Resectability and Prognosis of Gallbladder Cancer: An experience of 100 cases from a tertiary care centre of Eastern Nepal

Abstract

Introduction

Gallbladder cancer (GBC) is the most common cancer of the biliary tract and has an overall incidence of 3 per 100000 people [1]. Only 15%-47% of the preoperatively known gallbladder carcinomas are suitable for resection [2]. This is because of the aggressive tumor biology, thin walled gallbladder and close approximation of it to the liver, leading to early spread. Furthermore, the gallbladder is situated in the “busy area” of the portal triad leading to involvement of the major vascular structures, and hence unresectability. The outcome of GBC is poor, and the overall 5-year survival rate is less than 5%. In early-stage or incidentally detected disease, a 5-year survival rate up to 75% can be achieved, provided stage-adjusted therapy is performed [3]. On contrary, if GBC is locally advanced, and radicle resection combined with neo-/adjuvant chemotherapy is subjected, the 5-year overall survival is only 20–30% [3].

With reference to GBC cancer statistics (2018), Nepal ranks the fifth highest incidence rate in the world, with 6.7 cases/100,000 population per annum [4, 5]. Our centre caters 2.5 million populations, and we frequently observe cases of GBC in the outpatient clinic. The aim of our study was to evaluate the incidence of resection of GBC with curative intent and the overall survival.

Materials And Methods

After Institutional Review Board approval (10.082), a review of a prospectively collected database of all patients with GBC treated at our tertiary academic hospital between January 2014 and December 2019 was done. Data collected included patient demographics, incidental vs. non-incidental GBC, presence of gallstones, symptoms at presentation, presence of jaundice, stage of the disease, resectability, CA19-9 level, extents of resection, resection (R) status, complications, pathology, recurrence and survivals. The 7th edition of the American Joint Committee on cancer (AJCC) staging system was used for pathological and/or clinical staging. Only patients with a histological conformation of gallbladder cancer were included. Patients were excluded if the indication for surgery was xanthogranulomatous cholecystitis or benign disease, or were lost to follow-up. The primary endpoint was incidence of resectability and median survival of patients after curative intent surgery for GBC.

Patient Management

Preoperative staging routinely included CA 19 − 9 value determination and abdominal computed tomography (CT). Magnetic resonance cholangio-pancreatography (MRCP) was performed in all resectable jaundiced patients after CT. In Jaundiced patient with resectable disease, surgery was scheduled only if adequate FLR hypertrophy was observed. Preoperative biliary drainage was performed for deep jaundice (bilirubin > 10 mg/dl), cholangitis, major liver resection or malnutrition. Surgery was performed whenever complete resection was achievable. Distant metastases, extensive infiltration of the hepatoduodenal ligament and aorto-caval LN metastases were considered contraindications to surgery. Combined pancreatoduodenectomy was performed in case of infiltration of the duodeno-pancreatic area by the GBC or by large retropancreatic LN metastases. Colonic or gastric resection was performed in case of direct tumor infiltration. The standard scheduled procedure for GBC was wedge resection or bisegmentectomy (segment 4b-5-if large area of liver infiltration by tumor), en-bloc cholecystectomy and hepatoduodenal ligament node dissection.

Adjuvant Treatment And Follow-up

Postoperative chemotherapy was delivered according to the patient performance status and pathological findings. All patients were followed-up every 3 months with a physical examination, CA 19 − 9 determinations and abdominal CT. Six patients were lost to follow-up.

Definitions

Major hepatectomy was defined as resection of three Couinaud segments. Operative mortality was defined as death within 90 days after surgery or before discharge from the hospital. Morbidity included all postoperative complications and was classified according to the Clavien-Dindo classification.

Results

Surgery

The curative intent resection was possible in 30 (30%) patients; while 18 (18%) required palliative surgical treatment. Metastatic disease was dominant in 48 (48%) patients who were managed with best palliative treatment. The incidental GBC (IGBC) was observed in 7 (7%) patients. Curative intent surgery was possible in 4 out of seven patients with IGBC. The remaining IGBC were metastatic due to delayed presentation to our centre. Resectable tumor but inoperable disease (because of age and comorbidity) was observed in 4 patients. Of the 48 patients who were metastatic, 23 were clearly unresectable based on preoperative imaging. Further, twenty-five patients were found to have unresectable disease at staging laparoscopy/laparotomy. Figure 1. shows the flowchart of patients with GBC and the respective surgical intervention and outcome.

All patients except three had a wedge resection of liver. An extended right hepatectomy with bile duct resection was performed in two patients; one underwent hepatopancreatoduodenectomy; and one required segmental colectomy.

Pathology

At histopathological examination, adenocarcinoma was found in 95 patients and squamous cell carcinoma in 5 patients. After curative intent resection, out of 30 patients, only 12 received and completed adjuvant chemotherapy. R0 resection was achieved in 66.6% (20/30) patients. All except three patients were locally advanced (T3, N1) GBC in curative intent group. The median number of lymph nodes harvested was 4 (0–7) in extended cholecystectomy. Six patients who underwent extended cholecystectomy for presumed GBC were excluded because of xantho-granulomatous cholecystitis (XGC).

Outcome

The perioperative morbidity and mortality was observed in 23% (major- 20%; minor-80%) and 3% respectively. The overall survival of the entire group was 9 months; while those patients who underwent surgery with curative intent have median overall survival of 28 months after median follow-up of 42 months (12–64 months). Tumor recurrence occurred in 46% (14/30) patients (1 in IGBC group); following curative intent resection. Three patients had a local recurrence only, 3 patients had metastatic disease and local recurrence, and 8 patients had metastatic disease only. The incidence of resectability was 30% and the median survival of 42 months in curative intent surgery group (Fig. 2).

Discussion

Gallbladder carcinoma (GBC) is a common malignancy in our part. Unfortunately, majority (70%) of our patients present with advanced stage disease and are unresectable as compared to other similar studies from Indian subcontinent [6, 7]. Only 30% of patients are subjected to curative intent surgery with a median survival of approximately 28 months. The further findings observed in the present study was high number of IGBC (7%vs. 1%) and young-onset GBC- 10%, compared to similar study in the world .

In the study by Subedi et al from Nepal, the incidence of GBC was higher in the Kathmandu Valley than the cities of India and China. Cancer of gallbladder was among the top five commonest and lethal cancers in both sex [8]. In addition to high incidence of GBC in Nepal, the presentation of patients is usually late with advanced stage of disease. Some studies have shown association of history of gallstone, smoking, and early menarche with GBC in Nepal [9, 10]. Thus, locally tailored research is important to understand the reason behind the higher incidence of GBC and identify as to whether any preventive measures could be adopted.

According to the American Cancer Society, only about 1 in 5 GBC cases will be discovered when the disease is still localized to the gallbladder [11]. The remaining cases are diagnosed when the malignancy has spread outside of the gallbladder, which drastically limits the available options for curative treatment and lowers overall survival. In line with the aforementioned study, 90% of those who underwent curative intent surgery presented to us with advanced stage of tumor (T3,N1). Unfortunately, around 10% of our patients in the study were young (< 40 years) onset GBC. They were predominantly metastatic, advanced staged with less than a year survival even after extended resections. Seventy percent (70%) of the patients had associated gallstones. This recommends for proper GBC cancer surveillance, especially considering all benign cases of cholecystectomies with a histopathological examination and addressing the associated risk factors like gall stones in context to Nepal.

The majority of GBC patients who present with jaundice will have disseminated disease even if it is not detectable on preoperative work-up or operative exploration. The en-bloc resection of the CHD/CBD, which is frequently required in these patients, is difficult and associated with positive (R1) margin status in 40% of patients [12, 13]. Despite anecdotal reports of longer postoperative survival in GBC patients presenting with the rare combination of jaundice without nodal involvement, [14] even in patients with a negative (R0) margin, the median length of disease-free survival in preoperatively jaundiced patients is only 6 months [15]. Based on these data, preoperative jaundice is considered a relative contraindication to radical resection of GBC. In contrast to the aforementioned, 56% of our patients presented with jaundice. Out of 30% of patients who underwent curative intent surgery, median overall survival of 28 months after median follow-up of 42 months (12–64 months) was reported. Our published study has shown, curative resection was possible in 9% (5/56) patients in GBC with obstructive jaundice [16]. Thus, with reference to our study, GBC with jaundice can no longer be considered as a contraindication to resection, albeit with a low rate.

Likewise, long-term survival after radical resections that included major hepatectomy, CHD/CBD and/or vascular resection or reconstruction has been anecdotally reported, [17] but these radical resections have not been associated with longer disease-free or overall survival on a population basis. Instead, they are associated with increased morbidity and mortality. Radical resections of locally advanced primary tumours should, therefore, be performed only in medically fit patients after multidisciplinary discussion. Although R0 resection for GBC is associated with longer survival, tumour biology and stage, rather than the extent of resection, are the most important predictors of survival after surgery [18].

In our study, perioperative morbidity and mortality were (23%) and (3%) respectively. The overall survival of the entire group was 9 months. Out of 30 patients who underwent curative intent surgery, 20 (66.67%) had R0 resection. Median overall survival of 28 months after median follow-up of 42 months (12–64 months) was reported. This adequately supports that radical resection for GBC renders good prognosis and prolonged overall survival. According to our study, only 30% of those presenting to us, undergo curative intent surgery. Further, only 12 (40%) of them have completed adjuvant chemotherapy. This low adjuvant therapy completion is because of lack of health insurance coverage, financial burden, geographical status and poverty.

In our study, 7% (n = 7) had incidental GBC, quite a high incidence. Out of them, 57.1% (n = 4) underwent curative intent surgery with a good prognosis. The remaining had metastatic disease due to port site metastases and delayed presentation. GBC is suspected preoperatively in only 30% of all patients.¹ The remaining 70% of cases are diagnosed using postoperative incidental findings by a pathologist. Incidental GBC is high by 2–3 times compared to total GBC.In a study by Poudel et al, incidence of IGBC in cholecystectomies specimens for benign disease is 1.67% [19]. They recommended that routine histopathology of cholecystectomy specimen should be sent for early diagnosis and improve survival of patient with gall bladder cancer. Hence, gallbladder should be evaluated histo-pathologically in all patients after laparoscopic cholecystectomy, as these are the group of patients with early stage disease with better survival.

Few published studies have focused on the patterns and timing of recurrence after resection of GBC. Despite curative intent resection, up to 66% of resected patients develop recurrence, mostly within 2 years of surgery, often at the distant site [20]. In line to the aforementioned, out of 30 patients who underwent curative intent surgery, 46.6% (n = 14) had recurrence in the present study. Three patients had a local recurrence only, 3 patients had metastatic disease and local recurrence, and 8 patients had metastatic disease only. This high recurrence was because of low R0 resection, lack of completion of adjuvant chemotherapy and advanced stage disease.

Our study has some limitations. The study is limited by the small sample size of patients with GBC undergoing surgery with a curative intent. Also, this is a single centred study. Otherwise, more robust evidence could have been delivered with a multi-centre study. However, the best part of the study is that, it is one of the preliminary and prospective studies with 3 years follow-up from our part. A larger sample size, government health insurance coverage for overall treatment and multi-institutional involvement, henceforth, may provide a better insight to the incidence and prognosis of GBC.

Conclusion

The study demonstrates that in GBC, provided multimodality approach, aggressive surgical resection with curative intent is feasible in only one-third of patients with an acceptable operative morbidity/mortality. Surgery provides a survival benefit in curative and palliative group of patients. However, majority (70%) of GBC patients are at advanced stage disease and unresectable at time of presentation. Neoadjuvant therapy, health insurance, ultrasound surveillance for GB stone and prophylactic cholecystectomy may result in better outcome of these patients.

Declarations

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Competing Interests

The authors have no relevant financial or non-financial interests to disclose.

Author Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Narendra Pandit, Durga Neupane, Dinesh Nalbo, Sameer Bhattarai, Kunal Bikram Deo, Lokesh Shekher Jaiswal and Shailesh Adhikary. The first draft of the manuscript was written by Narendra Pandit and Durga Neupane and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Data Availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Ethics approval

Ethical approval for this study was obtained from Institutional Review Board approval (10.082), B.P. Koirala Institute of Health Sciences, Dharan, Nepal.

Consent to participate

Informed consent was obtained from all individual participants included in the study.

Consent to publish

The authors affirm that human research participants provided informed consent for publication of the findings in this research.

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table

Table 1. Clinical profile and treatment outcome of patients enrolled in the study (n=100).