[Borrmann type IV (2023) lecture note] Today¡¯s topic is endoscopic diagnosis of Borrmann type 4 advanced gastric cancers. I¡¯d like to discuss some of the major characteristics of Borrmann type 4 with a lot of endoscopic images. The definition of Borrmann type 4 is a diffusely infiltrated gastric carcinoma in which ulceration is not a marked feature. So, small ulcer or erosion can be seen in typical Borrmann type 4 cancers. The incidence of a Borrmann type 4 gastric cancer is 11 to 13% of all advanced gastric carcinomas. And it is more common in females. The odds ratio is 1.87. Histologically, Borrmann type 4 has higher incidence of poorly differentiated carcinoma, lymph node metastases, peritoneal metastases, serosal invasion, and lymphatic invasion. Treatment outcome is still very bad. The overall 5-year survival rate of Borrmann type 4 is much less than other types of gastric cancer even after surgery. This is a stage by stage comparison between Borrmann type 4 and other types of gastric cancers after surgery at Samsung Medical Center. [Click] For example, 5 year survival rate of stage IIIa cancers was 36% for Borrmann type 4 and 55% for other types of cancers. In patients with non-curative surgery, the prognosis is even worse. The pathogenesis of Borrmann type 4 is out of my topic today. But, I would talk about one important new finding. Claudin 18.2, a tight junction protein, is a new molecular target for chemotherapy. In a recent analysis, Claudin 18.2 is positive in 24% of advanced gastric cancers in Japan. One interesting aspect is that claudin 18.2 positive rate is significantly higher in Borrmann type 4 than other types of AGCs. Endoscopic findings of Borrmann type 4 advanced gastric cancer. Why Borrmann type 4 is so important? Endoscopic diagnosis of Borrmann type 1, 2, 3 is rather simple and easy. Biopsies for these lesions are mostly positive for malignancy. But Borrmann type 4 is easy to miss and biopsies for them are negative in many cases. So, I can say that Borrmann type 4 is the key of endoscopic diagnosis of advanced gastric cancers. A 59 years old lady was referred for the further evaluation of suspicious Borrmann type 4. Initial endoscopic biopsy at local clinic was negative for malignancy. In the endoscopy at my clinic, gastric folds looked thickened. Even after air infusion, the gastric body did not expand very well, and the border between lower body and antrum was narrowed. [Click] There was a small ulcerative lesion at the narrowed segment, and the biopsy was signet ring cell carcinoma. Biopsies from the thickened gastric folds were negative. This is a CT gastroscopy image. There is a narrowed segment at the border between antrum and lower body. We call it a pseudo-pyloric ring You can also identify the pseudo-pyloric ring in this transactional image. What is the most common endoscopic finding of Borrmann type 4 gastric cancer? Of course, it is a prominent fold thickening. The gastric wall itself is also thickened. Even after sufficient air infusion, the gastric lumen does not expand. There may be small ulcers or erosions. These findings are very important because biopsies from depressed area are more efficient. Small ulcer and/or erosion can be an important clue for the diagnosis of Borrmann type 4 gastric cancer. It is especially true, when the background gastric mucosa looks thickened or edematous. This is an example. In the screening endoscopy for a 39 years old lady, a small gastric ulcer was found and the biopsy was poorly differentiated adenocarcinoma. The endoscopist mentioned coarse edematous hyperemia. However, diffuse infiltrative lesion was not suspected. We repeated the endoscopy and found that the gastric folds were thickened and hyperemic. The distance between folds were narrowed, which we call the shoulder by shoulder pattern. Borrmann type 4 gastric cancer with small ulcerative lesion was suspected. The biopsy was poorly cohesive carcinoma. Total gastrectomy was done. It was T4a and N0 lesion. XELOX adjuvant chemotherapy was done. Mucosal surface pattern is variable, but usually mosaic. This is a typical Borrmann type 4. Gastric folds were thickened and very close to each other. The mucosal surface shows typical mosaic pattern. The antral mucosa is relatively saved. In many cases, curative resection is impossible. [Click] In an endoscopy for a 60 years old lady, a diffuse gastric wall thickening was found. [Click] Borrmann type 4 was suspected, so referred to my clinic at the same day. [Click] [Click] We repeated endoscopy immediately at the same day. It was a typical Borrmann type 4 with ulcerative lesion at lesser curvature side of the body. At the initial CT, T4N2 lesion was suspected. So, neoadjuvant chemotherapy was tried. After 3 cycles of XELOX chemotherapy, surgery was done. However, rectal shelf was found in the surgical field, and palliative total gastrectomy was done. Twenty three lymph nodes were involved. Local and peritoneal metastasis were found a few months later. In endoscopy small nodule was found at the anastomosis and the biopsy was poorly differentiated tubular adenocarcinoma. At the same time, multiple abdominal lymph nodes and seeding nodules were found. It is very easy to miss the Borrmann type 4 advanced gastric cancers. In a classic study from Kangbuk Samsung Hospital, researchers examined AGCs that were undetected by endoscopy within the last six months. Among 16 missed AGCs, 7 were Borrmann type 4 gastric cancers. At Samsung Medical Center, we recently evaluated interval gastric cancers. A total of 1,257 patients with gastric cancer within 6 to 36 months of a cancer-negative index EGD were enrolled. 102 AGCs (8.1%) and 1155 EGCs (91.9%) were identified. A shorter observation time less than 3 minutes during index EGD is an important predictor of interval AGC. Among interval AGCs, 23.5% were Borrmann type 4 cancers, and treatment outcome was very poor. Borrmann type 4 gastric cancer patient was referred to my clinic. The gastric fold at the greater curvature side of the body was thickened and irregular. There was a tiny erosive lesion just below the cardia. CT scan showed thickened folds with enhancement. Total gastrectomy was done. The pathology was 20 cm sized serosal invasive cancer with no lymph node metastasis. In this case, the last endoscopy was done just one year ago. What do you thick?... Umm. Not so good. Two years ago, it is very difficult to point out any abnormality. Is it possible to make a diagnosis of Borrmann type 4 advanced gastric cancer last year? [Click] In retrospect, we can point out thickened fold at the greater curvature side of the gastric body. However, it was missed last year. Borrmann type 4 gastric cancer is easy to miss. This is another similar case. Missed Borrmann type 4 gastric cancer at previous endoscopy. After the diagnosis, this patient had initial peritoneal seeding. His last endoscopy was one year ago. What¡¯s your impression? OK, thickened folds were missed at that time. Another similar case. Borrmann type 4 can have a small ulcerative lesion. The last endoscopy was only 7 months ago. So, the key aspect of Borrmann type 4 is that it can be easily missed. High level of suspicion is necessary. Histological confirmation of gastric cancer is quite difficult for Borrmann type 4 gastric cancer due to high rate of false negative biopsy. This is a typical case of Borrmann type 4 gastric cancer. The antrum and body was diffusely involved. Biopsies were taken from the antrum, greater curvature and the lesser curvature of the lower body. [Click] However, biopsies from the antrum and greater curvature of the lower body was negative. Only biopsy from a small depressed lesion at lesser curvature showed poorly differentiated adenocarcinoma. This barium gastrography shows the biopsy sites. Biopsies from the definitely involved area ? like, number 1 and number 2 ? were negative. Only number 3 biopsy was positive for malignancy. False negative biopsy is very common problem in the endoscopic diagnosis of Borrmann type 4 gastric cancers. Strategies for histological diagnosis includes careful observation and taking samples from the depressed area, bite on bite biopsy technique, EMR, EUS-guided fine needle aspiration, and laparoscopy Careful observation of the whole stomach and taking biopsy samples from the depressed area is very important. In this case, more than 2/3 of the stomach was diffusely involved by Borrmann type 4, but there was a single depressed lesion an the gastric angle. Biopsies should be taken from here Sometimes, the depressed area can be quite large. Despite of the ulcerative lesion, we can call it a Borrmann type 4 cancer, because other areas were diffusely involved by typical wall thickening non-ulcerative lesion. EMR strip biopsy can be tried but the sensitivity is still suboptimal. I¡¯d like to show you an example. A 42 years old lady was referred for the management of suspicious Borrmann type 4 gastric cancer with peritoneal seeding and colonic obstruction. The initial biopsy at outside hospital and repeated biopsy at my hospital were all negative for malignancy. Because of her symptoms, colonic stent was done. We performed a diagnostic EMR for the stomach mucosa, but the result was negative for malignancy. For the palliative chemotherapy, histological evidence is required. [Click] So, laparoscopic peritoneal biopsy was done, and metastatic adenocarcinoma was finally confirmed. EUS-guided fine needle aspiration can be tried. In a recent meta-analysis, the overall diagnostic yield of EUS-FNA for scirrhous gastric cancer was more than 80 percent.. Surgery without histological evidence can be tried in a highly suspicious B-4 cancers. A 56 years old lady was referred for the further evaluation of suspicious Borrmann type 4 gastric cancer. Outside biopsy was negative and repeated biopsy after referral was also negative. Based on the typical endoscopic findings and wall thickening at CT, I recommended immediate total gastrectomy. Pathologically, it was T4a N0 advanced gastric cancer. Special situations Special situations include Borrmann type 4 in areas without folds, antral type Borrmann type 4, Borrmann type 4 of the remnant stomach, and duodenal invasion. The hallmark of Borrmann type 4 gastric cancer is thickened folds. But, Borrmann type 4 may develop in areas without folds such as lesser curvature and posterior wall of the body, cardia and fundus, and finally antrum and pyloric ring. As you can expect, it is quite difficult to suspect Borrmann type 4 cancers in these areas. These are some examples. What¡¯s your impression? There is a diffuse mucosal irregularity at the posterior wall of mid to high body and around the cardia. It was 13 cm sized diffuse Borrmann type 4 with multiple lymph node metastasis. What¡¯s your impression? The lesser curvature side to posterior wall of mid to high body looked thickened. Actually, previous endoscopy was done just 10 months ago. Borrmann type 4 in areas without normal gastric folds was missed at that time. This is the previous endoscopy 10 months ago. [Click] [Click] [Click] And this is the recent endoscopy. [Click] [Click] [Click] It was a 12 cm sized diffuse Borrmann type 4 advanced gastric cancer. Antrum is especially difficult. [Click] Small flat discolorated lesion was found and the biopsy was signet ring cell carcinoma. Subtotal gastrectomy was done and the final pathology was 8cm sized diffuse Borrmann type 4. For me, the most challenging situation is antral Borrmann type 4 with or without pyloric involvement. This is a typical case of antral Borrmann type 4. The patient had recurrent vomiting, and the endoscopy showed pyloric narrowing, but there was no definite mucosal abnormality. Borrmann type 4 may develop in the remnant stomach. After partial gastrectomy, the mucosa of the remnant stomach is usually edematous, so the diagnosis of abnormal thickened fold is very difficult. Duodenum is sometimes involved by the gastric cancer. This is a huge Borrmann type 4 involving almost the whole stomach. There was a duodenal invasion in the upper left image. This is another case with Borrmann type 4 with duodenal invasion. Differential diagnosis It includes lymphoma, gastric metastasis, hypertrophic gastritis, and acute gastritis. In about 5% of diffuse large B cell lymphoma of the stomach, the gastric folds and the gastric wall is diffusely involved. In contrast to the typical Borrmann type 4, the lymphoma stomach is wall expanded by the air infusion and the gastric surface is usually glistening. Forceps biopsy is positive for lymphoma in most cases. Gastric metastasis from the breast cancer may mimic the Borrmann type 4 gastric cancer. In this case, the initial biopsy was negative. A few weeks later, her symptoms aggravated and biopsies were positive for malignancy. In the histology, it was a poorly differentiated carcinoma. Close up. GATA3 was positive And estrogen receptor was also positive. Final conclusion was gastric metastasis from the breast cancer. Hypertrophic gastritis is one of the important differential diagnoses. Gastric fold thickening was found in a patient with chronic renal failure. The biopsy was Helicobacter pylori associated active gastritis. EUS was done. Although the folds looked thickened, the gastric wall thickness was normal. Borrmann type 4 gastric cancer is a chronic process. It is quite different from acute gastritis. A 21 years old lady was referred for the evaluation of possible Borrmann type 4 gastric cancer. As you can see, the whole stomach looks edematous but her symptom developed just 2 days ago. Cancer is very unlikely. Follow-up endoscopy was completely normal. Ladies and gentlemen. I¡¯d like to conclude my talk by saying that Borrmann type 4 gastric cancers are very easy to miss during endoscopy. High index of suspicion is required. Thank you very much for your attention.