Granulocyte-Colony Stimulating Factor Producing Extrahepatic Bile Duct Carcinoma: A Case Report

Granulocyte-colony stimulating factor (G-CSF) producing tumors are rare and have been reported to occur in a variety of organs including the liver, biliary tract, and pancreas.^1–6 Previous studies have shown the extremely high malignant potential and aggressive clinical features of G-CSF producing tumors, regardless of the histologic type and location of tumor.^7,8 However, due to the rarity of these tumors, the precise biologic characteristics and optimal therapeutic strategies are largely unknown. Herein, we present the first operative case of G-CSF-producing extrahepatic bile duct cancer to provide the information of our multimodal treatment.

Case Report

A 59-year-old woman was admitted to our hospital for the treatment of obstructive jaundice and acute cholangitis. After endoscopic biliary drainage, she recovered from liver dysfunction and infection. However, leukocytosis persisted even after the resolution of cholangitis. Major serum tumor markers were within normal ranges. The serum concentration of G-CSF was 73.0 pg/mL (normal range, <39.0). Endoscopic retrograde cholangiography (ERC) showed defects in the dilated common bile duct. However, the tumor was too large to be entirely visualized by ERC. Furthermore, cytology of bile juice during ERC was negative. Computed tomography (CT) showed a large mass of 60 mm in the head of the pancreas and enlarged para-aortic lymph nodes (Fig. 1). Since other distant organ metastases were not detected, she eventually underwent pancreatoduodenectomy. The postoperative course was uneventful except for transient pancreatic fistula. After operation, the leukocytosis was resolved, and the serum concentration of G-CSF was normalized to 27.3 pg/mL.

View Figure

• Download as Powerpoint
• Download Figure

Grossly, the lower portion of the common bile duct was markedly dilated, and a large polypoid tumor measuring 8 × 5 cm fills the lumen of dilated bile duct. The cut surface of the tumor showed yellowish-white tissue with invasive growth to the adventitia/subserosa. Microscopically, spindle or polygonal tumor cells having enlarged pleomorphic nuclei proliferated in sheets or vague nests without tubular formation. Desmoplastic reaction is associated in tumor tissue. Bizarre, giant tumor cells are frequently observed (Fig. 2). Immunohistochemically, these tumor cells were weakly positive for epithelial membrane antigen (EMA) and CA19–9, and negative for MUC5AC, MUC2, MUC1, CEA, and CK19. The tumor was diagnosed as undifferentiated carcinoma. In addition, tumor cells were also positively stained for G-CSF (Fig. 3).

View Figure

• Download as Powerpoint
• Download Figure

View Figure

• Download as Powerpoint
• Download Figure

She received adjuvant chemotherapy of gemcitabine (1,000 mg/m² intravenously for 30 minutes). After a total of 8 doses of gemcitabine, CT revealed metastases in the lung and distant lymph nodes. Then she received the combination of cisplatin (25 mg/m² intravenously for 90 minutes) and gemcitabine (1,000 mg/m²). The therapy was effective especially for pulmonary metastasis leading to complete response. However, several paraaortic and mesenteric lymph nodes became enlarged thereafter. After 11 doses of cisplatin and gemcitabine therapy, chemotherapy was switched to the combination of oral S-1 (80 mg on alternate days) and gemcitabine (1,000 mg/m²). Although a total of 8 doses of S-1 and gemcitabine therapy were given, her condition gradually worsened due to tumor enlargement. She died 17 months after surgery.

Discussion

Previous reports have shown that G-CSF producing tumors can occur in various organs and tissues including gastrointestinal tract. Most of them also demonstrate the aggressive clinical features of G-CSF tumors regardless of organs or histologic types. Even after curative-intent surgery, G-CSF tumors rapidly recur and spread widely, leading to a fatal condition of patient. In biliary tumors, some G-CSF producing gallbladder carcinoma and intrahepatic cholangiocarcinoma (ICC) have been reported. There are only a few reported cases of gallbladder carcinoma with favorable outcome after surgery.^3,4 Furthermore, a few reported ICC had an extremely poor prognosis of patients.^5,6 These patients died only several days after diagnosis or palliative surgery. Furthermore, to our knowledge, only one autopsy case of G-CSF producing extrahepatic bile duct carcinoma has been reported.⁷ In that case, he did not receive any anticancer treatment such as surgery and chemotherapy, and he died at 28 days after admission. However, the underlying mechanisms in extremely high malignancy of G-CSF producing tumors remain largely unknown.

G-CSF is a cytokine known for its ability to stimulate migration of granulocyte precursor stem cells, leading to increased white blood cell counts. Besides this common function, G-CSF also has diverse effects in physiologic and pathologic conditions. G-CSF has been shown to enhance Ab-dependent cellular cytotoxicity and cytokine production in neutrophils.⁹ Furthermore, it also induces surface expression of important effector molecules, such as CD14, CD32, and CD64. These effects may lead to favorable clinical outcomes in patients with an increased risk of infections, such as cancer and immunocompromised patients. In sharp contrast, G-CSF has inhibitory effects in immune response. Previous studies have demonstrated that G-CSF exerts immunosuppressive effects on monocytes, macrophages, and dendritic cells under various conditions.^10–12 In addition, G-CSF has also been shown to be a potent immune regulator of allogeneic T-cells.¹³ Furthermore, a recent study has suggested that G-CSF is a cancer stem cell-specific growth factor.¹⁴ These diverse functions of G-CSF may contribute to high malignancy of various cancers, although the precise function in the tumor environment is not elucidated. In fact, Morris et al have shown that G-CSF and G-CSF receptors are highly expressed in human gastrointestinal cancers.¹⁵ They also demonstrated that G-CSF induces the proliferation and migration of gastrointestinal carcinoma cells, and expands a subpopulation of carcinoma cells expressing stem-like markers. Taken together, it is most likely that tumor-producing G-CSF plays a critical role and contributes to the nature of this lethal disease. However, further fundamental studies are clearly required to clarify the etiology of G-CSF producing tumors.

Biliary tract cancers are relatively rare malignancies especially in Western countries.¹⁶ Although complete surgical resection offers the only chance for a cure, recurrence often develops. Furthermore, many patients are not candidates for surgery owing to the high incidence of distant metastases at the time of diagnosis. Chemotherapy may be considered for patients with unresectable biliary tract cancers. A phase III clinical trial for metastatic biliary tract cancers has shown a survival benefit.¹⁷ The study demonstrated that gemcitabine plus cisplatin treatment was statistically significantly superior to gemcitabine monotherapy. The median overall survivals in the former and latter treatment groups were 11.7 and 8.1 months, respectively. In our case, distant metastasis other than enlarged paraaortic lymph nodes was not detected preoperatively. Furthermore, there is no evidence of survival benefit with neoadjuvant treatment for biliary tract cancers. Therefore, we tried to perform curative-intent surgery. Although the role of adjuvant therapy is unclear, we employed adjuvant chemotherapy of gemcitabine. Because metastases in the lung and distant lymph nodes were found during the treatment, the patient received the combination of cisplatin and gemcitabine. The therapy turned out to be effective especially for pulmonary metastasis. As a result, the patient survived more than 1.5 years. Although the outcome was not entirely satisfactory, our clinical experience suggests a certain effect of combined aggressive treatment for G-CSF producing tumors.

To our knowledge, this is the first report of multimodal treatment with surgery and systemic chemotherapy for G-CSF producing extrahepatic bile duct cancer. Our data highlight the potential of multidisciplinary treatment even for this lethal disease condition. Thus, this study may provide new insights into the pathogenesis and treatment of G-CSF producing tumors.