What is the initial treatment approach for signet ring gastric adenocarcinoma?

Initial Treatment Approach for Signet Ring Cell Gastric Adenocarcinoma

For localized signet ring cell gastric adenocarcinoma, surgery alone with D2 lymphadenectomy is the recommended initial treatment, as perioperative chemotherapy provides no survival benefit and is associated with worse outcomes in this histologic subtype. 1, 2, 3

Treatment Strategy Based on Stage

Early Stage Disease (Clinical Stage I)

• Surgery alone is the standard approach for clinical stage I signet ring cell gastric adenocarcinoma, with superior 5-year overall survival (71%) compared to perioperative chemotherapy (58%), neoadjuvant therapy (38%), or adjuvant therapy (52%). 4

• For pT1apN0 tumors after complete R0 resection, observation without additional adjuvant treatment is recommended. 5

• Endoscopic submucosal dissection (ESD) is NOT recommended for signet ring cell carcinoma because these lesions are multifocal and occur throughout the stomach, making endoscopic or limited resection inappropriate. 6, 1

Locally Advanced Disease (Stage II-III)

• Primary surgical resection with D2 lymphadenectomy remains the gold standard, as signet ring cell carcinoma demonstrates poor chemosensitivity compared to other gastric adenocarcinoma subtypes. 2

• For patients who undergo upfront surgery and are found to have pathologic stage II/III disease (which occurs in approximately 37% of clinical stage I patients), adjuvant therapy offers improved survival compared to those who received preoperative treatment. 4

• If perioperative chemotherapy is considered despite the evidence against it, the FLOT regimen (docetaxel, oxaliplatin, 5-FU/leucovorin) has replaced ECF/ECX as the preferred option based on superior outcomes in general gastric adenocarcinoma. 6

Surgical Principles

• Complete R0 resection with D2 lymphadenectomy is essential, as negative margins are a critical prognostic factor. 5, 2

• Subtotal gastrectomy is appropriate for distal tumors, while total gastrectomy is required for proximal lesions. 6

• The R0 resection rate is comparable between primary surgery (62.3%) and perioperative chemotherapy approaches (65.9%), but without the survival benefit of chemotherapy. 3

Critical Evidence Against Perioperative Chemotherapy

A multicenter study of 1,050 signet ring cell gastric cancer patients demonstrated that perioperative chemotherapy was an independent predictor of poor survival (HR = 1.4, P = 0.042), with median survival of 12.8 months versus 14.0 months for surgery alone. 3

• The increase in percentage of signet ring cells correlates directly with resistance to chemotherapy. 2

• Perioperative chemotherapy in advanced signet ring cell carcinoma is explained by treatment toxicity without corresponding benefit. 2

• 60 patients receiving perioperative chemotherapy did not undergo resection due to tumor progression (10 patients) or metastases found at operation (50 patients). 3

Hereditary Diffuse Gastric Cancer Considerations

For patients with CDH1 germline pathogenic variants:

• Prophylactic total gastrectomy between ages 20-30 years is the only effective prevention strategy for those with family history of diffuse gastric cancer. 1

• D1 lymphadenectomy is recommended as a pragmatic compromise for prophylactic procedures. 1

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

Metastatic Disease

For unresectable or metastatic disease, systemic chemotherapy based on fluoropyrimidine-platinum combinations is recommended, though response rates are poor in signet ring cell histology. 6

• HER2 testing should be performed, as trastuzumab plus chemotherapy is indicated for HER2-positive disease. 6

• Best supportive care alone is appropriate for patients with poor performance status. 6

Common Pitfalls to Avoid

• Do not routinely offer neoadjuvant chemotherapy for clinical stage I signet ring cell carcinoma based on presumed aggressive biology—this practice worsens outcomes. 4

• Do not attempt endoscopic resection even for small lesions, as multifocal disease is characteristic. 6, 1

• Do not delay surgery in resectable disease to administer chemotherapy, as this provides no benefit and risks disease progression. 2, 3

• Recognize that 37% of clinical stage I patients will be upstaged to pathologic stage II/III at surgery—adjuvant therapy is the appropriate rescue strategy in these cases. 4