What are the treatment guidelines for a patient diagnosed with signet ring cell gastric carcinoma?

Treatment Guidelines for Signet Ring Cell Gastric Carcinoma

For localized signet ring cell gastric carcinoma, surgery alone with D2 lymphadenectomy is the definitive treatment—perioperative chemotherapy provides no survival benefit and worsens outcomes in this specific histologic subtype. 1, 2

Stage-Specific Treatment Algorithm

Early Stage Disease (Clinical Stage I)

• Surgery alone with D2 lymphadenectomy is the standard of care for clinical stage I signet ring cell gastric carcinoma, with 5-year overall survival of 71% compared to only 58% with perioperative chemotherapy, 38% with neoadjuvant therapy, and 52% with adjuvant therapy 1, 2

• Endoscopic resection (EMR/ESD) is contraindicated for signet ring cell carcinoma, even for small early lesions, because these tumors are characteristically multifocal and occur throughout the stomach 1, 3

• For the rare pT1a tumors meeting strict criteria (well-differentiated, <2cm, non-ulcerative, no lymphovascular invasion), the Chinese guidelines technically allow extended endoscopic therapy 4, but this directly contradicts the British and American guidance that emphasizes the multifocal nature of signet ring cell disease 1, 3—surgical resection remains safer

• For pT1apN0 tumors after complete R0 resection, observation without adjuvant treatment is appropriate 1

Locally Advanced Resectable Disease (Clinical Stage II-III)

• D2 gastrectomy followed by adjuvant chemotherapy is the standard approach for locally advanced gastric cancer 4

• Neoadjuvant therapy is NOT recommended for signet ring cell histology specifically—this subtype shows poor chemosensitivity, and perioperative chemotherapy is an independent poor prognostic factor 1, 5, 2

• MSI-H/dMMR patients who receive preoperative chemotherapy have worse outcomes than those undergoing surgery alone, making MSI testing potentially useful to identify patients who should avoid neoadjuvant treatment 4

• If clinical stage I disease is upstaged to pathologic stage II/III (occurs in 37% of cases), adjuvant chemotherapy offers superior outcomes compared to patients who received preoperative therapy (5-year survival 55% vs 36% for stage II, and 34% vs 7% for stage III) 2

Surgical Principles

• Complete R0 resection with D2 lymphadenectomy is mandatory—negative margins are the critical prognostic factor 1

• Subtotal gastrectomy for distal tumors, total gastrectomy for proximal lesions 1

• Minimum 15 lymph nodes must be examined, optimally ≥25 nodes, for adequate staging 6, 4

• Staging laparoscopy with peritoneal washings should be performed preoperatively in all potentially resectable cases to exclude occult peritoneal metastases, which imaging frequently misses 1, 4

Metastatic Disease (Stage IV)

• For adequate performance status (Karnofsky ≥60% or ECOG <3), systemic chemotherapy with fluoropyrimidine-platinum combinations is recommended, though response rates remain poor in signet ring cell histology 1, 6, 4

• HER2 testing is mandatory—trastuzumab plus chemotherapy improves outcomes in HER2-positive disease 1, 6, 4

• Combination regimens include ECF (epirubicin 50 mg/m², cisplatin 60 mg/m²), or alternatives with oxaliplatin, irinotecan, or docetaxel 4

• Best supportive care alone is appropriate for poor performance status (Karnofsky <60% or ECOG ≥3) 6

Hereditary Diffuse Gastric Cancer (CDH1 Mutation)

• Prophylactic total gastrectomy between ages 20-30 years is the only effective prevention strategy for CDH1 germline pathogenic variant carriers 1, 3

• D1 lymphadenectomy is recommended as a pragmatic compromise for prophylactic procedures, balancing morbidity reduction with adequate staging 1, 3

• Baseline endoscopy is mandatory before prophylactic surgery to exclude established cancer requiring neoadjuvant treatment 1, 3

• Surgery generally not recommended for patients >70 years 3

Critical Pitfalls to Avoid

• Never attempt endoscopic resection even for small, early-appearing lesions—the multifocal nature of signet ring cell carcinoma makes limited resection inappropriate 1, 3

• Do not use perioperative chemotherapy for clinical stage I disease—it provides no benefit and worsens survival compared to surgery alone 1, 2

• Do not proceed to surgery without staging laparoscopy in potentially resectable cases—imaging misses peritoneal metastases that fundamentally change management 1

• Do not accept inadequate lymph node evaluation (<15 nodes examined)—this leads to understaging and suboptimal treatment planning 6, 4

• Do not use neoadjuvant chemotherapy routinely for signet ring cell histology—this subtype is chemoresistant and outcomes are worse with preoperative treatment 1, 5, 2

Key Biological Differences

Signet ring cell carcinoma demonstrates distinct molecular signatures that explain its poor chemosensitivity—the percentage of signet ring cells directly correlates with chemotherapy resistance 5, 7. This histologic subtype shows greater invasiveness and worse prognosis in advanced stages, but paradoxically shows less lymph node metastasis and better outcomes when detected early compared to other poorly differentiated gastric cancers 8, 7. This stage-dependent behavior explains why aggressive surgical resection for early disease yields excellent results, while systemic therapy for advanced disease remains largely ineffective 5, 9.