Difference between revisions of "Pancreas"

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[[Image:Gray 1100 Pancreatic duct.png|thumb|right|250px|A drawing of the pancreas. (WC/Gray's Anatomy)]]
The '''pancreas''' hangs-out in the upper abdomen.  It occasionally is afflicited by cancers, the most common of which is very fatal.   
The '''pancreas''' hangs-out in the upper abdomen.  It occasionally is afflicited by cancers, the most common of which is very fatal.   


A general introduction to GI pathology is in the ''[[GI pathology]]'' article.
Pancreatic cytopathology is dealt with in the ''[[gastrointestinal cytopathology]]'' article.
 
A general introduction to gastrointestinal pathology is in the ''[[gastrointestinal pathology]]'' article.


=Introduction=
=Introduction=
==Normal anatomy==
==Normal anatomy==
Divided into three portions: head, body & tail:
Divided into three portions: head, body & tail:<ref>URL: [http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2011/PancreasEndo_11protocol.pdf http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2011/PancreasEndo_11protocol.pdf]. Accessed on: 29 March 2012.</ref>
*Head:
*Head:
**Includes unicate process.
**Includes unicate process.
**Extend to superior mesenteric vein (by definition).
**Extends to the left edge of the superior mesenteric vein (SMV) - by definition.
***All of the SMV is with the head.  
*Body:
*Body:
**Superior mesenteric vein to left edge of aorta (by definition).
**Right edge of the superior mesenteric vein to the left edge of aorta - by definition.
***All of the aorta is with the body.
*Tail:
*Tail:
**Remainder of pancreas.
**Remainder of pancreas.
Line 16: Line 21:
==Pancreatic surgeries==
==Pancreatic surgeries==
Common pancreatic surgeries include:
Common pancreatic surgeries include:
*Whipple (includes duodenum).
*Whipple procedure ([[AKA]] pancreaticoduodenal resection) - includes [[duodenum]] and usually the distal [[stomach]] (antrum).
*Distal pancreatectomy.  
*Distal pancreatectomy.  
**Removal of tail +/- body.
**Removal of tail +/- body.
**Specimen usually comes with a [[spleen]].
**Specimen usually comes with the [[spleen]].
**Typically done form [[islet cell tumour]]s.
*Total pancreatectomy.
*Total pancreatectomy.
**Specimen usually comes with a spleen.
**Specimen usually comes with the spleen.
 
===Whipple procedure===
*[[AKA]] ''pancreaticoduodenectomy''.
 
Indications:
*Head of pancreas lesions, duodenal lesions.
 
[[Margins]]:<ref>URL: [http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2011/SmallbowelNET_11protocol.pdf http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2011/SmallbowelNET_11protocol.pdf]. Accessed on: 29 March 2012.</ref>
#Proximal mucosal margin (stomach or duodenum).
#Distal mucosal margin (duodenum or jejunum).
#Bile duct margin.
#Pancreatic retroperitoneal (uncinate process) margin.
#*At SB done ''on edge'' (not ''en face'').
#Pancreatic neck transection margin ([[AKA]] distal pancreatic resection margin);<ref name=pmid20485150>{{Cite journal  | last1 = Jamieson | first1 = NB. | last2 = Foulis | first2 = AK. | last3 = Oien | first3 = KA. | last4 = Going | first4 = JJ. | last5 = Glen | first5 = P. | last6 = Dickson | first6 = EJ. | last7 = Imrie | first7 = CW. | last8 = McKay | first8 = CJ. | last9 = Carter | first9 = R. | title = Positive mobilization margins alone do not influence survival following pancreatico-duodenectomy for pancreatic ductal adenocarcinoma. | journal = Ann Surg | volume = 251 | issue = 6 | pages = 1003-10 | month = Jun | year = 2010 | doi = 10.1097/SLA.0b013e3181d77369 | PMID = 20485150 }}</ref> usu. ''en face'' and ''in toto''.<ref>URL: [http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2011/PancreasEndo_11protocol.pdf http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2011/PancreasEndo_11protocol.pdf]. Accessed on: 6 April 2012.</ref>
#Sometimes superior mesenteric vein (SMV).
#Rarely superior mesenteric artery (SMA) margin.


===Whipple===
[[Opening]]:
Margins:
#Open the proximal (stomach) and distal (small bowel) stappled margins.
*Common bile duct (CBD).
#Open the duodenum along it length on the anterior aspect.
*Uncinate process.
#Open the stomach along the greater curvature.
**At SB done ''on edge'' (not ''en face'').
#Join the cuts that open the stomach and duodenum.
*Pancreatic neck transection margin.<ref name=pmid20485150>{{Cite journal  | last1 = Jamieson | first1 = NB. | last2 = Foulis | first2 = AK. | last3 = Oien | first3 = KA. | last4 = Going | first4 = JJ. | last5 = Glen | first5 = P. | last6 = Dickson | first6 = EJ. | last7 = Imrie | first7 = CW. | last8 = McKay | first8 = CJ. | last9 = Carter | first9 = R. | title = Positive mobilization margins alone do not influence survival following pancreatico-duodenectomy for pancreatic ductal adenocarcinoma. | journal = Ann Surg | volume = 251 | issue = 6 | pages = 1003-10 | month = Jun | year = 2010 | doi = 10.1097/SLA.0b013e3181d77369 | PMID = 20485150 }}</ref>
*Sometimes superior mesenteric vein (SMV).
*Rarely SMA margin.


==General classification of pancreatic tumours==
==General classification of pancreatic tumours==
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===Pancreas neoplasms in a table===
===Pancreas neoplasms in a table===
{| class="wikitable"
{| class="wikitable sortable"
!| Type
!| Type
!| Key feature  
!| Key feature  
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| cuboidal cells, clear cytoplasm
| cuboidal cells, clear cytoplasm
| cystadenoma, borderline t., cystadenocarcinoma
| cystadenoma, borderline t., cystadenocarcinoma
| [http://commons.wikimedia.org/wiki/File:Pancreatic_serous_cystadenoma_%281%29.jpg], [http://commons.wikimedia.org/wiki/File:Pancreatic_serous_cystadenoma_%282%29.jpg], [http://commons.wikimedia.org/wiki/File:Pancreatic_serous_cystadenoma_-_intermed_mag.jpg]
| [http://commons.wikimedia.org/wiki/File:Pancreatic_serous_cystadenoma_%281%29.jpg], [http://commons.wikimedia.org/wiki/File:Pancreatic_serous_cystadenoma_%282%29.jpg (WC)], [http://commons.wikimedia.org/wiki/File:Pancreatic_serous_cystadenoma_-_intermed_mag.jpg (WC)]
| IHC?
| IHC?
| cuboidal cells, clear cytoplasm, central nucleus
| cuboidal cells, clear cytoplasm, central nucleus
| body or tail
| body or tail
| cystadenoma may be assoc. with [[von Hippel-Lindau syndrome]]
| cystadenoma may be assoc. with [[von Hippel-Lindau syndrome]]
| clear cell RCC, oligomucinous mucinous tumours
| [[clear cell renal cell carcinoma|clear cell RCC]], oligomucinous mucinous tumours
|-
|-
| Intraductal papillary<br>mucinous tumour (IPMT)
| [[Intraductal papillary mucinous tumour]] (IPMT)
| mucin, no ovarian-like stroma  
| mucin, no ovarian-like stroma  
| clear cell variant
| clear cell variant
Line 70: Line 89:
| head
| head
| -
| -
| mucious neoplasms (other pancreatic, duodenal)
| mucious neoplasms (other pancreatic, duodenal), intra-ampullary papillary-tubular neoplasm (see [[ampullary carcinoma]])
|-
|-
| Mucinous tumour
| Mucinous tumour
| mucin, ovarian-like stroma  
| mucin, ovarian-like stroma  
| cystadenoma, borderline t., cystadenocarcinoma
| cystadenoma, borderline t., cystadenocarcinoma
| [http://commons.wikimedia.org/w/index.php?title=File:Benign_pancreatic_mucinous_cystic_neoplasm_-_intermed_mag.jpg], [http://commons.wikimedia.org/w/index.php?title=File:Benign_pancreatic_mucinous_cystic_neoplasm_-_high_mag.jpg]
| [http://commons.wikimedia.org/w/index.php?title=File:Benign_pancreatic_mucinous_cystic_neoplasm_-_intermed_mag.jpg (WC)], [http://commons.wikimedia.org/w/index.php?title=File:Benign_pancreatic_mucinous_cystic_neoplasm_-_high_mag.jpg (WC)]
| IHC?
| IHC?
| tall columnar mucin-producing cells, ovarian-like stroma
| tall columnar mucin-producing cells, ovarian-like stroma
| body or tail
| body or tail
| -
| -
| IPMT, metastatic mucinous tumours
| [[IPMT]], metastatic mucinous tumours
|-
|-
| [[Solid pseudopapillary tumour|Solid pseudopapillary<br>tumour]]
| [[Solid pseudopapillary tumour|Solid pseudopapillary<br>tumour]]
| eosinophilic intracytoplasmic globules  
| eosinophilic intracytoplasmic globules  
| clear cell variant (cytoplasm clear)
| clear cell variant (cytoplasm clear)
| [http://commons.wikimedia.org/w/index.php?title=File:Solid_pseudopapillary_tumour_-_intermed_mag.jpg], [http://jcp.bmj.com/content/61/11/1153/F1.large.jpg]
| [http://commons.wikimedia.org/w/index.php?title=File:Solid_pseudopapillary_tumour_-_intermed_mag.jpg (WC)], [http://jcp.bmj.com/content/61/11/1153/F1.large.jpg (bmj.com)]
| beta-catenin +ve, E-cadherin +ve, <br>synaptophysin +ve, chromogranin -ve
| beta-catenin +ve, E-cadherin +ve, <br>synaptophysin +ve, chromogranin -ve
| sheets of cells, focally loosely cohesive, eosinophilic cytoplasm, uniform nuclei with grooves
| sheets of cells, focally loosely cohesive, eosinophilic cytoplasm, uniform nuclei with grooves
| none
| none (head, body or tail)
| usu. younger women, tail of pancreas
| usu. younger women
| ductal adenocarcinoma, neuroendocrine tumours
| [[pancreatic ductal adenocarcinoma|ductal adenocarcinoma]], [[neuroendocrine tumour]]s
|-
|-
| [[Invasive ductal carcinoma of the pancreas|Ductal adenocarcinoma]]
| [[Invasive ductal carcinoma of the pancreas|Ductal adenocarcinoma]]
| irregular shaped glands, cytologic atypia
| irregular shaped glands, cytologic atypia
| mucinous, spindle cell, mixed ductal-endocrine  
| mucinous, spindle cell, mixed ductal-endocrine  
| [http://commons.wikimedia.org/wiki/File:Pancreas_adenocarcinoma_%284%29_Case_01.jpg], [http://commons.wikimedia.org/wiki/File:Pancreas_adenocarcinoma_%282%29_Case_01.jpg]
| [http://commons.wikimedia.org/wiki/File:Pancreas_adenocarcinoma_%284%29_Case_01.jpg (WC)], [http://commons.wikimedia.org/wiki/File:Pancreas_adenocarcinoma_%282%29_Case_01.jpg (WC)]
| IHC?
| IHC?
| glands, sheets, single cells, nuc. atypia, +/-mitoses, +/-[[necrosis]]
| glands, sheets, single cells, nuc. atypia, +/-mitoses, +/-[[necrosis]]
| head
| head
| arises from the precursor ''PanIN''
| arises from the precursor ''PanIN''
| ampullary carcinoma, chronic pancreatitis
| ampullary carcinoma, [[chronic pancreatitis]]
|-
|-
| Pancreatoblastoma
| [[Pancreatoblastoma]]
| squamoid nests, whorling
| squamoid nests, whorling
| -
| -
| Image?
| [http://www.nature.com/modpathol/journal/v20/n1s/fig_tab/3800686f16.html#figure-title (nature.com)]
| IHC?
| [[CK7]] (acinar comp.), CK8, CK18, [[CK19]]
| squamoid nests of cells, whorling, nested growth, +/-keratinization
| squamoid nests of cells, whorling, nested growth, +/-keratinization
| none
| none
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| acinar arch.
| acinar arch.
| -
| -
| [http://www.histopathology-india.net/acinar%20cell%20ca.JPG]
| [http://commons.wikimedia.org/wiki/File:Acinar_cell_carcinoma_of_the_pancreas_-_very_high_mag.jpg (WC)], [http://www.histopathology-india.net/acinar%20cell%20ca.JPG (histopathology-india.net)]
| IHC?
| trypsin, lipase
| nests or [[trabeculae]], nucleolus, mod. basophilic granular cytoplasm
| nests or [[trabeculae]], nucleolus, mod. basophilic granular cytoplasm
| head (slight predilection)
| head (slight predilection)
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| ?
| ?
| not a neoplasm, included here as it is in the (clinical) DDx
| not a neoplasm, included here as it is in the (clinical) DDx
| ductal adenocarcinoma
| [[pancreatic ductal adenocarcinoma|ductal adenocarcinoma]]
|}
|}


Line 158: Line 177:
*[[Pancreatic ductal adenocarcinoma|Ductal adenocarcinoma]].
*[[Pancreatic ductal adenocarcinoma|Ductal adenocarcinoma]].
**Mucinous noncystic carcinoma.
**Mucinous noncystic carcinoma.
**Signet ring cell carcinoma.
**[[Signet ring cell carcinoma]].
**Adenosquamous carcinoma.
**[[Adenosquamous carcinoma]].
**Undifferentiated carcinoma.
**Undifferentiated carcinoma.
**Undifferentiated carcinoma with osteoclast-like giant cells.
**Undifferentiated carcinoma with osteoclast-like giant cells.
Line 183: Line 202:


==Pancreatic acinar metaplasia==
==Pancreatic acinar metaplasia==
*[[AKA]] pancreatic metaplasia.
*Abbreviated ''PAM''.
*[[AKA]] ''pancreatic metaplasia''.<ref name=pmid8724024>{{Cite journal  | last1 = Stachura | first1 = J. | last2 = Konturek | first2 = JW. | last3 = Urbanczyk | first3 = K. | last4 = Bogdal | first4 = J. | last5 = Mach | first5 = T. | last6 = Domschke | first6 = W. | title = Endoscopic and histological appearance of pancreatic metaplasia in the human gastric mucosa: a preliminary report on a recently recognized new type of gastric mucosal metaplasia. | journal = Eur J Gastroenterol Hepatol | volume = 8 | issue = 3 | pages = 239-43 | month = Mar | year = 1996 | doi =  | PMID = 8724024 }}</ref>


===General===
===General===
*Common in the GI tract.
*Common in the GI tract.
*Found in ~ 20% of [[eosphageal]] biopsies above the GEJ.<ref name=pmid20012917>{{cite journal |author=Johansson J, Håkansson HO, Mellblom L, ''et al.'' |title=Pancreatic acinar metaplasia in the distal oesophagus and the gastric cardia: prevalence, predictors and relation to GORD |journal=J. Gastroenterol. |volume=45 |issue=3 |pages=291–9 |year=2010 |month=March |pmid=20012917 |doi=10.1007/s00535-009-0161-4 |url=}}</ref>
*Found in ~ 17-19% of [[stomach|gastro]][[esophagus|esophageal]] junction biopsies.<ref name=pmid23989798/><ref name=pmid20012917>{{cite journal |author=Johansson J, Håkansson HO, Mellblom L, ''et al.'' |title=Pancreatic acinar metaplasia in the distal oesophagus and the gastric cardia: prevalence, predictors and relation to GORD |journal=J. Gastroenterol. |volume=45 |issue=3 |pages=291–9 |year=2010 |month=March |pmid=20012917 |doi=10.1007/s00535-009-0161-4 |url=}}</ref>
*Associated with intestinal metaplasia.<ref name=pmid23989798>{{Cite journal  | last1 = Schneider | first1 = NI. | last2 = Plieschnegger | first2 = W. | last3 = Geppert | first3 = M. | last4 = Wigginghaus | first4 = B. | last5 = Höss | first5 = GM. | last6 = Eherer | first6 = A. | last7 = Wolf | first7 = EM. | last8 = Rehak | first8 = P. | last9 = Vieth | first9 = M. | title = Pancreatic acinar cells-a normal finding at the gastroesophageal junction? Data from a prospective Central European multicenter study. | journal = Virchows Arch | volume =  | issue =  | pages =  | month = Aug | year = 2013 | doi = 10.1007/s00428-013-1471-8 | PMID = 23989798 }}</ref>
**Not associated with changes of [[GERD]], or [[Helicobacter gastritis]].<ref name=pmid23989798/>
 
===Gross===
*May be a single lesion or a cluster of lesions.<ref name=pmid8724024/>
 
Note:
*''Not'' associated with the endoscopic diagnosis of esophagitis or [[Barrett's esophagus]].<ref name=pmid23989798/>


===Microscopic===
===Microscopic===
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*No islets of Langerhans (pancreatic islets).
*No islets of Langerhans (pancreatic islets).


Images:
====Images====
*[http://commons.wikimedia.org/w/index.php?title=File:Pancreatic_acinar_metaplasia_-_high_mag.jpg PAM - high mag. (WC)].
<gallery>
*[http://commons.wikimedia.org/wiki/File:Pancreatic_acinar_metaplasia_-_low_mag.jpg PAM - low mag. (WC)].
Image:Pancreatic_acinar_metaplasia_-_high_mag.jpg | PAM - high mag. (WC/Nephron)
Image:Pancreatic_acinar_metaplasia_-_low_mag.jpg | PAM - low mag. (WC/Nephron)
</gallery>
===IHC===
Features:<ref>{{Cite journal  | last1 = Doglioni | first1 = C. | last2 = Laurino | first2 = L. | last3 = Dei Tos | first3 = AP. | last4 = De Boni | first4 = M. | last5 = Franzin | first5 = G. | last6 = Braidotti | first6 = P. | last7 = Viale | first7 = G. | title = Pancreatic (acinar) metaplasia of the gastric mucosa. Histology, ultrastructure, immunocytochemistry, and clinicopathologic correlations of 101 cases. | journal = Am J Surg Pathol | volume = 17 | issue = 11 | pages = 1134-43 | month = Nov | year = 1993 | doi =  | PMID = 8214258 }}</ref>
*Trypase +ve.
*Lipase +ve.
 
===Sign out===
It can be debated whether it is worth reporting.
<pre>
ESOPHAGUS (DISTAL), BIOPSY:
- COLUMNAR EPITHELIUM WITH MODERATE CHRONIC, FOCALLY ACTIVE, INFLAMMATION, AND
  PANCREATIC ACINAR METAPLASIA.
- REACTIVE SQUAMOUS EPITHELIUM.
- NEGATIVE FOR INTESTINAL METAPLASIA.
- NEGATIVE FOR DYSPLASIA AND NEGATIVE FOR MALIGNANCY.
</pre>


==Pancreatic ectopia==
==Pancreatic ectopia==
Line 220: Line 265:
Mnemonic ''I GET SMASHED'':
Mnemonic ''I GET SMASHED'':
*Idiopathic.
*Idiopathic.
*Gallstones ~45%.
*[[Gallstones]] ~45%.
*Ethanol ~35%.
*Ethanol ~35%.
*Tumours (pancreas, ampulla).
*Tumours (pancreas, ampulla).
Line 228: Line 273:
*Surgery/trauma, e.g. ERCP, motor vehicle collision.
*Surgery/trauma, e.g. ERCP, motor vehicle collision.
*Hypercalcemia, hyperlipidemia/hypertriglyceridemia, [[hypothermia]].
*Hypercalcemia, hyperlipidemia/hypertriglyceridemia, [[hypothermia]].
*Emboli, e.g. post-CABG.
*Emboli, e.g. post-[[CABG]].
*Drugs - ''SAND'' = steroids & sulfonamides, azathioprine, NSAIDS, diuretics, such as furosemide.
*Drugs - ''SAND'' = steroids & sulfonamides, azathioprine, [[NSAID]]s, diuretics, such as furosemide.


==Acute pancreatitis==
==Acute pancreatitis==
===General===
{{Main|Acute pancreatitis}}
*Rarely comes to pathology.
*Usually diagnosed by abdominal CT, blood work (amylase, lipase).
 
===Microscopic===
Features:<ref>{{Ref Klatt|223}}</ref>
*Loss of acini.
*Neutrophils.
*Hemorrhage.
*+/-Loss of pancreatic islets.


==Chronic pancreatitis==
==Chronic pancreatitis==
===General===
{{Main|Chronic pancreatitis}}
*May be confused with [[pancreatic ductal adenocarcinoma|ductal adenocarcinoma]] radiologically... and pathologically.
 
====Autoimmune pancreatitis====
Subtypes of autoimmune pancreatitis:<ref>URL: [http://path.upmc.edu/cases/case651/dx.html http://path.upmc.edu/cases/case651/dx.html]. Accessed on: 28 January 2012.</ref>
#Lymphoplasmacytic sclerosing pancreatitis (LPSP).
#*IgG4 positive ~ 80%.<ref name=pmid20824290>{{Cite journal  | last1 = Kamisawa | first1 = T. | last2 = Takuma | first2 = K. | last3 = Tabata | first3 = T. | last4 = Inaba | first4 = Y. | last5 = Egawa | first5 = N. | last6 = Tsuruta | first6 = K. | last7 = Hishima | first7 = T. | last8 = Sasaki | first8 = T. | last9 = Itoi | first9 = T. | title = Serum IgG4-negative autoimmune pancreatitis. | journal = J Gastroenterol | volume = 46 | issue = 1 | pages = 108-16 | month = Jan | year = 2011 | doi = 10.1007/s00535-010-0317-2 | PMID = 20824290 }}</ref>
#Idiopathic duct-centric chronic pancreatitis (IDCP).
#*IgG4 negative ~ 20%.
 
=====Lymphoplasmacytic sclerosing pancreatitis=====
*[[AKA]] ''IgG4 sclerosing disease''.
 
General:
*Serum IgG4 +ve.<ref name=pmid17533077>{{Cite journal  | last1 = Krasinskas | first1 = AM. | last2 = Raina | first2 = A. | last3 = Khalid | first3 = A. | last4 = Tublin | first4 = M. | last5 = Yadav | first5 = D. | title = Autoimmune pancreatitis. | journal = Gastroenterol Clin North Am | volume = 36 | issue = 2 | pages = 239-57, vii | month = Jun | year = 2007 | doi = 10.1016/j.gtc.2007.03.015 | PMID = 17533077 }}</ref>
Microscopic:
*Lymphoplasmacytic infiltrate.
 
===Radiology===
Plain film findings:
*Calcifications.
 
===Microscopic===
Features of chronic pancreatitis:<ref name=pmid16273946>{{Cite journal  | last1 = Adsay | first1 = NV. | last2 = Bandyopadhyay | first2 = S. | last3 = Basturk | first3 = O. | last4 = Othman | first4 = M. | last5 = Cheng | first5 = JD. | last6 = Klöppel | first6 = G. | last7 = Klimstra | first7 = DS. | title = Chronic pancreatitis or pancreatic ductal adenocarcinoma? | journal = Semin Diagn Pathol | volume = 21 | issue = 4 | pages = 268-76 | month = Nov | year = 2004 | doi =  | PMID = 16273946 }}</ref>
*Preservation of lobular architecture - evenly spaced ductal units.
*Uniformly sized ductal elements.
*Smooth ductal contours.
*Ducts surrounded by acini or islets.
**Islets usu. preserved better than acini.<ref name=Ref_Klatt225>{{Ref Klatt|225}}</ref>
*Intraluminal mucoprotein plugs.
 
This contrasts with the features of adenocarcinoma:<ref name=pmid16273946>{{Cite journal  | last1 = Adsay | first1 = NV. | last2 = Bandyopadhyay | first2 = S. | last3 = Basturk | first3 = O. | last4 = Othman | first4 = M. | last5 = Cheng | first5 = JD. | last6 = Klöppel | first6 = G. | last7 = Klimstra | first7 = DS. | title = Chronic pancreatitis or pancreatic ductal adenocarcinoma? | journal = Semin Diagn Pathol | volume = 21 | issue = 4 | pages = 268-76 | month = Nov | year = 2004 | doi =  | PMID = 16273946 }}</ref>
*Ductal architecture:
**Random distribution of ductal structures.
**Irregular ductal contours.
**"Naked ducts in fat"; ducts without surrounding pancreatic elements or fibrous tissue.
**Ducts adjacent to arterioles.
*Nuclear atypia:
**Enlargement (>3 times the size of a lymphocyte).
**Pleomorphism.
**Distinct [[nucleoli]].
**Hyperchromatic raisinoid nucleoli.
*Generally assoc. with malignancy:
**Perineural and vascular invasion (rare).
**Mitosis.
**Necrotic cellular debris (intraluminal).
 
Notes:
*Memory device give 'em '''''fair'''''' chance at a benign Dx:
**Fat, adjacent to.
**Arteriole, adjacent to.
**Irregular ducts.
**Random distribution of ducts/non-lobular arrangement.
 
Images:
*[http://path.upmc.edu/cases/case651.html Autoimmune pancreatitis / IgG4 sclerosing disease - several images (upmc.edu)].
 
===IHC===
*IgG4 +ve plasma cells -- IgG4 sclerosing disease.


=Cystic lesions - overview=
=Cystic lesions - overview=
Line 308: Line 286:
*True cystic lesions are uncommon.
*True cystic lesions are uncommon.
**A true cystic lesion: ''must'' have an epithelial lining.
**A true cystic lesion: ''must'' have an epithelial lining.
***Only 10% of cystic lesions are true cystic lesions, i.e. 90% of cystic lesions are really pseudocysts.
***Only 10% of cystic lesions are true cystic lesions, i.e. 90% of cystic lesions are really [[Pancreatic pseudocyst|pseudocysts]].
*It is hard to differentiate pseudocysts & cysts.
*It is hard to differentiate pseudocysts & cysts.


Line 341: Line 319:
===Cystic tumours of the pancreas===
===Cystic tumours of the pancreas===
Khalifa's table of cystic tumours:
Khalifa's table of cystic tumours:
{| class="wikitable"
{| class="wikitable sortable"
|
!Tumour
|Usual sex
!Usual sex
|Age (years)
!Age (years)
|Usual site
!Usual site
|Typical <br>size (cm)
!Typical <br>size (cm)
|[[Gross pathology]]
![[Gross pathology]]
|-
|-
|Serous microcystic<br> adenoma
|[[serous microcystic adenoma|Serous microcystic<br> adenoma]]
|female
|female
|66
|66
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|[http://www.joplink.net/prev/200905/25_fig06.jpg (joplink.net]<ref>URL: [http://www.joplink.net/prev/200905/25.html http://www.joplink.net/prev/200905/25.html]. Accessed on: 15 February 2012.</ref>, [http://oac.med.jhmi.edu/cpc/images/cpc5/33.jpg (jhmi.edu)]<ref name=jhmi>URL: [http://oac.med.jhmi.edu/cpc/cases/cpc5/cpc5_answer.html http://oac.med.jhmi.edu/cpc/cases/cpc5/cpc5_answer.html]. Accessed on: 15 February 2012.</ref>
|[http://www.joplink.net/prev/200905/25_fig06.jpg (joplink.net]<ref>URL: [http://www.joplink.net/prev/200905/25.html http://www.joplink.net/prev/200905/25.html]. Accessed on: 15 February 2012.</ref>, [http://oac.med.jhmi.edu/cpc/images/cpc5/33.jpg (jhmi.edu)]<ref name=jhmi>URL: [http://oac.med.jhmi.edu/cpc/cases/cpc5/cpc5_answer.html http://oac.med.jhmi.edu/cpc/cases/cpc5/cpc5_answer.html]. Accessed on: 15 February 2012.</ref>
|-
|-
|Intraductal papillary<br>mucinous tumour (IPMT)
|[[IPMN|Intraductal papillary<br>mucinous tumour (IPMT)]]
|male
|male
|62
|62
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|[http://radiology.rsna.org/content/251/1/77/F8.expansion.html (rsna.org)]
|[http://radiology.rsna.org/content/251/1/77/F8.expansion.html (rsna.org)]
|-
|-
|Solid pseudopapillary<br> tumour
|[[solid pseudopapillary tumour|Solid pseudopapillary<br> tumour]]
|female
|female
|35
|35
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=Cystic lesions=
=Cystic lesions=
==Serous cystic tumours==
==Serous tumours - overview==
===General===
===General===
*Cell of origin: intralobular duct cells (ductular cells).
*Cell of origin: intralobular duct cells (ductular cells).
*Glycogen rich - but do not produce mucin.
*Glycogen rich - but do not produce mucin.


===Subclassication===
====Subclassication====
*Serous microcystic adenoma ([[AKA]] serous cystadenoma<ref name=Ref_Sternberg4_1630>{{Ref Sternberg4|1630}}</ref>).
*[[Serous microcystic adenoma]] ([[AKA]] serous cystadenoma<ref name=Ref_Sternberg4_1630>{{Ref Sternberg4|1630}}</ref>).
** Many small cysts.
** Many small cysts.
*Serous oligocystic adenoma.
*Serous oligocystic adenoma.
Line 394: Line 372:
*If one mucin +ve cell, tumour = a mucinous tumour.
*If one mucin +ve cell, tumour = a mucinous tumour.


===Characteristics of serous microcystic adenoma===
==Serous cystadenoma of the pancreas==
*1-2% of all exocrine pancratic tumours.
*[[AKA]] ''serous microcystic adenoma'',<ref name=Ref_Sternberg4_1630>{{Ref Sternberg4|1630}}</ref> [[AKA]] ''pancreatic serous cystadenoma''.
*Female > male.
{{Main|Serous cystadenoma of the pancreas}}
*Mean age 66 years.
*Truly benign with no malignant potenial.
*May not require surgical resection.
*May be part of [[von Hippel-Lindau syndrome]].
*50-70% occur in the body and tail.
*Average size 11 cm.
 
===Radiology===
*Honey comb appearance.
*"Coin lesion" - well demarcated border.
*May have characteristic central scar.<ref name=pmid15888617>{{cite journal |author=Kim YH, Saini S, Sahani D, Hahn PF, Mueller PR, Auh YH |title=Imaging diagnosis of cystic pancreatic lesions: pseudocyst versus nonpseudocyst |journal=Radiographics |volume=25 |issue=3 |pages=671–85 |year=2005 |pmid=15888617 |doi=10.1148/rg.253045104 |url=http://radiographics.rsna.org/content/25/3/671.abstract}}</ref>
 
===Gross===
*Bosulated surface.
**Lobulated.
*No (macroscopic) cysts apparent on gross.


===Microscopic===
==Mucinous cystic neoplasms of the pancreas==
Features:
*Cuboidal cells.
**Glycogen rich.
**Cilia. (???)
 
Images:
*[http://commons.wikimedia.org/wiki/File:Pancreatic_serous_cystadenoma_-_intermed_mag.jpg PSC - intermed. mag. (WC)].
*[http://commons.wikimedia.org/wiki/File:Pancreatic_serous_cystadenoma_-_very_high_mag.jpg PSC - very high mag. (WC)].
 
===DDx===
*Renal cell carcinoma.
*Lympangioma.
*Hemangiomas.
*Oligocystic mucinous cystic tumors and pseudocysts.
**Have mucin; PAS-D could be used to demonstrate its presence.
 
Notes:
*Serous adenoma my coexist with aggressive tumours.
 
==Mucinous cystic tumours==
*Gastro-entero-pancreatic cell differentiation with hypercellular ovarian-type stroma.
*Gastro-entero-pancreatic cell differentiation with hypercellular ovarian-type stroma.
**Stroma --> cellular.
**Stroma --> cellular.
Line 468: Line 410:
*"Ovarian-type stroma" under epithelium.
*"Ovarian-type stroma" under epithelium.
**Ovarin-type stroma: high density of small (non-wavy) spindle cells with eosinophilic cytoplasm.
**Ovarin-type stroma: high density of small (non-wavy) spindle cells with eosinophilic cytoplasm.
Images:
*[http://commons.wikimedia.org/w/index.php?title=File:Benign_pancreatic_mucinous_cystic_neoplasm_-_intermed_mag.jpg Benign mucinous cystic neoplasm - intermed. mag. (WC)].
*[http://commons.wikimedia.org/w/index.php?title=File:Benign_pancreatic_mucinous_cystic_neoplasm_-_high_mag.jpg Benign mucinous cystic neoplasm - should stroma (WC)].
*[http://radiology.uchc.edu/eAtlas/Images/GYN/5705b.gif Mucinous cystadenoma - ovary (uchc.edu)].


Notes:  
Notes:  
*Appearance similar to ''mucinous cystadenoma'' in the [[ovarian tumours|ovary]].
*Appearance similar to ''mucinous cystadenoma'' in the [[ovarian tumours|ovary]].
*Mucin stains +ve (intracytoplasmic).
*Mucin stains +ve (intracytoplasmic).
=====Images=====
<gallery>
Image:Benign_pancreatic_mucinous_cystic_neoplasm_-_very_low_mag.jpg | Benign mucinous cystic neoplasm - very low mag. (WC)
Image:Benign_pancreatic_mucinous_cystic_neoplasm_-_low_mag.jpg | Benign mucinous cystic neoplasm - low mag.(WC)
Image:Benign_pancreatic_mucinous_cystic_neoplasm_-_intermed_mag.jpg | Benign mucinous cystic neoplasm - intermed. mag. (WC)
Image:Benign_pancreatic_mucinous_cystic_neoplasm_-_high_mag.jpg | Benign mucinous cystic neoplasm - showing stroma - high mag. (WC)
</gallery>
www:
*[http://radiology.uchc.edu/eAtlas/Images/GYN/5705b.gif Mucinous cystadenoma - ovary (uchc.edu)].
[[File:4 477025809 sl 1.png|Mucinous cystic neoplasm of pancreas]]
[[File:4 477025809 sl 2.png|Mucinous cystic neoplasm of pancreas]]
[[File:4 477025809 sl 3.png|Mucinous cystic neoplasm of pancreas]]
[[File:4 477025809 sl 4.png|Mucinous cystic neoplasm of pancreas]]
[[File:4 477025809 sl 5.png|Mucinous cystic neoplasm of pancreas]]
[[File:4 477025809 sl 6.png|Mucinous cystic neoplasm of pancreas]]
[[File:4 477025809 sl 7.png|Mucinous cystic neoplasm of pancreas]]<br>
Benign mucinous cystic neoplasm of pancreas in a 62 year old woman. A. CT scan showed a peripherally calcified spheroidal mass at the tail of the pancreas. Cytology only showed debris and inflammatory cells, but CEA of the fluid was 2875.2 ng/mL. B. Almost all sections of the cyst showed acellular debris topping a fibrous, often calcified wall, consistent with a pseudocyst. C. Extensive sampling, undertaken because of the high CEA, revealed rare sections with a lining. D. Lining nuclei are bland, with even chromatin. Shape and size variation, as well as darkening when shrunken, are all explicable by degeneration. E. Within distal pancreas, a focus of changes of chronic pancreatitis is seen upper left, while a pancreatic duct in lower right shows an intraductal proliferation. F. Tumor cells show mucinous vacuoles, with better preserved nuclei.  Nuclear appearances remain bland. G. Cellular ovarian stroma appeared beneath epithelium of a separate focus of the cystic neoplasm.


====Borderline mucinous cystic tumour====
====Borderline mucinous cystic tumour====
Line 491: Line 446:
*Cells floating in mucin.
*Cells floating in mucin.


====Mucinous tumour vs. pseudocyst====
====Mucinous tumour versus pseudocyst====
{| class="wikitable"
{| class="wikitable sortable"
| || '''Mucinous tumour'''|| '''Pseudocyst'''
! Finding
! Mucinous tumour  
! Pseudocyst
|-
|-
|Amylase & lipase || low || high
|Amylase & lipase || low || high
Line 499: Line 456:
|Viscosity || high || low
|Viscosity || high || low
|-
|-
|CEA, CA125 || high || low         <!-- CA124??? was changed to CA125 -->
|[[CEA]], CA125 || high || low      
|}
|}


Line 509: Line 466:


==Intraductal papillary mucinous tumour==
==Intraductal papillary mucinous tumour==
*Often abbreviated ''IPMT''.
*Abbreviated ''IPMT''.
*[[AKA]] ''intraductal papillary mucinous neoplasm.
*[[AKA]] ''intraductal papillary mucinous neoplasm'', abbreviated ''IPMN''.
 
{{Main|Intraductal papillary mucinous tumour}}
===General===
*Papillomatous growth pattern.
*Morphologically and biologically distinct from ductal adenocarcinoma, mucinous cystic tumour and ductal papillary hyperplasia.
*Prognosis: favourable, if caught earlier; not much different than ductal adenocarcinoma if caught later.<ref name=pmid12377813>{{cite journal |author=Maire F, Hammel P, Terris B, ''et al.'' |title=Prognosis of malignant intraductal papillary mucinous tumours of the pancreas after surgical resection. Comparison with pancreatic ductal adenocarcinoma |journal=Gut |volume=51 |issue=5 |pages=717–22 |year=2002 |month=November |pmid=12377813 |pmc=1773420 |doi= |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=12377813}}</ref>
 
Another paper: <ref name=pmid20374620>{{cite journal |author=Baiocchi GL, Portolani N, Missale G, ''et al.'' |title=Intraductal papillary mucinous neoplasm of the pancreas (IPMN): clinico-pathological correlations and surgical indications |journal=World J Surg Oncol |volume=8 |issue= |pages=25 |year=2010 |pmid=20374620 |pmc=2858722 |doi=10.1186/1477-7819-8-25 |url=http://wjso.com/content/8/1/25}}</ref>
===Epidemiology===
*1% of all exocrine pancreatic tumours.
*More common in males.
*Mean age at presentation 62 years.
*60-80% occur in the head of the pancreas.
*Average size 4 cm.
 
Khalifa's theory:
*Nothing but dilation of pancreatic duct + hypersecretion.
 
===Gross===
*May be patchy/multifocal.
 
===Microscopic===
Features
*Cell enlargement.
*Increased [[NC ratio]].
*Nuclear crowding and [[nuclear pleomorphism|pleomorphism]].
*Papillary tufting.
*Mitotic activity.
*Increased mucin production.
 
===Classification IMPT===
*Adenoma.
*Borderline mucinous tumour.
*Carcinoma.
 
Notes:
*No ovarian like stroma.
*Tumour in duct.
*Patient usually not jaundiced... as no obstruction.
*Often diabetes... as pancreas is destroyed.
 
===Gross===
*Multiple cystic spaces.
 
===Microscopic===
Features:
*Some places -- fronds of benign looking mucin producing epithelium.
*No ovarian type stroma underneath.
 
Notes:
*If no viable cells in the mucin then not cancer.
**Mucin under pressure can disect through the tissue.
*Borderline tumours are rare.
 
Pitfalls
*Since it is multifocal may involve large segment of the ductal system.
**Patients often get a total pancreatectomy.
**If intralobular dilated ducts... carcinoma.
*Hard to get a negative margin.
 
NB - any margin with mucin cells -- badness!!!
*Dilated = mucin producing ducts (???).
**DDx: PAN-IN1.
***Needs a totally pancreatectomy.


==Solid pseudopapillary tumour==
==Solid pseudopapillary tumour==
*[[AKA]] ''solid pseudopapillary neoplasm''.
*[[AKA]] ''solid pseudopapillary neoplasm'', abbreviation ''SPN''.
*[[AKA]] ''solid and papillary epithelial neoplasm'', abbreviated ''SPEN''.<ref>URL: [http://brighamrad.harvard.edu/Cases/bwh/hcache/360/full.html http://brighamrad.harvard.edu/Cases/bwh/hcache/360/full.html]. Accessed on: 31 October 2011.</ref>
*[[AKA]] ''solid and papillary epithelial neoplasm'', abbreviated ''SPEN''.<ref>URL: [http://brighamrad.harvard.edu/Cases/bwh/hcache/360/full.html http://brighamrad.harvard.edu/Cases/bwh/hcache/360/full.html]. Accessed on: 31 October 2011.</ref>
 
{{Main|Solid pseudopapillary tumour}}
===General===
*Obscure cell of origin.
*Considered low grade, i.e. prognosis is usually good.
 
====Epidemiology====
Features:<ref name=Ref_GLP493>{{Ref GLP|493}}</ref>
*Usually females (M:F=1:9).
*Mean age of presentation third decade (20s).
 
====Management====
May be followed radiologically.
 
===Microscopic===
Features:<ref>{{Ref GLP|493-5}}</ref>
*Solid sheets of cells, focally dyscohesive.
*Eosinophilic cytoplasm.
**Occasionally clear cytoplasm.<ref name=pmid18708424>{{cite journal |author=Serra S, Chetty R |title=Revision 2: an immunohistochemical approach and evaluation of solid pseudopapillary tumour of the pancreas |journal=J. Clin. Pathol. |volume=61 |issue=11 |pages=1153–9 |year=2008 |month=November |pmid=18708424 |doi=10.1136/jcp.2008.057828 |url=http://jcp.bmj.com/content/61/11/1153}}</ref>
**Focal eosinophilic (intracytoplasmic) globules - '''key feature'''.
*Uniform nuclei with occasional nuclear grooves.
*+/-Necrosis - creating spaces/cavities.
 
Images:
*[http://commons.wikimedia.org/w/index.php?title=File:Solid_pseudopapillary_tumour_-_low_mag.jpg SPT - low mag. (WC)].
*[http://commons.wikimedia.org/w/index.php?title=File:Solid_pseudopapillary_tumour_-_high_mag.jpg SPT - high mag. (WC)].
*[http://commons.wikimedia.org/w/index.php?title=File:Solid_pseudopapillary_tumour_-_very_high_mag.jpg SPT - very high mag. (WC)].
*[http://jcp.bmj.com/content/61/11/1153/F1.large.jpg Solid pseudopapillary tumour (bmj.com)].
 
====DDx====
*Pseudocyst.
*Cystadenoma.
*Cystadenocarcinoma.
*[[Pancreatic neuroendocrine tumour]] - may have cytoplasmic vacuolation, [[hyaline globules]].<ref name=pmid18708424/>
 
===IHC===
Features:<ref name=pmid18708424>{{cite journal |author=Serra S, Chetty R |title=Revision 2: an immunohistochemical approach and evaluation of solid pseudopapillary tumour of the pancreas |journal=J. Clin. Pathol. |volume=61 |issue=11 |pages=1153–9 |year=2008 |month=November |pmid=18708424 |doi=10.1136/jcp.2008.057828 |url=http://jcp.bmj.com/content/61/11/1153}}</ref>
*Beta-catenin +ve ~100% (cytoplasmic & nuclear).
*E-cadherin +ve ~100% (cytoplasmic), -ve (membrane); antibody dependent.
*CD10 +ve ~ 80% (cytoplasmic + dot-like) '''key'''.
*Synaptophysin +ve (weak cytoplasmic) ~70%.
*Progesterone receptor +ve (nuclear) '''key'''.
 
Others:
*CD56 +ve.
*Chromogranin -ve.
 
Memory device ''PCB'': '''P'''R (nuclear), '''C'''D10 (cytoplasmic), '''b'''eta-catenin (cytoplasmic & nuclear).


=Pre-malignant lesions=
=Pre-malignant lesions=
==Pancreatic intraepithelial neoplasia==
==Pancreatic intraepithelial neoplasia==
*Abbreviated ''PanIN''.
*Abbreviated ''PanIN''.
 
{{Main|Pancreatic intraepithelial neoplasia}}
===General===
*PanIN is thought to be the precursor lesion for pancreatic carcinoma.<ref name=Ref_PBoD949>{{Ref PBoD|949}}</ref>
 
====Overview====
Putative preneoplasm-neoplasm-carcinoma sequence:
*PanIN1a.
**Not neoplastic, i.e. colonal.
*PanIN1b.
**Not neoplastic, i.e. colonal.
*PanIN2.
**Can be thought of as ''low-grade dysplasia'', e.g. a ''(colonic) tubular adenoma without high-grade dysplasia''.
*PanIN3.
**Can be thought of as ''high-grade dysplasia'', e.g. ''(colonic) villous adenoma''.
 
===Microscopic===
Features:<ref name=Ref_PBoD949>{{Ref PBoD|949}}</ref>
*PanIN1a - increased amount of cytoplasm.
**Nuclear size & stratification perserved, arch. perserved.
*PanIN1b - increased amount of cytoplasm, folding of epithelium/moderated arch. distortion.
**Nuclear size & stratification perserved.
*PanIN2 - increased cell size, and nuclear enlargement (increased NC ratio), moderate nuclear atypia with loss of (basal) nuclear polarization.
*PanIN3 - marked nuclear atypia with increased NC ratio.
**No invasion identified.
*Pancreatic carcinoma - cytologic features of PanIN3 with definite invasion.
 
Image: [http://commons.wikimedia.org/wiki/File:Pancreas_neoplasia_carcinoma_sequence.png Normal pancreas, pancreatic intraepithelial neoplasia and pancreatic carcinoma (WC)].


=Solid tumours=
=Solid tumours=
Line 662: Line 484:
*[[AKA]] ''ductal adenocarcinoma''.
*[[AKA]] ''ductal adenocarcinoma''.
*[[AKA]] ''pancreatic ductal adenocarcinoma''.
*[[AKA]] ''pancreatic ductal adenocarcinoma''.
===General===
*[[AKA]] ''pancreatic adenocarcinoma''.
*Most common type of pancreatic cancer.<ref name=Ref_WMSP>{{Ref WMSP|237}}</ref>
{{Main|Invasive ductal carcinoma of the pancreas}}
*Location: usually in the head ~60%.
**15% in the body, 5% tail, 20% diffuse (head, body & tail).<ref name=Ref_PBoD950>{{Ref PBoD|950}}</ref>
*Abysmal prognosis.
 
Molecular characteristics:<ref name=Ref_PCPBoD8_470-1>{{Ref PCPBoD8|470-1}}</ref>
*KRAS (oncogene) mutation in ~ 90% of cases.
*CDKN2A<ref name=omim600160>{{OMIM|600160}}</ref> (tumour suppressor) inactivation ~ 95% of cases.
**[[AKA]] p16.
 
===Microscopic===
Features:<ref name=Ref_PBoD951>{{Ref PBoD|951}}</ref>
*Often glandular, may be solid.
*Nuclei.
**May be bland - little pleomorphism.
**Often small nuclei.
**Sometimes [[coffee-bean nuclei|coffee-bean]] appearance.
*Cytoplasm - granular, abundant.
*Quasi endocrine look.
**May stain positive for endocrine markers.
 
Other features:
*+/-Necrosis.
*+/-Myxoid degeneration.
*+/-Cells around vessels.
 
Images:
*[http://commons.wikimedia.org/wiki/File:Pancreas_adenocarcinoma_(3)_Case_01.jpg Pancreatic adenocarcinoma (WC)].
*[http://commons.wikimedia.org/wiki/File:Pancreas_adenocarcinoma_(2)_Case_01.jpg Pancreatic adenocarcinoma (WC)].
*[http://commons.wikimedia.org/wiki/File:Pancreas_neoplasia_carcinoma_sequence.png Normal pancreas, pancreatic intraepithelial neoplasia and pancreatic carcinoma (WC)].
*[http://commons.wikimedia.org/wiki/File:Pancreas_FNA;_adenocarcinoma_vs._normal_ductal_epithelium_(200x).jpg?uselang=de Pancreatic adenocarcinoma - cytopathology (WC)].
*[http://path.upmc.edu/cases/case384.html Pancreatic adenocarcinoma - several images (upmc.edu)].
 
DDx:
*Chronic pancreatitis.<ref name=pmid16273946>{{Cite journal  | last1 = Adsay | first1 = NV. | last2 = Bandyopadhyay | first2 = S. | last3 = Basturk | first3 = O. | last4 = Othman | first4 = M. | last5 = Cheng | first5 = JD. | last6 = Klöppel | first6 = G. | last7 = Klimstra | first7 = DS. | title = Chronic pancreatitis or pancreatic ductal adenocarcinoma? | journal = Semin Diagn Pathol | volume = 21 | issue = 4 | pages = 268-76 | month = Nov | year = 2004 | doi =  | PMID = 16273946 }}</ref>
*[[Cholangiocarcinoma]].
 
===IHC===
*CD7 +ve.
*CD20 +ve.


==Pancreatic neuroendocrine tumour==
==Pancreatic neuroendocrine tumour==
{{Main|Neuroendocrine tumour}}
*Abbreviated ''PanNET''.<ref name=pmid22198808/>
*Abbreviated ''PanNET''.<ref name=pmid22198808/>
*[[AKA]] ''pancreatic islet cell tumour''.<ref name=pmid22198808>{{Cite journal  | last1 = Burns | first1 = WR. | last2 = Edil | first2 = BH. | title = Neuroendocrine Pancreatic Tumors: Guidelines for Management and Update. | journal = Curr Treat Options Oncol | volume =  | issue =  | pages =  | month = Dec | year = 2011 | doi = 10.1007/s11864-011-0172-2 | PMID = 22198808 }}</ref>
*[[AKA]] ''pancreatic islet cell tumour''<ref name=pmid22198808>{{Cite journal  | last1 = Burns | first1 = WR. | last2 = Edil | first2 = BH. | title = Neuroendocrine Pancreatic Tumors: Guidelines for Management and Update. | journal = Curr Treat Options Oncol | volume =  | issue =  | pages =  | month = Dec | year = 2011 | doi = 10.1007/s11864-011-0172-2 | PMID = 22198808 }}</ref> - considered to be an outdated term.
*[[AKA]] ''islet cell tumour''.
*[[AKA]] ''islet cell tumour'' - considered to be an outdated term.
 
{{Main|Neuroendocrine tumour of the pancreas}}
===General===
*Rare.
*Presentation depends on subtype, e.g. for ''insulinoma'' the typical presentation is hypoglycemia.
*May be part of a syndrome:
**[[MEN 1|Multiple endocrine neoplasia I]].
 
====Classification====
Based on peptide produced in the pancreatic islets:
#Glucagon from alpha cells (glucagonoma).
#Insulin from beta cells (insulinoma) - most common ~ 50% of islet cell tumours.
#Somatostatin from D cells (somatostatinoma).
#Pancreatic polypeptide from PP cells.
 
Others:
#Vasoactive intestinal peptide (VIPoma).
#Gastrin (gastrinoma).
#*May be seen in ''[[Zollinger-Ellison syndrome]]''.
#**Triad: pancreatic gastrinoma, gastric acid hypersecretion, marked peptic ulcers in the small bowel.<ref name=pmid13259432>{{cite journal |author=Zollinger RM, Ellison EH |title=Primary peptic ulcerations of the jejunum associated with islet cell tumors of the pancreas |journal=Ann. Surg. |volume=142 |issue=4 |pages=709–23; discussion, 724–8 |year=1955 |pmid=13259432|doi=10.1097/00000658-195510000-00015 |PMC = 1465210 |URL = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1465210/?page=1 }}</ref>
 
===Microscopic===
Features:
*Nests of cells.
*Stippled chromatin.
*+/-Hyaline globules.
 
DDx:
*[[Solid pseudopapillary neoplasm]].
 
Images:
*[http://path.upmc.edu/cases/case172/micro.html Islet cell tumour (upmc.edu)].
*[http://path.upmc.edu/cases/case339.html Pancreatic NET with features of SPT (upmc.edu)].
*[http://path.upmc.edu/cases/case501.html Pancreatic NET - another case (upmc.edu)].


==Acinar cell carcinoma of the pancreas==
==Acinar cell carcinoma of the pancreas==
:'''Not''' to be confused with ''[[acinic cell carcinoma]]''.
:'''Not''' to be confused with ''[[acinic cell carcinoma]]''.
*[[AKA]] ''acinar cell carcinoma''.
*[[AKA]] ''acinar cell carcinoma''.
*[[AKA]] ''pancreatic acinar cell carcinoma''.<ref name=pmid>{{Cite journal  | last1 = Thomas | first1 = PC. | last2 = Nash | first2 = GF. | last3 = Aldridge | first3 = MC. | title = Pancreatic acinar cell carcinoma presenting as acute pancreatitis. | journal = HPB (Oxford) | volume = 5 | issue = 2 | pages = 111-3 | month =  | year = 2003 | doi = 10.1080/13651820310001153 | PMID = 18332967 }}</ref>
{{Main|Acinar cell carcinoma of the pancreas}}


===General===
==Pancreatoblastoma==
*Rare.
{{Main|Pancreatoblastoma}}
*Solid epithelial exocrine tumour.<ref>URL: [http://brighamrad.harvard.edu/Cases/bwh/hcache/380/full.html http://brighamrad.harvard.edu/Cases/bwh/hcache/380/full.html]. Accessed on: 15 January 2012.</ref>
*Poor prognosis; mean survival of 18 months in one series.<ref name=pmid1384374/>
 
Clinical:<ref name=pmid1384374>{{Cite journal  | last1 = Klimstra | first1 = DS. | last2 = Heffess | first2 = CS. | last3 = Oertel | first3 = JE. | last4 = Rosai | first4 = J. | title = Acinar cell carcinoma of the pancreas. A clinicopathologic study of 28 cases. | journal = Am J Surg Pathol | volume = 16 | issue = 9 | pages = 815-37 | month = Sep | year = 1992 | doi =  | PMID = 1384374 }}</ref>
*Increased serum lipase.
**Associated with arthralgias (joint pain).
*Classic presentation - Schmid triad:<ref name=pmid20168061>{{Cite journal  | last1 = Jang | first1 = SH. | last2 = Choi | first2 = SY. | last3 = Min | first3 = JH. | last4 = Kim | first4 = TW. | last5 = Lee | first5 = JA. | last6 = Byun | first6 = SJ. | last7 = Lee | first7 = JW. | title = [A case of acinar cell carcinoma of pancreas, manifested by subcutaneous nodule as initial clinical symptom]. | journal = Korean J Gastroenterol | volume = 55 | issue = 2 | pages = 139-43 | month = Feb | year = 2010 | doi =  | PMID = 20168061 }}</ref>
*#Subcutaneous [[fat necrosis]].
*#Polyarthritis.
*#Eosinophilia.
 
===Gross===
*Usually head of pancreas.
 
===Microscopic===
Features:<ref name=pmid1384374/>
*Cells reminiscent of pancreatic acinus cells:
**Granular, basophilic cytoplasm - usu. abundant.
**Round/oval nucleus.
***Nucleolus prominent.
*Architecture:
**Nests, sheets, trabecular, glandular.
 
DDx:
*[[Pancreatic neuroendocrine tumour]].
*[[Invasive ductal carcinoma of the pancreas]].
 
Images:
*[http://path.upmc.edu/cases/case377.html Acinar cell carcinoma - several images (upmc.edu)].
*[http://brighamrad.harvard.edu/Cases/bwh/hcache/380/full.html Acinar cell carcinoma - several images (harvard.edu)].
 
===Stains===
Features:<ref name=pmid1384374/>
*PAS +ve (granular).
*PASD +ve.
 
===IHC===
*Trypsin +ve -- '''key stain'''.
*Chromogranin +ve (scattered, focal).
*CD56 -ve. (?)


=See also=
=See also=
Line 795: Line 507:
*[[Gastrointestinal pathology]].
*[[Gastrointestinal pathology]].
*[[Von Hippel-Lindau syndrome]].
*[[Von Hippel-Lindau syndrome]].
*[[IgG4-related systemic disease]].


=References=
=References=

Latest revision as of 18:19, 7 December 2020

A drawing of the pancreas. (WC/Gray's Anatomy)

The pancreas hangs-out in the upper abdomen. It occasionally is afflicited by cancers, the most common of which is very fatal.

Pancreatic cytopathology is dealt with in the gastrointestinal cytopathology article.

A general introduction to gastrointestinal pathology is in the gastrointestinal pathology article.

Introduction

Normal anatomy

Divided into three portions: head, body & tail:[1]

  • Head:
    • Includes unicate process.
    • Extends to the left edge of the superior mesenteric vein (SMV) - by definition.
      • All of the SMV is with the head.
  • Body:
    • Right edge of the superior mesenteric vein to the left edge of aorta - by definition.
      • All of the aorta is with the body.
  • Tail:
    • Remainder of pancreas.

Pancreatic surgeries

Common pancreatic surgeries include:

  • Whipple procedure (AKA pancreaticoduodenal resection) - includes duodenum and usually the distal stomach (antrum).
  • Distal pancreatectomy.
  • Total pancreatectomy.
    • Specimen usually comes with the spleen.

Whipple procedure

  • AKA pancreaticoduodenectomy.

Indications:

  • Head of pancreas lesions, duodenal lesions.

Margins:[2]

  1. Proximal mucosal margin (stomach or duodenum).
  2. Distal mucosal margin (duodenum or jejunum).
  3. Bile duct margin.
  4. Pancreatic retroperitoneal (uncinate process) margin.
    • At SB done on edge (not en face).
  5. Pancreatic neck transection margin (AKA distal pancreatic resection margin);[3] usu. en face and in toto.[4]
  6. Sometimes superior mesenteric vein (SMV).
  7. Rarely superior mesenteric artery (SMA) margin.

Opening:

  1. Open the proximal (stomach) and distal (small bowel) stappled margins.
  2. Open the duodenum along it length on the anterior aspect.
  3. Open the stomach along the greater curvature.
  4. Join the cuts that open the stomach and duodenum.

General classification of pancreatic tumours

  • Metstatses.
    • Most common = renal cell carcinoma.
  • Primary.
    • Endocrine.
      • Usually small as hormonally active.
    • Exocrine.

Pancreas neoplasms in a table

Type Key feature Subtypes Image IHC Detailed microscopic Usual location Other DDx
Serous tumours cuboidal cells, clear cytoplasm cystadenoma, borderline t., cystadenocarcinoma [1], (WC), (WC) IHC? cuboidal cells, clear cytoplasm, central nucleus body or tail cystadenoma may be assoc. with von Hippel-Lindau syndrome clear cell RCC, oligomucinous mucinous tumours
Intraductal papillary mucinous tumour (IPMT) mucin, no ovarian-like stroma clear cell variant (wjso.com), (upmc.edu) IHC? papillae, tall columnar mucin-producing cells head - mucious neoplasms (other pancreatic, duodenal), intra-ampullary papillary-tubular neoplasm (see ampullary carcinoma)
Mucinous tumour mucin, ovarian-like stroma cystadenoma, borderline t., cystadenocarcinoma (WC), (WC) IHC? tall columnar mucin-producing cells, ovarian-like stroma body or tail - IPMT, metastatic mucinous tumours
Solid pseudopapillary
tumour 		eosinophilic intracytoplasmic globules clear cell variant (cytoplasm clear) (WC), (bmj.com) beta-catenin +ve, E-cadherin +ve,
synaptophysin +ve, chromogranin -ve 		sheets of cells, focally loosely cohesive, eosinophilic cytoplasm, uniform nuclei with grooves none (head, body or tail) usu. younger women ductal adenocarcinoma, neuroendocrine tumours
Ductal adenocarcinoma irregular shaped glands, cytologic atypia mucinous, spindle cell, mixed ductal-endocrine (WC), (WC) IHC? glands, sheets, single cells, nuc. atypia, +/-mitoses, +/-necrosis head arises from the precursor PanIN ampullary carcinoma, chronic pancreatitis
Pancreatoblastoma squamoid nests, whorling - (nature.com) CK7 (acinar comp.), CK8, CK18, CK19 squamoid nests of cells, whorling, nested growth, +/-keratinization none usu. paediatric population acinar cell carcinoma
Acinar cell carcinoma acinar arch. - (WC), (histopathology-india.net) trypsin, lipase nests or trabeculae, nucleolus, mod. basophilic granular cytoplasm head (slight predilection) - pancreatoblastoma
Undifferentiated carcinoma with osteoclast-like giant cells giant cells - Image? IHC? giant cells, usu. with AIS or inv. ductal adenocarcinoma head - anaplastic carcinoma
Chronic pancreatitis fibrosis, loss of acinar tissue, preservation of lobular arch. - [2] IHC? loss of acinar tissue with preservation of islets, fibrosis ? not a neoplasm, included here as it is in the (clinical) DDx ductal adenocarcinoma

WHO classification

Benign epithelial:

Borderline epithelial:

Malignant epithelial:

Soft tissue tumours:

Ectopic pancreatic tissue

It comes in two flavours:[5]

  • Pancreatic ectopia.
  • Pancreatic (acinar) metaplasia.

Pancreatic acinar metaplasia

  • Abbreviated PAM.
  • AKA pancreatic metaplasia.[6]

General

Gross

  • May be a single lesion or a cluster of lesions.[6]

Note:

Microscopic

Features:

  • Pancreatic acini - only.
    • Intensely eosinophilic cytoplasm.

Negatives:

  • No pancreatic ducts.
  • No islets of Langerhans (pancreatic islets).

Images

  • PAM - high mag. (WC/Nephron)

  • PAM - low mag. (WC/Nephron)

IHC

Features:[9]

  • Trypase +ve.
  • Lipase +ve.

Sign out

It can be debated whether it is worth reporting. 

ESOPHAGUS (DISTAL), BIOPSY:
- COLUMNAR EPITHELIUM WITH MODERATE CHRONIC, FOCALLY ACTIVE, INFLAMMATION, AND
  PANCREATIC ACINAR METAPLASIA.
- REACTIVE SQUAMOUS EPITHELIUM.
- NEGATIVE FOR INTESTINAL METAPLASIA.
- NEGATIVE FOR DYSPLASIA AND NEGATIVE FOR MALIGNANCY.

Pancreatic ectopia

General

  • May be confused with something pathologic.

Microscopic

Features:

  • Consists of pancreatic acini and pancreatic ducts.
  • +/-Islets of Langerhans.

Inflammatory

Pancreatitis

Classification

Etiology

Mnemonic I GET SMASHED:

Acute pancreatitis

Main article: Acute pancreatitis

Chronic pancreatitis

Main article: Chronic pancreatitis

Cystic lesions - overview

General

  • True cystic lesions are uncommon.
    • A true cystic lesion: must have an epithelial lining.
      • Only 10% of cystic lesions are true cystic lesions, i.e. 90% of cystic lesions are really pseudocysts.
  • It is hard to differentiate pseudocysts & cysts.

Cystic tumours - clinical

General:

  • Usually diagnosed by imaging (CT/MRI, ERCP, Endoscopic ultrasound).
    • 50% incidental finding.
  • Vague symptoms
  • Abdominal mass.
  • Weight loss.
  • Jaundice.
  • Usually favourable prognosis - mostly benign.

Most important cystic lesions

  • Serous.
  • Mucinous.
    • Ovarian-like stroma.
  • Solid pseudopapillay tumours.
  • Intraductal papillary mucinous tumour (IPMT).
    • No ovarian-like stroma.

Mnemonic SIMS: Serous, IPMT, Mucinous, Solid pseudopapillary tumour.

Useful stains

  • PAS-D.

Mucinous vs. IMPT

IMPT:

  • No ovarian-like stroma.
  • Usually has total pancreatectomy.

Cystic tumours of the pancreas

Khalifa's table of cystic tumours:

Tumour Usual sex Age (years) Usual site Typical
size (cm) 		Gross pathology
Serous microcystic
adenoma 		female 66 body & tail 11 (joplink.net[10], (jhmi.edu)[11]
Intraductal papillary
mucinous tumour (IPMT) 		male 62 head 4 (jhmi.edu)[11]
Mucinous tumour female 49 body & tail 10 (rsna.org)
Solid pseudopapillary
tumour 		female 35 any 7.5 (ajronline.org), (flickr.com/humpath)

Cystic lesions

Serous tumours - overview

General

  • Cell of origin: intralobular duct cells (ductular cells).
  • Glycogen rich - but do not produce mucin.

Subclassication

Note:

  • If one mucin +ve cell, tumour = a mucinous tumour.

Serous cystadenoma of the pancreas

  • AKA serous microcystic adenoma,[12] AKA pancreatic serous cystadenoma.
Main article: Serous cystadenoma of the pancreas

Mucinous cystic neoplasms of the pancreas

  • Gastro-entero-pancreatic cell differentiation with hypercellular ovarian-type stroma.
    • Stroma --> cellular.
  • 2-2.5% of all exocrine pancreatic tumours.
  • Almost exclusively in women.
  • Mean age - 49 years.
  • >80% in body and tail.
  • Average size ~10 cm.

Note:

  • Looks different than serous tumour.

Subclassification

  • Mucinous cystadenoma.
  • Borderline mucinous cystic tumour.
  • Mucinous cystadenocarcinoma.

Borderline vs. Carcinoma

  • Few mitoses in borderline.

Radiology

  • Mucinous tumours: multilocular.
  • Generally larger than serous.
  • Often partially solid and cystic.
  • Often calcified.
    • Calcification rare in serous.
  • Usually tail & body.

Microscopic

Mucinous cystadenoma

Features:[14]

  • Simple tall columnar epithelium with large mucin vacuole on apical aspect.
  • "Ovarian-type stroma" under epithelium.
    • Ovarin-type stroma: high density of small (non-wavy) spindle cells with eosinophilic cytoplasm.

Notes:

  • Appearance similar to mucinous cystadenoma in the ovary.
  • Mucin stains +ve (intracytoplasmic).
Images

  • Benign mucinous cystic neoplasm - very low mag. (WC)

  • Benign mucinous cystic neoplasm - low mag.(WC)

  • Benign mucinous cystic neoplasm - intermed. mag. (WC)

  • Benign mucinous cystic neoplasm - showing stroma - high mag. (WC)

www:

Mucinous cystic neoplasm of pancreas Mucinous cystic neoplasm of pancreas Mucinous cystic neoplasm of pancreas Mucinous cystic neoplasm of pancreas Mucinous cystic neoplasm of pancreas Mucinous cystic neoplasm of pancreas Mucinous cystic neoplasm of pancreas

Benign mucinous cystic neoplasm of pancreas in a 62 year old woman. A. CT scan showed a peripherally calcified spheroidal mass at the tail of the pancreas. Cytology only showed debris and inflammatory cells, but CEA of the fluid was 2875.2 ng/mL. B. Almost all sections of the cyst showed acellular debris topping a fibrous, often calcified wall, consistent with a pseudocyst. C. Extensive sampling, undertaken because of the high CEA, revealed rare sections with a lining. D. Lining nuclei are bland, with even chromatin. Shape and size variation, as well as darkening when shrunken, are all explicable by degeneration. E. Within distal pancreas, a focus of changes of chronic pancreatitis is seen upper left, while a pancreatic duct in lower right shows an intraductal proliferation. F. Tumor cells show mucinous vacuoles, with better preserved nuclei.  Nuclear appearances remain bland. G. Cellular ovarian stroma appeared beneath epithelium of a separate focus of the cystic neoplasm.

Borderline mucinous cystic tumour

Features:

  • May have finger like projections.
  • Pseudostratification of epithelium.

Notes:

  • Surgery does not change based on diagnosis on frozen section.
    • Only question is "Is the margin clear?".
  • Borderline tumours are rare.

Carcinoma

  • Cells floating in mucin.

Mucinous tumour versus pseudocyst

Finding Mucinous tumour Pseudocyst
Amylase & lipase low high
Viscosity high low
CEA, CA125 high low

Prognosis:

  • Benign looking tumours have the potential to transform into carcinoma.
  • No report of assoc. pseudomyxoma peritonei.
    • US boards question -- it is an exception ... others one cause it.
  • Prognosis of m. cystadenocarcinoma is slightly better than that of ductal adenocarcinoma.

Intraductal papillary mucinous tumour

  • Abbreviated IPMT.
  • AKA intraductal papillary mucinous neoplasm, abbreviated IPMN.
Main article: Intraductal papillary mucinous tumour

Solid pseudopapillary tumour

  • AKA solid pseudopapillary neoplasm, abbreviation SPN.
  • AKA solid and papillary epithelial neoplasm, abbreviated SPEN.[15]
Main article: Solid pseudopapillary tumour

Pre-malignant lesions

Pancreatic intraepithelial neoplasia

  • Abbreviated PanIN.
Main article: Pancreatic intraepithelial neoplasia

Solid tumours

Invasive ductal carcinoma of the pancreas

  • AKA ductal adenocarcinoma.
  • AKA pancreatic ductal adenocarcinoma.
  • AKA pancreatic adenocarcinoma.
Main article: Invasive ductal carcinoma of the pancreas

Pancreatic neuroendocrine tumour

  • Abbreviated PanNET.[16]
  • AKA pancreatic islet cell tumour[16] - considered to be an outdated term.
  • AKA islet cell tumour - considered to be an outdated term.
Main article: Neuroendocrine tumour of the pancreas

Acinar cell carcinoma of the pancreas

Not to be confused with acinic cell carcinoma.
  • AKA acinar cell carcinoma.
  • AKA pancreatic acinar cell carcinoma.[17]
Main article: Acinar cell carcinoma of the pancreas

Pancreatoblastoma

Main article: Pancreatoblastoma

See also

References

  1. ↑ URL: http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2011/PancreasEndo_11protocol.pdf. Accessed on: 29 March 2012.
  2. ↑ URL: http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2011/SmallbowelNET_11protocol.pdf. Accessed on: 29 March 2012.
  3. ↑ Jamieson, NB.; Foulis, AK.; Oien, KA.; Going, JJ.; Glen, P.; Dickson, EJ.; Imrie, CW.; McKay, CJ. et al. (Jun 2010). "Positive mobilization margins alone do not influence survival following pancreatico-duodenectomy for pancreatic ductal adenocarcinoma.". Ann Surg 251 (6): 1003-10. doi:10.1097/SLA.0b013e3181d77369. PMID 20485150.
  4. ↑ URL: http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2011/PancreasEndo_11protocol.pdf. Accessed on: 6 April 2012.
  5. ↑ URL: http://test.pathologyportal.org/newindex.htm?92nd/specgasth2.htm. Accessed on: 14 March 2011.
  6. ↑ 6.0 6.1 Stachura, J.; Konturek, JW.; Urbanczyk, K.; Bogdal, J.; Mach, T.; Domschke, W. (Mar 1996). "Endoscopic and histological appearance of pancreatic metaplasia in the human gastric mucosa: a preliminary report on a recently recognized new type of gastric mucosal metaplasia.". Eur J Gastroenterol Hepatol 8 (3): 239-43. PMID 8724024.
  7. ↑ 7.0 7.1 7.2 7.3 Schneider, NI.; Plieschnegger, W.; Geppert, M.; Wigginghaus, B.; Höss, GM.; Eherer, A.; Wolf, EM.; Rehak, P. et al. (Aug 2013). "Pancreatic acinar cells-a normal finding at the gastroesophageal junction? Data from a prospective Central European multicenter study.". Virchows Arch. doi:10.1007/s00428-013-1471-8. PMID 23989798.
  8. ↑ Johansson J, Håkansson HO, Mellblom L, et al. (March 2010). "Pancreatic acinar metaplasia in the distal oesophagus and the gastric cardia: prevalence, predictors and relation to GORD". J. Gastroenterol. 45 (3): 291–9. doi:10.1007/s00535-009-0161-4. PMID 20012917.
  9. ↑ Doglioni, C.; Laurino, L.; Dei Tos, AP.; De Boni, M.; Franzin, G.; Braidotti, P.; Viale, G. (Nov 1993). "Pancreatic (acinar) metaplasia of the gastric mucosa. Histology, ultrastructure, immunocytochemistry, and clinicopathologic correlations of 101 cases.". Am J Surg Pathol 17 (11): 1134-43. PMID 8214258.
  10. ↑ URL: http://www.joplink.net/prev/200905/25.html. Accessed on: 15 February 2012.
  11. ↑ 11.0 11.1 URL: http://oac.med.jhmi.edu/cpc/cases/cpc5/cpc5_answer.html. Accessed on: 15 February 2012.
  12. ↑ 12.0 12.1 Mills, Stacey E; Carter, Darryl; Greenson, Joel K; Oberman, Harold A; Reuter, Victor E (2004). Sternberg's Diagnostic Surgical Pathology (4th ed.). Lippincott Williams & Wilkins. pp. 1630. ISBN 978-0781740517.
  13. ↑ Bano, S.; Upreti, L.; Puri, SK.; Chaudhary, V.; Sakuja, P. (Dec 2011). "Imaging of pancreatic serous cystadenocarcinoma.". Jpn J Radiol 29 (10): 730-4. doi:10.1007/s11604-011-0617-3. PMID 22009426.
  14. ↑ Iacobuzio-Donahue, Christine A.; Montgomery, Elizabeth A. (2005). Gastrointestinal and Liver Pathology: A Volume in the Foundations in Diagnostic Pathology Series (1st ed.). Churchill Livingstone. pp. 489. ISBN 978-0443066573.
  15. ↑ URL: http://brighamrad.harvard.edu/Cases/bwh/hcache/360/full.html. Accessed on: 31 October 2011.
  16. ↑ 16.0 16.1 Burns, WR.; Edil, BH. (Dec 2011). "Neuroendocrine Pancreatic Tumors: Guidelines for Management and Update.". Curr Treat Options Oncol. doi:10.1007/s11864-011-0172-2. PMID 22198808.
  17. ↑ Thomas, PC.; Nash, GF.; Aldridge, MC. (2003). "Pancreatic acinar cell carcinoma presenting as acute pancreatitis.". HPB (Oxford) 5 (2): 111-3. doi:10.1080/13651820310001153. PMID 18332967.

Further reading

Klimstra, DS.; Pitman, MB.; Hruban, RH. (Mar 2009). "An algorithmic approach to the diagnosis of pancreatic neoplasms.". Arch Pathol Lab Med 133 (3): 454-64. doi:10.1043/1543-2165-133.3.454. PMID 19260750.

External links

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