Diagnosis and treatment of gallbladder and gastric multiple primary malignancies

To the Editor: Gallbladder cancer (GBC) is a rare and aggressive form of cancer with a poor prognosis, primarily due to its late diagnosis and rapid progression. Early-stage GBC can potentially be cured with surgery and adjuvant therapy, but most patients present with advanced disease, limiting surgical options and leading to the use of chemotherapy. The standard chemotherapy regimens for GBC are cisplatin/gemcitabine and oxaliplatin/5-fluorouracil (5-FU), however, the effects are still limited.^[1]

When a person has 2 different cancers, such as gallbladder and gastric, it is called multiple primary malignancies (MPMs), which means more than one cancer is present, either at the same time or at different times. A multi-disciplinary approach is needed to create a treatment plan that effectively addresses both cancers without increasing side effects or drug interactions. Ethical approval was waived by the Institutional Review Board of Peking Union Medical College Hospital.

We reported on a 66-year-old female with a body mass index (BMI) of 22.43 kg/m² and a family history of gastric cancer. She was admitted due to upper abdominal pain, accompanied by gallstones. Laboratory tests and tumor markers were normal. Abdominal computerized tomography (CT) and ultrasound revealed a hypoechoic nodule near the right hepatic lobe gallbladder, heterogeneous enhancement of the gallbladder wall, and abnormal thickening at the lesser curvature of the gastric cardia. Gastroscopy found deep ulcers in the cardia and upper gastric body, and biopsy confirmed poorly differentiated gastric adenocarcinoma. Positron emission tomography (PET)-CT showed a soft tissue mass extending from the gallbladder fundus to the liver (4.0 × 2.6 cm, standard uptake value [SUV]max 9.4) (Fig. 1A), uneven thickening of the gastric wall (2.9 × 2.0 cm, SUVmax 7.9) (Fig. 1C), and multiple small lymph nodes detected at the lesser curvature of the stomach. All tumor markers were at normal levels (carbohydrate antigen 19-9 [CA19-9] <2 U/mL, carcinoma embryonic antigen [CEA] 1.9 ng/mL, carbohydrate antigen 125 [CA125] 12.8 U/mL). Considering the patient’s examination and pathological results, the possibility of gastric cancer metastasis to the gallbladder was high, and thus, neoadjuvant chemotherapy (NACT) treatment was administered. The patient received 3 cycles of the SOX regimen (Oxaliplatin [Hengrui, Lianyungang City, Jiangsu Province, China] 185 mg d1, Dexamethasone 3# bid D1–14, q3w). After NACT, CT and PET-CT indicated uneven radioactive uptake in the gallbladder wall and decreased metabolism at the gallbladder fundus. A low-density nodule was observed near the gallbladder fossa in the liver, with decreased metabolism (1.3 × 1.2 cm, SUVmax 3.6) (Fig. 1B). Uneven thickening and decreased metabolism of the gastric wall from the cardia to the greater curvature of the stomach (0.9 × 0.6 cm, SUVmax 2.7) (Fig. 1D) were noted, and the previously evident small lymph nodes at the lesser curvature of the stomach had disappeared. The tumor markers were still kept normal (CA19-9 <2 U/mL, CEA 2.0 ng/mL, CA125 9.4 U/mL). Considering the patient’s good response to NACT, surgical treatment was performed (laparoscopic radical cholecystectomy, laparoscopic radical total gastrectomy). Intraoperatively, the gallbladder was found to be sclerotic and swollen, and the gastric tumor was located in the lower curvature and posterior wall of the stomach, without serosal invasion. Postoperative pathology showed moderately differentiated gastric adenocarcinoma, with no cancer residue, and the possibility of metastasis to the gallbladder and liver could not be ruled out (Fig. 2). A total of 28 lymph nodes were dissected, and there were no metastatic lymph nodes (0/28). However, next-generation sequencing (NGS) testing results suggested dual primary cancers of the stomach and gallbladder (Supplement Fig. 1, https://links.lww.com/JP9/A111). The patient only received adjuvant chemotherapy after surgery and refused radiotherapy. After completing 3 cycles of the SOX regimen (Oxaliplatin [Hengrui] 185 mg d1, S-1 3# bid d1–14, q3w) chemotherapy and 1 cycle of oral S-1 (3# bid d1–14, q3w) treatment, the patient refused further adjuvant treatment. Six months post-surgery, CT showed liver metastasis, 9 months post-surgery, CT showed widespread intra-abdominal metastasis, and the patient passed away 11 months post-surgery.

Figure 1.

The PET-CT scan before (A: liver and gallbladder lesion; C: gastric lesion) and after (B: liver and gallbladder lesion; D: gastric lesion) NACT. (A) There was a soft tissue mass with abnormal radioactive uptake at the base of the gallbladder, extending into the adjacent liver parenchyma near the gallbladder fossa (about 4.0 × 2.6 cm, SUVmax 9.4). The demarcation between the mass and the liver parenchyma was indistinct. (B) The radioactivity uptake of the gallbladder wall was uneven, and the metabolism of the gallbladder bottom was less pronounced than before. A slightly lower density nodule was observed in the liver parenchyma adjacent to the gallbladder fossa (about 1.3 × 1.2 cm, SUVmax 3.6). The lesions with increased metabolism in the liver parenchyma adjacent to the gallbladder fossa had narrowed and the metabolism had decreased. (C) The gastric wall, extending from the cardia to the greater curvature of the stomach, exhibited uneven thickening along with variably increased radioactive uptake (about 2.9 × 2.0 cm, SUVmax 7.9). Multiple small lymph nodes were found in the lesser curvature of the stomach. (D) The gastric wall, from the cardia to the greater curvature of the stomach, was unevenly thickened, with unevenly increased radioactive uptake. The affected area had narrowed, and its metabolism was decreased (about 0.9 × 0.6 cm, SUVmax 2.7). The previously evident small lymph nodes in the lesser curvature of the stomach are no longer obvious. NACT = neoadjuvant chemotherapy, PET-CT = positron emission tomography computerized tomography, SUVmax = standard uptake value max.

Figure 2.

The postoperative pathology (gastric and gallbladder) and immunohistochemical (gallbladder). (A) A moderately differentiated adenocarcinoma of the stomach (Lauren type: intestinal type), which had invaded the muscular layer and reached the subserosa. (B) The poorly differentiated adenocarcinoma infiltrating the gallbladder wall and liver tissue. (C) Gallbladder immunohistochemistry of CDX-2(+). (D) Gallbladder immunohistochemistry of CK7(+). (E) Gallbladder immunohistochemistry of CK19(+). (F) Gallbladder immunohistochemistry of CK20(−).

Dual primary cancers of the stomach and gallbladder are uncommon, with limited cases documented in medical literature. We report a patient with both cancers who underwent complete neoadjuvant therapy with the SOX regimen and experienced good therapeutic effects. Despite the patient’s survival being 11 months post-surgery, the treatment approach is valuable.

Diagnosing multiple primary tumors is difficult due to the absence of specific markers, often leading to misdiagnosis as metastasis. This can affect treatment choices and surgical opportunities. Early-stage tumors may be treated with surgery or chemoradiotherapy at each site. Advanced cases, particularly with synchronous tumors, require complex treatment decisions without clear guidelines. It is crucial to assess the stage and prognosis of each tumor and engage in detailed discussions with the patient and their family to develop a comprehensive treatment strategy

Preliminary examination results suggested the gallbladder tumor was from gastric cancer metastasis. We then used NACT for gastric cancer to maximize surgery chances. After 3 cycles, the patient’s tumor responded well, allowing surgery and improving the prognosis.

Postoperative pathology and gene tests revealed the patient had 2 primary cancers with distinct genetic mutations. Remarkably, the poorly differentiated adenocarcinoma in the gallbladder responded well to SOX chemotherapy. GBC treatment is limited and often leads to poor outcomes. Chemotherapy for advanced cases includes preoperative, postoperative, and therapeutic treatments. NACT is increasingly important as it can improve R0 resection rates and slow disease progression, potentially improving prognosis and survival rates.^[2]

Clinical data on neoadjuvant therapy are limited and still in the exploratory phase, with no preferred regimen endorsed by the National Comprehensive Cancer Network guidelines. In our case, the SOX regimen was effective against GBC with few side effects, suggesting it as a potential option for such therapy. Additionally, a case study by Zhang et al^[3] showed no recurrence in a 60-year-old female patient treated with SOX after surgery for GBC.

Acknowledgments

None.

Author contributions

X-DH and XL-H were responsible for the conception and design. Y-YQ and M-QS were accountable for the collection and assembly of data. J-RX, J-LL, and J-HH were responsible for the data analysis and interpretation. All authors read and approved the final manuscript for publication.

Financial support

This work was supported by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (CAMS) Initiative for Innovative Medicine (Grant No. 2021-I2M-1-022) and the National High Level Hospital Clinical Research Funding (No. 2022-PUMCH-B-003).

Conflicts of interest

The authors declare no conflicts of interest.