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{{CMG}}; {{AE}} {{Soroush}}
{{CMG}}; {{AE}} {{Soroush}}
==Overview==
==Overview==
The [[pathophysiology]] of appendix cancer depends on the histological subtype. There are two major subtypes of appendix cancer, adenocarcinomas and carcionid tumors. While carcinoid tumors arises from enterochromaffin cells ([[Enterochromaffin cell|Kulchitsky]] cells), which are secretory cells that are normally involved in [[neuroendocrine]] hormonal secretions, adenocarcinomas are the result of mutations in mucous producing epithelial cells. Their physiology, [[pathophysiology]], genetic pathways, prognosis as well as epidemiology are different and hence, discussed separately. The progression to adenocarcinoma usually involves the ''[[KRAS]], [[APC]], [[TP53]],'' and ''RAF'' pathways, While ''[[β-catenin]]'', ''[[NF1]]'', and ''[[MEN1]]'' genes are major contributors of [[Carcinoid Tumor|carcinoid]] tumors progression.
The [[pathophysiology]] of [[Vermiform appendix|appendix]] [[cancer]] depends on the [[Histological|histological subtype]]. There are two major subtypes of [[appendix cancer]], [[adenocarcinoma]]<nowiki/>s and [[Carcinoid Tumor|carcinoid tumors]]. While [[Carcinoid Tumor|carcinoid tumors]] arises from [[Enterochromaffin cell|enterochromaffin cells]] ([[Enterochromaffin cell|Kulchitsky]] cells), which are secretory cells that are normally involved in [[neuroendocrine]] [[Hormone|hormonal]] secretions, [[adenocarcinoma]]<nowiki/>s are the result of mutations in [[mucus]] producing [[Epithelium|epithelial cells]]. Their [[physiology]], [[pathophysiology]], [[Genetics|genetic]] pathways, [[prognosis]] as well as [[epidemiology]] are different and hence, discussed separately. The progression to [[adenocarcinoma]] usually involves the ''[[KRAS]], [[APC]], [[TP53]],'' and ''RAF'' pathways, while ''[[β-catenin]]'', ''[[NF1]]'', and ''[[MEN1]]'' genes are major contributors of [[Carcinoid Tumor|carcinoid]] [[Tumor|tumors]] progression.
 


==Pathophysiology==
==Pathophysiology==
===Physiology===
===Physiology===
*The normal physiology of entrochromaffin cells is secretion of serotonin (5-HT), histamine, kallikrein, prostaglandins, and tachykinins.  
*The normal [[physiology]] of [[Enterochromaffin cell|enterochromaffin]] cells is secretion of [[serotonin]] (5-HT), [[histamine]], [[kallikrein]], [[Prostaglandin|prostaglandins]], and [[Tachykinin peptides|tachykinin]]<nowiki/>s.<ref name="pmid21518048" />


*Glandular epithelial cells are responsible for mucous production.   
*[[Gland|Glandular]] [[Epithelium|epithelial cells]] are responsible for [[Mucus|mucus production]].   


===Pathogenesis===
===Pathogenesis===
*The pathophysiology of appendix cancer depends on the histological subtype.
*The [[pathophysiology]] of [[Vermiform appendix|appendix]] [[cancer]] depends on the [[Histology|histological]] subtype.<ref name="pmid12569593">Modlin IM, Lye KD, Kidd M (2003) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=12569593 A 5-decade analysis of 13,715 carcinoid tumors.] ''Cancer'' 97 (4):934-59. [http://dx.doi.org/10.1002/cncr.11105 DOI:10.1002/cncr.11105] PMID: [https://pubmed.gov/12569593 12569593]</ref>
*Adenocarcinoma arises from epithelial glandular cells, which are normally involved in mucous production.
*[[Adenocarcinoma]] arises from epithelial glandular cells, which are normally involved in mucous production.
*Carcinoid tumors arise from entrochromaffin cell, which are neuroendocrine cells that are normally involved in secretion of serotonin (5-HT), histamine, kallikrein, prostaglandins, and tachykinins.
*[[Carcinoid Tumor|Carcinoid tumors]] arise from [[enterochromaffin cell]], which are [[neuroendocrine]] cells that are normally involved in secretion of [[serotonin]] (5-HT), [[histamine]], [[kallikrein]], [[prostaglandin|prostaglandi]]<nowiki/>[[prostaglandin|n]]<nowiki/>s, and [[Tachykinin peptides|tachykinins]].<ref name="pmid21518048">Gunawardene AR, Corfe BM, Staton CA (2011) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=21518048 Classification and functions of enteroendocrine cells of the lower gastrointestinal tract.] ''Int J Exp Pathol'' 92 (4):219-31. [http://dx.doi.org/10.1111/j.1365-2613.2011.00767.x DOI:10.1111/j.1365-2613.2011.00767.x] PMID: [https://pubmed.gov/21518048 21518048]</ref>
*The pathogenesis of appendix cancer is characterized by an initial [[Dysplasia|epithelial dysplasia]], followed by the formation of cystic structures and angiolymphatic invasion. Subsequently, in the advanced stages of appendix cancer, tumor cells detach from the primary tumor mass and gain access to the peritoneal cavity.<ref name="pmid22084738">{{cite journal |vauthors=Ruoff C, Hanna L, Zhi W, Shahzad G, Gotlieb V, Saif MW |title=Cancers of the appendix: review of the literatures |journal=ISRN Oncol |volume=2011 |issue= |pages=728579 |year=2011 |pmid=22084738 |pmc=3200132 |doi=10.5402/2011/728579 |url=}}</ref>
*The [[pathogenesis]] of appendix cancer is characterized by an initial [[Dysplasia|epithelial dysplasia]], followed by the formation of cystic structures and angiolymphatic invasion. Subsequently, in the [[Cancer staging|advanced stages]] of [[Vermiform appendix|appendix]] [[cancer]], [[tumor]] cells detach from the primary tumor mass and gain access to [[Peritoneal cavity|the peritoneal cavity]].<ref name="pmid22084738">{{cite journal |vauthors=Ruoff C, Hanna L, Zhi W, Shahzad G, Gotlieb V, Saif MW |title=Cancers of the appendix: review of the literatures |journal=ISRN Oncol |volume=2011 |issue= |pages=728579 |year=2011 |pmid=22084738 |pmc=3200132 |doi=10.5402/2011/728579 |url=}}</ref>
==Genetics==
==Genetics==
Genes involved in the pathogenesis of carcinoid tumors of appendix include:
[https://rarediseases.info.nih.gov/diseases/9316/carcinoid-tumor Genes involved in the pathogenesis of carcinoid tumors] of [[Vermiform appendix|appendix]] include:<ref name="pmid16794389">Modlin IM, Kidd M, Latich I, Zikusoka MN, Eick GN, Mane SM et al. (2006) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=16794389 Genetic differentiation of appendiceal tumor malignancy: a guide for the perplexed.] ''Ann Surg'' 244 (1):52-60. [http://dx.doi.org/10.1097/01.sla.0000217617.06782.d5 DOI:10.1097/01.sla.0000217617.06782.d5] PMID: [https://pubmed.gov/16794389 16794389]</ref><ref name="pmid18398037">Hassan MM, Phan A, Li D, Dagohoy CG, Leary C, Yao JC (2008) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=18398037 Family history of cancer and associated risk of developing neuroendocrine tumors: a case-control study.] ''Cancer Epidemiol Biomarkers Prev'' 17 (4):959-65. [http://dx.doi.org/10.1158/1055-9965.EPI-07-0750 DOI:10.1158/1055-9965.EPI-07-0750] PMID: [https://pubmed.gov/18398037 18398037]</ref>
*''[[β-catenin]]'',  
*''[[β-catenin]]'',  
*''[[NF1]]'',  
*''[[NF1]]'',  
*''[[MEN1]]''  
*''[[MEN1]]''  


The development of appendiceal adeocarcinoma is the result of multiple genetic mutations such as:
The development of appendiceal [[adenocarcinoma]] is the result of multiple [[Mutation|genetic mutations]] such as:<ref name="pmid18398037">Hassan MM, Phan A, Li D, Dagohoy CG, Leary C, Yao JC (2008) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=18398037 Family history of cancer and associated risk of developing neuroendocrine tumors: a case-control study.] ''Cancer Epidemiol Biomarkers Prev'' 17 (4):959-65. [http://dx.doi.org/10.1158/1055-9965.EPI-07-0750 DOI:10.1158/1055-9965.EPI-07-0750] PMID: [https://pubmed.gov/18398037 18398037]</ref>


*''[[KRAS]]''
*''[[KRAS]]''
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==Associated Conditions==
==Associated Conditions==
*Conditions associated with appendiceal cancers include:
*Conditions associated with appendiceal cancers include:
:*Chronic inflammatory disease such as [[ulcerative colitis]]
:*[[Cancer|Familial cancer syndrome]]<nowiki/>s<nowiki/>:<ref name="pmid18398037">Hassan MM, Phan A, Li D, Dagohoy CG, Leary C, Yao JC (2008) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=18398037 Family history of cancer and associated risk of developing neuroendocrine tumors: a case-control study.] ''Cancer Epidemiol Biomarkers Prev'' 17 (4):959-65. [http://dx.doi.org/10.1158/1055-9965.EPI-07-0750 DOI:10.1158/1055-9965.EPI-07-0750] PMID: [https://pubmed.gov/18398037 18398037]</ref>
::*[[Multiple endocrine neoplasia type 1|MEN1 Syndrome]]
::*[[Neurofibromatosis type I|Neurofibromatosis type 1]]
::*[[Hereditary nonpolyposis colorectal cancer history and symptoms|Hereditary Non-polyposis Colorectal Cancer (HNPCC)]]
::*[[Von Hippel-Lindau disease|Von Hippel-Lindau disease (VHL)]]
::*[[Li-Fraumeni syndrome|Li-Fraumeni Syndrome]]


**Chronic inflammatory disease such as [[Ulcerative colitis]]
**Familial cancer syndromes
***'''[[Multiple endocrine neoplasia type 1|MEN1 Syndrome]]'''
***[[Neurofibromatosis type I|Neurofibromatosis type 1]]
***[[Hereditary nonpolyposis colorectal cancer history and symptoms|Hereditary Non-polyposis Colorectal Cancer (HNPCC)]]
***[[Von Hippel-Lindau disease|Von Hippel-Lindau disease (VHL)]]
***[[Li-Fraumeni syndrome|Li-Fraumeni Syndrome]]
==Gross Pathology==
==Gross Pathology==
{| align="right"
|
[[image:800px-Appendiceal carcinoid 1.JPG|thumb|300px|Appendix carcinoid gross pathology. Courtesy of Dr.Robertson. Uploaded by James Heilman, MD. https://commons.wikimedia.org/wiki/File:Appendiceal_carcinoid_1.JPG]]
|}
*On gross pathology, findings of appendix cancer, include:<ref name="pmid22084738">{{cite journal |vauthors=Ruoff C, Hanna L, Zhi W, Shahzad G, Gotlieb V, Saif MW |title=Cancers of the appendix: review of the literatures |journal=ISRN Oncol |volume=2011 |issue= |pages=728579 |year=2011 |pmid=22084738 |pmc=3200132 |doi=10.5402/2011/728579 |url=}}</ref>
*On gross pathology, findings of appendix cancer, include:<ref name="pmid22084738">{{cite journal |vauthors=Ruoff C, Hanna L, Zhi W, Shahzad G, Gotlieb V, Saif MW |title=Cancers of the appendix: review of the literatures |journal=ISRN Oncol |volume=2011 |issue= |pages=728579 |year=2011 |pmid=22084738 |pmc=3200132 |doi=10.5402/2011/728579 |url=}}</ref>
:*Well-demarcated mass
:*Well-demarcated mass
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:* No gross tumor might be present
:* No gross tumor might be present
:*Thickened appendiceal wall
:*Thickened appendiceal wall
*''The image below demonstrates gross pathology of appendix cancer.''
<gallery>image:800px-Appendiceal_carcinoid_1.JPG | Gross pathology appendix cancer</gallery>


==Microscopic Pathology==
==Microscopic Pathology==
*On microscopic histopathological analysis findings will depend on the subtype of appendicular cancer.
{| align="right"
*Common histopathological findings, may include:<ref name="pmid22084738">{{cite journal |vauthors=Ruoff C, Hanna L, Zhi W, Shahzad G, Gotlieb V, Saif MW |title=Cancers of the appendix: review of the literatures |journal=ISRN Oncol |volume=2011 |issue= |pages=728579 |year=2011 |pmid=22084738 |pmc=3200132 |doi=10.5402/2011/728579 |url=}}</ref>
|
'''The images below demonstrate different<br>histopathological findings of appendix cancer'''
|-
|
[[Image:Adenocarcinoma of appendix, MUC2 staining.jpg|thumb|left|300px|Low grade appendiceal mucinous neoplasm, MUC2 staining. Courtesy of '''''Carlos Parra-Herran, M.D.'''''http://www.pathologyoutlines.com/topic/ovarytumorappendiceal.html]]
|-
|
[[image:Appendiceal adenocarcinoma.jpg|thumb|left|300px|Appendiceal adenocarcinoma, H and E staining. Courtesy of '''''Carlos Parra-Herran, M.D.'''''http://www.pathologyoutlines.com/topic/ovarytumorappendiceal.html]]
|-
|
[[image:Terminal-ileum-carcinoid-well-differentiated-neuroendocrine-tumour.jpg|thumb|left|300px|Typical microscopic appearance of a well differentiated carcinoid tumor (terminal illeum, H and E staining).Case courtesy of Dr Andrew Ryan, <a href="https://radiopaedia.org/">Radiopaedia.org</a>. From the case <a href="https://radiopaedia.org/cases/16308">rID: 16308</a>]]
|}
*On microscopic [[Histopathology|histopathologic]]<nowiki/>al analysis findings will depend on the subtype of appendicular cancer.
*Common [[Histopathology|histopathological]] findings, may include:<ref name="pmid22084738">{{cite journal |vauthors=Ruoff C, Hanna L, Zhi W, Shahzad G, Gotlieb V, Saif MW |title=Cancers of the appendix: review of the literatures |journal=ISRN Oncol |volume=2011 |issue= |pages=728579 |year=2011 |pmid=22084738 |pmc=3200132 |doi=10.5402/2011/728579 |url=}}</ref>
:*Cystic structures  
:*Cystic structures  
:*Angiolymphatic invasion
:*Angiolymphatic invasion


*'''Adenocarcinoma'''
*'''Adenocarcinoma'''
:*Intestinal, mucinous or signet ring cell types
:*Intestinal, [[mucinous]] or signet ring cell types
:*oexisting acute appendicitis is common '''IHC''' might be positive for the following '''stains:'''
:*Coexisting acute appendicitis is common
:*'''[[immunohistochemistry]] (IHC)''' might be positive for the following stains''':'''<ref name="pmid12748245">Lee MJ, Lee HS, Kim WH, Choi Y, Yang M (2003) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=12748245 Expression of mucins and cytokeratins in primary carcinomas of the digestive system.] ''Mod Pathol'' 16 (5):403-10. [http://dx.doi.org/10.1097/01.MP.0000067683.84284.66 DOI:10.1097/01.MP.0000067683.84284.66] PMID: [https://pubmed.gov/12748245 12748245]</ref>
:*MUC 2
:*MUC 2
:*'''MUC5AC'''
:*MUC5AC
:*CK 8/18
:*CK 8/18
:*CK 13
:*CK 13
Line 84: Line 100:
:*Retraction of peripheral tumor cells from stroma
:*Retraction of peripheral tumor cells from stroma
:*Angiolymphatic invasion is common
:*Angiolymphatic invasion is common
:*Granular eosinophilic cytoplasm with either diffusely scattered or peripherally clumped granules
:*Granular [[Eosinophilic Pneumonias|eosinophilic]] cytoplasm with either diffusely scattered or peripherally clumped granules
:*Two types of well differentiated tumors: EC cell (serotonin producing) and rarely L-cell (enteroglucagon or peptide YY producing) '''IHC''' might be positive for '''S100'''
:*Two types of well differentiated tumors: EC cell ([[serotonin]] producing) and rarely L-cell (enteroglucagon or peptide YY producing)<ref name="pmid2193876">Iwafuchi M, Watanabe H, Ajioka Y, Shimoda T, Iwashita A, Ito S (1990) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=2193876 Immunohistochemical and ultrastructural studies of twelve argentaffin and six argyrophil carcinoids of the appendix vermiformis.] ''Hum Pathol'' 21 (7):773-80. PMID: [https://pubmed.gov/2193876 2193876]</ref>
:*'''[[Immunohistochemistry|IHC]]''' might be positive for '''[[S-100 protein|S100]]'''
* '''Goblet cell'''
* '''Goblet cell'''
:*GCC Generally spares mucosa and infiltrates muscularis propria and periappendiceal fat
:*GCC generally spares mucosa and infiltrates muscularis propria and periappendiceal fat
:*Tumor cell clusters
:*Tumor cell clusters
:*Crypt-like structures
:*Crypt-like structures
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:**Nuclear pleomorphism
:**Nuclear pleomorphism
:**Increased mitotic activity
:**Increased mitotic activity
 
:*'''IHC might be positive for the followings:'''
 
:** [[Mucin]] (mucicarmine, PAS, [[PAS diastase]], [[Alcian blue]])
*The images below demonstrate different histopathological findings of appendix cancer.
:**[[CEA]]
<gallery>800px-Appendix_Carcinoid_Torsion_1X_PA.JPG | Appendiceal carcinoid<ref name=aaa>http://librepathology.org/wiki/index.php/Neuroendocrine_tumour_of_the_appendix</ref>
:**[[Cytokeratin]] (especially CK20)
800px-Appendix_Carcinoid_HP_14BR---.jpg | Appendiceal carcinoid<ref name=aaa>http://librepathology.org/wiki/index.php/Neuroendocrine_tumour_of_the_appendix</ref>
:**[[lysozyme]]
800px-Appendix_Carcinoid_Necrosis_PA.JPG | Appendiceal carcinoid with necrosis<ref name =aaa>http://librepathology.org/wiki/index.php/Neuroendocrine_tumour_of_the_appendix</ref>
:**[[Chromogranin A]]
800px-Appendix_Carcinoid_Synaptophysin_14BR---.jpg | Carcinoid synaptophysin<ref name=aaa>http://librepathology.org/wiki/index.php/Neuroendocrine_tumour_of_the_appendix</ref>
:**[[Serotonin]]
800px-Appendix_Carcinoid_HP_CTR.jpg | Appendiceal tumor<ref name=aaa>http://librepathology.org/wiki/index.php/Neuroendocrine_tumour_of_the_appendix</ref>
:**[[Synaptophysin]]
</gallery>


==References==
==References==
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[[Category: (name of the system)]]
[[Category:Surgery]]
[[Category:Medicine]]
[[Category:Emergency medicine]]
[[Category:Oncology]]
[[Category:Up-To-Date]]

Latest revision as of 19:56, 22 February 2019

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

Overview

The pathophysiology of appendix cancer depends on the histological subtype. There are two major subtypes of appendix cancer, adenocarcinomas and carcinoid tumors. While carcinoid tumors arises from enterochromaffin cells (Kulchitsky cells), which are secretory cells that are normally involved in neuroendocrine hormonal secretions, adenocarcinomas are the result of mutations in mucus producing epithelial cells. Their physiology, pathophysiology, genetic pathways, prognosis as well as epidemiology are different and hence, discussed separately. The progression to adenocarcinoma usually involves the KRAS, APC, TP53, and RAF pathways, while β-catenin, NF1, and MEN1 genes are major contributors of carcinoid tumors progression.


Pathophysiology

Physiology

Pathogenesis

Genetics

Genes involved in the pathogenesis of carcinoid tumors of appendix include:[4][5]

The development of appendiceal adenocarcinoma is the result of multiple genetic mutations such as:[5]

Associated Conditions

  • Conditions associated with appendiceal cancers include:

Gross Pathology

Appendix carcinoid gross pathology. Courtesy of Dr.Robertson. Uploaded by James Heilman, MD. https://commons.wikimedia.org/wiki/File:Appendiceal_carcinoid_1.JPG
  • On gross pathology, findings of appendix cancer, include:[3]
  • Well-demarcated mass
  • Average size between 1 and 5 cm
  • Gray or yellowish color
  • Deformed appendix
  • Adenocarcinoma
  • Gray/yellow color
  • Cystic structures with angiolymphatic invasion
  • Appendix might be buried within the mass
  • Carcinoid tumors
  • Prevalent at the tip of appendix
  • Generally less than 1 cm
  • Gray or yellow
  • Well-demarcated firm
  • Intramural nodules that may narrow or obliterate appendiceal lumen
  • Proximal tumors may cause obstruction and appendicitis
  • Goblet cell carcinoids
  • No gross tumor might be present
  • Thickened appendiceal wall

Microscopic Pathology

The images below demonstrate different
histopathological findings of appendix cancer

Low grade appendiceal mucinous neoplasm, MUC2 staining. Courtesy of Carlos Parra-Herran, M.D.http://www.pathologyoutlines.com/topic/ovarytumorappendiceal.html
Appendiceal adenocarcinoma, H and E staining. Courtesy of Carlos Parra-Herran, M.D.http://www.pathologyoutlines.com/topic/ovarytumorappendiceal.html
Typical microscopic appearance of a well differentiated carcinoid tumor (terminal illeum, H and E staining).Case courtesy of Dr Andrew Ryan, <a href="https://radiopaedia.org/">Radiopaedia.org</a>. From the case <a href="https://radiopaedia.org/cases/16308">rID: 16308</a>
  • Cystic structures
  • Angiolymphatic invasion
  • Adenocarcinoma
  • Intestinal, mucinous or signet ring cell types
  • Coexisting acute appendicitis is common
  • immunohistochemistry (IHC) might be positive for the following stains:[6]
  • MUC 2
  • MUC5AC
  • CK 8/18
  • CK 13
  • CK 19
  • CK 20
  • Carcinoid tumor
  • Insular growth pattern of solid islands of uniform polygonal cells with minimal pleomorphism
  • Retraction of peripheral tumor cells from stroma
  • Angiolymphatic invasion is common
  • Granular eosinophilic cytoplasm with either diffusely scattered or peripherally clumped granules
  • Two types of well differentiated tumors: EC cell (serotonin producing) and rarely L-cell (enteroglucagon or peptide YY producing)[7]
  • IHC might be positive for S100
  • Goblet cell
  • GCC generally spares mucosa and infiltrates muscularis propria and periappendiceal fat
  • Tumor cell clusters
  • Crypt-like structures
  • Tubules of mucus-secreting cells distended with mucin resembling goblet cells
  • Eosinophilic cytoplasm resembling carcinoid tumors
  • Pools of extracellular mucin
  • Scattered Paneth cells in tumors with crypt like structures
  • Extensive perineural invasion
  • Carcinomatous growth pattern:
    • Cribriform growth pattern, solid sheets of infiltrating signet ring cells
    • Nuclear pleomorphism
    • Increased mitotic activity
  • IHC might be positive for the followings:

References

  1. ↑ 1.0 1.1 Gunawardene AR, Corfe BM, Staton CA (2011) Classification and functions of enteroendocrine cells of the lower gastrointestinal tract. Int J Exp Pathol 92 (4):219-31. DOI:10.1111/j.1365-2613.2011.00767.x PMID: 21518048
  2. ↑ Modlin IM, Lye KD, Kidd M (2003) A 5-decade analysis of 13,715 carcinoid tumors. Cancer 97 (4):934-59. DOI:10.1002/cncr.11105 PMID: 12569593
  3. ↑ 3.0 3.1 3.2 Ruoff C, Hanna L, Zhi W, Shahzad G, Gotlieb V, Saif MW (2011). "Cancers of the appendix: review of the literatures". ISRN Oncol. 2011: 728579. doi:10.5402/2011/728579. PMC 3200132. PMID 22084738.
  4. ↑ Modlin IM, Kidd M, Latich I, Zikusoka MN, Eick GN, Mane SM et al. (2006) Genetic differentiation of appendiceal tumor malignancy: a guide for the perplexed. Ann Surg 244 (1):52-60. DOI:10.1097/01.sla.0000217617.06782.d5 PMID: 16794389
  5. ↑ 5.0 5.1 5.2 Hassan MM, Phan A, Li D, Dagohoy CG, Leary C, Yao JC (2008) Family history of cancer and associated risk of developing neuroendocrine tumors: a case-control study. Cancer Epidemiol Biomarkers Prev 17 (4):959-65. DOI:10.1158/1055-9965.EPI-07-0750 PMID: 18398037
  6. ↑ Lee MJ, Lee HS, Kim WH, Choi Y, Yang M (2003) Expression of mucins and cytokeratins in primary carcinomas of the digestive system. Mod Pathol 16 (5):403-10. DOI:10.1097/01.MP.0000067683.84284.66 PMID: 12748245
  7. ↑ Iwafuchi M, Watanabe H, Ajioka Y, Shimoda T, Iwashita A, Ito S (1990) Immunohistochemical and ultrastructural studies of twelve argentaffin and six argyrophil carcinoids of the appendix vermiformis. Hum Pathol 21 (7):773-80. PMID: 2193876

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