Gallbladder cancer pathophysiology: Difference between revisions
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== Overview == | == Overview == | ||
It is thought that gallbladder cancer (GBC) is the result of 2 or more different biological pathways based on morphological, genetic, and molecular evidence. | It is thought that [[gallbladder cancer]] (GBC) is the result of 2 or more different [[biological]] pathways based on morphological, [[Genetics|genetic]], and [[molecular]] evidence. | ||
== Pathophysiology == | == Pathophysiology == | ||
'''Pathogenesis''' | '''Pathogenesis''' | ||
* It is understood that GBC is the result of persistent irritation of the gallbladder mucosa over a period of years which predispose to malignant transformation or act as an enhancer for carcinogenic exposure. | * It is understood that GBC is the result of persistent irritation of the gallbladder [[mucosa]] over a period of years which predispose to malignant transformation or act as an enhancer for [[Carcinogen|carcinogenic]] exposure. | ||
* The primary mechanism involves cholelithiasis and resultant cholecystitis and appears to be the driving force in most areas of the arena | * The primary mechanism involves [[cholelithiasis]] and resultant [[cholecystitis]] and appears to be the driving force in most areas of the arena | ||
* Whereas GBC is strongly related to gallstone disease, female gender bias, and age over 65 | * Whereas GBC is strongly related to [[gallstone disease]], female gender bias, and age over 65 | ||
'''''Theory #1''''': | '''''Theory #1''''': | ||
* In the setting of a chronically inflamed gallbladder, metaplasia is not unusual.<ref name="pmid16724345">{{cite journal |vauthors=Roa I, de Aretxabala X, Araya JC, Roa J |title=Preneoplastic lesions in gallbladder cancer |journal=J Surg Oncol |volume=93 |issue=8 |pages=615–23 |year=2006 |pmid=16724345 |doi=10.1002/jso.20527 |url=}}</ref> | * In the setting of a chronically inflamed gallbladder, [[metaplasia]] is not unusual.<ref name="pmid16724345">{{cite journal |vauthors=Roa I, de Aretxabala X, Araya JC, Roa J |title=Preneoplastic lesions in gallbladder cancer |journal=J Surg Oncol |volume=93 |issue=8 |pages=615–23 |year=2006 |pmid=16724345 |doi=10.1002/jso.20527 |url=}}</ref> | ||
* Much like metaplasia of the stomach, gallbladder metaplasia happens in two forms | * Much like metaplasia of the stomach, gallbladder metaplasia happens in two forms | ||
** 1) Gastric form | ** 1) [[Gastric]] form | ||
** 2) Intestinal form | ** 2) [[Intestinal]] form | ||
* Chronically inflamed gallbladder may additionally express both pyloric gland and intestinal metaplasia | * Chronically inflamed gallbladder may additionally express both pyloric gland and intestinal metaplasia | ||
* But, fluke-infested gallbladders more commonly shows intestinal metaplasia and p53 mutations than sporadic gallbladder cancers.<ref name="pmid7780959">{{cite journal |vauthors=Wistuba II, Sugio K, Hung J, Kishimoto Y, Virmani AK, Roa I, Albores-Saavedra J, Gazdar AF |title=Allele-specific mutations involved in the pathogenesis of endemic gallbladder carcinoma in Chile |journal=Cancer Res. |volume=55 |issue=12 |pages=2511–5 |year=1995 |pmid=7780959 |doi= |url=}}</ref><ref name="pmid23268317">{{cite journal |vauthors=Hughes NR, Bhathal PS |title=Adenocarcinoma of gallbladder: an immunohistochemical profile and comparison with cholangiocarcinoma |journal=J. Clin. Pathol. |volume=66 |issue=3 |pages=212–7 |year=2013 |pmid=23268317 |doi=10.1136/jclinpath-2012-201146 |url=}}</ref> | * But, fluke-infested gallbladders more commonly shows intestinal metaplasia and [[P53 (protein)|p53]] mutations than sporadic gallbladder cancers.<ref name="pmid7780959">{{cite journal |vauthors=Wistuba II, Sugio K, Hung J, Kishimoto Y, Virmani AK, Roa I, Albores-Saavedra J, Gazdar AF |title=Allele-specific mutations involved in the pathogenesis of endemic gallbladder carcinoma in Chile |journal=Cancer Res. |volume=55 |issue=12 |pages=2511–5 |year=1995 |pmid=7780959 |doi= |url=}}</ref><ref name="pmid23268317">{{cite journal |vauthors=Hughes NR, Bhathal PS |title=Adenocarcinoma of gallbladder: an immunohistochemical profile and comparison with cholangiocarcinoma |journal=J. Clin. Pathol. |volume=66 |issue=3 |pages=212–7 |year=2013 |pmid=23268317 |doi=10.1136/jclinpath-2012-201146 |url=}}</ref> | ||
* The right relationship among metaplasia and dysplasia remains unwell-established. | * The right relationship among [[metaplasia]] and [[dysplasia]] remains unwell-established. | ||
* The first concept indicates that dysplasia progresses to carcinoma in situ (CIS) which will become invasive. | * The first concept indicates that dysplasia progresses to carcinoma in situ ([[CIS]]) which will become [[invasive]]. | ||
* This concept is supported via the finding that over 80% of invasive gallbladder cancers have adjoining areas of CIS and epithelial dysplasia. | * This concept is supported via the finding that over 80% of invasive gallbladder cancers have adjoining areas of CIS and epithelial dysplasia. | ||
* One study validated the presence of metaplasia, dysplasia, and CIS adjoining to cancer in 66%, 81.3%, and 69%, respectively. | * One study validated the presence of metaplasia, dysplasia, and CIS adjoining to cancer in 66%, 81.3%, and 69%, respectively. | ||
* Dysplastic lesions have molecular genetic proof that supports progression towards CIS. | * [[Dysplasia|Dysplastic]] lesions have molecular genetic proof that supports progression towards CIS. | ||
* It is well recognized that gallbladder dysplasia progresses to invasive most cancers normally over a path of 15 to 19 years | * It is well recognized that gallbladder dysplasia progresses to invasive most cancers normally over a path of 15 to 19 years | ||
'''''Theory #2''''' | '''''Theory #2''''' | ||
* There are also histologic and molecular differences in GBCs related to anomalous pancreaticobiliary duct junction and in the ones related to gallstones, Providing further proof that two different pathogenetic pathways are involved. | * There are also histologic and molecular differences in GBCs related to anomalous pancreaticobiliary duct junction and in the ones related to [[gallstones]], Providing further proof that two different pathogenetic pathways are involved. | ||
* GBC arising in Japan within the setting of an anomalous pancreaticobiliary duct junction is characterized by means of KRAS mutations and relatively late onset of p53 mutations.<ref name="pmid24589178">{{cite journal |vauthors=Solaini L, Sharma A, Watt J, Iosifidou S, Chin Aleong JA, Kocher HM |title=Predictive factors for incidental gallbladder dysplasia and carcinoma |journal=J. Surg. Res. |volume=189 |issue=1 |pages=17–21 |year=2014 |pmid=24589178 |doi=10.1016/j.jss.2014.01.064 |url=}}</ref> <ref name="pmid8950352">{{cite journal |vauthors=Mano H, Roa I, Araya JC, Ohta T, Yoshida K, Araki K, Kinebuchi H, Ishizu T, Nakadaira H, Endoh K, Yamamoto M, Watanabe H |title=Comparison of mutagenic activity of bile between Chilean and Japanese female patients having cholelithiasis |journal=Mutat. Res. |volume=371 |issue=1-2 |pages=73–7 |year=1996 |pmid=8950352 |doi= |url=}}</ref> | * GBC arising in Japan within the setting of an anomalous pancreaticobiliary duct junction is characterized by means of [[KRAS]] mutations and relatively late onset of [[P53 (protein)|p53]] [[mutations]].<ref name="pmid24589178">{{cite journal |vauthors=Solaini L, Sharma A, Watt J, Iosifidou S, Chin Aleong JA, Kocher HM |title=Predictive factors for incidental gallbladder dysplasia and carcinoma |journal=J. Surg. Res. |volume=189 |issue=1 |pages=17–21 |year=2014 |pmid=24589178 |doi=10.1016/j.jss.2014.01.064 |url=}}</ref> <ref name="pmid8950352">{{cite journal |vauthors=Mano H, Roa I, Araya JC, Ohta T, Yoshida K, Araki K, Kinebuchi H, Ishizu T, Nakadaira H, Endoh K, Yamamoto M, Watanabe H |title=Comparison of mutagenic activity of bile between Chilean and Japanese female patients having cholelithiasis |journal=Mutat. Res. |volume=371 |issue=1-2 |pages=73–7 |year=1996 |pmid=8950352 |doi= |url=}}</ref> | ||
* By means of comparison, as a minimum in Chilean patients with cholelithiasis and chronic cholecystitis, KRAS mutations are uncommon, while p53 mutations rise up early at some stage in multistage pathogenesis.<ref name="pmid10364037">{{cite journal |vauthors=Hanada K, Tsuchida A, Iwao T, Eguchi N, Sasaki T, Morinaka K, Matsubara K, Kawasaki Y, Yamamoto S, Kajiyama G |title=Gene mutations of K-ras in gallbladder mucosae and gallbladder carcinoma with an anomalous junction of the pancreaticobiliary duct |journal=Am. J. Gastroenterol. |volume=94 |issue=6 |pages=1638–42 |year=1999 |pmid=10364037 |doi=10.1111/j.1572-0241.1999.01155.x |url=}}</ref><ref name="pmid10676628">{{cite journal |vauthors=Hidaka E, Yanagisawa A, Seki M, Takano K, Setoguchi T, Kato Y |title=High frequency of K-ras mutations in biliary duct carcinomas of cases with a long common channel in the papilla of Vater |journal=Cancer Res. |volume=60 |issue=3 |pages=522–4 |year=2000 |pmid=10676628 |doi= |url=}}</ref> | * By means of comparison, as a minimum in Chilean patients with cholelithiasis and chronic cholecystitis, [[KRAS]] mutations are uncommon, while p53 mutations rise up early at some stage in multistage pathogenesis.<ref name="pmid10364037">{{cite journal |vauthors=Hanada K, Tsuchida A, Iwao T, Eguchi N, Sasaki T, Morinaka K, Matsubara K, Kawasaki Y, Yamamoto S, Kajiyama G |title=Gene mutations of K-ras in gallbladder mucosae and gallbladder carcinoma with an anomalous junction of the pancreaticobiliary duct |journal=Am. J. Gastroenterol. |volume=94 |issue=6 |pages=1638–42 |year=1999 |pmid=10364037 |doi=10.1111/j.1572-0241.1999.01155.x |url=}}</ref><ref name="pmid10676628">{{cite journal |vauthors=Hidaka E, Yanagisawa A, Seki M, Takano K, Setoguchi T, Kato Y |title=High frequency of K-ras mutations in biliary duct carcinomas of cases with a long common channel in the papilla of Vater |journal=Cancer Res. |volume=60 |issue=3 |pages=522–4 |year=2000 |pmid=10676628 |doi= |url=}}</ref> | ||
'''''Theory #3''''' | '''''Theory #3''''' | ||
* Less than 3% of early gallbladder carcinomas have adenomatous remnants, indicating this mechanism has less importance within the carcinogenic pathway.<ref name="pmid26421012">{{cite journal |vauthors=Kanthan R, Senger JL, Ahmed S, Kanthan SC |title=Gallbladder Cancer in the 21st Century |journal=J Oncol |volume=2015 |issue= |pages=967472 |year=2015 |pmid=26421012 |pmc=4569807 |doi=10.1155/2015/967472 |url=}}</ref> | * Less than 3% of early gallbladder carcinomas have [[adenomatous]] remnants, indicating this mechanism has less importance within the [[carcinogenic]] pathway.<ref name="pmid26421012">{{cite journal |vauthors=Kanthan R, Senger JL, Ahmed S, Kanthan SC |title=Gallbladder Cancer in the 21st Century |journal=J Oncol |volume=2015 |issue= |pages=967472 |year=2015 |pmid=26421012 |pmc=4569807 |doi=10.1155/2015/967472 |url=}}</ref> | ||
* It's hard to predict which of those will go through malignant transformation | * It's hard to predict which of those will go through [[malignant]] transformation | ||
* In contrast to properly-established carcinogenic pathways in colorectal most cancers, It remains debated within the literature whether or not or not adenomas are actual precursors of invasive gallbladder carcinomas | * In contrast to properly-established carcinogenic pathways in colorectal most cancers, It remains debated within the literature whether or not or not adenomas are actual precursors of [[invasive]] gallbladder carcinomas | ||
* Only 1% of cholecystectomy specimens have adenomatous polyps as preneoplastic lesions | * Only 1% of [[cholecystectomy]] specimens have adenomatous polyps as preneoplastic lesions | ||
== Gross Pathology == | == Gross Pathology == | ||
* On gross pathology, Fibrosis and thickening of the gallbladder are characteristic findings of the gallbladder cancer. | * On [[gross pathology]], Fibrosis and thickening of the gallbladder are characteristic findings of the gallbladder cancer. | ||
* Most of the times associated with gallstones > 3 cm in diameter. | * Most of the times associated with gallstones > 3 cm in diameter. | ||
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== Microscopic Pathology == | == Microscopic Pathology == | ||
* On microscopic histopathological analysis, outer portion is often better differentiated than deeper portion are characteristic findings of gallbladder cancer. | * On [[microscopic]] histopathological analysis, outer portion is often better differentiated than deeper portion are characteristic findings of gallbladder cancer. | ||
* On microscopic analysis tumor May extend to Rokitansky-Aschoff sinuses. | * On microscopic analysis tumor May extend to Rokitansky-Aschoff sinuses. | ||
* Atypical cuboidal cells are one of the microscopical findings of the high grade tumor. | * Atypical [[cuboidal cells]] are one of the microscopical findings of the high grade tumor. | ||
* Infiltrative or exophytic. | * Infiltrative or exophytic. | ||
* Well formed glands in papillary architecture with wide lumina are noted in microscopical findings | * Well formed glands in [[papillary]] architecture with wide [[Luminal|lumina]] are noted in microscopical findings | ||
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]
Overview
It is thought that gallbladder cancer (GBC) is the result of 2 or more different biological pathways based on morphological, genetic, and molecular evidence.
Pathophysiology
Pathogenesis
- It is understood that GBC is the result of persistent irritation of the gallbladder mucosa over a period of years which predispose to malignant transformation or act as an enhancer for carcinogenic exposure.
- The primary mechanism involves cholelithiasis and resultant cholecystitis and appears to be the driving force in most areas of the arena
- Whereas GBC is strongly related to gallstone disease, female gender bias, and age over 65
Theory #1:
- In the setting of a chronically inflamed gallbladder, metaplasia is not unusual.[1]
- Much like metaplasia of the stomach, gallbladder metaplasia happens in two forms
- 1) Gastric form
- 2) Intestinal form
- Chronically inflamed gallbladder may additionally express both pyloric gland and intestinal metaplasia
- But, fluke-infested gallbladders more commonly shows intestinal metaplasia and p53 mutations than sporadic gallbladder cancers.[2][3]
- The right relationship among metaplasia and dysplasia remains unwell-established.
- The first concept indicates that dysplasia progresses to carcinoma in situ (CIS) which will become invasive.
- This concept is supported via the finding that over 80% of invasive gallbladder cancers have adjoining areas of CIS and epithelial dysplasia.
- One study validated the presence of metaplasia, dysplasia, and CIS adjoining to cancer in 66%, 81.3%, and 69%, respectively.
- Dysplastic lesions have molecular genetic proof that supports progression towards CIS.
- It is well recognized that gallbladder dysplasia progresses to invasive most cancers normally over a path of 15 to 19 years
Theory #2
- There are also histologic and molecular differences in GBCs related to anomalous pancreaticobiliary duct junction and in the ones related to gallstones, Providing further proof that two different pathogenetic pathways are involved.
- GBC arising in Japan within the setting of an anomalous pancreaticobiliary duct junction is characterized by means of KRAS mutations and relatively late onset of p53 mutations.[4] [5]
- By means of comparison, as a minimum in Chilean patients with cholelithiasis and chronic cholecystitis, KRAS mutations are uncommon, while p53 mutations rise up early at some stage in multistage pathogenesis.[6][7]
Theory #3
- Less than 3% of early gallbladder carcinomas have adenomatous remnants, indicating this mechanism has less importance within the carcinogenic pathway.[8]
- It's hard to predict which of those will go through malignant transformation
- In contrast to properly-established carcinogenic pathways in colorectal most cancers, It remains debated within the literature whether or not or not adenomas are actual precursors of invasive gallbladder carcinomas
- Only 1% of cholecystectomy specimens have adenomatous polyps as preneoplastic lesions
Gross Pathology
- On gross pathology, Fibrosis and thickening of the gallbladder are characteristic findings of the gallbladder cancer.
- Most of the times associated with gallstones > 3 cm in diameter.
- Liver spread is usually evident at time of diagnosis
Microscopic Pathology
- On microscopic histopathological analysis, outer portion is often better differentiated than deeper portion are characteristic findings of gallbladder cancer.
- On microscopic analysis tumor May extend to Rokitansky-Aschoff sinuses.
- Atypical cuboidal cells are one of the microscopical findings of the high grade tumor.
- Infiltrative or exophytic.
- Well formed glands in papillary architecture with wide lumina are noted in microscopical findings
References
- ↑ Roa I, de Aretxabala X, Araya JC, Roa J (2006). "Preneoplastic lesions in gallbladder cancer". J Surg Oncol. 93 (8): 615–23. doi:10.1002/jso.20527. PMID 16724345.
- ↑ Wistuba II, Sugio K, Hung J, Kishimoto Y, Virmani AK, Roa I, Albores-Saavedra J, Gazdar AF (1995). "Allele-specific mutations involved in the pathogenesis of endemic gallbladder carcinoma in Chile". Cancer Res. 55 (12): 2511–5. PMID 7780959.
- ↑ Hughes NR, Bhathal PS (2013). "Adenocarcinoma of gallbladder: an immunohistochemical profile and comparison with cholangiocarcinoma". J. Clin. Pathol. 66 (3): 212–7. doi:10.1136/jclinpath-2012-201146. PMID 23268317.
- ↑ Solaini L, Sharma A, Watt J, Iosifidou S, Chin Aleong JA, Kocher HM (2014). "Predictive factors for incidental gallbladder dysplasia and carcinoma". J. Surg. Res. 189 (1): 17–21. doi:10.1016/j.jss.2014.01.064. PMID 24589178.
- ↑ Mano H, Roa I, Araya JC, Ohta T, Yoshida K, Araki K, Kinebuchi H, Ishizu T, Nakadaira H, Endoh K, Yamamoto M, Watanabe H (1996). "Comparison of mutagenic activity of bile between Chilean and Japanese female patients having cholelithiasis". Mutat. Res. 371 (1–2): 73–7. PMID 8950352.
- ↑ Hanada K, Tsuchida A, Iwao T, Eguchi N, Sasaki T, Morinaka K, Matsubara K, Kawasaki Y, Yamamoto S, Kajiyama G (1999). "Gene mutations of K-ras in gallbladder mucosae and gallbladder carcinoma with an anomalous junction of the pancreaticobiliary duct". Am. J. Gastroenterol. 94 (6): 1638–42. doi:10.1111/j.1572-0241.1999.01155.x. PMID 10364037.
- ↑ Hidaka E, Yanagisawa A, Seki M, Takano K, Setoguchi T, Kato Y (2000). "High frequency of K-ras mutations in biliary duct carcinomas of cases with a long common channel in the papilla of Vater". Cancer Res. 60 (3): 522–4. PMID 10676628.
- ↑ Kanthan R, Senger JL, Ahmed S, Kanthan SC (2015). "Gallbladder Cancer in the 21st Century". J Oncol. 2015: 967472. doi:10.1155/2015/967472. PMC 4569807. PMID 26421012.