Gallbladder carcinomas can involve the fundus (60 %), body (30 %), and neck (10 %) [2]. Although early stage tumors can be difficult to recognize grossly, most gallbladder carcinomas produce a grossly recognizable mass. They can appear as localized or diffuse wall thickening, a raised plaque, a submucosal nodule, a polypoid growth, or a combination of all these patterns (Fig. 2). Infiltrative growth is often present and is considered an independent predictor of recurrence in gallbladder carcinoma [81]. Certain tumor subtypes have a characteristic gross appearance. For instance, papillary carcinomas have a sessile polypoid or cauliflower-like gross appearance, and mucinous tumors have a mucoid/gelatinous cut surface.

Microscopically, carcinoma in situ (CIS) is defined as carcinoma that is confined to the epithelium, usually growing upward or laterally, without evidence of stromal invasion. Histologic subtypes of CIS include intestinal type, signet ring cell type, and squamous cell CIS. When CIS is found in the gallbladder, multiple sections should be taken to exclude invasion. If no invasion is found and the margins are free, the survival is excellent (virtually 100 % at 5 years) and no further treatment is necessary [2].

More than 98 % of malignant gallbladder tumors are carcinomas [2], and adenocarcinoma is the most common type (87 %) [28] of invasive carcinoma. Adenocarcinoma is characterized by infiltrative growth of variably sized and irregularly shaped glands, usually with desmoplastic response (Fig. 3). It is important to differentiate adenocarcinoma from other benign entities such as adenomyomatous hyperplasia [3]. Variants of adenocarcinoma include the following:

Other carcinomas known to involve the gallbladder include adenosquamous carcinoma: (5–9 % of gallbladder carcinoma) [2, 28, 76], which consists of a mixture of squamous cell carcinoma and adenocarcinoma, squamous cell carcinoma (1–7 % of gallbladder carcinoma) [28], small cell carcinoma (4 % of gallbladder carcinoma), and undifferentiated carcinoma. Small cell carcinoma is morphologically similar to pulmonary small cell carcinoma and has a highly aggressive clinical behavior [2, 4, 84]. This histologic type should be reported even if it is a minor component of a gallbladder carcinoma, as such combined tumors still behave aggressively. Undifferentiated carcinoma has four variants, the commonest of which are spindle/giant cell type [2, 16] and small cell type [2]. In undifferentiated carcinoma, good sampling can unveil a better-differentiated invasive carcinoma component or CIS in most cases. Recording the histologic type is important, since some types (e.g., papillary carcinoma) have a better survival rate, whereas others (e.g., undifferentiated carcinoma and small cell carcinoma) have the worst prognosis (patients usually survive less than 1 year) [2]. This is also important for treatment purposes; for instance, chemotherapeutic choice for small cell carcinoma is different from that of adenocarcinoma. When there is more than one histologic pattern, it is recommended to record all patterns in the pathologic diagnosis. It is also recommended to record the tumor’s histologic grade because it is a significant predictor of patient outcome [11, 28] and an independent predictor of recurrence in gallbladder carcinoma [81]. Grading adenocarcinoma can be evaluated by assessing the glandular versus solid component of the tumor histologically (grade 1: >95 % glands, grade 2: 50–95 % glands, grade 3: <49 % or less glands, and grade 4: undifferentiated). Gallbladder adenocarcinoma is most commonly in grades 1 and 2 [28].

TNM stage is a significant predictor of patient outcome [11, 20, 28, 64, 105]. In fact, disease stage is the single most important factor in determining patient survival at the time of diagnosis. The depth/extent of tumor invasion has prognostic value; the incidence of lymph node and distant metastasis increases progressively with increased T stage [66, 88]. Invasion beyond one-third of the subserosal layer carries significantly increased risk of tumor spread and may warrant para-aortic lymph node sampling [88]. Tables 1 and 2 outline the current TNM and overall staging of gallbladder carcinoma. Of note, cystic duct carcinomas are now included in the gallbladder TNM classification scheme. Carcinomas of the gallbladder are staged according to their depth of invasion into the wall and extension into adjacent structures. Tumors confined to the gallbladder are classified as T1 or T2 depending on the depth of tumor invasion. Tumors extending beyond the gallbladder wall, through the serosa, and/or involving adjacent structures are designated T3. Because invasion of hilar structures usually renders the cancer unresectable, such tumors are designated T4.

Because the gallbladder has a thin wall, tumors extend quickly into the perimuscular connective tissue, gaining access to a rich vascular and lymphatic network, and facilitating tumor spread. Hence, gallbladder carcinoma often metastasizes early, even before the diagnosis is made. Gallbladder tumors can involve the liver, stomach, duodenum, or colon by direct extension, can implant on peritoneal surfaces, or metastasize to regional lymph nodes and distant organs. Regional lymph node metastasis is a significant independent predictor of patient survival [25, 86, 107]. It occurs frequently early in gallbladder cancer (found in 19–50 % of patients at the time of diagnosis) [25]. Regional lymph nodes are limited to the hilar (cystic, pericholedochal, hepatic artery, and portal vein) lymph nodes staged as N1 and other regional (para-aortic, pericaval, superior mesenteric artery, and celiac artery) staged as N2 [51]. Hence, involvement of peripancreatic nodes along the body and tail of the pancreas is considered distant metastases (M1). In addition to topographic location, which determines the N stage, the number of involved lymph nodes is also important in predicting survival [31]. Therefore, the surgical pathologist should document the number of examined and number of positive lymph nodes. Accurate N staging requires sampling of a minimum of three regional lymph nodes for microscopic examination [66]. In addition to histologically evident metastases, one study showed that immunohistochemically detected micrometastases, regardless of size, are associated with poor survival and should be designated N1 [86]. Because these findings are limited to one study and remain unvalidated by larger series, the data are currently insufficient to recommend routine immunohistochemical evaluation of regional lymph nodes. Hence, routine assessment of regional lymph nodes is currently limited to H&E sections. Distant metastases are found in 57 % of patients with gallbladder carcinoma [28]. They most often involve the liver, peritoneum, and lung [66]. The liver is involved in 13–70 % of patients at the time of surgery, either by direct extension (most common) or by metastasis [25].

Additional important pathologic features in gallbladder carcinoma include perineural invasion, angiolymphatic invasion, and surgical margin status. Perineural invasion occurs in most (71 %) gallbladder carcinomas and is associated with significantly lower 5 year survival rate [20], but there is conflicting data in regard to its value as an independent predictor of survival [7, 20, 86, 105]. Perineural invasion is also significantly associated with extrahepatic bile duct invasion [107]. Likewise, angiolymphatic invasion is a significant prognostic factor in gallbladder carcinoma and its absence is significantly associated with long-term survival [7, 20, 105]. In fact, vascular invasion seen histologically has the effect of reducing outcome to the next disease stage. It is therefore important to report it. The surgical margin status is a significant prognostic factor in gallbladder carcinoma [105]; long-term survival is significantly associated with complete resection [11].

Gallbladder carcinoma is often identified in laparoscopically resected gallbladders. Laparoscopic cholecystectomy carries a risk of cancer implantation/dissemination; it should not be performed in gallbladders with high suspicion of malignancy [9, 34, 68, 92]. Nevertheless, invasive carcinoma, undetected clinically, is occasionally discovered first by the pathologist evaluating laparoscopic cholecystectomy specimens. These tumors are often low stage (T1 or T2) [23], but specimen disruption can complicate pathologic staging. Port-site recurrence is also a serious complication of gallbladder cancers resected laparoscopically [80] usually treated by follow-up surgery, which includes port-sites excision if the cancer is resectable (T1 and T2) [35]. Because carcinoma can be found incidentally, careful gross examination and mandatory histologic evaluation (especially if the gallbladder wall is thickened) are essential in detecting such tumors. In addition, when a polyp or a distinct lesion is present, the entire lesion should be examined microscopically.