Hereditary Diffuse Gastric Cancer: Updated Guidelines
Hereditary Diffuse Gastric Cancer: Updated Guidelines
Prophylactic gastrectomy should be strongly advised in carriers of a proven pathogenic germline CDH1 mutation. Some argue that the term 'prophylactic gastrectomy' is inaccurate and favour the term 'risk reduction gastrectomy' because most mutation carriers already have microscopic SRCCs at the time of their surgery. Total gastrectomy for these patients, however, completely eliminates their risk of GC and is truly prophylactic in terms of preventing their death from invasive GC.
The optimal timing of prophylactic gastrectomy is unknown and is usually highly individualised. Since this surgery has major impact on the quality of life, the decision to undergo prophylactic gastrectomy should be well informed, balanced, prepared and timed. Decisional counselling, outweighing the pros and the cons of the intervention is essential. The current consensus is that the procedure should be discussed and offered to pathogenic germline CDH1 mutation carriers in early adulthood, generally between ages 20 and 30. Based upon the physical fitness of the mutation carrier and of surgery-related complications, prophylactic gastrectomy at an age >75 should be carefully considered. Family phenotype, especially age of onset of clinical cancer in probands, should be taken into account. There is likely to be a dormant period in which the signet ring cell adenocarcinoma does not spread or progress since they have a low proliferative index and the age of prophylactic gastrectomy is generally lower than that of overt cancer. This may explain why so many individuals are found to have T-1 N-0 stage tumours after prophylactic gastrectomy. Patients who develop symptomatic, widely invasive DGC have a poor prognosis with as few as 10% having potentially curable disease. Even if potentially curable, 5-year survival rate still does not exceed 30%. As our understanding of the natural history of mucosal SRCC improves, it may be possible to safely postpone prophylactic gastrectomy in some patients, but until such time it is safer to recommend surgery early in adult life. This has implications for the long-term follow-up of patients with prophylactic gastrectomy and reinforces the need for MDTs to care for these patients for the rest of their lives, similar to patients who have undergone bariatric malabsorptive surgery for obesity.
The requisite operation is a total gastrectomy with Roux-en-Y reconstruction, ensuring that the jejunojejunal anastomosis is at least 50 cm distal to the oesophagogastric anastomosis, to reduce the risk of biliary reflux. The proximal resection line must be across the distal oesophagus containing squamous epithelium to ensure that no gastric cardiac mucosa is left behind. This can be confirmed by frozen section or examination of the opened resection specimen in operating room, and can be guided by the use of on-table endoscopy to mark the squamocolumnar junction during the surgery.
The optimal extent of lymph node dissection (LND) in prophylactic gastrectomy is controversial. Lymph node metastases are not reported in asymptomatic CDH1 mutation carriers with negative preoperative surveillance biopsies or small foci of pT1a intramucosal carcinoma. Among patients with early-stage intestinal adenocarcinoma of the stomach, the frequency of lymph node metastasis in patients with early intramucosal (pT1a) tumours is 2–5%, and up to 6% in the undifferentiated or diffuse types. In pT1b tumours, with invasion of the submucosal layer, lymph node metastases are found in 17–28%, increasing with the depth of submucosal invasion. The majority of patients undergoing prophylactic gastrectomy for HDGC will have at least T1a cancers. Because a preoperative gastroduodenoscopy cannot exclude the presence of T1b lesions with their higher risk of metastases during the operation, a D1 LND (with the inclusion of lymph node stations 1–7) is reasonable.
The formation of a jejunal pouch may improve eating for the first year after surgery, but, as yet, prospective trials comparing pouch to straight Roux-en-Y reconstruction have not convincingly demonstrated significant long-term benefits to justify the routine application of this more complex reconstructive procedure. Surgeons should therefore use the reconstruction they are most familiar with. This also applies to whether the preferred surgical approach is open or laparoscopic. There are potential advantages of laparoscopic gastrectomy with reduced wound pain and faster overall return to full activities, but conclusive evidence for the superiority of this approach is still lacking. Any surgeon proposing to do a laparoscopic PTG must be able to reassure the patient that this is without additional risk compared with open surgery.
Prophylactic mastectomy is not routinely recommended but may be a reasonable option for some women. Literature about prophylactic mastectomy in HDGC is scarce, and it is reasonable to consider prophylactic mastectomy on a case-by-case basis taking into account the family pedigree. National guidelines for high-risk women should be followed with respect to chemoprevention using selective oestrogen receptor modulators or aromatase inhibitors.
Gastrectomy and Mastectomy
Prophylactic Gastrectomy: Indications for and Timing of Surgery
Prophylactic gastrectomy should be strongly advised in carriers of a proven pathogenic germline CDH1 mutation. Some argue that the term 'prophylactic gastrectomy' is inaccurate and favour the term 'risk reduction gastrectomy' because most mutation carriers already have microscopic SRCCs at the time of their surgery. Total gastrectomy for these patients, however, completely eliminates their risk of GC and is truly prophylactic in terms of preventing their death from invasive GC.
The optimal timing of prophylactic gastrectomy is unknown and is usually highly individualised. Since this surgery has major impact on the quality of life, the decision to undergo prophylactic gastrectomy should be well informed, balanced, prepared and timed. Decisional counselling, outweighing the pros and the cons of the intervention is essential. The current consensus is that the procedure should be discussed and offered to pathogenic germline CDH1 mutation carriers in early adulthood, generally between ages 20 and 30. Based upon the physical fitness of the mutation carrier and of surgery-related complications, prophylactic gastrectomy at an age >75 should be carefully considered. Family phenotype, especially age of onset of clinical cancer in probands, should be taken into account. There is likely to be a dormant period in which the signet ring cell adenocarcinoma does not spread or progress since they have a low proliferative index and the age of prophylactic gastrectomy is generally lower than that of overt cancer. This may explain why so many individuals are found to have T-1 N-0 stage tumours after prophylactic gastrectomy. Patients who develop symptomatic, widely invasive DGC have a poor prognosis with as few as 10% having potentially curable disease. Even if potentially curable, 5-year survival rate still does not exceed 30%. As our understanding of the natural history of mucosal SRCC improves, it may be possible to safely postpone prophylactic gastrectomy in some patients, but until such time it is safer to recommend surgery early in adult life. This has implications for the long-term follow-up of patients with prophylactic gastrectomy and reinforces the need for MDTs to care for these patients for the rest of their lives, similar to patients who have undergone bariatric malabsorptive surgery for obesity.
Operation Details
The requisite operation is a total gastrectomy with Roux-en-Y reconstruction, ensuring that the jejunojejunal anastomosis is at least 50 cm distal to the oesophagogastric anastomosis, to reduce the risk of biliary reflux. The proximal resection line must be across the distal oesophagus containing squamous epithelium to ensure that no gastric cardiac mucosa is left behind. This can be confirmed by frozen section or examination of the opened resection specimen in operating room, and can be guided by the use of on-table endoscopy to mark the squamocolumnar junction during the surgery.
The optimal extent of lymph node dissection (LND) in prophylactic gastrectomy is controversial. Lymph node metastases are not reported in asymptomatic CDH1 mutation carriers with negative preoperative surveillance biopsies or small foci of pT1a intramucosal carcinoma. Among patients with early-stage intestinal adenocarcinoma of the stomach, the frequency of lymph node metastasis in patients with early intramucosal (pT1a) tumours is 2–5%, and up to 6% in the undifferentiated or diffuse types. In pT1b tumours, with invasion of the submucosal layer, lymph node metastases are found in 17–28%, increasing with the depth of submucosal invasion. The majority of patients undergoing prophylactic gastrectomy for HDGC will have at least T1a cancers. Because a preoperative gastroduodenoscopy cannot exclude the presence of T1b lesions with their higher risk of metastases during the operation, a D1 LND (with the inclusion of lymph node stations 1–7) is reasonable.
The formation of a jejunal pouch may improve eating for the first year after surgery, but, as yet, prospective trials comparing pouch to straight Roux-en-Y reconstruction have not convincingly demonstrated significant long-term benefits to justify the routine application of this more complex reconstructive procedure. Surgeons should therefore use the reconstruction they are most familiar with. This also applies to whether the preferred surgical approach is open or laparoscopic. There are potential advantages of laparoscopic gastrectomy with reduced wound pain and faster overall return to full activities, but conclusive evidence for the superiority of this approach is still lacking. Any surgeon proposing to do a laparoscopic PTG must be able to reassure the patient that this is without additional risk compared with open surgery.
Prophylactic Mastectomy
Prophylactic mastectomy is not routinely recommended but may be a reasonable option for some women. Literature about prophylactic mastectomy in HDGC is scarce, and it is reasonable to consider prophylactic mastectomy on a case-by-case basis taking into account the family pedigree. National guidelines for high-risk women should be followed with respect to chemoprevention using selective oestrogen receptor modulators or aromatase inhibitors.