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{{Linitis plastica}}
{{Linitis plastica}}
{{CMG}}{{AE}} {{STM}}
{{CMG}};{{AE}}{{HM}}


==Overview==
==Overview==
On [[gross pathology]], thick, rigid, leather bottle-like stomach from diffuse infiltration of the stomach wall by the [[tumor cell]]s are characteristic findings of linitis plastica.<ref name=lp>Linitis plastica. Wikipedia. https://en.wikipedia.org/wiki/Linitis_plastica Accessed on November 18, 2015.</ref> On microscopic histopathological analysis, atypical [[signet ring cell]]s diffusely infiltrating the stomach wall, [[submucosal]] [[fibrosis]] and thickening, with minimal [[mucosa]]l involvement are characteristic findings of linitis plastica. Development of linitis plastica is the result of genetic mutation in the ''CDH1'' ([[E-cadherin]]) gene, that is responsible for intercellular adhesions.<ref name name=mk>Gastric linitis plastica. Orphanet. http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=36273 Accessed on December 8, 2015.</ref>
It is thought that linitis plastica is generally a sporadic disease that may be inherited as a result of abnormal molecular pathways (Beta catenin/Wnt signaling) that causes defective [[Cell adhesion|intracellular adhesions]].


==Pathophysiology==
==Pathophysiology==
*Linitis plastica is a morphological variant of diffuse (or infiltrating) gastric adenocarcinoma ([[stomach cancer]]).<ref name=lp>Linitis plastica. Wikipedia. https://en.wikipedia.org/wiki/Linitis_plastica Accessed on November 12, 2015.</ref>
*In diffuse type [[Stomach cancer|gastric cancer]], the cells experience a loss of expression for [[Cell adhesion|cell adhesion protein]] [[Cadherin|E-cadherin]].<ref name="pmid14630673">{{cite journal |vauthors=Graziano F, Humar B, Guilford P |title=The role of the E-cadherin gene (CDH1) in diffuse gastric cancer susceptibility: from the laboratory to clinical practice |journal=Ann. Oncol. |volume=14 |issue=12 |pages=1705–13 |year=2003 |pmid=14630673 |doi= |url=}}</ref>  
*[[Adenocarcinoma]] is the most common type of gastric cancer accounting to almost 90% of the same, of which about 10% constitute linitis plastica.<ref>Malignant tumours of the stomach. Canadian cancer society. http://www.cancer.ca/en/cancer-information/cancer-type/stomach/stomach-cancer/malignant-tumours/?region=nb Accessed on November 12, 2015.</ref>
*The [[Cadherin|E-cadherin]] gene ([[CDH1 (gene)|CDH1]]) codes for a transmembrane cellular adhesion protein that provides a tail that adheres to other cells.
*The tail interacts with catenins in the neighbouring cell and forms a cell to cell complex in what is known as Beta catenin/Wnt signaling.
*The loss of these cellular interactions leads to the formation of cancerous cells that trigger a stromal reaction leading to diffuse schirrous (fibrous) changes.


===Genetics===
==Genetics==
*[[Germline]] mutations in the ''CDH1'' ([[E-cadherin]]) gene, resulting in altered intercellular adhesions, may be involved in the pathogenesis of diffuse gastric adenocarcinoma.<ref name=mk>Gastric linitis plastica. Orphanet. http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=36273 Accessed on November 19, 2015.</ref><ref name="WolfGeigl2010">{{cite journal|last1=Wolf|first1=E.-M.|last2=Geigl|first2=J.B.|last3=Svrcek|first3=M.|last4=Vieth|first4=M.|last5=Langner|first5=C.|title=Hereditäres Magenkarzinom|journal=Der Pathologe|volume=31|issue=6|year=2010|pages=423–429|issn=0172-8113|doi=10.1007/s00292-010-1353-7}}</ref>
*Linitis plastica is transmitted in an [[autosomal dominant]] pattern in hereditary diffuse gastric cancer.<ref name="pmid9537325">{{cite journal |vauthors=Guilford P, Hopkins J, Harraway J, McLeod M, McLeod N, Harawira P, Taite H, Scoular R, Miller A, Reeve AE |title=E-cadherin germline mutations in familial gastric cancer |journal=Nature |volume=392 |issue=6674 |pages=402–5 |year=1998 |pmid=9537325 |doi=10.1038/32918 |url=}}</ref><ref name="pmid18788075">{{cite journal |vauthors=Barber M, Murrell A, Ito Y, Maia AT, Hyland S, Oliveira C, Save V, Carneiro F, Paterson AL, Grehan N, Dwerryhouse S, Lao-Sirieix P, Caldas C, Fitzgerald RC |title=Mechanisms and sequelae of E-cadherin silencing in hereditary diffuse gastric cancer |journal=J. Pathol. |volume=216 |issue=3 |pages=295–306 |year=2008 |pmid=18788075 |doi=10.1002/path.2426 |url=}}</ref><ref name="pmid19269290">{{cite journal |vauthors=Oliveira C, Sousa S, Pinheiro H, Karam R, Bordeira-Carriço R, Senz J, Kaurah P, Carvalho J, Pereira R, Gusmão L, Wen X, Cipriano MA, Yokota J, Carneiro F, Huntsman D, Seruca R |title=Quantification of epigenetic and genetic 2nd hits in CDH1 during hereditary diffuse gastric cancer syndrome progression |journal=Gastroenterology |volume=136 |issue=7 |pages=2137–48 |year=2009 |pmid=19269290 |doi=10.1053/j.gastro.2009.02.065 |url=}}</ref>
*Hereditary form of diffuse gastric adenocarcinoma is transmitted in an [[autosomal dominant]] fashion, with a 70% disease [[penetrance]].<ref name=mk>Gastric linitis plastica. Orphanet. http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=36273 Accessed on November 19, 2015.</ref><ref name="WolfGeigl2010">{{cite journal|last1=Wolf|first1=E.-M.|last2=Geigl|first2=J.B.|last3=Svrcek|first3=M.|last4=Vieth|first4=M.|last5=Langner|first5=C.|title=Hereditäres Magenkarzinom|journal=Der Pathologe|volume=31|issue=6|year=2010|pages=423–429|issn=0172-8113|doi=10.1007/s00292-010-1353-7}}</ref>
*Genes involved in the pathogenesis of linitis plastica include [[CDH1 (gene)|CDH1 gene]], located on chromosome 16q22.1, which codes for the [[Cadherin|E-cadherin]] protein.
*The development of linitis plastica is the result of germline truncating mutations spread over several [[Exon|exons]].
*Consequently, the second [[allele]] coding for [[Cadherin|E-cadherin]] is inactivated in a two-hit theoretical manner.
*Mutations include:
**[[Promoter]] hypermethylation
**[[Loss of heterozygosity]]
**Silencing mutation


===Gross pathology===
==Associated conditions==
*On gross pathology, thick, rigid, leather bottle-like stomach from diffuse infiltration of the stomach wall by the tumor cells are characteristic findings of linitis plastica.<ref name=lp>Linitis plastica. Wikipedia. https://en.wikipedia.org/wiki/Linitis_plastica Accessed on November 18, 2015.</ref>
*Women with diffuse type gastric cancer are also at an increased risk of [[Breast cancer|lobular breast cancer]].
*As a result of the tumor cell infiltration and [[fibrosis]], there is diffuse thickening and rigidity of the gastric wall, making the process of digestion difficult.
*Susceptibility to diffuse [[Stomach cancer|gastric cancer]] may also be linked to inherited [[polymorphisms]] in the [[PSCA (gene)|PSCA]] ([[prostate]] stem cell antigen) gene, which is possibly involved in regulating gastric [[Epithelial cells|epithelial cell]] [[Cell growth|proliferation]].<ref name="pmid18488030">{{cite journal |vauthors=Sakamoto H, Yoshimura K, Saeki N, Katai H, Shimoda T, Matsuno Y, Saito D, Sugimura H, Tanioka F, Kato S, Matsukura N, Matsuda N, Nakamura T, Hyodo I, Nishina T, Yasui W, Hirose H, Hayashi M, Toshiro E, Ohnami S, Sekine A, Sato Y, Totsuka H, Ando M, Takemura R, Takahashi Y, Ohdaira M, Aoki K, Honmyo I, Chiku S, Aoyagi K, Sasaki H, Ohnami S, Yanagihara K, Yoon KA, Kook MC, Lee YS, Park SR, Kim CG, Choi IJ, Yoshida T, Nakamura Y, Hirohashi S |title=Genetic variation in PSCA is associated with susceptibility to diffuse-type gastric cancer |journal=Nat. Genet. |volume=40 |issue=6 |pages=730–40 |year=2008 |pmid=18488030 |doi=10.1038/ng.152 |url=}}</ref>
*[[Metastasis]] to the [[peritoneum]], [[lymph node]]s  and/or other organs usually occurs by the time linitis plastica is diagnosed. Linitis plastica may also occur secondary to metastasis from other primary cancers, particularly infiltrating lobular carcinoma of breast.<ref name=mk>Gastric linitis plastica. Orphanet. http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=36273 Accessed on December 7, 2015.</ref>


<gallery>
==Gross Pathology==
image:Linitis_plastica1.jpg|Endoscopic image of linitis plastica, a type of stomach cancer where the entire stomach is invaded, leading to a leather bottle-like appearance with blood coming out of it.<ref>Linitis Plastica. Wikimedia. https://en.wikipedia.org/wiki/Linitis_plastica#/media/File:Linitis_plastica_2.jpg Accessed on December 13, 2015</ref></gallery>
*On gross pathology, a thickened, rigid, and leather-like stomach wall is a characteristic finding of linitis plastica.
*Linitis plastica may appear as [[Plaque|plaques]] of [[fibrosis]], which give the appearance of a segmental infiltration with a lack of distensibility.  


===Microscopic pathology===
[[Image:lp.jpg|thumb|center|500px|Shown is diffuse cancer of the stomach, giving a "leather bottle appearance".Source: commons.wikimedia.org by http://en.wikipedia.org/wiki/User:Samir_%28The_Scope%29 - http://en.wikipedia.org/wiki/Image:Linitis_plastica.jpg, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=1649074]]
*In diffuse type adenocarcinoma (mucinous, [[colloid]]), tumour cells are discohesive and secrete mucus, which is delivered in the [[interstitium]], producing large pools of mucus or colloid (optically "empty" spaces). If the mucus remains inside the tumour cell, it pushes the nucleus to the periphery, leaving a "signet-ring cell" appearance.
 
*On microscopic histopathological analysis, poorly differentiated, atypical [[signet ring cell]]s diffusely infiltrating the stomach wall, submucosal fibrosis and thickening, with minimal [[mucosa]]l involvement are characteristic findings of linitis plastica.<ref name="SchauerPeiper2011">{{cite journal|last1=Schauer|first1=M|last2=Peiper|first2=M|last3=Theisen|first3=J|last4=Knoefel|first4=W|title=Prognostic factors in patients with diffuse type gastric cancer (linitis plastica) after operative treatment|journal=European Journal of Medical Research|volume=16|issue=1|year=2011|pages=29|issn=2047-783X|doi=10.1186/2047-783X-16-1-29}}</ref><ref>Stomach cancer. Wikipedia. https://en.wikipedia.org/wiki/Stomach_cancer Accessed on November 19, 2015.</ref>
==Microscopic Pathology==
*Superficial mucosal layers are usually spared and rarely show superficial ulcers on endoscopy, that has a wide differential diagnosis, making the diagnosis even more difficult. The biopsies are falsely negative, as the disease remains mostly in the [[submucosa]] and muscularis propria.<ref name="SchauerPeiper2011">{{cite journal|last1=Schauer|first1=M|last2=Peiper|first2=M|last3=Theisen|first3=J|last4=Knoefel|first4=W|title=Prognostic factors in patients with diffuse type gastric cancer (linitis plastica) after operative treatment|journal=European Journal of Medical Research|volume=16|issue=1|year=2011|pages=29|issn=2047-783X|doi=10.1186/2047-783X-16-1-29}}</ref>
On microscopic histopathological analysis, tumor cells are seen invading surrounding tissue, with no glandular formation and abundant [[mucin]] that push the [[Cell nucleus|nucleus]] to one side producing what is known as a [[signet ring cell]]. [[Signet cell|Signet ring cell]]<nowiki/>s are a characteristic finding of linitis plastica.<ref name="pmid19855261">{{cite journal |vauthors=Piessen G, Messager M, Leteurtre E, Jean-Pierre T, Mariette C |title=Signet ring cell histology is an independent predictor of poor prognosis in gastric adenocarcinoma regardless of tumoral clinical presentation |journal=Ann. Surg. |volume=250 |issue=6 |pages=878–87 |year=2009 |pmid=19855261 |doi=10.1097/SLA.0b013e3181b21c7b |url=}}</ref>
*Although the lower [[mucosa]]l and [[submucosa]]l layers are mostly involved, the muscular and subserosal layers may also be infiltrated with the neoplastic cells.<ref>{{Cite journal
[[Image:sc.jpg|thumb|center|500px|Arrow indicates a signet ring cell characteristic of linitis plastica. Source:commons.wikimedia.org by Ed Uthman from Houston, TX, USA - Signet Ring CellsUploaded by CFCF, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=30103742 ]]
| author = [[Bing Hu]], [[Nassim El Hajj]], [[Scott Sittler]], [[Nancy Lammert]], [[Robert Barnes]] & [[Aurelia Meloni-Ehrig]]
| title = Gastric cancer: Classification, histology and application of molecular pathology
| journal = [[Journal of gastrointestinal oncology]]
| volume = 3
| issue = 3
| pages = 251–261
| year = 2012
| month = September
| doi = 10.3978/j.issn.2078-6891.2012.021
| pmid = 22943016
}}</ref>


<gallery>
image:Gastric_signet_ring_cell_carcinoma.jpg|A signet ring cell carcinoma of the stomach. Signet ring cells are seen in the lower half of the image. Gastric epithelium is seen in the upper half of the image. H&E stain.<ref>Linitis Plastica. Wikimedia. https://en.wikipedia.org/wiki/Signet_ring_cell_carcinoma#/media/File:Signet_ring_cell_carcinoma_-_very_high_mag.jpg Accessed on December 13, 2015</ref></gallery>


<gallery>image:Gastric_signet_ring_cell_carcinomahistopatholgy.jpg|Gastric signet ring cell carcinoma. H&E stain.<ref>Linitis Plastica. Wikimedia.https://en.wikipedia.org/wiki/Signet_ring_cell_carcinoma#/media/File:Gastric_signet_ring_cell_carcinoma_histopatholgy_%281%29.jpg  Accessed on December 13, 2015.</ref></gallery>


==References==
==References==

Latest revision as of 19:32, 16 January 2018

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Hadeel Maksoud M.D.[2]

Overview

It is thought that linitis plastica is generally a sporadic disease that may be inherited as a result of abnormal molecular pathways (Beta catenin/Wnt signaling) that causes defective intracellular adhesions.

Pathophysiology

  • In diffuse type gastric cancer, the cells experience a loss of expression for cell adhesion protein E-cadherin.[1]
  • The E-cadherin gene (CDH1) codes for a transmembrane cellular adhesion protein that provides a tail that adheres to other cells.
  • The tail interacts with catenins in the neighbouring cell and forms a cell to cell complex in what is known as Beta catenin/Wnt signaling.
  • The loss of these cellular interactions leads to the formation of cancerous cells that trigger a stromal reaction leading to diffuse schirrous (fibrous) changes.

Genetics

  • Linitis plastica is transmitted in an autosomal dominant pattern in hereditary diffuse gastric cancer.[2][3][4]
  • Genes involved in the pathogenesis of linitis plastica include CDH1 gene, located on chromosome 16q22.1, which codes for the E-cadherin protein.
  • The development of linitis plastica is the result of germline truncating mutations spread over several exons.
  • Consequently, the second allele coding for E-cadherin is inactivated in a two-hit theoretical manner.
  • Mutations include:

Associated conditions

Gross Pathology

  • On gross pathology, a thickened, rigid, and leather-like stomach wall is a characteristic finding of linitis plastica.
  • Linitis plastica may appear as plaques of fibrosis, which give the appearance of a segmental infiltration with a lack of distensibility.
Shown is diffuse cancer of the stomach, giving a "leather bottle appearance".Source: commons.wikimedia.org by http://en.wikipedia.org/wiki/User:Samir_%28The_Scope%29 - http://en.wikipedia.org/wiki/Image:Linitis_plastica.jpg, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=1649074

Microscopic Pathology

On microscopic histopathological analysis, tumor cells are seen invading surrounding tissue, with no glandular formation and abundant mucin that push the nucleus to one side producing what is known as a signet ring cell. Signet ring cells are a characteristic finding of linitis plastica.[6]

Arrow indicates a signet ring cell characteristic of linitis plastica. Source:commons.wikimedia.org by Ed Uthman from Houston, TX, USA - Signet Ring CellsUploaded by CFCF, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=30103742


References

  1. Graziano F, Humar B, Guilford P (2003). "The role of the E-cadherin gene (CDH1) in diffuse gastric cancer susceptibility: from the laboratory to clinical practice". Ann. Oncol. 14 (12): 1705–13. PMID 14630673.
  2. Guilford P, Hopkins J, Harraway J, McLeod M, McLeod N, Harawira P, Taite H, Scoular R, Miller A, Reeve AE (1998). "E-cadherin germline mutations in familial gastric cancer". Nature. 392 (6674): 402–5. doi:10.1038/32918. PMID 9537325.
  3. Barber M, Murrell A, Ito Y, Maia AT, Hyland S, Oliveira C, Save V, Carneiro F, Paterson AL, Grehan N, Dwerryhouse S, Lao-Sirieix P, Caldas C, Fitzgerald RC (2008). "Mechanisms and sequelae of E-cadherin silencing in hereditary diffuse gastric cancer". J. Pathol. 216 (3): 295–306. doi:10.1002/path.2426. PMID 18788075.
  4. Oliveira C, Sousa S, Pinheiro H, Karam R, Bordeira-Carriço R, Senz J, Kaurah P, Carvalho J, Pereira R, Gusmão L, Wen X, Cipriano MA, Yokota J, Carneiro F, Huntsman D, Seruca R (2009). "Quantification of epigenetic and genetic 2nd hits in CDH1 during hereditary diffuse gastric cancer syndrome progression". Gastroenterology. 136 (7): 2137–48. doi:10.1053/j.gastro.2009.02.065. PMID 19269290.
  5. Sakamoto H, Yoshimura K, Saeki N, Katai H, Shimoda T, Matsuno Y, Saito D, Sugimura H, Tanioka F, Kato S, Matsukura N, Matsuda N, Nakamura T, Hyodo I, Nishina T, Yasui W, Hirose H, Hayashi M, Toshiro E, Ohnami S, Sekine A, Sato Y, Totsuka H, Ando M, Takemura R, Takahashi Y, Ohdaira M, Aoki K, Honmyo I, Chiku S, Aoyagi K, Sasaki H, Ohnami S, Yanagihara K, Yoon KA, Kook MC, Lee YS, Park SR, Kim CG, Choi IJ, Yoshida T, Nakamura Y, Hirohashi S (2008). "Genetic variation in PSCA is associated with susceptibility to diffuse-type gastric cancer". Nat. Genet. 40 (6): 730–40. doi:10.1038/ng.152. PMID 18488030.
  6. Piessen G, Messager M, Leteurtre E, Jean-Pierre T, Mariette C (2009). "Signet ring cell histology is an independent predictor of poor prognosis in gastric adenocarcinoma regardless of tumoral clinical presentation". Ann. Surg. 250 (6): 878–87. doi:10.1097/SLA.0b013e3181b21c7b. PMID 19855261.


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