Cancer de la vésicule biliare de découverte fortuite, à propos de 30 cas.

S. OMRANI OMRANI |

La tunisie chirurgicale - 2015 ; Vol 25

Resumé

Pré-requis : Le carcinome de la vésicule biliaire représente 98% de toutes les tumeurs malignes de la vésicule biliaire. C’est le sixième cancer digestif dansle monde. Découvert fortuitement, après une cholécystectomie,son incidence est entre 0,19 à 3,3% dans la littérature. Objectif : Etablir le taux du cancer de la vésicule biliaire, découvert fortuitement, sur pièce de cholécystectomie, chez les patients subissant une cholécystectomie pour maladie biliaire bénigne (lithiase vésiculaire simple ou cholécystite) et d'étudier l'approche thérapeutique. Méthodes : Nous avons étudié les patients qui ont subi une cholécystectomie par laparotomie ou laparoscopie, pour un calcul vésiculaire, chez qui nous avons trouvé, fortuitement, en post opératoire, un cancer de la vésicule biliaire. Les critères épidémiologiques, cliniques et pathologiques ont été analysés. La survie a été calculée par la méthode de Kaplan-Meier. Résultats : Trente patients qui avaient un cancer, de la vésicule biliaire, de découverte fortuite, étaient analysés au cours d'une étude rétrospective, sur 3624 patients ayant eu une cholécystectomie. Il s’agissait de 8 hommes et 22 femmes. L'âge moyen était de 61,3 ans. Tous les patients étaient d'abord opérés pour lithiase biliaire, avec un délai moyen de 33 jours, depuis le début des symptômes. La classification pTNM : pTis était trouvé dans 1 cas, pT1a dans 3 cas, pT1b dans 3 cas, pT2 dans 16 cas et pT3 dans 7 cas. Dans notre étude, dix patients n’étaient pas opérés : quatre patients (13,33%), en raison du stade précoce de la maladie (1pTis, 3pT1a), cinq patients (16%) en raison, des métastases et un patient (3%) pour une contre-indication anesthésique. Dans 18 cas (60%), la ré-intervention était réalisée pour obtenir une résection étendue. Le délai moyen de la ré-intervention était de 72 jours. La mortalité post opératoire était nulle. La morbidité était de 22,33%. Dans notre série, la survie globale, pour tous les stades de la maladie était de 56,7% après 12 mois, 40% après 24 mois et de 36,7% après 3 ans. Conclusion : Le cancer de la vésicule biliaire, découvert sur une pièce de cholécystectomie, est rare, et de pronostic sévère. Elle peut conduire à une ré-intervention avec résection étendue. Cette résection est possible dans un groupe de patients sélectionnés (stade ≥ T1b, sans métastases) et doit répondre à des critères chirurgicaux, bien définis : pour les tumeurs Tis ou T1a, la cholécystectomie seule est recommandée, pour les tumeurs T1b, la résection du lit vésiculaire et un curage ganglionnaire du pédicule hépatique sont recommandés, pour les tumeurs T2, T3, T4, N+, l’objectif est l’obtention de marges de résection R0, en adaptant l’étendue de la résection hépatique.

Mots Clés

Cancer

Introduction :

The common use of laparoscopic techniques has led to an increase in recommendations for cholecystectomy. With the advantage of a shorter hospital stay, decreased post-operative pain and an early resumption of normal activities, this procedure has now become usual in the treatment of benign gallbladder disease in surgical units all over the world [1]. The incidental finding of a gallbladder cancer at an earlier stage has changed the management and the outcome of the disease [2]. The incidence of incidental gallbladder cancer (IGBC) has been reported to be between 0.19 to 3.3% at various centers [1]. This cancer can only be cured by radical surgical resection. The goal of radical resection should be cholecystectomy with an “en bloc” resection of the invaded surrounding organs to obtain free margins and to resect regional lymph nodes. However, there is still a debate about the extent of hepatic resection and the extent of regional lymphadenectomy [3] IGBC is an uncommon cancer that has traditionally been associated with a poor prognosis. This prognosis depends primarily on the stage, histological grade, surgical margins, lymphatic, vascular and/or perineural spread of the tumor [4]. In Tunisia, the incidence and prognosis of IGBC has not been the subject of many studies. Through this retrospective study, our aim is to establish the rate of incidental gallbladder carcinoma in patients undergoing cholecystectomy for benign gallbladder diseases in order to study the demographic profile and the therapeutic approach of these patients.

Article

Material and methods

Data collection From 2000 to 2011, in the Department of General Surgery of Mongi Slim Hospital, 3624 patients underwent cholecystectomy. Within this group of patients, all the cases of GBC were retrospectively reviewed. Routine preoperative assessment was performed in all patients, including liver function test and abdominal ultrasonography of the hepatobiliary tree. Exclusion criteria were the suspicion of malignancy and/or the existence of gallbladder polyps detected during preoperative ultrasonography. Patients’ demographic data, as well as type of operation, surgical morbidity and mortality, histopathological classification, and survival rate were collected in a database for further analysis. The staging of gallbladder neoplasm was made by physical examination, laboratory and imaging studies [ultrasonography and computed tomography (CT)]. Postoperative followup was done with clinical examination and determination of CA19-9 and carcinoembryonic antigen (CEA) levels, ultrasound and computed tomography (CT) scans were performed regularly.

Surgical procedure

All operations were carried out by senior surgeons or trainees under supervision using the standard four-port, two-hand technique, in laparoscopy approach. Following direct 10 mm trocar insertion, a 13 mmHg CO2 pneumoperitoneum was created. In laparotomy approach, an incision under the right costal is used. The Intraoperative cholangiograms were used when necessary (cholestasis or suspicion of bile duct stone). Drains were used, depending on the choice of the surgeon. The presence of a nodular pattern and/or irregularity in the gallbladder wall after dissection was evaluated as a cause of suspicion of a cancer.

Pathologic examination

Pathological examination focused initially on the macroscopic study of specimen cholecystectomy, fixed in formalin 10%. This study follows a well-established protocol : first the opening of the piece, then a careful palpation of the wall followed by a description of any injuries and the realization of samples. Several samples were taken systematically : - A Collection at the collar of bladder with cystic ganglion if present. - One or two specimens in the body, depending on the length of the bladder. - Two samples at the bottom. The samples were also interested all macroscopically visible lesions with identification of cassettes. Specimen were kept in reserve for possible reversal. In some situations, especially in case of suspicion of tumor, some parts have been included in full. In our work, we have identified from the initial reports : the site of the tumor, its appearance, its size and the presence or absence of gallstones. For histological study, the samples were included in paraffin blocks, sectioned and stained by standard staining with hematoxylin-eosin (HE). Histological data were : histological type, degree of differentiation, the degree of infiltration of the wall and possibly the adjacent liver, the presence of vascular emboli of and perineural invasion. The histological classification adopted is that of WHO digestive tumors published in 2010. The staging was evaluated according to pTNM classification proposed by the Union of international cancer control (UICC) in its 7th edition, 2009. A positive margin was defined as a margin of < 1mm and lymph node involvement (N1 disease) as tumor involvement in at least one removed lymph node. Histological differentiation was categorized as well, moderate or poorly differentiation.Immunohistochemical study was performed for typing poorly differentiated tumors. The markers used were : cytokeratin and neuroendocrine markers : Chromogranin A and synaptophysin.

Statistical analyses

The data was summarized by descriptive statistics (means and frequencies) and analyzed using SPSS 11.5. Data are shown as percentage, mean and standard deviation (SD). Differences in proportions were analyzed by chi-square or Fischer test ; differences in mean quantitative value were analyzed by student’s t-test. P value less than 0.05 was accepted as statistically significant. Survival rate were established using the Kaplan-Meier method and differences between curves were demonstrated using the log-rank test.

Result

During a retroprospective study, including 3624 patients operated, who underwent a cholecystectomy, surgery was performed for gallstones in 56.6% of cases, acute cholecystitis in 36.6% and peritoneal syndrome in 6.6% of cases. No patient had evidence of symptoms of cancer before surgery. The middle time of surgery was 33 days (range : 1-740 days). Twenty five patients underwent a laparoscopic cholecytectomy (83.3%) and five underwent an open laparotomy (16.6%). During laparoscopic cholecystectomy, incidental gallbladder wall perforation and unprotected extraction of the gall bladder were noted respectively in 3 and 2 cases. During this study, 30 patients affected by incidental gallbladder cancer have been found. There were 22 women and 8 men. The incidence was 0.8%. The male to female ratio was 0.36 and the mean age was 61.3 years (range : 38-80 years). The stage of the IGBC was pTis in 1 patient (3.3%), pT1a in 3 patients (10%), pT1b in 3 patients (10%), pT2 in 16 patients (53.3%) and pT3 in 7 patients (23.3%) (Table 1). Seventy three percent of the incidental cases were discovered at an early stage (≤ 6). All the cases were diagnosed postoperatively during the pathological examination. Patients with pathologically confirmed gallbladder polyps and suspicion of malignancy before surgery were excluded. After the postoperative diagnosis of the incidental gallblad-der cancer, all the 28 patients were called for staging (2 patients died due to : a heart failure for one, pulmonary embolism for the second one). Ten patients were not suitable for reoperation because of 5 distant metastases (2 cases of liver metastases (6.6%) and 3 cases of peritoneal carcinomatosis (10%)), one contraindication for general anesthesia (acute coronary syndrome), and 4 early stage of cancer (1 pTis and 3 pT1a). The median time between cholecystectomy and reoperation was 72 days. A number of 18 patients were re-explored. No postoperative mortality was noted. 16.6% of the morbidity was due to heart failure (1 case), urinary infection (1 case), and a biliary fistula in 1 case. The distribution of histologic subtypes in the current study noted one case of liver invasion (pT2), lymph node involvement in 2 cases (1 pT2, 1 pT3), cystic resection margin was invaded in 2 cases (2 pT2), port-site metastases were found in one case (p T2). Two of the 18 patients reoperated, had no extensive resection, due to peritoneal carcinomatosis (1 case) and a lymph node invasion (1 case). Data and results of surgical procedure in 2nd time operation are resumed in table 2 and 3.

Five patients (16.6%) underwent adjuvant chemotherapy. Patients received a variety of dose and number of cycles of chemotherapy. Parenteral chemotherapy based on 5-fluorouracil + adriamycin and cisplatin was prescribed for three patients. Thistherapy was discontinued due to side effectsin 2 cases.An enteral chemotherapy based on Xeloda was prescribed for two patients. The remaining patients (68.7%) did not receive adjuvant therapy. Overall survival in operated patients was better than those who were not (Figure 1). Three-year overall survival for all stages was 36.7%.

We compared the survival of all our patients by stage pT. Survival at 24 months was different depending on the histological stages with a significant difference (p = 0.021). The stage pT3 had zero survival rate 2 years, the pt1 stages pt2 had better survival at 2 years (53.03%) (Figure 2). We studied survival by stage N, in all patients, and in patients who underwent extensive resection. The N2 disease had the lowest survival at 12 months (36.9%), N0 and N1 stages had better survival at 12 months. Survival at 1 year in all patients, was different depending on the N with a significant difference (Figure 3).

Three-year overall survival for patients managed by complementary resection was 49.2% (Figure 4). The two-year survival rate was statistically lower (0%) in the incidental gallbladder cancer pT3 stage in comparison with pT1 and pT2 stage (53%) (p=0.021). In the absence of recurrence, the two-year survival rate was statistically higher (90%) than in cases of recurrence (0%) (p=0.0017).

Discussion

Gallbladder cancer is known to have a poor prognosis. The incidence of incidentally diagnosed gallbladder cancer has been reported to vary up to 2.85% [6]. A review of the literature showed that 0.09% to 2.12% of the patients who have had cholecystectomy for presumed benign diseases were found to have carcinomas of the gallbladder (table 4) [1,7-12]. In the present study, the rate of incidental gallbladder cancer diagnosis was 0.8%. The widespread use of laparoscopic cholecystectomy has led to the discovery of this deadly disease at an earlier stage, changing the management and the outcome of these patients [2]. However, Clemente et al, consider the prognosis of unexpected gallbladder cancer has been worsened when laparoscopic cholecystectomy is performed for acute cholecystitis [13].

Female gender and advanced age are considered as risk factors for gallbladder carcinoma [1,12]. In our study, the male to female ratio was 0.36 in patients with incidental gallbladder cancer, with a mean age of 61.3 years. In most studies mean age was > 60 years (table 2). The therapeutic approach for gallbladder cancer was applied according to the stage of the tumors. Contrary to other gastrointestinal carcinomas, the depth of invasion of gallbladder cancer dictates the extent of surgical resection. In case of carcinoma in situ or tumor invading the mucosa (Tis and T1a), simple cholecystectomy with negative surgical margin can be considered as curative surgery [2]. In our study, 4 early stage of cancer (1 pTis and 3 pT1a) underwent a simple cholecystectomy without any additional surgery. Malignancy was not suspected in our cases, and only histopathological studies revealed the diagnosis. The 5-year survival after simple cholecystectomy is between 99% and 100% [14]. When the muscularis layer is involved (T1b), a 20%-50% local-regional recurrence can be expected after simple cholecystectomy [14]. The recommended procedure is cholecystectomy associated with resection of at least 3 cm of liver parenchyma (wedge resection), plus adequate lymphadenectomy (Glenn’s resection) [2,14]. However, some authors recommended simple cholecystectomy for T1b tumors [12]. In our study, one patient (T1b) has benefited from cholecystectomy associated to a wedge resection and a lymphadenectomy, the 2 others patients underwent only cholecystectomy because of peritoneal carcinosis in one case and hepatic metastasis in the other case. For T2 tumors, Chijiiwa et al and Choi et al, suggest that radical surgery including lymph node removal should be performed to achieve R0 resection. Tumors with infiltrative types and suspicious lymph node metastasis in the intraoperative findings were candidates for aggressive surgical management to improve patient survival [15,16]. In the present study, IVb-V wedge liver resection associated with lymph node resection was performed in 10 patient with pT2 IGBC and 5 patients with pT3. When the tumor extends beyond the serosa and invades the liver or an adjacent structure, there is a 36% incidence of residual disease at the liver level and 45- 75% incidence of lymph node dissemination [2,17]. In our series, only cholecystectomy was performed for 2 patients with pT3 IGBC because of peritoneal carcinomatosis and hepatic metastasis. Cavallaro et al concluded in their review that bile duct resection should be performed only when the patients have a positive involvement of the cystic duct margins, discovered either on the pathological review of the initial cholecystectomy or through biopsy of the cystic duct at the time of the second operation [2]. In our study, thirteen patients underwent a port-site excision. The supportive physiopathological mechanisms of the postoperative port-site metastasis are debated. Assumptions include trauma and spilling the contents of the gallbladder, the dissemination of malignant cells during the extraction through a narrow opening in the abdominal wall or via the abdominal drain, pneumoperitoneum and CO2 insufflations [4]. The increased intraperitoneal pressure induced by CO2 pneumoperitoneum can spread and redistribute cancer cells within the peritoneal cavity and in damaged surfaces [2,18]. Some authors recommended the routinely use of retrieval bag in laparoscopic cholecystectomy to minimize port-site metastases in case of incidental gallbladder [4,19]. Maker et al concluded in their study that in patients with incidental gallbladder cancer, port site metastases were associated with peritoneal disease and decreased survival. Port site resection was not associated with improved survival or disease recurrence and should not be considered mandatory during definitive surgical treatment [20]. Incidental gallbladder cancer has a significantly better median survival [21]. When we examined the literature, prognostic factors include age, TNM stage, gallbladder perforation during cholecystectomy and less-than-optimal resection at re-operation [21-25]. However, the other factors, such as surgical approach, tumor incisional implantation were not related to the prognosis (P > 0.05) [22]. However, Mazer et al showed that preoperative suspicion remains a strong risk factor (odds ratio, 2.0; confidence interval, 1.5-2.9; p<0.0001) [21]. In our study, and according to the T stage, the 2-year survival was significantly better in pT1 and pT2 (53%) than pT3 (0%) (p=0.021). In D’Hondt study, for patients with radical resection (42 patients), there was no difference between incidental gallbladder cancer and non incidental gallbladder cancer. The incidence of liver involvement was respectively 0%, 20.8%, 58.3%, 100% for pT1, pT2, pT3 and pT4 tumors. Univariate analysis showed that survival rate was significantly affected by perineural invasion, T, N and M-stage, R0 resection, liver involvement, CA-19.9. In multivariate analysis, liver involvement was the only independent factor [26]. Goetze et al analyzed 124 patients with pT1 cancer with a 5-year survival of 48% and found that extended re-resection have increased the 5-year survival up to 68% for pT1 incidental gallbladder carcinoma. Analysis shows a statistically significant survival benefit for reresection of pT1b cancers from 34% to 75% [27]. In the present study, Three-year overall survival for patients managed by complementary resection was 49.2%. In Goetze study, nodal-positive status is a significant negative prognostic factor in pT1 to pT3 IGBC. Patients with radical re-resection show a better survival rate than those without it. Lymph node dissection is to be highly recommended up to stage pT1b. In the case of pT2 carcinomas, lymph node resection of the hepatoduodenal ligament seems to be the minimum volume of lymph node resection required, but more radical procedures could be beneficial for tumors invading the serosa or beyond [28]. Through the literature we tried to answer practical questions (table 2).

Conclusion

The discovery of IGBC (0, 8% of 0.8% of cholecystectomy for cholelithiasis or cholecystitis) requires a second surgical time from the stage T1b. The gesture is to define according data of pathologic examination of specimen of cholecystectomy (T stage, lymph node cystic duct) and the operative report (accidental opening of the gallbladder, extraction protected). The delay of second time operation should not be long (< 2 months) to avoid the appearance of oncological or general contraindication. The instead of chemotherapy remains to be defined.

 

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