CASE REPORT
Dr. Ang: The patient is a 42-year-old man who developed abdominal discomfort, anorexia, and weight loss. The ensuing workup, performed at an outside institution, included an esophagogastroduodenoscopy (EGD) that showed a 3 × 7 cm ulcerated mass, located 37 cm from the incisors, in the distal gastric antrum. The mass was confirmed on endoscopic ultrasound (EUS) and was staged as uT2N1 based on the presence of gastrohepatic lymphadenopathy measuring up to 1.6 cm in maximum diameter. A biopsy revealed a poorly differentiated adenocarcinoma with extensive ulceration and signet ring features. Staging computed tomography (CT) of the chest, abdomen, and pelvis showed marked soft tissue prominence of the gastric antrum and a small amount of free fluid lateral to the right hepatic lobe. No intrahepatic lesions were seen, and the other abdominal organs were unremarkable. Given that the disease appeared localized, surgery was planned.
Dr. Intlekofer: What is the appropriate staging algorithm for gastric cancer?
Dr. Janjigian: The initial workup should consist of an EGD and EUS for localization and determination of tumor depth and regional lymph node involvement. I would also recommend a CT scan of the chest, abdomen, and pelvis as well as a positron emission tomography (PET) scan to exclude distant metastases. If disseminated disease is not identified on imaging, a staging laparoscopy with biopsies of suspicious areas and peritoneal washings should be performed. The peritoneum is one of the most common sites of gastric cancer metastases, particularly among tumors involving the gastroesophageal junction (GEJ) or entire stomach.1 Cross-sectional imaging misses peritoneal carcinomatosis in 13–37% of cases.2 Laparoscopy has a sensitivity and specificity of 84% and 100%, respectively, for detecting occult metastases and can spare 20–30% of patients from an unnecessary laparotomy.2–4
Dr. Al-Kutoubi: Is peritoneal cytology indicated in the absence of gross metastatic deposits?
Dr. Janjigian: This is a point of debate and practice varies by center. At MSKCC, peritoneal washings are typically obtained in this context because positive cytology can be present in about a third of such cases and denotes M1 disease, which portends a poor prognosis, even if this is the only site of metastasis.5
Dr. Lowery: Can you elaborate further on the role of PET scans in gastric cancer staging?
Dr. Kelsen: Studies have shown that a hybrid PET-CT scan is more sensitive for identifying nodal and distant metastases compared to a CT scan alone.6,7 PET scans may also provide prognostic information; a retrospective study conducted at MSKCC showed that the preoperative SUVmax appears to be predictive of survival in patients with localized esophageal cancer.8 PET scans for the staging of gastroesophageal cancers have been endorsed by expert panels9 and are routinely performed at MSKCC, though this is not the standard practice everywhere. Some caveats should be noted; about 40% of gastric cancers are not FDG-avid, especially the nonintestinal and nonmucinous-containing histologies.10 Also, false positives occur in up to 20% of cases.6 Thus, before making a decision to forego curative therapy, it would be important to confirm the presence of metastatic disease by biopsying areas of suspicion on PET scan.
Dr. Ang: Intraoperatively, the patient was found to have bulky, unresectable lymph node and peritoneal metastases. A partial gastrectomy was performed, and all visible tumor was resected. The rationale for the surgery was palliation.
Dr. Kelsen: Should the surgery have been aborted?
Dr. Faraj: At the present time, the benefit of palliative gastrectomy with or without metastasectomy is debatable and has not been studied prospectively. Recent retrospective studies examining this issue suggest that surgery in addition to chemotherapy may be beneficial, but mainly in carefully selected patients with a limited metastases burden who are able to undergo maximal debulking.11,12 Palliative surgery alone without chemotherapy does not appear to improve survival, and surgical morbidity and mortality must be considered.13 In this particular case, I would not have proceeded with surgery and would have referred the patient for chemotherapy.
Dr. O'Reilly: What did the pathology show?
Dr. Tawil: Pathology demonstrated a poorly differentiated, poorly cohesive, diffuse-type adenocarcinoma with signet ring features invading the adjacent omentum (Figure 1). The background mucosa demonstrated chronic active gastritis and was Helicobacter pylori negative. All 18 of the resected regional lymph nodes as well as a perihepatic lymph node were involved with tumor. All surgical margins were negative.
Figure 1.
Poorly differentiated gastric adenocarcinoma.
Dr. Ang: The patient was seen at MSKCC about 1.5 months after his surgery. A baseline postoperative CT scan revealed left supraclavicular and bilateral hilar lymphadenopathy, a 3.2 × 1.8 cm liver hypodensity, and a 1.3 × 0.9 cm left paraaortic lymph node. A PET scan showed FDG-avidity in the left cervical lymph node (SUVmax 11.7); mediastinal and hilar lymph nodes (SUVmax 6.8–9.4), porta hepatis (SUVmax 8.8), a left adrenal mass vs. lymphadenopathy (SUVmax 5.0), and diffuse axial skeletal metastases (SUVmax 4.2–8.8).
Dr. Geara: This patient developed gastric cancer at quite a young age. Did he have any risk factors?
Dr. Ang: The patient was known to have diet-controlled hyperlipidemia and denied any history of gastroesophageal reflux disease. There was no history of prior surgeries and no known history of cancer in other family members. Hereditary diffuse gastric cancer is an autosomal dominant condition caused by a mutation in the CDH1 gene that encodes E-cadherin. Patients harboring this mutation have a >70% lifetime risk of developing gastric cancer and are often considered for prophylactic gastrectomy. Gastric cancers occurring in the setting of a CDH1 mutation are often proximal, have a diffuse histology with signet ring features, are highly invasive, and are associated with a poor prognosis. These patients may also have a personal or family history of lobular breast cancer.14,15
Dr. Shamseddine: Was Her-2 testing performed?
Dr. Ang: A liver biopsy was performed to confirm the presence of metastatic disease and to obtain additional tissue for Her-2 testing. The tumor was Her-2 (3+) positive by immunohistochemistry (IHC) (Figure 2). Her-2 positivity occurs in about 15–20% of gastric cancers.16 It appears that the subtypes of gastric cancers that test positive for Her-2 and those that do not can be separated along anatomic and histologic lines. At MSKCC, we found that 27% of Her-2-positive tumors were located in the proximal stomach or GEJ compared to 8% in the distal stomach.17 Her-2 positivity is uncommon (∼5%) in tumors with diffuse as opposed to intestinal histology.18–20 Thus, the patient's presentation is somewhat unusual given that his tumor had a diffuse type histology and was strongly positive for Her-2.
Figure 2.
Her-2 positive gastric adenocarcinoma liver metastasis.
Dr. Olayan: How does Her-2 testing in gastric cancer differ from breast cancer?
Dr. Tawil: A different scoring system is used for the classification of Her-2 status by IHC in gastric cancer in order to account for the greater inter- and intratumoral variability as well as the different membrane staining patterns seen in gastric compared to breast cancer cells.21,22 Key differences are that the threshold for Her-2 positivity in gastric vs. breast cancer is immunoreactivity in 10% vs. 30% of cells, respectively. Also, although complete circumferential membrane staining is required in breast cancer, basolateral membrane involvement is considered positive in gastric cancer.21 Tumors that are IHC 3+ are considered Her-2 positive, whereas for IHC 2+ tumors, the standard practice is to send these patients for FISH analysis as is done in breast cancer. Differences in Her-2 testing between gastric and breast cancer are summarized as shown in Table 1.
Table 1.
Differences in Her-2 scoring between gastric and breast cancer
| Score | Gastric cancer16,25 | Breast cancer22 |
|---|---|---|
| IHC 0 | No immunoreactivity or membranous reactivity in <10% tumor cells | No immunoreactivity |
| IHC 1+ | Faint/barely perceptible membranous reactivity in >10% tumor cells; only partial membrane reactivity | Weak, incomplete membrane reactivity in any proportion of tumor cells |
| IHC 2+ | Weak to moderate complete/basolateral/lateral membranous reactivity in >10% of tumor cells | Nonuniform or weak but otherwise circumferential reactivity in >10% of cells Intense, complete membrane staining in <30% of cells |
| IHC 3+ | Strong complete/basolateral/lateral membrane reactivity in >10% tumor cells | Uniform, intense membrane staining in >30% tumor cells |
| FISH + | Her-2/CEP 17 > 2 | >6 Her-2 gene copies/nucleus; Her-2/CEP 17 > 2.2 |
| FISH equivocal | None | >4–<6 Her-2 gene copies/nucleus; Her-2/CEP 17 1.8–2.2 |
| FISH− | Her-2/CEP 17 < 2 | <4 Her-2; Her-2/CEP 17 < 1.8 |
Dr. Janjigian: Consideration may be given to sending even IHC 1+ tumors for FISH testing given a reported lower concordance between IHC and FISH in gastric compared to breast cancer (62.5% vs. 82–100%).23 Although the discrepancy tends to be greatest among IHC 2+ tumors,24 most of the differences in the ToGA study were in IHC 0 or 1+ tumors.25 In addition, the small amount of tissue yielded by biopsy may be distorted by crush and edge artifacts, making the separation between IHC 1+ and 2+ more challenging.17 At MSKCC, IHC 1+ and 2+ tumors are sent for FISH testing.
Dr. Lowery: What are the clinical implications of Her-2 testing in gastric cancer?
Dr. Janjigian: Her-2 positivity in gastric cancer is a predictive biomarker for sensitivity to trastuzumab. The Trastuzumab for Gastric Cancer (ToGA) study was a randomized phase III clinical trial that compared cisplatin/fluoropyrimidine chemotherapy given alone or with trastuzumab in patients with Her-2 positive advanced or metastatic gastric/GEJ cancer.25 The addition of trastuzumab to chemotherapy significantly improved overall survival (11.1 vs. 13.8 months, HR 0.74, P = .0046). Of note, the margin of benefit with trastuzumab was significantly greater among patients demonstrating stronger Her-2 immunoreactivity (16.0 months for IHC 3+ or 2+/FISH+ tumors vs. 11.8 months for IHC 1+, HR 0.65, P = .036). Furthermore, progression-free survival, response rates and duration, and time to progression were all superior in the trastuzumab-containing arm.25 Based on these results, trastuzumab is now the first biologic agent to be approved by both the United States. Food and Drug Administration and European Medicines Agency for the clinical management of advanced gastroesophageal cancers.
Dr. Ang: The patient was enrolled in a clinical trial evaluating modified DCF (docetaxel, cisplatin, and 5-fluorouracil) and trastuzumab given every 2 weeks. He was also started on zoledronic acid for his bone metastases. After two treatments, a protocol-mandated PET scan demonstrated near normalization of FDG activity in all previously noted sites of disease (Figure 3). A follow-up CT scan showed decreases in the size of the liver lesion, mediastinal, upper abdominal, and retroperitoneal lymphadenopathy and also showed signs of treatment effect in the bones. Cisplatin was discontinued after the eleventh treatment because of an infusion reaction. Five months after initiating therapy, he continues to have stable disease and is tolerating docetaxel, 5-fluorouracil, and trastuzumab very well. An echocardiogram also shows a stable ejection fraction at 57% (55% at baseline).
Figure 3.
Pre- and post-treatment PET scans showing dramatic response to treatment.
Dr. Olayan: Is it standard practice to perform a PET scan to monitor response to therapy?
Dr. Kelsen: The data on the use of PET scans to monitor responses to therapy are compelling but remain investigational. In the locally advanced setting, metabolic responses on PET (≥35% decrease in SUVmax from baseline) are associated with histologic responses and an improved prognosis compared to metabolic nonresponders.26,27
Dr. Abou-Alfa: Is Her-2 a prognostic biomarker?
Dr. Janjigian: In breast cancer, Her-2 positivity confers a worse prognosis, although the introduction of trastuzumab seems to have altered the natural history of this disease.28 The prognostic implications of Her-2 in gastric cancer are less clear. Some studies have found Her-2 positivity to be associated with poor survival,23,29 whereas several other studies purport that Her-2 has no prognostic significance in either advanced19,30,31 or early-stage gastroesophageal cancer.32,33
SUMMARY
The paradigm for the management of advanced gastric cancer is changing as our understanding of the molecular biology of this heterogeneous disease evolves. Our patient's clinical features were somewhat unique: a young age at diagnosis with histologic features suggesting a potential underlying E-cadherin mutation and diffuse-type histology that was PET as well as Her-2 positive. This case illustrates the importance of a thorough clinical and pathologic workup, as well as the profound effects that new targeted therapies (eg trastuzumab) combined with cytotoxic chemotherapy can have on patient management.
Acknowledgments
This case was presented at the MSKCC/American University of Beirut/National Guard Hospital, Riyadh, case conference in October 2011. This conference is supported by an endowment gift of Mrs. Mamdouha El- Sayed Bobst and the Bobst Foundation.
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