Signet Ring Cell Carcinoma: Symptoms, Types, Causes and Treatment

Signet ring cell carcinoma (SRCC) is a rare and aggressive form of adenocarcinoma, distinguished by the presence of cells that resemble signet rings under the microscope. These cells are characterized by abundant mucin pushing the nucleus to the cell’s periphery. SRCC can arise in various organs, most commonly the stomach, but also in the colon, bladder, urachus, and other locations. Its elusive symptoms, unique pathology, and challenging treatment make it a critical entity for clinicians and patients to understand. In this comprehensive article, we explore the symptoms, types, causes, and current treatment strategies for SRCC, synthesizing the latest research and clinical insights.

Symptoms of Signet Ring Cell Carcinoma

Recognizing the symptoms of SRCC can be difficult due to their nonspecific nature and overlap with many benign conditions. Early detection is often hampered, resulting in later-stage diagnoses and a poorer prognosis. The symptoms vary depending on the organ involved but share common features related to tumor growth and invasion.

Symptom	Site(s)	Clinical Significance	Source(s)
Abdominal pain	Stomach, colon	Common first complaint	2 3 8
Nausea/vomiting	Stomach, colon	Often leads to misdiagnosis	1 2
Weight loss	All sites	Marker of advanced disease	2 8
Shortness of breath	Lungs involvement	Sign of metastasis	1
Irritative urinary symptoms	Urachus, bladder	Suggests local invasion	3
Chest pain	Lungs, advanced gastric	Indicates spread	1
Ascites	Peritoneum	Denotes peritoneal spread	2 8
Hiccups	Colon	Rare initial symptom	2
Fatigue/anemia	All sites	Non-specific, common	1 2 8

Table 1: Key Symptoms of Signet Ring Cell Carcinoma

Overview of Symptom Presentation

SRCC typically presents with vague symptoms that can be easily attributed to more common, benign conditions. This non-specificity is a major reason for delayed diagnosis and poorer outcomes in many patients.

Common Gastrointestinal Symptoms

• Abdominal Pain: Frequently reported in gastric and colorectal SRCC, it is often persistent and may be accompanied by bloating.
• Nausea and Vomiting: These symptoms overlap with benign gastrointestinal disorders and are especially confounding in special populations like pregnant women, where they may be misattributed to pregnancy itself 1.
• Weight Loss: Significant and unintended weight loss over weeks or months is a red flag for malignancy, including SRCC 2 8.
• Ascites: Accumulation of fluid in the peritoneal cavity is more common in advanced disease, often indicating peritoneal spread 2 8.

Respiratory and Systemic Symptoms

• Shortness of Breath and Chest Pain: These are less frequent but signal advanced disease, particularly when the lungs are involved via lymphangitic carcinomatosis or metastasis 1.
• Fatigue and Anemia: Non-specific but common, resulting from chronic disease and possible blood loss from tumor ulceration 1 2 8.

Unusual Presentations

• Hiccups: As illustrated in a case of colonic SRCC, persistent hiccups can be an early and overlooked symptom 2.
• Irritative Urinary Symptoms: Seen in rare cases like urachal SRCC, with symptoms such as frequent urination, urgency, or pain 3.

Types of Signet Ring Cell Carcinoma

SRCC is not confined to a single organ, and its clinical behavior, prognosis, and treatment approaches can differ based on its site of origin. Understanding these types is crucial for accurate diagnosis and management.

Type	Primary Site(s)	Distinctive Features	Source(s)
Gastric SRCC	Stomach	Most common, rising incidence	4 5 8
Colorectal SRCC	Colon, rectum	Rare (<1%), aggressive	2 6 11
Urachal SRCC	Urachus/bladder	Very rare, high stage	3
Eyelid SRCC	Eyelid/periocular	Extremely rare, locally invasive	12
Esophagogastric Junction SRCC	GE junction	Increasingly recognized	10 13

Table 2: Main Types of Signet Ring Cell Carcinoma

Gastric Signet Ring Cell Carcinoma

• Epidemiology: Gastric SRCC is the most prevalent type and accounts for about 10% of all gastric cancers. Notably, while the overall incidence of gastric cancer has declined, the incidence of SRCC subtype is rising 4 5 8.
• Features: It often presents at a younger age, is more infiltrative, and is associated with a diffuse growth pattern (e.g., linitis plastica) 4 8.
• Prognosis: Early-stage gastric SRCC has a favorable outcome, but advanced disease is associated with poor prognosis and chemoresistance 5 8 15.

Colorectal Signet Ring Cell Carcinoma

• Epidemiology: SRCC makes up less than 1% of colorectal cancers 2 6 11.
• Features: Characterized by aggressive local invasion, high rates of lymphatic and peritoneal spread, and frequent diagnosis at advanced stages 2 6 11.
• Prognosis: Very poor, especially with peritoneal metastasis; limited response to standard chemotherapy 2 11.

Rare and Unusual Types

• Urachal and Bladder SRCC: These present with urinary symptoms and are usually high-grade, high-stage tumors at diagnosis 3.
• Ocular (Eyelid) SRCC: Extremely rare, presents as a slowly enlarging mass but can invade locally and metastasize. Shares molecular features with gastric and breast SRCC 12.

Esophagogastric Junction SRCC

• Emerging Recognition: Increasingly identified as distinct from gastric or esophageal SRCC. Management is evolving with stage-stratified approaches 10 13.

Causes of Signet Ring Cell Carcinoma

The development of SRCC involves a complex interplay of genetic, molecular, and environmental factors. Recent research has shed light on the unique pathways and mutations driving this carcinoma.

Factor	Mechanism/Role	Associated Mutation/Pathway	Source(s)
Genetic mutations	Loss of cell adhesion, increased mucin	CDH1, BRAF, ARID1A, TP53	6 9 11 12
Molecular signaling	Disruption of cell junctions, mucin overproduction	ErbB2/ErbB3, PI3K, MAPK	9 7
Epigenetic changes	Tumor progression	Not fully defined	10
Hereditary syndromes	Familial clustering, early onset	CDH1 (E-cadherin)	6 12
Environmental	Possibly similar to other adenocarcinomas	H. pylori (gastric), diet	4 5

Table 3: Causative Factors and Mechanisms in SRCC

Genetic and Molecular Underpinnings

• CDH1 Mutation: Central to hereditary diffuse gastric cancer and some sporadic cases, loss of E-cadherin function disrupts cell adhesion, promoting invasion and mucin accumulation 6 9 12.
• Other Mutations:
  • BRAF: Frequently mutated in colorectal SRCC; linked to poor prognosis and limited chemotherapy response 6 11.
  • ARID1A, TP53: Common in both gastric and colorectal SRCC 6.
• Molecular Signaling Pathways:
  • ErbB2/ErbB3-PI3K-MAPK Axis: Drives loss of cell-cell junctions and mucin secretion, leading to the characteristic “signet ring” appearance 9.
  • Immune Evasion: SRCC cells show higher immune evasion and immunosuppressive microenvironments, facilitating aggressive progression 7.

Hereditary and Familial Factors

• Hereditary Diffuse Gastric Cancer Syndrome: Caused by germline mutations in CDH1, leads to an increased risk of early-onset gastric SRCC and sometimes lobular breast cancer 6 12.
• Familial Clustering: Observed in some cases, suggesting a genetic predisposition 6.

Environmental and Epigenetic Contributions

• Helicobacter pylori Infection: Well-established risk factor for gastric adenocarcinoma; may also play a role in SRCC, though less directly than in intestinal-type cancers 4 5.
• Diet and Lifestyle: High salt intake, smoked foods, and low fruit/vegetable diets may contribute risk, as in other gastric cancers 4 5.
• Epigenetic Changes: Aberrant methylation and chromatin remodeling participate in tumor progression, but specific mechanisms in SRCC are still being elucidated 10.

Treatment of Signet Ring Cell Carcinoma

Treatment of SRCC remains a significant challenge due to its aggressive behavior, tendency for late presentation, and resistance to standard therapies. Management strategies differ by tumor location, stage at diagnosis, and individual molecular features.

Approach	Indication/Site	Rationale/Outcome	Source(s)
Surgery	Early/resectable disease	Mainstay, best for cure	5 8 14 15
Chemotherapy	Advanced/metastatic, perioperative	Limited efficacy in SRCC	5 8 14 15
Neoadjuvant therapy	Locally advanced, selected cases	Controversial benefit	13 14 15
Targeted therapy	Molecularly selected cases	Under investigation	6 10 12
Multimodal therapy	Advanced, high-risk cases	Personalized approaches	10 13

Table 4: Main Treatment Modalities for Signet Ring Cell Carcinoma

Surgery

• Curative Resection: Remains the gold standard for early and resectable SRCC, particularly in gastric and colonic tumors 5 8 14 15.
  • Total gastrectomy: More often required for gastric SRCC due to its infiltrative nature 8.
• Lymphadenectomy: Standardized node removal enhances staging and improves outcomes, especially in gastric SRCC 15.
• Role in Rare Sites: Exenteration may be needed for ocular SRCC, while urachal tumors often require aggressive surgical approaches 3 12.

Chemotherapy

• Perioperative Chemotherapy: Standard in many gastric cancers, but SRCC is less sensitive and may even have worse outcomes with conventional regimens 5 8 15.
• Neoadjuvant Chemotherapy: The benefit is controversial; some studies show no survival advantage, and the toxicities may offset potential gains 14 15.
  • Selected Benefit: In some locally advanced esophagogastric SRCC, neoadjuvant therapy may improve resection rates and survival 13.
• Chemoresistance: SRCC, especially with a high proportion of signet ring cells, is more resistant to standard chemotherapy agents 15.

Targeted and Personalized Approaches

• Molecular Targeted Therapy: Ongoing research is exploring drugs targeting CDH1, ERBB2, PIK3CA, and immune checkpoints in SRCC 6 10 12.
• Stratified Treatment: Future protocols may include molecular profiling to guide therapy choices 6 10.

Multimodal Therapy

• Given SRCC’s aggressiveness and tendency for peritoneal spread, combining surgery, chemotherapy, and potentially targeted agents is recommended in selected advanced-stage patients 10 13.

Prognosis and Follow-Up

• Early Detection is Key: Early-stage SRCC, especially gastric, is amenable to curative surgery and has favorable outcomes 8.
• Advanced Disease: Prognosis remains poor; recurrence often involves the peritoneum in gastric and colorectal SRCC 2 8.
• Surveillance: Close follow-up is essential due to high recurrence risk, especially in the first few years post-treatment 8.

Conclusion

Signet ring cell carcinoma is a rare, distinct, and challenging form of cancer with unique symptoms, molecular mechanisms, and therapeutic hurdles. Across organ sites, its subtle symptoms often delay detection, leading to advanced disease at diagnosis. The rise in incidence, especially in the stomach and esophagogastric junction, underscores the need for increased awareness and tailored management.

Key points:

• Symptoms are subtle and non-specific, often leading to delayed diagnosis and poorer outcomes 1 2 3 8.
• SRCC arises in multiple organs, but is most common and best studied in the stomach and colon 2 4 5 8 11.
• Distinct molecular mechanisms, particularly involving cell adhesion and mucin secretion, drive the aggressive nature of SRCC 6 9 12.
• Surgery remains the cornerstone of treatment for resectable disease, but SRCC responds poorly to standard chemotherapy, especially in advanced stages 5 8 14 15.
• Personalized and multimodal approaches are emerging, with ongoing research into targeted therapies based on molecular profiling 6 10 12.
• Early detection and individualized care are vital for improving outcomes in this aggressive cancer subtype.

By understanding the nuances of signet ring cell carcinoma, clinicians and patients can better navigate the complexities of diagnosis and treatment, moving toward improved prognoses and personalized care.