Bony Secondaries and Dissemination in Advance Carcinoma Gallbladder: A Longitudinal Study

Introduction

Carcinoma of the gallbladder (GBC) is the most common malignancy of the biliary tract and the third most common gastrointestinal malignancy in eastern Uttar Pradesh [1]. It is a common disease in countries such as Chile (16-27/100,000), Japan (7/100,000), India, Central Europe – Poland (14/100,000), Israel (5/100,000) and southern Pakistan (11/100,000); however, it is uncommon in the United States (1.5/100,000) [2]. In India, GBC is most prevalent in northern and north eastern states of Uttar Pradesh, Bihar, Orissa, West Bengal, Assam [3] and Gangetic delta [4]. GBC is two times higher in women than men and is the leading digestive cancer in women in northern India cities [5] GBC ranks amongst the first 10 cancers in the ICMR registries (2006-2008) of Delhi, Dibrugarh, Kolkata, Bhopal and Mumbai [6]. The incidence of GBC increases after the age of 45 years and found to be highest at the age of 65 years [7]. The incidence rate also varies within the Indian population. It is very high in Northern India, 4.5 per 100,000 for males and 10.1 per 100,000 for females, but low in South India, 1.2 per 100,000 for males and 0.9 per 100,000 for females as reported by the population- based cancer registry, Delhi [8]. Apart from gallstones, female gender, ethnicity, genetic susceptibility and lifestyle factors are associated risk factors in the development of GBC either as initiators, such as unknown endo- and exobiotic mutagens, or as promoters, including chronic inflammation and infection [9].

The Mode of Spread

GBC is an aggressive tumour with early dissemination to lymph nodes. The prognosis is poor except when detected incidentally in early stages. It has a five year survival rate of about 5% with a median survival of about seven months [10].

The surgical management of GBC depends on mode of spread to liver, lymphatic and vascular invasion; direct spread to contiguous organs and intraperitoneal seeding and intraductal i.e. through the cystic duct. Ito and Mishima [11] proposed three pathways of lymphatic drainage from the gallbladder, level I (cholecystoretropancreatic), level II (cholecystoceliac) and level III (cholecystomesenteric). Tsukada, et al. [12] confirmed this theory using the surgical specimens from radical resections. The overall rate of lymph node metastasis in GBC ranges from 54% to 64% and is strongly collated with the depth of invasion [13]. Vascular invasion is reported in 15% of cases [14]. Trans- peritoneal spread is common and involves liver, common bile duct, colon, duodenum, pancreas, omentum and stomach. Neural spread, which is reported in 25% to 35% of cases, is a poor prognostic sign [15]. Skeletal metastasis in gallbladder carcinoma is extremely rare [16]. Only few such case reports are available in English literature showing metastasis to femur, skull or vertebrae [17, 18, 19, 20].

Subjects and Methods

This study was carried from 2010 to 2014. The study was approved by the review board and ethical committee of Institute of Medical Sciences, Banaras Hindu University Varanasi. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki (6th revision, 2008). Informed consent was obtained from patients. A total of 95 patients were examined clinically with detailed systemic examination. Stress was made on symptoms and signs like bony pain or pathological fracture. Ultrasound (US) is the primary imaging modality of investigation for screening. USG has high diagnostic accuracy in GBC, but it has limitations in staging of tumour. Philips IU 22 was used for screening all cases. Further, ultrasonographically diagnosed and histopathologically proven cases of GBC were subjected to volumetric CT examination of abdomen and pelvis (plain, post contrast and delayed phase). On clinical suspicion of any extra-abdominal organ involvement additional scan of that particular region were included. Reconstructed images were obtained and detailed assessment of cases was done by experienced radiologists of our department. In case of difference in opinion, common consensus was taken. Data were analyzed using the Statistical Package for Social Sciences (SPSS 16, Chicago, IL, USA).

Results

In our study of the ninety six cases ( n= 96) ,Based on staging 7% were T2(n=7),43.1% were T3 (n = T3),49.4 % were T4 (n= 47) , the incidence of bony metastasis was four cases , two cases each in T4 and T3 stages respectively Table 1.

Based on the incidence of loco-regional and distal spread of carcinoma gallbladder, hepatic invasion was the most common constituting 77.8% , followed by lymph nodal metastasis (61%), hepatic metastasis (43.1%), porta invasion (40%), mass replacing GB fossa (40%) and the incidence of bony metastasis constituted 4.7%(n=4), Table 2.

In case of lumbar vertebral and iliac wing involvement the lesions were hyper dense suggesting osteoblastic metastasis (Figure 1). In second case hypodense lesions was noted involving dorsal vertebra which suggest osteolytic metastasis (Figure 2). Ala of sacrum showed both osteolytic and osteoblastic type of metastasis (Figure 3). All 4 cases involved axial skeleton. All cases were seen in advanced stage of carcinoma (T3 and T4). Among patients of Gall bladder carcinoma with skeletal secondaries, two presented clinically with features related to secondaries, while the other two had advanced metastatic disease presenting with obstructive jaundice (Table 3).

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Carcinoma gallbladder (GBC) is a lethal malignancy with marked ethnic and geographical variations. The presenting symptoms are vague so that its diagnosis occurs at an advanced stage. The overall 5-year survival of patients remains low. Carcinoma gall bladder mostly presents in advanced stage with abdominal symptoms and obstructive jaundice. In presence of metastasis, the management is palliative and role of chemotherapy is limited for palliation of symptoms. There is a clear worldwide association between chronic cholelithiasis and GBC [9, 21]. Aside from gallstones, female gender, ethnicity, genetic susceptibility and lifestyle factors a number of associated risk factors appear to favour the development of Ca GB [9, 22]. A CT scan is used for assessing gallbladder mass, wall thickening, polyp and tumour staging. CT reveals depth of infiltration into the liver and extension into stomach, duodenum, colon or pancreas [23]. Ancillary findings on CT include gall stones, wall calcification, and dilated biliary radicals. When vascular invasion occurs, it leads to localized involvement of the liver in the neighbourhood of the primary lesion rather than disseminated multiple nodules [24]. Disseminated metastases occur late in the course of the disease and are probably due to invasion of the retroperitoneal veins. CT also helps to assess peritoneal deposits, hepatic metastasis and lymphatic dissemination thereby helping in staging the disease more accurately [23, 24]. High positive predictive value of CT means that it is useful for determining resectability and assisting treatment planning [25]. Infiltrated lymph nodes are > 1cm, ring shaped with heterogeneous uptake after contrast administration [26]. Pericholedochal nodes are most frequently involved followed by cystic nodes [12]. The sensitivity of CT is 0.36 to 0.47 for N-staging (PPV: 0.94; NPV: 0.92); 0.65 for hepatic infiltration of <2 cm (PPV: 0.77) and 1.0 for >2 cm (PPV: 1.0); 0.50 for spread to extrahepatic bile duct (PPV: 0.90), 0.57 for gastrointestinal or pancreas (PPV: 0) and 0.71 for detection of hepatic metastases (PPV: 1.0) [27]. Koo, et al. [28] found bone metastases in only 2 out of 100 cases of metastatic carcinoma of the gall bladder studied by them. The incidence of bone metastasis in carcinoma gall bladder is very low and, when present, it is usually associated with advanced disease. Hence, a bone scan is not included in the routine work-up of gall bladder cancer patients.

In our study, the stage distribution according to the TNM system revealed n=0 patients at stages I, n=7 in stage II, n=41 in stage III and n=47 in stage IV. Among these, 4 cases were found metastasizing to bones i.e. Dorsal and lumbar vertebrae, ala of sacrum and iliac wing was involved. All These cases were seen in advanced stage of carcinoma (T3 & T4). Preoperative staging using helical CT has an overall accuracy ranging from 83 to 86% [27, 28, 29]. Most of the time the disease is diagnosed in advanced stage, making the prognosis poor. The overall prognosis was significantly determined by metastatic spread to the lymph nodes [30]. The present study shows that the incidence of skeletal metastasis in cases of Gall bladder carcinoma might be under-reported in the literature. Moreover, two patients in the present study presented with complaints pertaining to the bony metastasis with clinically silent Gall bladder disease. To the best of our knowledge, less than 10 cases have been reported in literature with gall bladder malignancy, clinically presenting with clinical features of skeletal secondaries. The reported sites of skeletal secondaries were femur, clavicle, humerus, calvaria, and lumbar vertebrae [31, 32, 33, 34]. The recognition of skeletal metastasis is clinically important to tailor the appropriate palliative care, even when the bony disease is clinically silent. This study was performed with a 64-row CT scanner, which was associated with radiation exposure. Positron emission tomography is a sensitive imaging modality for detection of metastases, but it is also associated with radiation exposure like computerised tomography and is expensive [35]. Recent developments and new clinical applications of conventional imaging techniques (eg, dual-energy spectral computed tomography [CT], elastography, and virtual colonoscopy) may offer additional information in patients undergoing metastatic work up. Moreover, imaging findings derived from functional and molecular imaging with diffusion-weighted imaging (DWI), dynamic contrast material–enhanced (DCE) imaging, blood oxygen level–dependent imaging, positron emission tomography (PET) with different radiotracers, and MR spectroscopy may be critical in decision making for patients with secondaries [36].

Bone scan was not performed to provide a complete skeletal survey in any of the patients which can be attributed to the retrospective nature of this study. The authors' conclude that addition of bone scans to imaging protocol of these patients would further add up to the total number of cases with skeletal secondaries. The overall implication of the presence of bony metastasis on the patient’s survival could not be ascertained as most of the patients were lost in follow up.

Conclusion

The presence of undiagnosed systemic and bony metastases from gallbladder cancer might explain its poor prognosis despite radical surgery. To our knowledge, till date no longitudinal study has been done to assess incidence, type (osteolytic or osteoblastic or mixed), predisposing site and time of presentation (stage) of skeletal metastasis in GBC. The present study provides new and important information regarding skeletal metastases which may be more common with the introduction of laparoscopic cholecystectomy and should be excluded before radical resection is contemplated. We further emphasize that skeletal metastasis might be more common than presently reported and an addition of skeletal survey in diagnostic algorithm will help in guiding the palliative therapy.