What is the treatment for signet ring cell carcinoma?

Treatment of Signet Ring Cell Carcinoma

The treatment of signet ring cell carcinoma depends critically on the primary site of origin, with gastric signet ring cell carcinoma requiring total gastrectomy as the definitive curative approach, while colorectal and bladder variants follow site-specific oncologic resection protocols with multimodal therapy.

Gastric Signet Ring Cell Carcinoma

Hereditary Diffuse Gastric Cancer (HDGC) - Prophylactic Setting

For patients with CDH1 germline pathogenic variants and family history of diffuse gastric cancer, prophylactic total gastrectomy (PTG) is the only effective strategy to prevent gastric cancer and should be performed ideally between ages 20-30 years 1.

• PTG should still be considered for CDH1 carriers without family history of diffuse gastric cancer or with only lobular breast cancer family history 1
• Surgery is not generally recommended for patients older than 70 years 1
• There is no role for endoscopic or limited gastric resection in HDGC treatment, as signet ring cell foci are multifocal and occur throughout the stomach 1

Surgical Technique for Prophylactic Gastrectomy

• The aim is complete eradication of all gastric mucosa with intra-operative confirmation of oesophageal squamous mucosa in the proximal margin and duodenal mucosa in the distal margin 1
• D1 (perigastric) lymphadenectomy is recommended as a pragmatic compromise between reducing morbidity and providing adequate staging 1
• Both minimally invasive and open approaches are acceptable, with laparoscopic approach associated with median one-day shorter hospital stay 1

Pre-operative Requirements

• Baseline endoscopy is mandatory to ensure established gastric cancer is not present, as this would require full staging with consideration of neoadjuvant treatment 1
• Detailed mucosal evaluation with targeted and random biopsies following the Cambridge protocol 1
• Pre-operative psychosocial counselling and assessment for comorbid mental illness, particularly eating disorders and addiction, given the significant lifestyle and nutritional consequences 1

Alternative to Prophylactic Surgery

• Annual endoscopic surveillance as an alternative to PTG has been demonstrated safe in specialist HDGC referral centers for patients who defer surgery 1
• If signet ring cell lesions are identified during surveillance, PTG is recommended at that point 1

Established Gastric Signet Ring Cell Carcinoma

Early Gastric Cancer (EGC)

• Surgical resection remains the primary curative treatment 2
• Patients with early gastric signet ring cell carcinoma show similar survival to other histological types when treated surgically 2

Advanced Gastric Cancer (AGC)

• Patients with advanced gastric signet ring cell carcinoma have significantly worse prognosis compared to other histological types, with surgery offering benefit only in carefully selected patients 2, 3
• Well-selected patients undergoing surgical management demonstrate one-year survival of 81% and five-year survival of 28.6%, compared to 19.1% and 1.5% respectively in nonoperative groups 3
• Multivariate analysis shows that surgical management, lower stage of disease, and lower Charlson Comorbidity Index significantly improve survival 3
• Gastric signet ring cell carcinoma demonstrates chemoradioresistance and poor response to adjuvant and neoadjuvant chemoradiotherapy 4

Metastatic Disease

• Platinum-based combination chemotherapy regimens are typically recommended for adenocarcinomas, though response rates are poor 1
• Modified BEMA regimen (oxaliplatin, leucovorin, 5-fluorouracil) combined with nivolumab has been used, though disease progression may continue despite treatment 5

Colorectal Signet Ring Cell Carcinoma

Signet ring cell adenocarcinoma of the colon and rectum is defined as having >50% of tumor demonstrating signet-ring cell morphology and is associated with worse stage-for-stage survival relative to conventional adenocarcinoma 1.

• Strong association with microsatellite instability and BRAF V600E mutation 1
• Standard oncologic resection principles apply with appropriate lymphadenectomy 1
• Adjuvant chemotherapy and radiation therapy follow standard colorectal cancer protocols based on stage 1

Bladder Signet Ring Cell Carcinoma

For poorly differentiated bladder adenocarcinoma with signet ring cell features, radical cystectomy with pelvic lymphadenectomy followed by adjuvant chemotherapy and/or radiation therapy is recommended 6.

Surgical Management

• Radical cystectomy includes removal of bladder, prostate, seminal vesicles, proximal vas deferens, and proximal urethra 6
• Complete removal of the prostate is essential in cases of prostate base infiltration 6
• Pelvic lymphadenectomy is standard 6

Adjuvant Therapy

• Adjuvant chemotherapy should be strongly considered due to advanced local stage, poor differentiation, and signet ring cell histology 6
• Platinum-based combination chemotherapy regimens are typically recommended 6
• Adjuvant radiation therapy (45-50.4 Gy to tumor bed and regional lymph nodes with boost to 66-70 Gy for residual disease or positive margins) should be considered for locally advanced disease 6

Surveillance

• Cystoscopy and imaging studies every 3-6 months for first 2 years 6
• Bone scan if clinically indicated 6

General Prognostic Considerations

Signet ring cell carcinomas across all sites demonstrate earlier age of onset, higher rates of regional or distant disease at presentation, poor tumor differentiation, and worse overall survival compared to conventional adenocarcinomas 7.

• Identifying signet ring cell carcinomas at earlier disease stages is the single most important intervention to improving outcomes 7
• Advanced disease at diagnosis is the primary driver of poor prognosis 7