What is the treatment for signet cell adenocarcinoma?

Treatment of Signet Ring Cell Adenocarcinoma

Treatment of signet ring cell adenocarcinoma is site-specific and requires aggressive surgical resection as the primary modality, with the addition of systemic chemotherapy and/or radiation therapy based on tumor location, stage, and specific histologic features.

Gastric Signet Ring Cell Carcinoma

Hereditary Diffuse Gastric Cancer (HDGC)

• For patients with CDH1 germline pathogenic variants and family history of diffuse gastric cancer, prophylactic total gastrectomy is the only effective strategy to prevent gastric cancer and should be performed ideally between ages 20-30 years 1
• Prophylactic total gastrectomy 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
• The surgical technique must achieve complete eradication of all gastric mucosa with intra-operative confirmation of esophageal squamous mucosa in the proximal margin and duodenal mucosa in the distal margin 1
• D1 lymphadenectomy is recommended as a pragmatic compromise between reducing morbidity and providing adequate staging 1
• Baseline endoscopy is mandatory to ensure established gastric cancer is not present, as this would require full staging with consideration of neoadjuvant treatment 1

Sporadic Clinical Stage I Gastric SRCC

• Surgery alone is the standard-of-care for clinical stage I gastric signet ring cell adenocarcinoma, with superior 5-year overall survival (71%) compared to perioperative chemotherapy (58%), neoadjuvant therapy (38%), or adjuvant therapy (52%) 2
• For patients upstaged to pathologic stage II/III (which occurs in 37% of clinical stage I cases), adjuvant therapy offers a favorable rescue strategy with improved outcomes compared to preoperative treatment 2
• Annual endoscopic surveillance as an alternative to prophylactic total gastrectomy has been demonstrated safe in specialist HDGC referral centers for patients who defer surgery 1
• If signet ring cell lesions are identified during surveillance, prophylactic total gastrectomy is recommended at that point 1

Colorectal Signet Ring Cell Carcinoma

Colon SRCC

• Standard oncologic resection principles apply with appropriate lymphadenectomy for colonic signet ring cell adenocarcinoma 1
• Adjuvant chemotherapy and radiation therapy follow standard colorectal cancer protocols based on stage 1
• Signet ring cell adenocarcinoma 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
• There is a strong association with microsatellite instability and BRAF V600E mutation 1

Rectal SRCC

• For locally advanced rectal signet ring cell carcinoma, definitive treatment with either long course chemoradiation or short course radiation followed by chemotherapy should be employed, though both strategies show high peritoneal progression rates (59.4% of progressions) and treatment failures (33.9%) 3
• Minimally invasive surgery shows no significant difference in outcomes compared to open surgery, with mean disease-free survival of 29 months for MIS versus 25.8 months for open approach 4
• The peritoneum is the commonest site of progression, occurring in 59.4% of cases that progress 3
• Pathological complete response is achieved in only 9.7% of cases, reflecting the aggressive biology of this disease 3

Esophageal Signet Ring Cell Adenocarcinoma

• Esophageal adenocarcinoma with any component of signet ring cells (even <50%) demonstrates resistance to standard trimodality therapy with significantly poorer survival compared to usual-type adenocarcinoma 5
• Pathologic complete response rates are markedly reduced in tumors with any SRC component (10%) compared to usual-type adenocarcinoma (25%) 5
• The percentage of SRC component does not independently affect the rate of pathologic complete response, meaning any presence of SRC portends poor prognosis 5
• Alternative therapies in patients with any SRC component may be indicated, though specific regimens are not yet established 5

Bladder Signet Ring Cell Adenocarcinoma

• 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 1, 6
• Radical cystectomy should include removal of the bladder, prostate, seminal vesicles, proximal vas deferens, and proximal urethra, with complete removal of the prostate essential in cases of prostate base infiltration 6
• Platinum-based combination chemotherapy regimens are typically recommended for adenocarcinomas, though response rates are poor 1
• Adjuvant radiation therapy should be considered for locally advanced disease, with radiation doses of 45-50.4 Gy to the tumor bed and regional lymph nodes with boost to areas of residual disease or positive margins to 66-70 Gy 6
• Regular surveillance with cystoscopy and imaging studies every 3-6 months for the first 2 years is recommended 6

Urachal Signet Ring Cell Adenocarcinoma

• Partial cystectomy with en-bloc excision of the urachus and umbilicus is the surgical approach for localized disease 7
• Local radiotherapy should be considered for positive surgical margins 7
• For metastatic disease, combination chemotherapy with methotrexate, vinblastine, adriamycin and cisplatinum may be considered, though response duration is limited (approximately 8 months) 7

Key Clinical Pitfalls

• Do not overtreat clinical stage I gastric SRCC with preoperative therapy, as surgery alone provides superior outcomes with adjuvant therapy available as an effective rescue strategy for upstaged patients 2
• Do not assume that only tumors with >50% SRC component are clinically significant in esophageal cancer, as any component of SRC predicts poor response to neoadjuvant therapy and worse survival 5
• Recognize that signet ring cell carcinomas have multifocal distribution, particularly in gastric primaries, making endoscopic or limited resections inadequate 1
• Be aware of the extremely high peritoneal progression rates in rectal SRCC (59.4%), which should inform surveillance strategies and patient counseling 3