.
Original Article
Histopathological View on Gallbladder Carcinoma: An Update Abdullah S. Alkhamiss
Department of Pathology, College of Medicine, Qassim University, Buraidah, Qassim, Saudi Arabia.
For correspondence: [email protected]
Abstract
Background: Gallbladder carcinoma is a primary malignant tumor arising from the epithelium of the gallbladder. In general, the occurrence of gallbladder carcinoma is rare and its epidemiology varies wildly in different geographic areas, ethnicity, and cultures.
Gallbladder carcinoma is aggressive with the reported survival rate of only six months.
Despite of its rapid progressive nature, the disease is still not properly diagnosed at an early stage.
Objective: This review was aimed to summarize the most recent updates on gallbladder carcinoma with the special emphasizes on the histopathological point of view.
Methods: Literature on the gallbladder carcinoma in context with histopathological point of view was searched using the PubMed, Scopus and Google search.
Findings: Gallbladder carcinoma occurs in elderly age group in general. The median age is 67 years old and the incidence generally is increase with the age. It’s a multifactorial disorder of unknown etiology but the role of genetics and environmental factors are involved in its onset. Histopathologically, gallbladder carcinoma has many types but the most common type was found to be adenocarcinoma. The complete surgical resection was reported to be the only treatment of choice and the pathological staging is the most prognostic factor for this disease.
Conclusions: Gallbladder carcinoma is one of the aggressive tumors that has poor prognosis. It is more in female gender. It has a wide variable geographic distribution.
The cause is a combination of genetic and environmental factors. The tumor has many risk factors in which gallstone is the most important one. Clinically, it is usually asymptomatic or presented with vague symptoms until it reach to an advance stage.
Keywords: Gallbladder carcinoma, Histopathology, Risk factors, Adenocarcinoma.
Citation: Alkhamiss AS. Histopathological View on Gallbladder Carcinoma: An Update. JUMJ, September 1, 2018; 5(3): 1 - 14.
Introduction
The World Health Organization (WHO) defines gallbladder carcinoma as a malignant epithelial neoplasm arising in the gallbladder(1). This tumor was firstly described in 1777(2). Carcinoma is the commonest type of malignancy arising in the biliary tract in general and in the gallbladder specifically(2,3). This finding is proved by many autopsy studies in which the authors find that carcinoma represent 80-95% of all the biliary tract malignant cases in the world(2,3).
Although generally the incidence of gallbladder carcinoma is rare, the incidence and epidemiology of this neoplasm varies wildly between the geographic areas, ethnicity, and culturally(2-8). This variability is very clear between some countries and the rest of the world(2-7). For example, the incidence of gallbladder carcinoma is high in Eastern Europe (like Poland, Czech Republic, & Slovakia), some Asian countries (like north of India, south of Pakistan, Korea, & Japan), some Latin American countries (like Chile &
. Mexico) and areas where Mapuche
American Indians are living(2-7). In these countries, the incidence rate is ranging between 3.7 to 21.5 per 100.000, whereas in the rest of the world, the incidence rate is below 2 per 100.000(2-5,7-10). This wildly variability in the incidence of gallbladder carcinoma suggest that there is role of both genetics and environmental factors in the development of this disease (as will be discussed later in this article)(2-8). Regarding to the gender distribution, gallbladder carcinoma affects females 2-3 times more than males with the exception of some countries in Asia like Korea and Japan in which there is no gender predominance pattern(2-6).
Gallbladder carcinoma usually occurs in elderly age group in general(2-3,6). The median age is 67 years old and the incidence generally is increase with the age(2-3,6).
1. Causes:
There is no single causative agent for gallbladder carcinoma(6). Therefore, multifactorial elements including both genetics and environmental factors are involved in the development of this disease(5-6).
2. Risk Factors:
As in any other diseases, identifying the risk factors of gallbladder carcinoma is a critical issue since knowing them will be helpful in: a) understanding the pathogenesis, b) plaining the management strategies, and c) providing some insight about the prognosis of this disease(3,5-7). Unfortunately because it is relatively a rare disease, most of the published articles about gallbladder carcinoma contain small number of cases which make it difficult to study this disease in an extensive way(3). Summary of the most common risk factors of gallbladder carcinoma are shown in Figure 1(2-3,5-7,11).
Figure 1: Possible risk factors involved in the prognosis of gallbladder carcinoma.
Gallstones:
Gallstone is the most known important risk factor for the gallbladder carcinoma since it present in 75-90% of the cases(2-
3,6-7,11).This fact makes all the risk factors of cholelithiasis are relatively risk factors for gallbladder carcinoma in indirect way like female gender, obesity, multiparty, positive family history of cholelithiasis, etc. The exact mechanism by which cholelithiasis helps in the development of gallbladder carcinoma is still not entirely clear. The most accepted hypothesis is
that gallstone is a chronic irritation that can induce epithelial injury and chronic inflammation leading to DNA damage and malignant transformation(12-13).
Although the presence of gallstone is the most important risk factor for gallbladder carcinoma, only less than 3% of cholelithiasis cases develop this type of malignancy(2-3,6-7,11) & only 0.5 - 1.5% of patients who undergo simple cholecystectomies for presumed gallstone condition are discovered incidentally to have gallbladder carcinoma(6-11). It is not
. only the presence of the gallstone is the
only parameter that links the development of gallbladder carcinoma with cholelithiasis. The characteristic of the gallstone itself as well as the length of the time period are also involved in this relationship(2-3,7,12,14-17)
.
The size of the gallstone is associated with increased risk of gallbladder carcinoma. Patients with gallstones that are 3cm or more in maximum dimension carry tenfold increase risk of gallbladder carcinoma in comparison to those with smaller ones(11,14-15,18). There is a link between the length of the period of gallstone and the development of the gallbladder carcinoma(11,14-16,18). The more time of presence of the gallstone, the more risk of developing gallbladder carcinoma. This may explain partially why most of the patients of gallbladder carcinoma are elderly female with long- standing gallstones. More period of time will provide the necessarily time for more chronic inflammation and subsequently malignant changes(14,16). The components of the gallstone itself play a role in the development of gallbladder carcinoma.
Cholesterol gallstones increase the risk of gallbladder carcinoma more than the other types of gallstones. The reason for this is that cholesterol act as a local mucosal irritating substance which helps in the development and maintenance of chronic inflammation(12,17). Lastly, since cholelithiasis is more common in Caucasians than in black peoples, this fact may explain relatively why gallbladder carcinoma is more in Caucasians ethnicity in comparison with the African ethnicity(3,19-20).
Chronic inflammation of the gallbladder:
Because chronic inflammation is a main player in the carcinogenesis in general, chronic cholecystitis is a major risk factor for gallbladder carcinoma(3,6-7,12). Chronic inflammation leads to repeated tissue injury as well as repairing processes. This leads high chance for DNA damage by the cytokines, growth factors, free radicals & eventually malignant transformation(3,6-7,12-13). Chronic inflammation can also help in the deposition of calcium in the wall of the gallbladder leading to the formation of
"porcelain gallbladder", which is a known risk factor for gallbladder carcinoma (as it will be discussed later)(12,13).
Calcification and porcelain gallbladder:
There is an association between calcification/porcelain gallbladder and gallbladder carcinoma, which make the former a premalignant condition(3,7,21-22). However, not all the types of gallbladder calcification are premalignant conditions, only those with stippled calcification should be counted as premalignant ones(7-
22).
Chronic infection:
Chronic infection is another risk factor for gallbladder carcinoma(3-7,13,23). The most common microorganisms that are involved in this process are Salmonella spp. (like S. typhi & S. paratyphi) and Helicobacter spp. (like H. bilis)(3,6-7). There are many hypotheses by which these microorganisms can contribute in the formation and development of gallbladder carcinoma like: a) they produce chronic cholecystitis, b) they help in the formation of gallstones, c) they alter some tumor-suppressor genes (like p53), d) they alter some proto-oncogenes (like K-ras), and, e) they produce some carcinogens from microorganism-bile degradation process(3-7,13,23).
Female gender:
Female gender is a non-modifiable risk factor for gallbladder carcinoma(3,5,11). Here, estrogen hormone plays a role in this process since its increase cholesterol super saturation in the bile and eventually gallstone formation(5,24). Also, there is a published article mention the possible relationship between the estrogen receptor expression and the gallbladder carcinoma differentiation(5,25). Based on the this hormonal issue, some authors claim that multiple pregnancies, early age of first- time of pregnancy, late menopause, and intake of oral contraceptive drugs, all are risk factors for gallbladder carcinoma(5-6). Age:
Age is other non-modifiable risk factors for gallbladder carcinoma. As mentioned earlier, the he median age of the patients is 67 years old & the incidence generally is increase with the age(2-3,6). This fact has been linked to the length period of the
. gallstone and its relation with gallbladder
carcinoma(11,14-16,18). Obesity:
Obesity is a risk factor for gallbladder carcinoma(3-7,11). It may be because obesity is a major risk factor for cholelithiasis which is the most important risk factor of this type of carcinoma(4,7). Dietary factors:
According to some published papers, there is a relationship between the nutrition and the development of the gallbladder carcinoma especially excessive intake of carbohydrate, some kinds of oils (like mustard oil, argemone oil, butter, fried food, & reused oil), and red chili pepper(4-6,11). This is probably related to their role in the development of obesity and gallstone formation.
Drugs and environmental exposures:
The exposure to many environmental materials have been hypothesized to be risk factors for gallbladder carcinoma(3,5-
6,11,26)
. This includes: smoking, tobacco, heavy metals (like nickel & cadmium), benzene, and radon(3,5-6,11,26)
. Therefore, people who are working in the following places are at increased risk of gallbladder carcinoma: oil factories, paper factories, shoes, textile, and cellulose acetate fiber manufactures(6). Drug intake is a controversial issue(6), although some authors claim that certain types of drugs (like oral contraceptives drugs) play a role in the development of gallbladder carcinoma(5-6).
Pancreatico-biliary diseases:
Any disease that leads to bile reflux to the gallbladder or regurgitation of pancreatic juice back to the gallbladder is relatively a risk factor for gallbladder carcinoma(5,27) like: Mirizzi's syndrome, primary sclerosing cholangitis (PSC), and pancreatico-biliary malformation(3-5,27-32). If this can happen then there may be inflammation in the gallbladder and subsequently risk of gallbladder carcinoma(3-4). PSC is a chronic fibro- inflammatory syndrome of the biliary system(3). With the time, this disease leads to obstruction of the biliary ducts and bile refluxes to the gallbladder that lead to chronic inflammation and gallbladder carcinoma(3-5,28). Therefore, PSC patients
must be undergo annual gallbladder carcinoma surveillance (by the radiology) to screen for any possible gallbladder mass(3,29-30). Pancreatico-biliary duct malformation is a known risk factor for gallbladder carcinoma(3-7,31-32). It is a congenital malformation characterized by union of pancreatic duct with common bile duct outside the duodenal wall. This leads to regurgitation of pancreatic juice to the gallbladder and eventually chronic inflammation and carcinoma(3-7,31-32). This anomaly is more common in Asia (especially Korea & Japan) and rare in the western countries, which may partially explain why this type of malignancy is geographically distributed more in Asia(3-
4,6-7)
. Gallbladder carcinoma due to this anomaly are usually young & do not have gallstones(3-4,6-7,31)
. Histopathologically for unknown reason, the majority of those patients develop gallbladder adenocarcinoma of papillary type(3,7,32). Gallbladder polyps:
Although around 5% of adult population has gallbladder polyps/pseudopolyps, the vast majority of these lesions have no malignant potential like cholesterol polyp and adenomyosis(3,7,12,31,33-35). Most of these lesions are discovered incidentally either on radiological examination or in gross examination of simple cholecystectomies specimens that had
been done for chronic
cholecystitis/cholelithiasis(3,7,31,33-34). The following parameters are signs of potential malignant growth of any gallbladder polyp: a) polyp with a size of 1cm or more in maximum dimension, b) single polyp, c) sessile polyp, d) rapidly growing polyp, e) K-ras mutation positive polyp (as will be discussed later), f) patient over 50 years of age, g) adenoma or inflammatory types polyp, and, h) coexistence of gallstone with the polyp(3,6-
7,12,35). Therefore, any gallbladder polyp that is over 1.8cm in maximum dimension must be removed(7,36).
Familial and family history:
There are few articles proved that there are some familial clustering of gallbladder carcinoma(5,37-38). This clustering of gallbladder carcinoma within families suggests of a critical role of genetics in its development(5,37-38).
. Genetics:
It will be discussed later.
3. Pathogenesis:
Gallbladder carcinoma is a multistep process involves combination of genetics and environmental factors that leads to: a) activation of oncogenes, b) inactivation of tumor-suppressor genes, c) microsatellite instability, and, d) methylation of gene promoter areas(3,7,12,38-39). The exact sequence of these genetics changes is still not entirely cleared(3).
In general, there are two main accepted pathways for the development of gallbladder carcinoma(3-4,7,12,40).
First: Cholelithiasis/chronic cholecystitis pathway:
It is the predominant one. In this pathway,
there will be chronic
irritation/inflammation of the mucosa of the gallbladder leading to local production of carcinogens and repeated tissue repair that leads to high chance of p53 mutation.
The later will lead to many other genetic alternations, causing epithelial dysplasia and eventually gallbladder carcinoma.
Second: K-ras mutation pathway:
It happens only in minority of the patients which most of them having either pancreatico-biliary malformation or gallbladder polyp. K-ras mutation leads to arising of atypical epithelium and eventually gallbladder carcinoma.
4. Genetics:
There are many genes involved in the development of gallbladder carcinoma, especially p53 and K-ras genes. Role of allele specific mutations in pathogenesis of gallbladder carcinoma had been reported in the literatures(5,41). There is higher frequency of gallbladder carcinoma in patients with A+ and AB+ blood groups(5,42). The reason is still not clear. Some of these mutations can be targeted by targeted specific therapy like K-ras and EGFR mutations(12,43-45). 5. Clinical Presentation:
Gallbladder carcinoma is usually presented with one of three ways(6): a) suspected malignancy pre-operatively by the clinician &/or the radiologist, b) discovered intra-operatively by the surgeon, and c) incidental finding post-
operatively by the pathologist. Almost ½ to ⅔ of gallbladder carcinoma cases are discovered post-operatively by the pathologist when he/she examine specimens of simple cholecystectomies for inflammatory cases(12,46-51). The rest are diagnosed pre-operatively by combination of clinical examination and radiological studies(12,46-51). The reason for this is because of the vague overlaps signs
& symptoms of gallbladder carcinoma with benign inflammatory gallbladder diseases like cholecystitis &
cholelithiasis(7,48-52). Therefore, for the above mentioned reason and for the partial absence of the covering serosal layer around the gallbladder (which usually delayed the spread to the malignant cells), most of the gallbladder carcinoma cases discovered in advance stage(7). Since the signs and symptoms of the gallbladder carcinoma is similar to cholecystitis/cholelithiasis, symptomatic cases may presented with right upper quadrant/epigastric pain, nausea, vomiting, jaundice, anorexia, and weight loss(6). The more advance cases may present with signs & symptoms of metastasis.
6. Gross:
Anatomically, the vast majority of the gallbladder carcinomas are located in the fundus, which represent around (60%) of the cases, followed by the body (30%) and the neck (10%)(6-7,54). Grossly, most of the gallbladder carcinomas show diffuse growth pattern (70%) which create some difficulty in distinguishing this disease from chronic cholecystitis(54-55). The rest of the cases show nodular, polypoidal, and papillary growth patterns(54-55). It is important to know that around 30% of the gallbladder carcinomas do not appear grossly(54). Therefore, each simple cholecystectomy specimen must be examined microscopically with at least 3 sections including body, fundus, and cystic duct margin(53-54). Gallbladder carcinomas can spread to other sites by 4 routs: a) local direct extension to the nearby structures (like liver, bile duct, &
intestines), b) lymphatic spread, c) hematogenous spread, and d) peritoneal spread(6-7).
. 7. Histopathology:
Figure 2 summarizing the types of gallbladder carcinomas. The vast majority of gallbladder carcinomas are of adenocarcinoma type which represents more than 80% of the cases(3,6-7,12,56-57). The remaining cases are represented by squamous cell carcinoma, adenosquamous cell carcinoma, neuroendocrine tumors, and undifferentiated carcinoma(12,57). Gallbladder adenocarcinoma by itself has many subtypes including: pancreatico-
biliary, gastric, intestinal, mucinous (colloid), signet-ring, papillary, micropapillary, clear cell, cribriform, lymphoepithelioma-like, and hepatoid subtypes(57). These subtypes are different genetically and immunohistochemically.
Interestingly, there is a correlation between the type of gallbladder carcinoma and the risk factors. For example, most of the patients with pancreatico-biliary anomalies develop papillary subtype adenocarcinoma(12).
Figure 2: Histopathological types of gallbladder carcinomas.
Regarding to the origin of adenocarcinoma, the most accepted theory is that the process started around 5- 15 years before the time of diagnosis as metaplasia that progress to low-grade dysplasia followed by high-grade dysplasia then carcinoma in situ and finally invasive carcinoma of the gallbladder(2-3,53). Therefore, it is recommended that whenever you find focal area of dysplasia in a routine microscopic examination of any simple cholecystectomy specimen, you should submit the entire specimen for microscopic evaluation to make sure that no missing invasive adenocarcinoma (by sampling error) is happen(53). Malignant cells of invasive gallbladder adenocarcinoma (by definition) must form glandular architecture &/or produce mucin. Also, they must invade the underlying basement membrane which practically difficult to be distinguished from carcinoma insitu that is extending to the Rokitansky-Aschoff sinuses(58).
Pancreatico-biliary subtype:
It is the commonest subtype(54-55). The tumor cells are arranged in glandular, cords, sheets, &/or cribriform architectures(54-55,57-59). These cells are cuboidal to columnar in shape with round- oval basally to centrally located nuclei(54-
55,57-59)
. The amount, content, and color of the cytoplasm is variable. It could be eosinophilic, pale, granular, or clear(54-
55,57-59). Number of mitoses is also variable(54-55,57-59)
. There is desmoplastic stroma arranged concentrically around the neoplastic glands(54-55,57-59). This stroma contains variable amount of inflammatory cells(54-55,57-59). Immunohistochemically, these tumor cells are positive for CK7, CK20 (focal), CK19, claudin-4, CA19-9, CEA, MUC1, and MUC2(54-55,57-59). Gastric foveolar subtype:
Here, the neoplastic cells are tall columnar with basally located nuclei comprised by abundant intracellular mucin(57). Immunohistochemically, these
. tumor cells share same phenotype with
pancreatico-biliary plus its positivity for MUC5AC(57).
Intestinal subtype:
This subtype is identical to colonic adenocarcinoma microscopically,
histochemically, and
immunohistochemically(57-58). Here, the neoplastic cells are tall columnar with pseudostratified hyperchromic nuclei, scanty cytoplasmic mucin, and many mitotic figures(57-58). Goblet cells are few except in goblet cell predominant variant(57-58). Areas of extensive intraluminal necrosis (dirty necrosis) are present as in Figure 3A(57-58). The cells are positive for CK20 (diffusely), CDX2, &
MUC2 and negative for CK7(57-58). Papillary subtype:
The neoplastic cells grow on finger-like projection with a true fibrovascular stalk as in Figure 3B(57). The neoplasm is mostly arising in patients with pancreatico-biliary anomalies(57). It is associated with K-ras mutation and relatively it has good prognosis(57). Micropapillary subtype:
In contrast to papillary subtype, this subtype has no true fibrovascular core and it has poor prognosis(63).
Mucinous (colloid) subtype:
Grossly, this subtype appears gelatinous mass with a gallbladder lumen filled with mucin(54,57,60). Under the microscope, this tumor is composed of neoplastic epithelial cells fluting in a sea of extracellular mucin which is clear in Figure 3C and 3D(54,57,60). The later (by definition) must form at least more than 50% of the bulk of the neoplasm(54,57,60). The neoplastic cells are arranged in small clusters(54,57,60). This subtype has poor prognosis(54,57,60). Signet-ring subtype:
This subtype mimics those in the breast &
GIT(54,57,61-62)
. Here, the tumor cells arranged individually, in small clusters, and in cords(54,57,61-62). Each neoplastic cell has flat eccentric nuclei comprised by a cytoplasm stuffed with mucin as in Figure 3E(54,57,61-62). Again, by definition, these cells must form at least more than 50% of the bulk of the tumor to make such diagnosis(54,57,61-62).
Clear cell subtype:
It composed of glands, nests, trabeculae, or sheets formed by neoplastic cells with clear cytoplasm(54,57,64). This clearing is because of the glycogen in the cytoplasm of these cells that have been proved by special stains and electron microscopy(54,57,64). Therefor the tumor cells are PAS-positive diastase-sensitive and negative for mucinous stains(54,57,64). By definition, tumor cells with clear cytoplasm must be at least form more than 50% of the bulk of the tumor(54,57,64). The pitfall of this subtype is metastatic clear cell renal cell carcinoma and clear cell variant of squamous cell carcinoma(54,57,64).
Cribriform subtype:
It formed by uniform neoplastic epithelial cells with hyperchromic nuclei(57,65). These cells are arranged in nests with well-formed punched-out spaces(57,65). It has poor prognosis(57,65).
Lymphoepithelioma-like subtype:
It resembles lymphoepithelioma. The tumor composed of poorly differentiated tumor cells are infiltrated by inflammatory cells especially lymphocytes (58). Some of the cases are associated with Epstein-Barr Viral infection(66), others are not(67).
Hepatoid subtype:
It is a very rare subtype(57). It should has foci resample hepatocellular carcinoma
(microscopically and
immunohistochemically) forming at least more than 50% of the bulk of the tumor(57-
58). The pitfall of this subtype is metastatic hepatocellular carcinoma to the gallbladder.
Squamous cell carcinoma of the gallbladder:
It is a malignant neoplasm composed entirely of malignant squamous cells that resample squamous cell carcinoma of the skin as in Figure 3F(12,57-58,68)
. It is a rare tumor with worse prognosis than adenocarcinoma because it is a chemotherapy-resistant malignancy(12,57-
58,68)
.
Adeno-squamous carcinoma of the gallbladder:
. It is a malignant tumor formed by mixed
of malignant glandular and squamous components in which the squamous
component must form at least 25% of the bulk of the tumor as in Figure 3G(57,68).
Figure 3: Histological view on different gallbladder carcinomas. A) Intestinal subtype adenocarcinoma showing malignant glands with luminal dirty necrosis. B) Papillary subtype of adenocarcinoma showing true fibrovascular core lined by malignant cells. C) Colloid subtype of adenocarcinoma showing scattered malignant glands floating in a sea of mucin. D) Colloid subtype of adenocarcinoma showing scattered malignant glands floating in a sea of mucin. E) Signet-ring adenocarcinoma showing malignant cells with compressed eccentric nuclei and cytoplasm filled with mucin. F) Well-differentiated squamous cell carcinoma formed by malignant squamous cells with intracellular keratinization. G) Adenosquamous carcinoma formed by malignant glandular and squamous cells. H) Perineural invasion in which the malignant cells attached to the nerve.
. Neuroendocrine tumors:
These tumors represent less than 3% of all gallbladder carcinomas cases(69-73). Most of the cases are associated with gallstones(69-73). The microscopic features and immunohistochemical stains pattern of these tumors are similar to those in the
GIT & lung(57); there are low-grade (like carcinoid), intermediate-grade, and high- grade (like small and large cell neuroendocrine carcinoma)(57,69-73). The morphological features are summarized in Table 1.
Table 1: Microscopic Features of Neuroendocrine Tumors of the Gallbladder.
Features Carcinoid Small cell carcinoma Large cell carcinoma
Architecture
Well-demarcated tumor formed by cords and nests of neoplastic cells that are separated by network of capillaries
Irregular infiltrative tumor formed by sheet of round blue neoplastic cells that are easy to crushed
Similar to small cell carcinoma but with larger cells
Cells
Bland uniform cells with moderate amount of cytoplasm, round/oval nuclei, smooth nuclear membrane, salt-&-paper chromatin, and inconspicuous nucleoli
Small round blue cells with scanty cytoplasm, hyperchromic irregular smudgy molded nuclei, and no nucleoli
Large cells with abundant cytoplasm, large vesicular
nuclei, and
prominent nucleoli Mitosis and
Necrosis Extremely rare Extensive mitoses,
apoptosis, and necrosis
Similar to small cell carcinoma
Undifferentiated carcinoma:
Also known as anaplastic, pleomorphic, spindle, and sarcomatoid carcinoma of the gallbladder(57,74-76). It is a wastebasket for all high-grade carcinomas cases that cannot be categorized to any known specific type of carcinomas. By definition, this type of tumor must not have any glandular, squamous, or neuroendocrine differentiation(57,74-76). Microscopically, the tumors are characterized by high-grade pleomorphic cells, polygonal cells, spindle cells, and multinucleated giant cells(57,74-76). There are many mitoses (including atypical ones) and areas of tumor necrosis(57,74-76). The stroma is desmoplastic and contains mixed inflammatory cells(57,74-76). The tumor cells are positive for CK by focally(57,74-76).
8. Pathological Grading and Staging:
Histological grading of adenocarcinoma and neuroendocrine tumors of the gallbladder has an impact on the prognosis, whereas grading of squamous cell carcinoma has a little impact on it.
Based on College of American Pathologist (CAP) 2017 guidelines, Table 2 represent the grading system for adenocarcinoma, Table 3 for squamous cell carcinoma, and Table 4 for neuroendocrine tumors of gallbladder.
According to the CAP, pathological staging is the most prognostic factor of gallbladder carcinoma. The staging system is depends on: a) the degree of up to which layer of the gallbladder wall the tumor is invading, b) lymph node metastasis statues, and c) distant metastasis status as in the summarized Table 5 (for more details, see the CAP criteria and guidelines).
Table 2: Grading of Adenocarcinoma of the Gallbladder.
Grading Features
Grade-1: Well-differentiated > 95% of the tumor is composed of glands Grade-2: Intermediate-differentiated > 50-95% of the tumor is composed of glands Grade-3: Poorly-differentiated < 50% of the tumor is composed of glands
Grade-3: Undifferentiated No glandular, squamous, or neuroendocrine differentiation
Grading is based on the least differentiated area.
.
Table 3: Grading of Squamous Cell Carcinoma of the Gallbladder.
Grading Keratinization &
Intracellular Bridges
Nuclear Pleomorphism and Number of Mitoses Grade-1: Well-differentiated Abundant Mild pleomorphism with few
mitoses
Grade-2: Intermediate-differentiated Intermediate Moderate pleomorphism with some mitoses
Grade-3: Poorly-differentiated Rare Marked pleomorphism with many mitoses
Grading is based on the least differentiated area.
Table 4: Grading of Neuroendocrine Tumors of the Gallbladder.
Grading Mitoses per 10 High Power Field Ki67
Grade-1: Well-differentiated) <2 <3%
Grade-2: Intermediate-differentiated) 2-20 3-20%
Grade-3: Poorly-differentiated >20 >20%
Grading is based on the most mitotically active area.
Table 5: Staging of Gallbladder Carcinoma According to the CAP Criteria.
TNM Staging System Symbol Criteria
Degree of Tumor Invasion
TX Primary tumor cannot be assessed T0 No evidence of primary tumor Tis Carcinoma in situ
T1 Tumor invades the lamina propria or muscular layer T1a Tumor invades the lamina propria
T1b Tumor invades the muscular layer T2
Tumor invades perimuscular connective tissue on the peritoneal side, without involvement of the serosa (visceral peritoneum) or tumor invades the perimuscular connective tissue on the hepatic side, with no extension into the liver.
T2a
Tumor invades perimuscular connective tissue on the peritoneal side, without involvement of the serosa (visceral peritoneum).
T2b Tumor invades the perimuscular connective tissue on the hepatic side, with no extension into the liver.
T3
Tumor perforates the serosa (visceral peritoneum) and/or directly invades the liver and/or one other adjacent organ or structure, such as the stomach, duodenum, colon, pancreas, omentum, or extrahepatic bile ducts.
T4 Tumor invades main portal vein or hepatic artery or invades two or more extrahepatic organs or structures.
Lymph Node Status
NX Regional lymph nodes cannot be assessed.
N0 No regional lymph node metastasis.
N1 Metastases to one to three regional lymph nodes.
N2 Metastases to four or more regional lymph nodes.
Distant Metastasis
Status M1 Positive for distant metastasis.
9. Management:
Complete surgical resection with wide free surgical margin is the only effective way to treat patients with gallbladder carcinoma(7,53,58,77)
. Unfortunately because most of the cases diagnosed at advance unresectable stages, this option is less likely available. In case of suspected gallbladder carcinoma pre-operatively, laparoscopic simple cholecystectomy is contraindicated due to the risk of
incomplete resection, perforation, and bile leakage(48-51). Only open surgical procedure is allowed. The recommended current management is based on the stage of the tumor(7,53,58,77) which is summarized in Table 6. Some types of gallbladder carcinomas respond to chemotherapy and EGFR-targeted therapy (like papillary type gallbladder adenocarcinoma), others (like squamous cell carcinoma and adenosquamous carcinoma) are not(12,43-
45).
.
Table 6: General Guidelines for the Management of Gallbladder Carcinoma.
Staging Status Management
Tis & T1a Simple open cholecystectomy with free negative surgical margins.
T1b
Although the management is still controversial, the most recommended one is radical resection with lymph node dissection due to high chance of metastasis compared to T1a.
T2 Radical cholecystectomy and lymphadenectomy.
T3
Depending on the resectability of the tumor and the patient’s fitness for surgery. If the patient fit, radical cholecystectomy with lymph node dissection is the treatment of choice. Otherwise, palliative treatment.
T4 Unresectable. Only palliative treatment.
10. Prognosis:
The prognosis of any cases of gallbladder carcinoma is depending on many factors(7,58,78,80-84)
including: 1) Time of the diagnosis: Early diagnosis is better than late one, 2) Resectability status:
Resectable tumors have better prognosis than unresectable one, 3) Histological type: For example, papillary adenocarcinoma has better prognosis than other types of adenocarcinoma, 4) Tumor stage: Staging is the most important prognostic factor, 5) Tumor grade: The more grade, the worst prognosis, 6) Lymphovascular invasion: Presence of lymph vascular invasion indicate poor prognosis, 7) Perineural invasion:
Presence of perineural invasion indicate poor prognosis (Figure 3H), 8) Lymph node status: Positive lymph node metastasis is a bad prognostic sign, and, 9) Distant metastasis status: Similar to the lymph node status, positive distant metastasis is a bad prognostic sign.
Regardless of all of these factors, gallbladder carcinoma is usually has poor prognosis with 6 months mean survival rate and less than 5% five-years survival rate(2,7,53,58,77-79). The reason for this is that more than 90% of the gallbladder carcinoma cases are diagnosed late in advance unresectable stage in which the tumor is already invading the adjacent organs and metastasis distantly(7,78-79). This can be facilitated partially by the focal absence of the serosal layer around the gallbladder(3,5).
Conclusion
Gallbladder carcinoma is one of the aggressive tumors that has poor prognosis. It is more in female gender. It has a wide variable geographic distribution. The cause is a combination
of genetic and environmental factors. The tumor has many risk factors in which gallstone is the most important one.
Clinically, it is usually asymptomatic or presented with vague symptoms until it reach an advance unresectable stage.
Complete surgical resection is the only treatment of choice & staging is the most important prognostic factor.
Histopathologically, gallbladder carcinoma has many types, among which, adenocarcinoma is the most common one.
These types are varies in their risk factors, pathogenesis, and prognosis.
Funding
This review was funded by Qassim University as a part of the author's employment duties.
Conflict of Interest
The author declared no conflict of interests.
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