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Poorly differentiated gastric adenocarcinoma with signet ring cell features
A 19-year-old black woman presented to the ER with worsening nausea, vomiting and abdominal pain for the last few days. On examination, she had generalized abdominal tenderness. Several investigations, including blood tests and CT scan of the abdomen and pelvis, indicated inflammatory bowel disease, and she was treated conservatively without significant improvement. Eventually, she proceeded to the operating room for an exploratory laparotomy with an anticipation of bowel obstruction secondary to adhesions.
To everyone’s surprise, the patient was found to have multiple dilated small bowel loops, and both the entire cecum and ascending colon were heavily involved with a neoplastic process that was difficult to characterize. Due to this infiltrative process, the patient underwent resection of her terminal ileum, the entire ascending colon, and transverse colon to relieve the obstruction.
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Unresectable tumor implants were noted on the mesentery of the small bowel. Pathology showed a poorly differentiated adenocarcinoma with signet ring cell features. She recovered well after surgery and underwent an upper endoscopy that showed edematous, friable, loss of normal gastric folds and ulcerated gastric mucosa involving the entire stomach sparing the pylorus and part of the antrum. The biopsy showed adenocarcinoma with signet ring cell appearance.
Discussion
Gastric cancer is the second most common cause of cancer-related death in the world. Many Asian countries, including Korea, China, Taiwan and Japan, have very high rates of gastric cancer, as opposed to the incidence of gastric cancer in the United States, which has declined dramatically since the 1930s. Approximately 21,500 patients are diagnosed annually, and 10,880 are expected to die from this disease.
Prognosis has improved only marginally over the last two decades despite the declining incidence and significant advances in surgical therapy and postoperative care. The overall five-year survival rate for all stages combined was 24% between 1996 and 2003, compared to 15% between 1975 and 1977.
Until the early 1990s, active chemotherapeutic agents in advanced gastric cancer were bleomycin, mitomycin-C, methotrexate, 5-FU, etoposide, cisplatin and doxorubicin. All were associated with modest response rates of short duration. Combination chemotherapy revealed higher response rates in phase-2 trials, but randomized trials had lower response rates. The combination of cisplatin and 5-FU (CF) was the most commonly used regimen in the setting of metastatic gastric and esophageal cancer. The response rate of this regimen, as depicted by a randomized phase-2 trial, was 35%, but one-year survival was not much different than single-agent cisplatin.
Recent studies have compared the addition of docetaxel (Taxotere, Sanofi Aventis) to cisplatin-based regimens. The final results of the TAX 325 Study, which compared DCF (docetaxel, cisplatin and 5-FU) to CF were reported in 2005 and published in 2007. Response rate was 37% vs. 25%, progression free survival was 5.6 months vs. 3.7 months, and overall survival was 10.5 months vs. 9.6 months (all in favor of DCF). The two-year survivals were 18% vs. 9% (in favor of DCF). This was the highest reported two-year overall survival in gastric cancer at the time. Toxicities for both regimens were substantial but manageable.
The use of other regimens such as ECF (epirubicin, cisplatin, 5-FU) has shown promise in advanced disease, but that regimen has potential cardiac risk, and reported overall survival is only eight to nine months. Also, the previous regimens included cisplatin with bolus 5-FU, but the ECF regimen has infusional 5-FU, which may have affected the better response rate. Therefore, the benefit of adding epirubicin to the CF regimen remains unknown.
There are multiple trials still ongoing for this indication, and several new abstracts were presented in ASCO 2008. One of them was by Enzinger et al who reported that bevacizumab (Avastin, Genentech), cisplatin, docetaxel and irinotecan in a three-week cycle produced a response rate of 63% in metastatic esophageal/gastric cancer. Another abstract by Han et al showed the outcome of using cetuximab (Erbitux, ImClone) in combination with FOLFOX6. The response rate was 50%, with 5.5 months time to progression and 9.9 months overall survival. Randomized trials are needed to confirm these results.
Approximately 25% of metastatic gastric cancers over express HER2. It is more common with intestinal type gastric cancers than with diffuse type. Recently, the results of phase-3 ToGA trial showed significantly higher response rates in patients with HER2–over-expressing tumors when treated with CF and trastuzumab (Herceptin, Genentech; 47% vs. 35%). These are the preliminary results; however, I think it is reasonable to screen metastatic gastric cancer patients for HER2 over expression.
The above mentioned patient was started on chemotherapy with DCF and HER2 status to date is pending.
Wajeeha Razaq, MD, is an Assistant Professor of Medicine at the University of Nebraska, Omaha.
For more information:
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