Pancreas

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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

General

  • Rarely comes to pathology.
  • Usually diagnosed by abdominal CT, blood work (amylase, lipase).

Microscopic

Features:[10]

  • Loss of acini.
  • Neutrophils.
  • Hemorrhage.
  • +/-Loss of pancreatic islets.

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[11], (jhmi.edu)[12]
Intraductal papillary
mucinous tumour (IPMT) 		male 62 head 4 (jhmi.edu)[12]
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,[13] 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:[15]

  • 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:

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.

General

  • Morphologically and biologically distinct from ductal adenocarcinoma, mucinous cystic tumour and ductal papillary hyperplasia.
  • Prognosis:
    • Favourable if caught early; not much different than ductal adenocarcinoma if caught late.[16]
    • Dependent what is involved:[17]
      • Main duct (bad prognosis).
      • Branch (good prognosis).

Clinical:

  • Patient usually not jaundiced... as no obstruction.
  • Often diabetes... as pancreas is destroyed.
  • Patients may get a total pancreatectomy - as the disease is often multifocal.

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.

Gross

  • May be patchy/multifocal.
  • Multiple cystic spaces.

Microscopic

Features:

  • Pancreatic duct lining cells jut into the duct lumen - papillomatous growth pattern.
  • Cytology:
    • Cell enlargement.
      • Increased mucin production.
    • Nuclear changes:
    • Mitotic activity.

Note:

  • No ovarian type stroma underneath (as seen in mucinous tumours).

DDx:

Classification of IMPT

Commonly classified by the duct involvement:[18]

  1. Main duct type.
    • Commonly associated with invasive carcinoma.
  2. Branch duct type.
    • Less commonly associated with invasive carcinoma.
Behaviour - Khalifa
  • Adenoma.
  • Borderline mucinous tumour.
  • Carcinoma.

Notes:

  • Borderline tumours are rare.
  • If intralobular dilated ducts... carcinoma.
  • Any margin with mucin cells in thought to be badness!

Solid pseudopapillary tumour

  • AKA solid pseudopapillary neoplasm, abbreviation SPN.
  • AKA solid and papillary epithelial neoplasm, abbreviated SPEN.[19]
Main article: Solid pseudopapillary tumour

Pre-malignant lesions

Pancreatic intraepithelial neoplasia

  • Abbreviated PanIN.

General

  • PanIN is thought to be the precursor lesion for pancreatic carcinoma.[20]

Overview

Putative preneoplasm-neoplasm-carcinoma sequence:

  • PanIN1a.
    • Not neoplastic, i.e. clonal.
  • PanIN1b.
    • Not neoplastic, i.e. clonal.
  • 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.
    • May be referred to as carcinoma in situ.[21]

Microscopic

Features:[20]

  • 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.

Images

  • Normal pancreas, pancreatic intraepithelial neoplasia and pancreatic carcinoma. (WC)

www:

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.[22]
  • AKA pancreatic islet cell tumour[22] - 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.[23]
Main article: Acinar cell carcinoma of the pancreas

Pancreatoblastoma

General

  • Very rare.
  • Tumour of childhood - age of diagnosis ~5 years old.[24]
  • Prognosis ~80% year survival in children[25] more aggressive in adults.
  • May be seen in adults.[26]

Associations:[27]

Microscopic

Features:[27][28]

  • Acinar-like structures.
  • Squamoid corpuscles.
  • Undifferentiated component.

Image:

IHC

Features:[28]

  • CK7 +ve -- acinar, undifferentiated component.
  • CK8 +ve -- squamous component.
  • CK18 +ve -- squamous component.
  • CK19 +ve -- squamous component.

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. ↑ Klatt, Edward C. (2006). Robbins and Cotran Atlas of Pathology (1st ed.). Saunders. pp. 223. ISBN 978-1416002741.
  11. ↑ URL: http://www.joplink.net/prev/200905/25.html. Accessed on: 15 February 2012.
  12. ↑ 12.0 12.1 URL: http://oac.med.jhmi.edu/cpc/cases/cpc5/cpc5_answer.html. Accessed on: 15 February 2012.
  13. ↑ 13.0 13.1 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ Maire F, Hammel P, Terris B, et al. (November 2002). "Prognosis of malignant intraductal papillary mucinous tumours of the pancreas after surgical resection. Comparison with pancreatic ductal adenocarcinoma". Gut 51 (5): 717–22. PMC 1773420. PMID 12377813. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=12377813.
  17. ↑ Baiocchi GL, Portolani N, Missale G, et al. (2010). "Intraductal papillary mucinous neoplasm of the pancreas (IPMN): clinico-pathological correlations and surgical indications". World J Surg Oncol 8: 25. doi:10.1186/1477-7819-8-25. PMC 2858722. PMID 20374620. http://wjso.com/content/8/1/25.
  18. ↑ Ikeuchi, N.; Itoi, T.; Sofuni, A.; Itokawa, F.; Tsuchiya, T.; Kurihara, T.; Ishii, K.; Tsuji, S. et al. (Apr 2010). "Prognosis of cancer with branch duct type IPMN of the pancreas.". World J Gastroenterol 16 (15): 1890-5. PMID PMC = 2856831 20397268 PMC = 2856831.
  19. ↑ URL: http://brighamrad.harvard.edu/Cases/bwh/hcache/360/full.html. Accessed on: 31 October 2011.
  20. ↑ 20.0 20.1 Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Nelso Fausto; Robbins, Stanley L.; Abbas, Abul K. (2005). Robbins and Cotran pathologic basis of disease (7th ed.). St. Louis, Mo: Elsevier Saunders. pp. 949. ISBN 0-7216-0187-1.
  21. ↑ Matthaei, H.; Hong, SM.; Mayo, SC.; dal Molin, M.; Olino, K.; Venkat, R.; Goggins, M.; Herman, JM. et al. (Nov 2011). "Presence of pancreatic intraepithelial neoplasia in the pancreatic transection margin does not influence outcome in patients with R0 resected pancreatic cancer.". Ann Surg Oncol 18 (12): 3493-9. doi:10.1245/s10434-011-1745-9. PMID 21537863.
  22. ↑ 22.0 22.1 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.
  23. ↑ 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.
  24. ↑ Glick, RD.; Pashankar, FD.; Pappo, A.; Laquaglia, MP. (May 2012). "Management of pancreatoblastoma in children and young adults.". J Pediatr Hematol Oncol 34 Suppl 2: S47-50. doi:10.1097/MPH.0b013e31824e3839. PMID 22525406.
  25. ↑ Bien, E.; Godzinski, J.; Dall'igna, P.; Defachelles, AS.; Stachowicz-Stencel, T.; Orbach, D.; Bisogno, G.; Cecchetto, G. et al. (Oct 2011). "Pancreatoblastoma: a report from the European cooperative study group for paediatric rare tumours (EXPeRT).". Eur J Cancer 47 (15): 2347-52. doi:10.1016/j.ejca.2011.05.022. PMID 21696948.
  26. ↑ Balasundaram, C.; Luthra, M.; Chavalidthamrong, D.; Chow, J.; Khan, H.; Endres, PJ. (May 2012). "Pancreatoblastoma: a rare tumor still evolving in clinical presentation and histology.". JOP 13 (3): 301-3. PMID 22572137.
  27. ↑ 27.0 27.1 Saif, MW. (2007). "Pancreatoblastoma.". JOP 8 (1): 55-63. PMID 17228135.
  28. ↑ 28.0 28.1 Nishimata, S.; Kato, K.; Tanaka, M.; Ijiri, R.; Toyoda, Y.; Kigasawa, H.; Ohama, Y.; Nakatani, Y. et al. (Jun 2005). "Expression pattern of keratin subclasses in pancreatoblastoma with special emphasis on squamoid corpuscles.". Pathol Int 55 (6): 297-302. doi:10.1111/j.1440-1827.2005.01829.x. PMID 15943785.
  29. ↑ Klimstra, DS. (Feb 2007). "Nonductal neoplasms of the pancreas.". Mod Pathol 20 Suppl 1: S94-112. doi:10.1038/modpathol.3800686. PMID 17486055.

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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