Colon

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The colon and rectum smell like poo... 'cause that's where poo comes from. It commonly comes to pathologists because there is a suspicion of colorectal cancer or a known history of inflammatory bowel disease (IBD).

An introduction to gastrointestinal pathology is found in the gastrointestinal pathology article.

Surgery

Introduction to colorectal surgery:

  1. Colonic resection - remove a piece of large bowel.
  2. Total colectomy - leaves rectum and anus.[1]
  3. Subtotal colectomy - part of colon removed --or-- some of the rectum remains.
  4. Right hemicolectomy - right colon + distal ileum.
  5. Lower anterior resection (LAR) - proximal rectum +/- sigmoid (for proximal rectal malignancies).
  6. Abdominoperineal resection (APR) - anus + rectum - results in a permanent stoma (for distal rectal malignancies).

Grossing

Identifying the piece

  • Transverse colon - has omentum.
  • Ascending colon - usu. comes with ileocecal valve and a bit of ileum.
  • Descending colon - has a bare area.
  • Rectum - has adventitia. (???)

Lymph nodes

Quirke method

  • Bowel is not opened - it is fixed... then sliced.[3], [4].

Standard method

  • Bowel is prep'ed by opening it along the antimesenteric side.
  • Dimensions - length, circumference at both margins.
  • Radial margin/circumferential margin - should be painted.
    • Rectum starts/sigmoid ends @ place where serosa ends on the posterior aspect of the bowel.
      • The proximal, anterior aspect of the rectum has serosa, i.e. it is not painted.

Common clinical problems

Obstruction

Top three (in adults):[5]

Bleeding

Mnemonic CHAND:[6]

  • Colitis (radiation, infectious, ischemic, IBD (UC >CD), iatrogenic (anticoagulants)).
  • Hemorrhoids.
  • Angiodysplasia.
  • Neoplastic.
  • Diverticular disease.

Infectious colitis with bleeding - causes:

  • Enterohemorrhagic Escherichia coli (EHEC) -- commonly 0157:H7.
  • Campylobacter jejuni.
  • Clostridium difficile.
  • Shigella.

Infectious colitis in the immunosuppressed:

Inflammatory bowel disease

Main article: Inflammatory bowel disease

The bread 'n butter of gastroenterology. A detailed discussion of IBD is in the inflammatory bowel disease article. It comes in two main flavours (Crohn's disease, ulcerative colitis).

Microscopic

Features helpful for the diagnosis of IBD - as based on a study:[9]

  • Basal, i.e. crypt base, plasmacytosis with severe chronic inflammation,
  • Crypt architectural abnormalities, and
  • Distal Paneth cell metaplasia.
    • Paneth cells should not be in the left colon[10] - if you see 'em think of IBD and other long-standing injurious processes.
    • Some claim that (friendly right colonic) paneth cells and paneth cell metaplasia look quite different and can be distinguished.[11]

Bowel ischemia

General

Gross

Features:[12]

  • Luminal part (mucosa & submucosa) affected.
  • Splenic flexture of colon commonly affected (vascular watershed).

Note:

  • May have pseudomembranes (classically assoc. with C. difficile colitis), i.e. mimics an infectious process.
  • DDx for pseudomembranes:[13]
    • C. difficile induced pseudomembranous colitis.
    • Ischemic colitis.
    • Volvulus.
    • Necrotizing infections.
    • ... anything that causes severe mucosal injury.

Radiologic correlate

  • Bowel wall thickening.

Microscopic

Features:[14]

  • Crypt loss.
  • Lamina propria fibrosis.
  • Submucosa fibrosis.

Pseudomembranes (microscopic):[13]

  • Loss of surf. epithelium.
  • PMNs in lamina propria.
  • +/-Capillary fibrin thrombi.

Note:

  • Pseudomembranes arise from the crypts.

Images:

DDx:

  • IBD.
  • Radiation.
  • Toxins/drugs.

Angiodysplasia

General

  • Causes (lower) GI haemorrhage.
  • Generally, not a problem pathologists see.
  • May be associated with aortic stenosis; known as Heyde syndrome.[15]

Location:

  • Cecum.

Epidemiology:

  • Older people.

Etiology:

  • Thought to be caused by the higher wall tension of cecum (due to larger diameter) and result from (intermittent) venous occulsion/focal dilation of vessels.[16]

Diverticular disease

  • AKA diverticulosis.

General

  • Very common.

Complications:

  • Diverticulitis.
  • Diverticular-associated colitis[17] - rare.

Gross

  • Corrugated - like cardboard.
  • Wall thickening (reactive).[18]

Endoscopic image: DD (WC).

Microscopic

Features:

  • Mucosa/submucosa invagination into the musuclaris propria (MP).
    • At the site the blood vessels supplying the mucosa and submucosa penetrate the MP.[19]

Image:

Pseudomelanosis coli

  • AKA melanosis coli.[21]

General

  • Not melanin as the name melanosis coli suggests; it is actually lipofuscin (in macrophages).[22]
  • Endoscopist may see brown pigmentation of mucosa and suspect the diagnosis.

Epidemiology

  • Classically associated with anthracene containing laxative (e.g. Senokot) use and herbal remedies.[22]

Gross

  • Brown pigmentation of the mucosa.

Image:

Microscopic

Features:

  • Brown granular pigment - in the lamina propria.
    • Typically more prominent in the cecum and proximal colon.[22]

Images:

Notes:

  • DDx of brown pigment:
    • Lipofuscin - comes with age (can be demonstrated with a PAS stain[23] or Kluver-Barrera stain[24]).
      • Melanosis coli.
    • Old haemorrhage, i.e. hemosiderin-laden macrophages (may be demonstrated with Prussian blue stain[25]).
    • Melanin (from melanocytes) - rare in colon (may be demonstrated with a Fontana-Masson stain[26] -- though not so useful in the GI tract).
    • Foreign material (e.g. tattoo pigment) - not seen in GI tract.

Stains

Microscopic colitis

General

Definition:

  • As the name suggests, they are microscopic, i.e. endoscopic examination is normal.

Presentation:

  • Chronic diarrhea, non-bloody.[28]

Notes:

Microscopic colitis - types

  • Lymphocytic colitis (LC).
  • Collagenous colitis (CC).

Some believe that LC and CC are different time points in the same process-- but this is unproven.[28]

Epidemiology

  • Age: a disease of adults - usually 50s.
  • Sex:
    • LC males ~= females,[28]
    • CC females:males = 20:1.[28]
  • Drugs are associated with LC and CC.
    • NSAIDs - posulated association/weak association,
    • SSRIs (used primarily for depression) - moderate association, dependent on specific drug.
  • Associated with autoimmune disorders - celiac disease, diabetes mellitus, thyroid disorders and arthritis.[29]
  • No increased risk of colorectal carcinoma.[29]

Treatment

  • Sometimes just follow-up.
  • Steroids - budesonide -- short-term treatment.[29]

Characteristics

Lymphocytic colitis

  • Lots of intraepithelial lymphocytes (>=20/100 lymphocytes/surface epithelial cells[29]) and
  • lymphocytes in the lamina propria.
  • NEGATIVES:[30]
    • No PMNs.
    • No crypt distortion.

Collagenous colitis

  • Intraepithelial lymphocytes, and
  • lymphocytes in the lamina propria.
  • Collagenous material in the lamina propria (pink on H&E) -- key feature.
    • Can be demonstrated with a trichrome stain -- collagen = green on trichrome.
    • Subepithelial collagen needs to be >= 10 micrometres thick for Dx.[29]
      • 8 micrometres is the diameter of a RBC.
      • The normal thickness of the subepithelial collagen is 3 micrometres.[29]
    • Thickening "follows the crypts from the surface" - useful for differentiating from tangential sections of the basement membrane.[31]
    • Collagen may envelope capillaries - useful to discern from basement membrane.[32]

Images:

Notes:

  • CC is typically more prominent in the proximal colon - may reflect concentration gradient of offending causitive agents.[29]
  • Significant negative findings:[30]
    • No PMNs.
    • No crypt distortion.

Intestinal spirochetosis

  • AKA intestinal spirochetes; more specifically colonic spirochetes, colonic spirochetosis.

General

  • Caused by spirochetes[33][34] - specifically Brachyspira piloicoli[35] (previously Serpulina pilosicoli[36]) and Brachyspira aalborgi.
  • Very rare cause of diarrhea, associated with male homosexual behaviour.

Symptoms:[34]

  • Watery diarrhea, abdominal pain, +/-blood per rectum.

Treatment:[37]

  • Metronidazole.

Microscopic

Features:

  • Hyperchromatic fuzz on luminal aspect of epithelial cells; at brush border.

Images:

Special stains

  • Silver stains highlight 'em (e.g. Warthin-Starry stain).

Amebiasis

General

  • Infection with Entamoeba histolytica.[38]
  • May also be spelling amoebiasis.
  • May mimic colon cancer.[39]

May cause:[40]

  • Dysentery (diarrhea containing mucus and/or blood in the feces).
  • Colitis.
  • Liver abscess.

Microscopy

Features:

  • Entamoeba histolytica are round/ovoid eosinophilic bodies ~ 40-60 micrometers in maximal dimension.
    • Found in bowel lumen.
    • Ingest RBCs.

Image:

Cryptosporidiosis

Main article: Cryptosporidiosis

General

  • Usually in immune incompetent individuals, e.g. HIV/AIDS.

Microscopic

Features:

  • Uniform spherical nodules 2-4 micrometres in diameter, typical location - GI tract brush border.
    • Bluish staining of brush border key feature - low power.

Polyps

Main article: Intestinal polyps

Polyps are the bread & butter of GI pathology. They are very common.

Main types:

  • Hyperplastic - most common, benign.
  • Adenomatous - quite common, pre-malignant.
  • Hamartomatous - rare, weird & wonderful.
  • Inflammatory, AKA inflammatory pseudopolyps - associated with IBD.

Most common (images):

Colorectal Tumours

Main article: Colorectal tumours

These are very common. The are covered in a separate article entitled colorectal tumours.

Solitary rectal ulcer

General

  • Clinically may be suspected to a malignancy - biopsied routinuely.
  • Mucosal ulceration.
  • "Three-lies disease":[41]
  1. May not be solitary.
  2. May not be rectal -- can be in left colon.
  3. May not be ulcerating -- non-ulcerated lesions: polypoid and/or erythematous.

Note: Each of the words in solitary rectal ulcer is a lie.

Epidemiology

  • Typically younger patients - average age of presentation ~30 years in one study.[42]
  • Rare.

Clinical

  • Usually presents as BRBPR ~ 85% of cases.[42]
  • Abdominal pain present in approx. 1/3.[42]
    • May be very painful.

Treatment:

  • Usually conservative, i.e. non-surgical.
  • Resection - may be done for fear of malignancy.

Microscopic

Features:[41]

  • Fibrosis of the lamina propria - should be obliterated.
  • Thickened muscularis mucosa - abnormally extends to the lumen.

Histologic DDx:

Rectal prolapse

Generally

  • Usually close to the anal verge.
  • Rare forms can occasionally be confused with cancer.[43]

Microscopic

Features:[44]

  • "Fibromuscular hyperplasia" - key feature:
    • Fibrosis (submucosa, lamina propria).
    • Muscularis mucosae is "too superficial" (muscle in the lamina propria).
  • Surface ulceration + inflammation (neutrophils).
  • +/-Serration of epithelium at the surface.

Notes:

  • Important NEGATIVE: no nuclear atypia.

Images:

Mucosal prolapse syndrome

  • Similar to rectal prolapse???

Weird stuff

Drugs

Kayexalate (sodium polystyrene sulfonate):[45]

Image: Sodium polystyrene crystals (WC).

Graft-versus host disease

Main article: Graft-versus-host disease
  • Abbreviated as GVHD.
  • Seen in the context of bone marrow transplants.

Bowel transplant

The histology of bowel transplant rejection is identical to GVHD - see GVHD.

Chronic constipation

This is occasionally an indication for colectomy.

Causes:

  • Tumour.
  • Adhesions - due to previous surgery.
  • Neuropathy.
  • Congenital defect (Hirschsprung's disease).
  • Medications/substance use.
  • Idiopathic.

Work-up if no tumour is identified:[46]

  • Routine H&E.
  • Pan-actin.
  • Gomori trichrome.
  • CD117 - to look for the interstitial cells of Cajal.
  • HU - neuronal marker.[47]

Neuroendocrine tumour

Main article: Neuroendocrine neoplasms#GI tract

Goblet cell carcinoid

Described in detail in the appendix article.
  • AKA crypt cell carcinoma.
  • Biphasic tumour; features of carcinoid tumour and adenocarcinoma.

Stoma

Main article: Ditzels#Stoma

These are often done emergently and then get cut-out after the patient's condition has settled.

See also

References

  1. ↑ http://www.allaboutbowelsurgery.com/shared/stoma_care/stoma_surgery/procedures/surgery_colon/subtotal.htm
  2. ↑ Bilimoria KY, Bentrem DJ, Stewart AK, et al. (September 2008). "Lymph node evaluation as a colon cancer quality measure: a national hospital report card". J. Natl. Cancer Inst. 100 (18): 1310–7. doi:10.1093/jnci/djn293. PMID 18780863. http://www.medscape.com/viewarticle/581463.
  3. ↑ West NP, Morris EJ, Rotimi O, Cairns A, Finan PJ, Quirke P (September 2008). "Pathology grading of colon cancer surgical resection and its association with survival: a retrospective observational study". Lancet Oncol. 9 (9): 857–65. doi:10.1016/S1470-2045(08)70181-5. PMID 18667357.
  4. ↑ West NP, Finan PJ, Anderin C, Lindholm J, Holm T, Quirke P (July 2008). "Evidence of the oncologic superiority of cylindrical abdominoperineal excision for low rectal cancer". J. Clin. Oncol. 26 (21): 3517–22. doi:10.1200/JCO.2007.14.5961. PMID 18541901.
  5. ↑ URL: http://www.emedicine.com/EMERG/topic65.htm. Accessed on: 28 June 2011.
  6. ↑ TN 2007 G29.
  7. ↑ Golden MP, Hammer SM, Wanke CA, Albrecht MA (September 1994). "Cytomegalovirus vasculitis. Case reports and review of the literature". Medicine (Baltimore) 73 (5): 246–55. PMID 7934809.
  8. ↑ Kandiel A, Lashner B (December 2006). "Cytomegalovirus colitis complicating inflammatory bowel disease". Am. J. Gastroenterol. 101 (12): 2857–65. doi:10.1111/j.1572-0241.2006.00869.x. PMID 17026558.
  9. ↑ Tanaka M, Riddell RH, Saito H, Soma Y, Hidaka H, Kudo H (January 1999). "Morphologic criteria applicable to biopsy specimens for effective distinction of inflammatory bowel disease from other forms of colitis and of Crohn's disease from ulcerative colitis". Scand. J. Gastroenterol. 34 (1): 55–67. PMID 10048734.
  10. ↑ Tanaka M, Saito H, Kusumi T, et al (December 2001). "Spatial distribution and histogenesis of colorectal Paneth cell metaplasia in idiopathic inflammatory bowel disease". J. Gastroenterol. Hepatol. 16 (12): 1353–9. PMID 11851832. http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0815-9319&date=2001&volume=16&issue=12&spage=1353.
  11. ↑ Rubio CA, Nesi G (2003). "A simple method to demonstrate normal and metaplastic Paneth cells in tissue sections". In Vivo 17 (1): 67–71. PMID 12655793.
  12. ↑ 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. 852. ISBN 0-7216-0187-1.
  13. ↑ 13.0 13.1 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. 837-8. ISBN 0-7216-0187-1.
  14. ↑ Kirsch, R. 8 August 2011.
  15. ↑ Hui YT, Lam WM, Fong NM, Yuen PK, Lam JT (August 2009). "Heyde's syndrome: diagnosis and management by the novel single-balloon enteroscopy". Hong Kong Med J 15 (4): 301–3. PMID 19652242. http://www.hkmj.org/abstracts/v15n4/301.htm.
  16. ↑ 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. 854. ISBN 0-7216-0187-1.
  17. ↑ Mulhall, AM.; Mahid, SS.; Petras, RE.; Galandiuk, S. (Jun 2009). "Diverticular disease associated with inflammatory bowel disease-like colitis: a systematic review.". Dis Colon Rectum 52 (6): 1072-9. doi:10.1007/DCR.0b013e31819ef79a. PMID 19581849.
  18. ↑ Nicholson, BD.; Hyland, R.; Rembacken, BJ.; Denyer, M.; Hull, MA.; Tolan, DJ. (Aug 2011). "Colonoscopy for colonic wall thickening at computed tomography: a worthwhile pursuit?". Surg Endosc 25 (8): 2586-91. doi:10.1007/s00464-011-1591-7. PMID 21359889.
  19. ↑ West, AB.. "The pathology of diverticulitis.". J Clin Gastroenterol 42 (10): 1137-8. doi:10.1097/MCG.0b013e3181862a9f. PMID 18936652.
  20. ↑ URL: http://histology-group28.wikispaces.com/DigestiveSystemProject. Accessed on: 23 August 2011.
  21. ↑ URL: http://www.medicinenet.com/melanosis_coli/article.htm. Accessed on: 4 March 2011.
  22. ↑ 22.0 22.1 22.2 Freeman HJ (July 2008). ""Melanosis" in the small and large intestine". World J. Gastroenterol. 14 (27): 4296-9. PMID 18666316. http://www.wjgnet.com/1007-9327/14/4296.asp.
  23. ↑ Kovi J, Leifer C (July 1970). "Lipofuscin pigment accumulation in spontaneous mammary carcinoma of A/Jax mouse". J Natl Med Assoc 62 (4): 287–90. PMC 2611776. PMID 5463681. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2611776/pdf/jnma00512-0077.pdf.
  24. ↑ URL: http://education.vetmed.vt.edu/curriculum/VM8054/labs/Lab2/Examples/exkluvbarr.htm. Accessed on: 5 May 2010.
  25. ↑ URL: http://education.vetmed.vt.edu/curriculum/VM8054/labs/Lab2/Examples/exprussb.htm. Accessed on: 5 May 2010.
  26. ↑ URL: http://education.vetmed.vt.edu/curriculum/VM8054/labs/Lab2/Examples/exfontana.htm. Accessed on: 5 May 2010.
  27. ↑ Benavides SH, Morgante PE, Monserrat AJ, Zárate J, Porta EA (August 1997). "The pigment of melanosis coli: a lectin histochemical study". Gastrointest. Endosc. 46 (2): 131–8. PMID 9283862.
  28. ↑ 28.0 28.1 28.2 28.3 URL: http://emedicine.medscape.com/article/180664-overview. Accessed on: 31 May 2010.
  29. ↑ 29.0 29.1 29.2 29.3 29.4 29.5 29.6 Tysk C, Bohr J, Nyhlin N, Wickbom A, Eriksson S (December 2008). "Diagnosis and management of microscopic colitis". World J. Gastroenterol. 14 (48): 7280-8. PMID 19109861. http://www.wjgnet.com/1007-9327/14/7280.asp.
  30. ↑ 30.0 30.1 http://hopkins-gi.nts.jhu.edu/pages/latin/templates/index.cfm?pg=disease1&disease=29&organ=6&lang_id=1
  31. ↑ BEC 4 Mar 2009
  32. ↑ BEC 4 Mar 2009
  33. ↑ Amat Villegas I, Borobio Aguilar E, Beloqui Perez R, de Llano Varela P, Oquiñena Legaz S, Martínez-Peñuela Virseda JM (January 2004). "[Colonic spirochetes: an infrequent cause of adult diarrhea]" (in Spanish; Castilian). Gastroenterol Hepatol 27 (1): 21–3. PMID 14718105.
  34. ↑ 34.0 34.1 URL: http://www.jhasim.com/files/articlefiles/pdf/XASIM_Master_6_5_May_Vignette.pdf. Accessed on: 25 April 2011.
  35. ↑ Margawani, KR.; Robertson, ID.; Hampson, DJ. (Feb 2009). "Isolation of the anaerobic intestinal spirochaete Brachyspira pilosicoli from long-term residents and Indonesian visitors to Perth, Western Australia.". J Med Microbiol 58 (Pt 2): 248-52. doi:10.1099/jmm.0.004770-0. PMID 19141744. http://ukpmc.ac.uk/abstract/MED/19141744/abstract/MED/19141744?ukpmc_extredirect=http://dx.doi.org/10.1099/jmm.0.004770-0.
  36. ↑ URL: http://www.cdc.gov/ncidod/eid/vol12no05/05-1180.htm. Accessed on: 28 June 2011.
  37. ↑ Calderaro A, Bommezzadri S, Gorrini C, et al. (November 2007). "Infective colitis associated with human intestinal spirochetosis". J. Gastroenterol. Hepatol. 22 (11): 1772–9. doi:10.1111/j.1440-1746.2006.04606.x. PMID 17914949.
  38. ↑ URL: http://www.health.state.ny.us/diseases/communicable/amebiasis/fact_sheet.htm. Accessed on: 17 June 2010.
  39. ↑ Fernandes, H.; D'Souza, CR.; Swethadri, GK.; Naik, CN.. "Ameboma of the colon with amebic liver abscess mimicking metastatic colon cancer.". Indian J Pathol Microbiol 52 (2): 228-30. PMID 19332922. http://www.ijpmonline.org/article.asp?issn=0377-4929;year=2009;volume=52;issue=2;spage=228;epage=230;aulast=Fernandes.
  40. ↑ Mortimer, L.; Chadee, K. (Mar 2010). "The immunopathogenesis of Entamoeba histolytica.". Exp Parasitol. doi:10.1016/j.exppara.2010.03.005. PMID 20303955.
  41. ↑ 41.0 41.1 Crespo Pérez L, Moreira Vicente V, Redondo Verge C, López San Román A, Milicua Salamero JM (November 2007). "["The three-lies disease": solitary rectal ulcer syndrome"] (in Spanish; Castilian). Rev Esp Enferm Dig 99 (11): 663–6. PMID 18271667. http://www.grupoaran.com/mrmUpdate/lecturaPDFfromXML.asp?IdArt=459864&TO=RVN&Eng=1.
  42. ↑ 42.0 42.1 42.2 Chong VH, Jalihal A (December 2006). "Solitary rectal ulcer syndrome: characteristics, outcomes and predictive profiles for persistent bleeding per rectum". Singapore Med J 47 (12): 1063–8. PMID 17139403. http://www.sma.org.sg/smj/4712/4712a7.pdf.
  43. ↑ Brosens LA, Montgomery EA, Bhagavan BS, Offerhaus GJ, Giardiello FM (November 2009). "Mucosal prolapse syndrome presenting as rectal polyposis". J. Clin. Pathol. 62 (11): 1034–6. doi:10.1136/jcp.2009.067801. PMC 2853932. PMID 19861563. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2853932/.
  44. ↑ Schneider A, Fritze C, Bosseckert H, Machnik G (1988). "[Primary clinical, endoscopic and histologic findings in solitary rectal ulcer]" (in German). Dtsch Z Verdau Stoffwechselkr 48 (3-4): 183–9. PMID 3234303.
  45. ↑ Abraham SC, Bhagavan BS, Lee LA, Rashid A, Wu TT (May 2001). "Upper gastrointestinal tract injury in patients receiving kayexalate (sodium polystyrene sulfonate) in sorbitol: clinical, endoscopic, and histopathologic findings". Am. J. Surg. Pathol. 25 (5): 637-44. PMID 11342776. http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0147-5185&volume=25&issue=5&spage=637.
  46. ↑ IAV. 15 December 2009.
  47. ↑ Barami K, Iversen K, Furneaux H, Goldman SA (September 1995). "Hu protein as an early marker of neuronal phenotypic differentiation by subependymal zone cells of the adult songbird forebrain". J. Neurobiol. 28 (1): 82–101. doi:10.1002/neu.480280108. PMID 8586967.
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