Difference between revisions of "Prostate gland"

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===Criteria as a list===
===Criteria as a list===
Major criteria (the ABCs of prostate pathology):<ref name=pmid17213347>{{cite journal |author=Humphrey PA |title=Diagnosis of adenocarcinoma in prostate needle biopsy tissue |journal=J. Clin. Pathol. |volume=60 |issue=1 |pages=35–42 |year=2007 |month=January |pmid=17213347 |pmc=1860598 |doi=10.1136/jcp.2005.036442 |url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1860598/?tool=pubmed}}</ref>
Major criteria (the ABCs of prostate pathology):<ref name=pmid17213347>{{cite journal |author=Humphrey PA |title=Diagnosis of adenocarcinoma in prostate needle biopsy tissue |journal=J. Clin. Pathol. |volume=60 |issue=1 |pages=35–42 |year=2007 |month=January |pmid=17213347 |pmc=1860598 |doi=10.1136/jcp.2005.036442 |url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1860598/?tool=pubmed}}</ref>
#Architecture - "infiltrative growth" pattern.
#Architecture.
#*"Infiltrative growth" pattern  
#**Image: [http://www.nature.com/modpathol/journal/v17/n3/fig_tab/3800050f1.html#figure-title Infiltrative growth pattern (nature.com)].
#*Increased gland density.
#*Small circular glands and occasionally large branching gland.
#Basal cells lacking.
#Basal cells lacking.
#Cytological abnormalities:
#Cytological abnormalities:

Revision as of 02:20, 21 June 2010

The prostate adds juice to the sperm. In old men it creates lotsa problems... nodular hyperplasia (commonly called BPH or benign prostatic hypertrophy) and cancer (adenocarcinoma).

Normal

Prostate

  • Glands have two cell layers (similar to glands in breast).
    • Second cell layer may be difficult to see (like in breast).
  • Epithelium in glands is "folded" or "tufted".
    • Very important - helps on differentiate from Gleason pattern 3.
  • Luminal epithelium often clear cytoplasm.
  • Single nucleus.

Benign normal:

  • Corpora amylacea.
    • Round/ovoid-eosinophilic bodies -- with laminations (layered appearance).
    • In gland lumina.
    • Usually in benign glands - but cannot be used to exclude cancer.[1]
    • Very common.
    • These should be differentiated from eosinophilic proteinaceous debris - which is associated with cancer.

Negatives:

  • No nucleoli present (if you see nuclei think: cancer, HGPIN, reactive changes, basal cell hyperplasia).
  • No mitoses - these are uncommon... even in high grade prostate cancer.

Notes:

  • Tufted epithelium is a strong indicator of benignancy; however two uncommon prostate cancer typically have tufted epithelium:
    • Pseudohyperplastic adenocarcinoma.
    • Foamy gland carcinoma.

IHC of normal prostate

Normal prostate:

  • AMACR -ve (mark epithelial cells).
  • p63 +ve, HMWCK +ve (mark basal cells).
  • PSA +ve, PSAP +ve.

Other accessory glands

Bulbourethral gland

  • AKA Cowper's gland.
  • Mucinous glands at the apex of the prostate.

Image: Mucinous/serous salivary gland (duke.edu).

Seminal vesicles

  • Leaf-like architecture - epithelial component clustered closely, looks like it connects.
    • Epithelium surrounded by a thick layer of muscle (>10 cells across ~80 microns).
  • Lipofuscin (coarse cytoplasmic yellow granules approximately 1-2 micrometers) - key feature.
  • Nucleoli - common.
  • Nuclear inclusions - common.

Images:

Common diagnoses

  • Benign.
    • Atrophy - may resemble adenocarcinoma - typically not reported.
    • Adenosis - may resemble adenocarcinoma - typically not reported.
  • Prostate adenocarcinoma.
    • Most common Grade is 3+3=6.
  • HGPIN (high-grade prostatic intraepithelial neoplasia) - prostate adenocarcinoma precursor lesion.
  • ASAP (atypical small acinar proliferation) - used if you have a few abnormal appearing glands... but can't decide between prostate adenocarcinoma & benign.
  • Chronic inflammation.
  • Acute inflammation - can result in an elevated PSA and may have prompted the biopsy you're looking at.
  • Nodular hyperplasia of the prostate; AKA benign prostatic hypertrophy (BPH).
    • Not diagnosed on needle biopsies.
    • BPH is technically incorrect -- the process is a hyperplasia.
      • Hyperplasia = proliferation of cells, hypertrophy = enlargement of cells.
        • How to remember? A. Prostate... hyperPlasia.

Clinical history

  • PSA (serum).
    • >10 ng/mL worrisome for prostate cancer.
    • Normal is age dependent - increases with age, usu. cut-off ~ 4 ng/mL.
  • HIFU = High Intensity Focused Ultrasound - an ablation procedure for prostate cancer.[3]

Atrophy

General

  • Small glands (may mimic Gleason score 3 pattern).

Microscopic

Features:

  • Glands often have a jagged edges/prows (in cancer the glands tend to have round edges) - key feature.
    • Prow = forward most part of a ship's bow that cuts through the water.[4]
      • You may have come across prow in the context of breast cancer, i.e. tubular carcinoma.
  • Gland density is usually lower than in prostate carcinoma, i.e. glands are not back-to-back - key feature.
  • Atrophic glands are often hyperchromatic.[5]
  • Scant cytoplasm - usually.

Negatives:

  • Nuclei like normal, i.e. nucleoli uncommon.
  • Should have two cell layers, i.e. epithelial and myoepithelial (may be difficult to see).

Atrophy vs. cancer

Atrophy Cancer
Glandular architecture/
arrangement 		angulated glands, may
look like they originate
from one large duct 		round glands,
often back-to-back
Nuclear
hyperchromasia 		marked moderate
Cytoplasm scant/minimal moderate, may
be amphophilic
Basal cells may be visible absent
Nucleoli absent present
Secretions in
glands 		no yes - eosinophilic
or blue

Basal cell hyperplasia

General

  • Atypical appearing glands - typically in transition zone.[6]
  • May have nucleoli.

Differentiating between diagnoses

Basal cell hyperplasia vs. cancer[1]

  • Low power gland architecture near normal.[2][3]
    • Glands not as small as cancer.
    • Folds in gland lumina.
    • No hyperchromasia.
    • Two cell layers (as in normal prostate glands).

High grade prostatic intraepithelial neoplasia

General

  • Abbreviated as HGPIN.
  • Thought to be a precursor lesion for prostate adenocarcinoma.

Low-grade PIN:

  • Not reported and generally believed to be irrelevant biologically/clinically.
    • PIN not otherwise specified refers to HGPIN.
    • Low-grade PIN has the architecture of HGPIN but lacks the nuclear atypia.

Microscopy

Features:

  • Diagnosed on basis of nuclear changes.
    • Hyperchromatic nuclei.
    • Nucleoli present - key feature.
    • Often increased N/C ratio.
  • Different architectures (e.g. micropapillary).
  • Usually epithelial hyperplasia.

HGPIN architecture

There are several forms:[7][8]

  • Flat - uncommon.
  • Tufting - common.
  • Micropapillary - common.
  • Cribriform - rare.

Note: The architectural pattern is NOT thought to have any prognostic significance -- may, however, be useful for picking it out from benign prostate.

Images:

Differentiating between diagnoses

HGPIN vs. adenocarcinoma:

  • Glands with HGPIN have two or more distinct cells layers.

HGPIN vs. normal:

  • HPGIN has nuclear changes.

May need IHC (especially for cancer vs. HGPIN).

IHC patterns:

  • Cancer: AMACR +ve, p63 -ve, HMWCK -ve.
  • HGPIN: AMACR +ve, p63 +ve, HMWCK +ve.
  • Normal: AMACR -ve, p63 +ve, HMWCK ve+.

Atypical small acinar proliferation

General

  • Abbreviated ASAP.
  • It is a waffle diagnosis, i.e. it is not considered an entity with a distinct pathobiology.[9]
    • It is the same as suspicious for carcinoma.[10]
      • ASAP is preferred as it does not contain the word carcinoma and, thus, cannot be misread as carcinoma, i.e. positive for malignancy.
    • Analogous to ASCUS on a pap test.
    • ASAP should be used sparingly.
      • One benchmark is < 3-5% of biopsies.[11]
  • Never diagnosed on excision, i.e. prostatectomy specimen.

Histologic characteristics

  • Atypical appearing acini.
  • Limited extent, e.g. 2-3 glands.
  • IHC not contributory.
  • Deeper cuts didn't yield anything.

Association with adenocarcinoma

Management

  • ASAP is considered an indication for re-biopsy;[13] in one survey of urologists[14] 41/42 (~98%) of respondents considered it a sufficient reason to re-biopsy.

Common prostate cancer

Criteria as a list

Major criteria (the ABCs of prostate pathology):[15]

  1. Architecture.
  2. Basal cells lacking.
  3. Cytological abnormalities:
    • Nuclear enlargement.
    • Nucleoli.

Minor criteria:[15]

  1. Nuclear hyperchromasia.
  2. Wispy blue mucin.
  3. Pink amorphous secretions.
  4. Intraluminal crystalloid.
  5. Amphophilic cytoplasm.
  6. Adjacent HGPIN.
  7. Mitoses - quite rare.

Extent/quantity criteria:

  • There is no agreed upon minimum number of glands; however, one paper suggests that agreement among experts is low with 5 or less glands.[18]
    • Thus, it has been suggested that six or more glands should be present to diagnose cancer.[18]

Low power features

  • Architecture is the key to diagnosing low grade cancer.
    • Back-to-back glands or crowding of glands -- think low grade cancer (Gleason pattern 3).
    • Sharp transition between gland border and lumen.
      • Loss of epithelial folding at the epithelium-gland lumen interface - "punched-out" appearance.
    • Eosinophilic debris within the gland lumen (pink amorphous secretions, intraluminal crystalloid).
    • Blue-tinged acellular material within the gland lumen (mucin) -- uncommon.
    • "Infiltrative": small round/oval (malignant) glands (approx. 5 cells across) interspersed with larger (benign) glands that are 2-3 times larger.

High power features

  • Nuclei.
    • Hyperchromatic nuclei (like in HGPIN).
    • Nuclear enlargement.
      • Difficult to appreciate (if cancer isn't side-by-side with normal prostate).
      • Difficult to see if not on high power.
  • Nucleoli visible on high power (200x or 100X)
    • May be difficult to see - especially if light intensity is low.
      • One should not use 400x to look for nucleoli (it is a waste of time + you risk overcalling something benign).
    • If I see three good nucleoli in a gland I'm usually confident it is cancer.
  • Loss of basal cells - diagnostic feature.
    • Like in breast pathology (where one looks for loss of myoepithelial cells) - this may be difficult to see.

Notes:

  • Mitoses are not a common feature - don't waste time looking for them.

IHC

  • AMACR +ve, p63 -ve, HMWCK (34betaE12) -ve .
  • Usually positive: PSA, PSAP.

Mimics

Mimics of prostate adenocarcinoma:[19]

Entity Key feature Detailed microscopic Other Image
Adenosis (AKA atypical adenomatous hyperplasia) gradual transition between normal & small gland (NOT two populations) many small glands, lack nuclear size variation, basal layer present nucleoli may be present; may need to do p63 or 34betaE12 to find basal layer Image
Sclerosing adenosis gradual transition between normal & small gland (NOT two populations), fibrosis many small glands, lack nuclear size variation, basal layer present analogous to sclerosing adenosis of breast (???) Image
Atropy sharp angulation of gland nuclear hyperchromasia, scant cytoplasm may appear right beside non-atrophic tissue Image
Basal cell hyperplasia two distinct cell populations (in epithelial component) abundant epithelial cells; nucleoli in pale ('blue') nuclei of basal cells, glandular cell nuclei darker ('purple') vaguely similar to epithelial hyperplasia of usual type (EHUT) in breast Image
Bulbourethral gland no nuclear atypia clear cytoplasm apex of prostate Image
Seminal vesicles lipofuscin (yellow granular material in cytoplasm) fern-like arrangement of epithelium, nucleoli, surrounded by muscle involvement by cancer changes staging Image
Radiation exposure marked nuclear size variation increased stroma (fibrosis), lack nucleoli ??? history of Rx; uniform nuc. size with Hx of Rx should raise susp. of cancer Image
Prostatitis inflammatory cells (lymphocytes, plasma cells, PMNs) no nuclear atypia, normal gland arch. clinical mimic of cancer (elevated PSA); usu. not a problem for the pathologist [4]

Memory device: AAABBRS = atropy, adenosis, adenosis (sclerosing), basal cell hyperplasia, bulbourethral gland, seminal vescicles, radiation.

Grading

There is only one grading system that any one talks about...

Gleason grading system

  • Score range: 2-10.
  • Reported as on biopsy as: (primary pattern) + (secondary pattern or tertiary pattern with the highest grade) = sum.
    • e.g. Gleason grade 3+4=7 means: pattern 3 is present and dominant, pattern 4 is the remainder of the tumour - but present in a lesser amount than pattern 3.
  • Reported as on prostatectomies as: (primary pattern) + (secondary pattern) = sum, (tertiary pattern)
  • Tertiary Gleason pattern - definition: a pattern that is seen in than 5% of the tumour (volume), that is higher grade than the two dominant patterns.[20]
    • The presence of a tertiary patterns adversely affect the prognosis; however, the prognosis is not as bad as when the tertiary pattern is the secondary pattern, i.e. 3+4 tertiary 5 has a better prognosis than 3+5 (with some small amount of pattern 4).[21]

Examples:

  • A biopsy has 80% pattern 4, 15.1% pattern 3 and 4.9% pattern 5... it would be reported as: 4+5=9.
  • A prostatectomy has 80% pattern 4, 15.1% pattern 3 and 4.9% pattern 5... it would be reported as: 4+3=7 with tertiary pattern 5.

Gleason pattern 1 & 2

  • Academic thing - you can forget about 'em.

Gleason pattern 3

  • Glands smaller than normal prostate glands + loss of epithelial folding.
  • Can draw a line around each gland.

Notes:

  • All cribriform is now classified as Gleason pattern 4.[22]

Gleason pattern 4

  • Loss of gland lumina.
  • Gland fusion.
  • Benign looking cords ('hypernephroid pattern').
  • Cribriform.
  • One gland is not enough to call Gleason 4.

Gleason pattern 5

  • Sheets.
    • Must be differentiated from intraductal growth (which like in the breast are well circumscribed nests).
  • Single cells.
    • May be confused with stromal/lymphocytic infiltration.
      • Look for nucleoli, cells should be round (prostatic stroma cells are spindle cells).
  • Cords.
  • Nests of cells with necrosis at centre.

Testing yourself:

Management

The management changes between Gleason 6, 7 & 8; typically, the implications are:

  • Gleason 6: watchful waiting or radioactive seeds, surgery if patient wants.
  • Gleason 7: do something.
  • Gleason 8+: bad cancer - do something quickly!

Bottom line: You want to be sure when you call something Gleason pattern 4.

Note:

  • The usual caveats apply to the above; if the patient is moribund-- nothing is done, if the patient refuses treatment... nothing is done et cetera.

Margins + Extension

Definitions:

  • Extraprostatic extension (EPE) is difficult to assess (in prostatectomy specimens) as there is no consensus definition.
    • The prostate does NOT have a well defined capsule.
      • Intraobserver agreement for EPE is fair-moderate and lower than for the surgical margin.[24]
  • Surgical margin - where the surgeon cut.
    • It is possible to have EPE without a positive margin.
    • It is possible to have a positive margin without EPE.

Important:

  • EPE cannot be called on a biopsy unless the tumour is next to adipose tissue.[25]

Extraprostatic extension (EPE)

  • Prostatectomy specimens: EPE is present if there is a "significant bulge" in the contour of the prostate at low power.
  • Prostate biopsy: EPE is present if tumour touches adipose tissue.[26]
    • The prostate, at the apex, may have some skeletal muscle -- it is hard to define the extent... ergo no EPE at apex. (????)

Reporting prostate cancer

Elements of a prostate biopsy report with cancer

Important elements:[15]

  1. Type of cancer, e.g. "prostatic adenocarcinoma, acinar type".
  2. Gleason score including primary and secondary pattern, e.g. "Gleason score 3+4=7".
  3. Number of cores and number involved, e.g. "2/3 cores involved by cancer".
  4. Percent area involved, i.e. how much of the core is cancer, e.g. "75% of specimen is tumour".
  5. Percent area involved that is Gleason pattern 4 or 5, e.g. "25% of the tumour is Gleason pattern 4 or 5".
  6. Presence of perineural invasion.
  7. Presence of extension into fat (extraprostatic extension).

Notes:

  • "Percent area involved" may seem like an odd thing to request 'cause it is sampling dependent, i.e. if the radiologist sticks the biopsy needle deeper into the lesion more of the core is positive, but urologists think it is important -- more important than perineural invasion.[27]

Prostatectomy specimens

See: CAP checklist.

Unusual forms of prostate cancer

Ductal adenocarcinoma

Features:

  • Crowded columnar (or cigar-shaped) nuclei.
    • Vaguely resembles colonic adenocarcinoma.
  • Usually seen in association with conventional (acinar) prostate adenocarcinoma.

Foamy gland carcinoma

Features:

  • Tufted glandular border.
  • Abundant eosinophilic (or hyperchromatic) cytoplasm - key feature.
  • Gland size larger than "typical" prostate cancer.

Image: Foamy gland carcinoma (nature.com).

Pseudohyperplastic prostatic adenocarcinoma

Features:[28][29]

  • Medium to large glands with an atypical morphology - key low power feature:
    • Papillary or pseudopapillary infoldings, luminal undulations, branching or cystic dilatation.
  • Nuclear features of conventional prostate cancer (nucleoli, nuclear enlargement).

Image: Pseudohyperplastic prostatic adenocarcinoma (nature.com).

Notes:

  • Usually associated with conventional (acinar) prostate adenocarcinoma.
  • Pale abundant cytoplasm - similar to normal prostate.

See also

References

  1. ↑ Christian JD, Lamm TC, Morrow JF, Bostwick DG (January 2005). "Corpora amylacea in adenocarcinoma of the prostate: incidence and histology within needle core biopsies". Mod. Pathol. 18 (1): 36–9. doi:10.1038/modpathol.3800250.
  2. ↑ PR. September 2009.
  3. ↑ URL: http://www.internationalhifu.com/what-is-hifu-mainmenu-132.html. Accessed on: 15 June 2010.
  4. ↑ http://en.wikipedia.org/wiki/Prow
  5. ↑ SN. June 3, 2009.
  6. ↑ URL: http://pathologyoutlines.com/prostate.html#bch. Accessed on: 19 June 2010.
  7. ↑ Humphrey, Peter A; Dehner, Louis P; Pfeifer, John D (2008). The Washington Manual of Surgical Pathology (1st ed.). Lippincott Williams & Wilkins. pp. 380. ISBN 978-0781765275.
  8. ↑ Bostwick, DG.; Qian, J. (Mar 2004). "High-grade prostatic intraepithelial neoplasia.". Mod Pathol 17 (3): 360-79. doi:10.1038/modpathol.3800053. PMID 14739906. http://www.nature.com/modpathol/journal/v17/n3/pdf/3800053a.pdf.
  9. ↑ Flury SC, Galgano MT, Mills SE, Smolkin ME, Theodorescu D (January 2007). "Atypical small acinar proliferation: biopsy artefact or distinct pathological entity". BJU International 99 (4): 780-5. PMID 17378841. http://www3.interscience.wiley.com/journal/118508438/abstract.
  10. ↑ THvdK. 19 June 2010.
  11. ↑ THvdK. 19 June 2010.
  12. ↑ Leite KR, Camara-Lopes LH, Cury J, Dall'oglio MF, Sañudo A, Srougi M (June 2008). "Prostate cancer detection at rebiopsy after an initial benign diagnosis: results using sextant extended prostate biopsy". Clinics 63 (3): 339–42. PMID 18568243. http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1807-59322008000300009&lng=en&nrm=iso&tlng=en.
  13. ↑ Bostwick DG, Meiers I (July 2006). "Atypical small acinar proliferation in the prostate: clinical significance in 2006". Arch. Pathol. Lab. Med. 130 (7): 952–7. PMID 16831049. http://journals.allenpress.com/jrnlserv/?request=get-abstract&issn=0003-9985&volume=130&page=952.
  14. ↑ Rubin MA, Bismar TA, Curtis S, Montie JE (July 2004). "Prostate needle biopsy reporting: how are the surgical members of the Society of Urologic Oncology using pathology reports to guide treatment of prostate cancer patients?". Am. J. Surg. Pathol. 28 (7): 946–52. PMID 15223967.
  15. ↑ 15.0 15.1 15.2 Humphrey PA (January 2007). "Diagnosis of adenocarcinoma in prostate needle biopsy tissue". J. Clin. Pathol. 60 (1): 35–42. doi:10.1136/jcp.2005.036442. PMC 1860598. PMID 17213347. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1860598/?tool=pubmed.
  16. ↑ 16.0 16.1 16.2 Epstein JI (March 2004). "Diagnosis and reporting of limited adenocarcinoma of the prostate on needle biopsy". Mod. Pathol. 17 (3): 307–15. doi:10.1038/modpathol.3800050. PMID 14739905. http://www.nature.com/modpathol/journal/v17/n3/full/3800050a.html.
  17. ↑ URL: http://pancreaticcancer2000.com/page1.htm. Accessed on: 3 June 2010.
  18. ↑ 18.0 18.1 Van der Kwast, TH.; Evans, A.; Lockwood, G.; Tkachuk, D.; Bostwick, DG.; Epstein, JI.; Humphrey, PA.; Montironi, R. et al. (Feb 2010). "Variability in diagnostic opinion among pathologists for single small atypical foci in prostate biopsies.". Am J Surg Pathol 34 (2): 169-77. doi:10.1097/PAS.0b013e3181c7997b. PMID 20061936.
  19. ↑ Weedman Molavi, Diana (2008). The Practice of Surgical Pathology: A Beginner's Guide to the Diagnostic Process (1st ed.). Springer. pp. 100-3. ISBN 978-0387744858.
  20. ↑ Zhou, Ming; Magi-Galluzzi, Cristina (2006). Genitourinary Pathology: A Volume in Foundations in Diagnostic Pathology Series (1st ed.). Churchill Livingstone. pp. 72. ISBN 978-0443066771.
  21. ↑ Zhou, Ming; Magi-Galluzzi, Cristina (2006). Genitourinary Pathology: A Volume in Foundations in Diagnostic Pathology Series (1st ed.). Churchill Livingstone. pp. 72. ISBN 978-0443066771.
  22. ↑ Epstein JI (February 2010). "An update of the Gleason grading system". J. Urol. 183 (2): 433–40. doi:10.1016/j.juro.2009.10.046. PMID 20006878.
  23. ↑ Kronz, JD.; Silberman, MA.; Allsbrook, WC.; Bastacky, SI.; Burks, RT.; Cina, SJ.; Mills, SE.; Ross, JS. et al. (Sep 2000). "Pathology residents' use of a Web-based tutorial to improve Gleason grading of prostate carcinoma on needle biopsies.". Hum Pathol 31 (9): 1044-50. doi:10.1053/hupa.2000.16278. PMID 11014569.
  24. ↑ Evans, AJ.; Henry, PC.; Van der Kwast, TH.; Tkachuk, DC.; Watson, K.; Lockwood, GA.; Fleshner, NE.; Cheung, C. et al. (Oct 2008). "Interobserver variability between expert urologic pathologists for extraprostatic extension and surgical margin status in radical prostatectomy specimens.". Am J Surg Pathol 32 (10): 1503-12. doi:10.1097/PAS.0b013e31817fb3a0. PMID 18708939.
  25. ↑ AE. 4 June 2010.
  26. ↑ Epstein, JI.; Srigley, J.; Grignon, D.; Humphrey, P. (Sep 2007). "Recommendations for the reporting of prostate carcinoma.". Hum Pathol 38 (9): 1305-9. doi:10.1016/j.humpath.2007.05.015. PMID 17707261.
  27. ↑ Rubin MA, Bismar TA, Curtis S, Montie JE (July 2004). "Prostate needle biopsy reporting: how are the surgical members of the Society of Urologic Oncology using pathology reports to guide treatment of prostate cancer patients?". Am. J. Surg. Pathol. 28 (7): 946–52. PMID 15223967.
  28. ↑ Zhou, Ming; Magi-Galluzzi, Cristina (2006). Genitourinary Pathology: A Volume in Foundations in Diagnostic Pathology Series (1st ed.). Churchill Livingstone. pp. 77. ISBN 978-0443066771.
  29. ↑ PMID 14688829.

External links

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