar cases follows (

Table 1. Case reports describing signet-ring-cell carcinomas (SRCCs).

Authors [Ref.]	Patient Description	Clinical Presentation	Histopathology	Treatment and Follow-Up
Farraj et al., 2019 [53]	19-year-old male, Caucasian, non-smoker	Acute epigastric pain, radiating to the right upper quadrant, recurrent episodes of projectile and non-bloody vomiting, watery non-bloody diarrhea for 2 months.	Poorly differentiated signet-ring-cell adenocarcinoma of the ascending colon with metastasis to the omentum and involvement of the pericolonic fat; stage IV (T4a N0 M1, with peritoneal seeding). No mutations detected in KRAS, NRAS, and BRAF genes.	Right hemicolectomy followed by an ileotransverse anastomosis. 11 cycles bevacizumab and oxaliplatin with capecitabine. On one-year follow-up, a PET scan revealed complete remission of the tumor.
Mora-Guzman et al., 2018 [16]	89-year-old woman with no family history of colon cancer	3-month anorexia, weight loss, and abdominal pain.	Signet-ring-cell adenocarcinoma—poorly differentiated adenocarcinoma of the colon with >50% signet-ring-cell pattern with multiple tumor nodules and countless lymphatic embolisms, disperse tumor implants, and stage T4aN2bM1b (2010 ICC/AJCC TNM classification, 7th Edition). Immunohistochemistry: microsatellite instability in the PMS-2 and MLH-1 genes.	Right oncologic hemicolectomy. Adjuvant oncologic treatment rejected.
Mora-Guzman et al., 2018 [16]	38-year-old man with no family history of colon cancer, HIV positive	10-day abdominal pain, nausea, vomiting, absence of bowel transit, and great abdominal distension.	Poorly differentiated adenocarcinoma of the colon with >50% signet-ring cells, multiple metastatic peritoneal implants, lymph node conglomerates, and stage T4aN2bM1b. Immunohistochemistry showed microsatellite instability in the PMS-2 and MLH-1 genes and mutated KRAS gene.	Emergency right hemicolectomy. Palliative chemotherapy was decided upon.
Chen et al., 2023 [54]	41-year-old man	Bright-red blood per rectum caused by ulcerating rectosigmoid stricture.	Metastatic poorly cohesive signet-ring cells. Immunostains revealed neoplastic cells strongly and diffusely positive for CDX2 and cytokeratin 20 while negative for cytokeratin 7, confirming the colorectal origin of the cancer. Immunostains for neuroendocrine markers (synaptophysin and chromogranin)—negative.	After the small bowel obstruction improved with conservative management, the patient was discharged with outpatient oncology follow-up for palliative chemotherapy.
Gaskin et al., 2022 [55]	68-year-old male	Intermittent periumbilical pain for two days, no symptoms of abdominal obstruction.	Mucinous adenocarcinoma: pT3 N0 Mx signet-ring-cell carcinoma; no evidence of lymphovascular or perineural invasion. Immunohistochemistry: proficiency for all MMR proteins. Absence of KRAS mutation in codons 12, 13, 59, 61, 117, and 146.	Anterior resection with anastomosis; patient referred to oncology for continued care.
Seog et al., 2022 [56]	57-year-old male with a past medical history of cerebral palsy, autism, mental disability, and a 25-year history of Crohn’s disease with perirectal abscesses	Chronic rectal pain secondary to numerous perirectal abscesses drained 3 months prior; episodes of hematochezia during the admission.	Cytokeratin (CK) 7 positive, CK20 positive, and SATB2 positive. The tumor was positive for hMLH1, hMSH2, hMSH6, and PMS2. T3N2 disease.	Chemotherapy with folinic acid (leucovorin)–fluorouracil–oxaliplatin (mFOLFOX6) and then considering surgical resection and hospice care.
Marone et al., 2012 [57]	17-year-old male child	One month of progressive abdominal pain, right-sided, aggravated by eating and playing sports.	Signet-ring-cell carcinoma, T4N2M1.	Right colon resection with ileocolic anastomosis followed by 20 cycles of FOLFOX-6. One year later, presented with symptoms and signs of bowel obstruction, underwent diagnostic laparoscopy and debulking—passed away 1 week after the debulking procedure.
Anas et al., 2022 [58]	37-year-old man	At the emergency department with bowel obstruction and altered general condition.	Primary signet-ring-cell carcinoma of the cecum.	Right ileo-colectomy and ileocolostomy. In good health after six months of follow-up. After completing the chemotherapy, the patient was scheduled for a colonoscopy and reversal of colostomy.
Park et al., 2015 [59]	36-year-old female	New-onset progressive right-lower-quadrant pain without any significant past medical or family history.	pT3, pN0, pMx-stage IIA; microsatellite instability testing showed the preservation of MLH1, PMS2, MSH2, and MSH6 proteins by IHC and PCR.	Right hemicolectomy plus adjuvant fluropyrimidine (5-FU)-based therapy with the single agent capecitabine for 6 months, disease free for approximately 18 months.
Pamukçu et al., 2013 [60]	21-year-old boy	Abdominal pain at the emergency center.	Signet-ring-cell carcinoma of the sigmoid colon.	The patient was accepted as inoperable with an advanced stage and underwent a palliative colostomy. The FOLFOX regimen included 5 fluorouracil, calcium folinate, oxaliplatin, and bevacizumab (FOLFOX + bevacizumab), which was started with the diagnosis of metastatic colon cancer.

).

3. Case Presentation

The presented case concerns a 69-year-old woman with an uneventful previous medical history. The background of the patient and her parental and sibling histories were unavailable. She was admitted to the surgery department with progressive pains in the abdomen, accompanied by nausea and general weakness, which started a few days prior to her visit.

Physical examination revealed a blood pressure of 150/90 mm Hg and a heart rate of 108 beats per minute. The Blumberg sign was found to be positive. Blood test examinations showed leukocytosis and low hemoglobin levels. Native X-ray of the abdominal area showed no evidence of air–fluid levels of free gas under the diaphragm domes. Emergency surgery was performed because of acute appendicitis, and the acute abdomen was clinically suspected. The subsequent operation detected irregular thickening of the cecum with complete obstruction of the colon and pericecal fat infiltration. A right hemicolectomy with lymphadenectomy was performed.

Histological analysis of the resected tissues was performed using the automatic tissue processor “DIAPATHEN ISO 9001:2000”, and 4–5 μm formalin-fixed, paraffin-embedded tissue sections underwent routine staining with hematoxylin–eosin (H&E). A complete morphological examination of the material revealed, in over 50% of the tumor population, a diffuse tissue proliferation of signet-ring cells with intracellular mucin that displaced the nucleus to the periphery. Pools of extracellular mucin were present in the remainder of the tumor tissue. The tumor invaded the lymphatic vessels and the visceral peritoneum. These histological features give grounds for establishing the diagnosis of invasive, poorly differentiated PSRCCR of the ileocecal junction stage pT4a, N1, M0 (AJCC 7th edition TNM classification).

In Figure 3, we present the histological imaging of the patient, visualizing the poorly differentiated colorectal adenocarcinoma, where the signet-ring-cell pattern is presented in more than 50% of the tumors with multiple lymphatic embolisms. Additional histological images of the poorly differentiated signet-ring-cell carcinoma of the colon with abundant extracellular mucin are seen in Figure 4.

Our patient presented with no typical CRC symptoms, such as blood in stools, unintentional weight loss, and changes in bowel habits [61], but severe abdominal pain and general weakness. Additionally, our case and a few other cases of SRCC did not adopt the usual presentation of CRC and instead mainly involved episodes of general weakness and abdominal pain [9,10,11]. Our patient was also not a young adult, being diagnosed with SRCC at the age of 69. The patient did not undergo extended examination, such as a CT colonoscopy with biopsy at the time of hospital admission, due to the emergency and need for surgery (for acute appendicitis). After the appendectomy and surgical resection of the tumor, the patient recovered well and underwent one course of adjunct chemotherapy as per recommendations according to the improvement of survival rate and did not manage to take more standard-for-the-condition chemotherapeutic regimens [62] on account of being deceased.

4. Discussion

Our case of PSRCCR of the ileocecal junction in a 69-year-old woman, stage pT4a, N1, M0 (AJCC 7th edition TNM classification) demonstrated that, when neoplasia with a morphological feature of signet-ring-cell carcinoma is detected, clinical and/or immunohistochemical exclusion of the possibility of metastatic spread of the primary tumor in the stomach is mandatory.

The therapeutic landscape for PSRCCR in the colorectum faces several constraints that limit the effectiveness and availability of treatments. One major constraint is the aggressive nature and rarity of PSRCCR, making it difficult to develop standardized treatment protocols [62]. The heterogeneity of the disease, with its varying degrees of progression and response to treatment, necessitates personalized treatment regimens that are not always feasible with current therapies. Additionally, the long-term safety and efficacy of many chemotherapeutic and targeted agents remain uncertain, constraining their widespread use [62]. Financial constraints also play a significant role, as advanced therapies, including novel targeted treatments and immunotherapies, are often prohibitively expensive, limiting access for many patients.

Additionally, several challenges hinder the effective management of PSRCCRs. Early and accurate diagnosis is a primary challenge, as symptoms such as abdominal pain, weight loss, and bowel changes are non-specific and can overlap with other conditions, leading to a delayed diagnosis or a misdiagnosis [7]. Another significant challenge is the limited availability of effective biomarkers for predicting disease progression and treatment response, complicating clinical decision-making. The side effects and potential toxicities associated with the long-term use of aggressive chemotherapy regimens pose additional challenges, requiring careful monitoring and often leading to the discontinuation of treatment [61]. Furthermore, the complexity of conducting large-scale, multicenter clinical trials in a relatively rare and aggressive disease like PSRCCR limits the generation of robust clinical evidence to guide treatment protocols.

And, finally, despite these constraints and challenges, the prospects for managing PSRCCR appear promising. Molecular and genetic research advances are paving the way for personalized-medicine approaches, which could tailor treatments based on individual patient profiles, improving efficacy and reducing adverse effects [34,35]. The development of novel targeted agents and immunotherapies that specifically address the unique biological characteristics of PSRCCR holds the potential for more effective interventions. Additionally, ongoing research into biomarkers for early detection and disease monitoring is expected to enhance early diagnosis and improve treatment outcomes. Integrating advanced imaging techniques and artificial intelligence in clinical practice could further refine diagnostic accuracy and treatment planning. With continued investment in research and innovation, there is hope for significantly improved therapeutic strategies and patient outcomes in the near future.

5. Conclusions

In conclusion, PSRCCR represents a formidable challenge in colorectal oncology due to its aggressive nature and diagnostic complexities. Despite advancements in treatment modalities, the prognosis remains poor, necessitating further research into novel therapeutic approaches and prognostic markers. Early detection, accurate histopathological diagnosis, and multidisciplinary management are paramount in optimizing patient outcomes. Additionally, collaborative efforts in genetic profiling and targeted therapy development hold promise for improving survival rates and quality of life for individuals afflicted with this rare malignancy. Continued research endeavors and clinical vigilance are imperative to address the unmet needs of patients with this carcinoma.

We also emphasize that PSRCCR adenocarcinoma of the colon is an independent, rare type of colorectal cancer with highly aggressive biological behavior regardless of the clinical stage at presentation. Early diagnosis and personalized therapy are the only way to achieve a favorable prognosis.