Difference between revisions of "Rhabdomyosarcoma"

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'''Rhabdomyosarcoma''', often abbreviated ''RMS'', is a malignant tumour of skeletal muscle.
{{ Infobox diagnosis
| Name      = {{PAGENAME}}
| Image      = Alveolar_rhabdomyosarcoma_-_very_high_mag.jpg
| Width      =
| Caption    = Alveolar rhabdomyosarcoma. [[H&E stain]].
| Synonyms  =
| Micro      = +/-rhabdomyoblasts (eccentric nucleus, moderate amount of intensly eosinophilic cytoplasm, striations - not common); alveolar RMS: alveolus-like pattern (classic); embryonal RMS: [[small round cell tumour]]
| Subtypes  = embryonal (spindle cell subtype, botryoid), alveolar (translocation-positive, translocation-negative), undifferentiated
| LMDDx      = [[small round cell tumours]] - esp. [[small cell carcinoma]] and (large cell) [[lymphoma]]s
| Stains    =
| IHC        = desmin (best marker) +ve, actin +ve, myogenin +ve, CD56 +ve (common), synaptophysin -ve/+ve, chromogranin -ve/+ve, cytokeratins -ve/+ve
| EM        = sarcomeric like structures - typically in U-shaped cells
| Molecular  = alveolar RMS (~85% of cases): t(2,13) PAX3/FKHR fusion gene ''or'' t(1,13) PAX7/FKHR fusion gene
| IF        =
| Gross      =
| Grossing  =
| Site      = [[soft tissue]] - skeletal muscle site (alveolar RMS), non-skeletal muscle site (embryonal RMS)
| Assdx      =
| Syndromes  = [[DICER1 syndrome]] for ''embryonal rhabdomyosarcoma''
| Clinicalhx = alveolar RMS: young adult or adolescent; embryonal RMS: typically <10 years old
| Signs      =
| Symptoms  =
| Prevalence = not common
| Bloodwork  =
| Rads      =
| Endoscopy  =
| Prognosis  =
| Other      =
| ClinDDx    = other soft tissue tumours
| Tx        =
}}
'''Rhabdomyosarcoma''', often abbreviated '''RMS''', is a [[malignant]] tumour of skeletal muscle.


==General==
==General==
*Most common paediatric sarcoma.
*Most common paediatric [[sarcoma]].
**Classically in the head and neck region.<ref name=pmid10465231>{{Cite journal  | last1 = Rosenthal | first1 = TC. | last2 = Kraybill | first2 = W. | title = Soft tissue sarcomas: integrating primary care recognition with tertiary care center treatment. | journal = Am Fam Physician | volume = 60 | issue = 2 | pages = 567-72 | month = Aug | year = 1999 | doi =  | PMID = 10465231 | URL = http://www.aafp.org/afp/1999/0801/p567.html }}</ref>
**Classically in the head and neck region.<ref name=pmid10465231>{{Cite journal  | last1 = Rosenthal | first1 = TC. | last2 = Kraybill | first2 = W. | title = Soft tissue sarcomas: integrating primary care recognition with tertiary care center treatment. | journal = Am Fam Physician | volume = 60 | issue = 2 | pages = 567-72 | month = Aug | year = 1999 | doi =  | PMID = 10465231 | URL = http://www.aafp.org/afp/1999/0801/p567.html }}</ref>
*Most common sarcoma in [[Li-Fraumeni syndrome]].<ref name=PST14feb11>PST. 14 February 2011.</ref>
*Most common sarcoma in [[Li-Fraumeni syndrome]].<ref name=PST14feb11>Thorner, Paul S. 14 February 2011.</ref>
*~6% of all childhood cancer.
*~6% of all childhood cancer.


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#*Usually young adults/adolescents.
#*Usually young adults/adolescents.
#*Early mets common.
#*Early mets common.
#*Usu. arises in regions with skeletal muscle.
#*Usually arises in regions with skeletal muscle.
#Embryonal rhabdomyosarcoma.
#Embryonal rhabdomyosarcoma.
#*Usual <10 years old.
#*Usual <10 years old.
#*Typically locally invasive.
#*Typically locally invasive.
#*Usu. arises in regions '''without''' skeletal muscle.
#*Usually arises in regions '''without''' skeletal muscle.


Less common types:<ref name=pmid12110339>{{Cite journal  | last1 = Hicks | first1 = J. | last2 = Flaitz | first2 = C. | title = Rhabdomyosarcoma of the head and neck in children. | journal = Oral Oncol | volume = 38 | issue = 5 | pages = 450-9 | month = Jul | year = 2002 | doi =  | PMID = 12110339 }}</ref>
Less common types:<ref name=pmid12110339>{{Cite journal  | last1 = Hicks | first1 = J. | last2 = Flaitz | first2 = C. | title = Rhabdomyosarcoma of the head and neck in children. | journal = Oral Oncol | volume = 38 | issue = 5 | pages = 450-9 | month = Jul | year = 2002 | doi =  | PMID = 12110339 }}</ref>
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#Botryoid - may be considered a subtype of embryonal RMS.
#Botryoid - may be considered a subtype of embryonal RMS.
#Spindle cell - may be considered a subtype of embryonal RMS.
#Spindle cell - may be considered a subtype of embryonal RMS.
#Anaplastic.
 
Notes:
*How to remember the special types ''BUS'': '''b'''otryoid, '''u'''ndifferentiated, '''s'''pindle.
*The above is the international classification. Several classification of RMS exist - see: [http://www.nature.com/modpathol/journal/v14/n5/fig_tab/3880339t1.html#figure-title Classifications of Rhabdomyosarcoma].<ref name=pmid11353062>{{Cite journal  | last1 = Parham | first1 = DM. | title = Pathologic classification of rhabdomyosarcomas and correlations with molecular studies. | journal = Mod Pathol | volume = 14 | issue = 5 | pages = 506-14 | month = May | year = 2001 | doi = 10.1038/modpathol.3880339 | PMID = 11353062 }}
</ref>


====Molecular and histologic====
====Molecular and histologic====
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Notes:
Notes:
*Translocation-negative alveolar RMS shares gene expression prolifing characteristics with embryonal RMS -- suggesting these can be grouped together.
*Translocation-negative alveolar RMS shares gene expression profiling characteristics with embryonal RMS -- suggesting these can be grouped together.
*Several classification of RMS exist - see: [http://www.nature.com/modpathol/journal/v14/n5/fig_tab/3880339t1.html#figure-title Classifications of Rhabdomyosarcoma].<ref name=pmid11353062>{{Cite journal  | last1 = Parham | first1 = DM. | title = Pathologic classification of rhabdomyosarcomas and correlations with molecular studies. | journal = Mod Pathol | volume = 14 | issue = 5 | pages = 506-14 | month = May | year = 2001 | doi = 10.1038/modpathol.3880339 | PMID = 11353062 }}
</ref>


==Gross==
==Gross==
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==Microscopic==
==Microscopic==
===Alveolar rhabdomyosarcoma===
===Alveolar rhabdomyosarcoma===
Features:<ref name=PST14feb11>PST. 14 February 2011.</ref>
Features:<ref name=PST14feb11/>
*Alveolus-like pattern -- '''key low-power feature'''.
*Alveolus-like pattern -- '''key low-power feature'''.
**Fibrous septae lined by tumour cells.
**Fibrous septae lined by tumour cells.
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Other features:
Other features:
*Nuclear pleomorphism - common.
*[[Nuclear pleomorphism]] - common.
*Mitoses - common.
*Mitoses - common.


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DDx:
DDx:
*[[Alveolar soft part sarcoma]].
*[[Alveolar soft part sarcoma]].
*Skeletal muscle regeneration.<ref name=pmid9762546>{{Cite journal  | last1 = Guillou | first1 = L. | last2 = Coquet | first2 = M. | last3 = Chaubert | first3 = P. | last4 = Coindre | first4 = JM. | title = Skeletal muscle regeneration mimicking rhabdomyosarcoma: a potential diagnostic pitfall. | journal = Histopathology | volume = 33 | issue = 2 | pages = 136-44 | month = Aug | year = 1998 | doi =  | PMID = 9762546 }}</ref>


Images:
====Images====
*[[WC]]:
<gallery>
**[http://commons.wikimedia.org/wiki/File:Alveolar_rhabdomyosarcoma_-_intermed_mag.jpg Alveolar RMS - intermed. mag. (WC)].
Image:Alveolar_rhabdomyosarcoma_-_intermed_mag.jpg | Alveolar RMS - intermed. mag. (WC)
**[http://commons.wikimedia.org/wiki/File:Alveolar_rhabdomyosarcoma_-_very_high_mag.jpg Alveolar RMS - very high mag. (WC)].
Image:Alveolar_rhabdomyosarcoma_-_very_high_mag.jpg | Alveolar RMS - very high mag. (WC)
*www:
</gallery>
**[http://path.upmc.edu/cases/case489.html Alveolar RMS - several images (upmc.edu)].
www:
*[http://path.upmc.edu/cases/case489.html Alveolar RMS - several images (upmc.edu)].


===Embryonal rhabdomyosarcoma===
===Embryonal rhabdomyosarcoma===
Features:<ref name=PST14feb11>PST. 14 February 2011.</ref>
Features:<ref name=PST14feb11/>
*Randomly arranged small cells.
*Randomly arranged small cells.
*[[Myxoid]] matrix.
*[[Myxoid]] matrix.
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*Actin.
*Actin.
*Myogenin.
*Myogenin.
For [[head and neck pathology|head and neck]] RMS:<ref name=pmid18487991>{{Cite journal  | last1 = Bahrami | first1 = A. | last2 = Gown | first2 = AM. | last3 = Baird | first3 = GS. | last4 = Hicks | first4 = MJ. | last5 = Folpe | first5 = AL. | title = Aberrant expression of epithelial and neuroendocrine markers in alveolar rhabdomyosarcoma: a potentially serious diagnostic pitfall. | journal = Mod Pathol | volume = 21 | issue = 7 | pages = 795-806 | month = Jul | year = 2008 | doi = 10.1038/modpathol.2008.86 | PMID = 18487991 }}</ref>
*CD56 +ve.
*Synaptophysin -ve/+ve (seen in 12 of 37 cases<ref name=pmid18487991/>).
*Chromogranin A -ve/+ve (seen in 8 of 36 cases<ref name=pmid18487991/>).
*Wide-spectrum cytokeratin -ve/+ve.
*CAM5.2 -ve/+ve.
For [[urinary bladder]] RMS in adults:
*Myogenin +ve.
*Desmin +ve.
*Keratins -ve.<ref name=pmid21762516>{{Cite journal  | last1 = Bing | first1 = Z. | last2 = Zhang | first2 = PJ. | title = Adult urinary bladder tumors with rhabdomyosarcomatous differentiation: clinical, pathological and immunohistochemical studies. | journal = Diagn Pathol | volume = 6 | issue =  | pages = 66 | month =  | year = 2011 | doi = 10.1186/1746-1596-6-66 | PMID = 21762516 }}</ref>
**Keratin positive tumours are considered ''rhabdomyosarcomatous sarcomatoid carcinoma'' or ''sarcomatoid carcinoma with rhabdomyosarcomatous differentiation''.


===Subtyping via IHC===
===Subtyping via IHC===
PST proposes<ref name=PST14feb11>PST. 14 February 2011.</ref> the following (presumably based on Makawitz et al.<ref name=pmid18788888>{{cite journal |author=Makawita S, Ho M, Durbin AD, Thorner PS, Malkin D, Somers GR |title=Expression of insulin-like growth factor pathway proteins in rhabdomyosarcoma: IGF-2 expression is associated with translocation-negative tumors |journal=Pediatr. Dev. Pathol. |volume=12 |issue=2 |pages=127–35 |year=2009 |pmid=18788888 |doi=10.2350/08-05-0477.1 |url=}}</ref>):
PST proposes<ref name=PST14feb11/> the following (presumably based on Makawitz et al.<ref name=pmid18788888>{{cite journal |author=Makawita S, Ho M, Durbin AD, Thorner PS, Malkin D, Somers GR |title=Expression of insulin-like growth factor pathway proteins in rhabdomyosarcoma: IGF-2 expression is associated with translocation-negative tumors |journal=Pediatr. Dev. Pathol. |volume=12 |issue=2 |pages=127–35 |year=2009 |pmid=18788888 |doi=10.2350/08-05-0477.1 |url=}}</ref>):
{| class="wikitable sortable" style="margin-left:auto;margin-right:auto"
{| class="wikitable sortable" style="margin-left:auto;margin-right:auto"
| '''IHC'''
| '''IHC'''
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==[[Electron microscopy]]==
==[[Electron microscopy]]==
Features:
Features:
*Sarcomeric like structures - usu. in "bent" cells; cells that are U-shaped.
*Sarcomeric like structures - usually in "bent" cells; cells that are U-shaped.


==Molecular diagnostics==
==Molecular diagnostics==
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*t(1,13) vs. t(2,13) -- t(1,13) usually: younger age, extremity lesion, localized disease, better survival.
*t(1,13) vs. t(2,13) -- t(1,13) usually: younger age, extremity lesion, localized disease, better survival.
*Several uncommon [[translocations]] exist.
*Several uncommon [[translocations]] exist.
*'''Important''' for [[urinary bladder]] lesions in adults: the presence of a translocation is more-or-less required for the diagnosis of RMS.<ref name=pmid21762516>{{Cite journal  | last1 = Bing | first1 = Z. | last2 = Zhang | first2 = PJ. | title = Adult urinary bladder tumors with rhabdomyosarcomatous differentiation: clinical, pathological and immunohistochemical studies. | journal = Diagn Pathol | volume = 6 | issue =  | pages = 66 | month =  | year = 2011 | doi = 10.1186/1746-1596-6-66 | PMID = 21762516 }}</ref>
**It is suggested that keratin negative tumours without molecular testing to corroborate the impression of RMS be referred to as ''rhabdomyomatous tumours''.<ref name=pmid21762516/>
===Embryonal rhabdomyosarcoma===
*Chromosome 11p loss of heterozygosity.<ref name=pmid17652054>{{Cite journal  | last1 = Gallego Melcón | first1 = S. | last2 = Sánchez de Toledo Codina | first2 = J. | title = Molecular biology of rhabdomyosarcoma. | journal = Clin Transl Oncol | volume = 9 | issue = 7 | pages = 415-9 | month = Jul | year = 2007 | doi =  | PMID = 17652054 }}</ref>
Note:
*Not used for diagnosis.


==See also==
==See also==

Latest revision as of 12:40, 24 March 2024

Rhabdomyosarcoma
Diagnosis in short

Alveolar rhabdomyosarcoma. H&E stain.
LM +/-rhabdomyoblasts (eccentric nucleus, moderate amount of intensly eosinophilic cytoplasm, striations - not common); alveolar RMS: alveolus-like pattern (classic); embryonal RMS: small round cell tumour
Subtypes embryonal (spindle cell subtype, botryoid), alveolar (translocation-positive, translocation-negative), undifferentiated
LM DDx small round cell tumours - esp. small cell carcinoma and (large cell) lymphomas
IHC desmin (best marker) +ve, actin +ve, myogenin +ve, CD56 +ve (common), synaptophysin -ve/+ve, chromogranin -ve/+ve, cytokeratins -ve/+ve
EM sarcomeric like structures - typically in U-shaped cells
Molecular alveolar RMS (~85% of cases): t(2,13) PAX3/FKHR fusion gene or t(1,13) PAX7/FKHR fusion gene
Site soft tissue - skeletal muscle site (alveolar RMS), non-skeletal muscle site (embryonal RMS)
Syndromes DICER1 syndrome for embryonal rhabdomyosarcoma
Clinical history alveolar RMS: young adult or adolescent; embryonal RMS: typically <10 years old
Prevalence not common
Clin. DDx other soft tissue tumours

Rhabdomyosarcoma, often abbreviated RMS, is a malignant tumour of skeletal muscle.

General

Classification

Histologic

  1. Alveolar rhabdomyosarcoma.
    • Usually young adults/adolescents.
    • Early mets common.
    • Usually arises in regions with skeletal muscle.
  2. Embryonal rhabdomyosarcoma.
    • Usual <10 years old.
    • Typically locally invasive.
    • Usually arises in regions without skeletal muscle.

Less common types:[3]

  1. Undifferentiated rhabdomyosarcoma.
  2. Botryoid - may be considered a subtype of embryonal RMS.
  3. Spindle cell - may be considered a subtype of embryonal RMS.

Notes:

  • How to remember the special types BUS: botryoid, undifferentiated, spindle.
  • The above is the international classification. Several classification of RMS exist - see: Classifications of Rhabdomyosarcoma.[4]

Molecular and histologic

  1. Translocation-positive alveolar RMS.
  2. Translocation-negative alveolar RMS.
  3. Embryonal RMS.

Notes:

  • Translocation-negative alveolar RMS shares gene expression profiling characteristics with embryonal RMS -- suggesting these can be grouped together.

Gross

Sarcoma botryoides (embryonal RMS) - distinctive appearance:

Image:

Microscopic

Alveolar rhabdomyosarcoma

Features:[2]

  • Alveolus-like pattern -- key low-power feature.
    • Fibrous septae lined by tumour cells.
      • Cells may "fall-off" the septa, i.e. be detached/scattered in the alveolus-like space.
      • Space between fibrous sepate may be filled with tumour = solid variant of alveolar rhabdomyosarcoma.
  • Rhabdomyoblasts - essentially diagnostic.
    • Eccentric nucleus.
    • Moderate amount of intensly eosinophilic cytoplasm.
    • Striations -- if you're really lucky; these are not common.

Other features:

Notes:

  • Well-differentiated rhabdomyoblasts are uncommon in alveolar RMS.

DDx:

Images

  • Alveolar RMS - intermed. mag. (WC)

  • Alveolar RMS - very high mag. (WC)

www:

Embryonal rhabdomyosarcoma

Features:[2]

  • Randomly arranged small cells.
  • Myxoid matrix.
  • Strap cells:
    • Tadpole-like morphology.
  • Rhabdomyoblasts - essentially diagnostic.
    • Eccentric nucleus.
    • Moderate amount of intensly eosinophilic cytoplasm.
    • Striations -- if you're really lucky; these are not common.

DDx:

Images:

Subtypes of embryonal RMS

There are two common subtypes of embryonal RMS. Both of them have a better prognosis that embryonal RMS not otherwise specified (NOS).

Common subtypes:

  1. Botryoid subtype (AKA sarcoma botryoides):
    • Gross: Grape-like morphology.
    • Microscopic: Non-proliferating layer deep to the surface ("Cambium layer").
  2. Spindle cell subtype.
    • General: may mimic leiomyosarcoma (complete with vesicular pattern) -- which is not common in the pediatric population.
    • Microscopic: vesicular growth pattern, spindle cells.

Notes:

  • Cambium layer = cellular region deep to epithelial component.[7]
    • Can be thought of as the opposite of a "Grenz zone" -- which is a paucicellular zone between tumour and epithelium.

Anaplasia

Criteria:

  1. Hyperchromatic nuclei with size variation greater or equal to 3x.
  2. Multipolar (atypical) mitotic figures.

Subclassification:

  1. Focal - a few cells.
  2. Diffuse - cluster or sheets of anaplasia.

Notes:

  • Not subtle - can identify at low power.
  • Seen in 10-15% of RMS.
    • More common in older individuals.
  • Poorer prognosis in embryonal RMS.
    • No change in prognosis in alveolar RMS.

IHC

Panel of muscle markers -- DAM:

  • Desmin (best marker).
  • Actin.
  • Myogenin.

For head and neck RMS:[8]

  • CD56 +ve.
  • Synaptophysin -ve/+ve (seen in 12 of 37 cases[8]).
  • Chromogranin A -ve/+ve (seen in 8 of 36 cases[8]).
  • Wide-spectrum cytokeratin -ve/+ve.
  • CAM5.2 -ve/+ve.

For urinary bladder RMS in adults:

  • Myogenin +ve.
  • Desmin +ve.
  • Keratins -ve.[9]
    • Keratin positive tumours are considered rhabdomyosarcomatous sarcomatoid carcinoma or sarcomatoid carcinoma with rhabdomyosarcomatous differentiation.

Subtyping via IHC

PST proposes[2] the following (presumably based on Makawitz et al.[10]):

IHC Translocation positive
alveolar RMS 		Embryonal RMS Translocation negative
alveolar RMS
myogenin +ve -- diffuse +ve -- focal +ve -- diffuse
EGFR -ve +ve -ve
P-cadherin +ve -ve -ve
IGF2 -ve +ve +ve

A paper by Wachtel at al.[11] proposes the use of:

  • AP2beta and P-cadherin +ve in translocation positive alveolar RMS, and
  • EGFR and fibrillin-2 +ve in embryonal RMS and translocation negative alveolar RMS.

Electron microscopy

Features:

  • Sarcomeric like structures - usually in "bent" cells; cells that are U-shaped.

Molecular diagnostics

Alveolar rhabdomyosarcoma

Common translocations (~85% of cases):

  • t(1,13).
    • PAX7/FKHR fusion gene.
    • Seen in approx. 15% of cases.
  • t(2,13).[12]
    • PAX3/FKHR fusion gene.
    • Seen in approx. 70% of cases.

Notes:

  • t(1,13) vs. t(2,13) -- t(1,13) usually: younger age, extremity lesion, localized disease, better survival.
  • Several uncommon translocations exist.
  • Important for urinary bladder lesions in adults: the presence of a translocation is more-or-less required for the diagnosis of RMS.[9]
    • It is suggested that keratin negative tumours without molecular testing to corroborate the impression of RMS be referred to as rhabdomyomatous tumours.[9]

Embryonal rhabdomyosarcoma

  • Chromosome 11p loss of heterozygosity.[13]

Note:

  • Not used for diagnosis.

See also

References

  1. ↑ Rosenthal, TC.; Kraybill, W. (Aug 1999). "Soft tissue sarcomas: integrating primary care recognition with tertiary care center treatment.". Am Fam Physician 60 (2): 567-72. PMID 10465231.
  2. ↑ 2.0 2.1 2.2 2.3 Thorner, Paul S. 14 February 2011.
  3. ↑ Hicks, J.; Flaitz, C. (Jul 2002). "Rhabdomyosarcoma of the head and neck in children.". Oral Oncol 38 (5): 450-9. PMID 12110339.
  4. ↑ Parham, DM. (May 2001). "Pathologic classification of rhabdomyosarcomas and correlations with molecular studies.". Mod Pathol 14 (5): 506-14. doi:10.1038/modpathol.3880339. PMID 11353062.
  5. ↑ Guillou, L.; Coquet, M.; Chaubert, P.; Coindre, JM. (Aug 1998). "Skeletal muscle regeneration mimicking rhabdomyosarcoma: a potential diagnostic pitfall.". Histopathology 33 (2): 136-44. PMID 9762546.
  6. ↑ Chen, S.; Wang, S.; Gao, J.; Zhang, S. (May 2010). "[Pleuropulmonary blastoma: a clinicopathological analysis].". Zhongguo Fei Ai Za Zhi 13 (5): 550-3. doi:10.3779/j.issn.1009-3419.2010.05.31. PMID 20677658.
  7. ↑ URL: http://www.medilexicon.com/medicaldictionary.php?t=48297. Accessed on: 9 August 2011.
  8. ↑ 8.0 8.1 8.2 Bahrami, A.; Gown, AM.; Baird, GS.; Hicks, MJ.; Folpe, AL. (Jul 2008). "Aberrant expression of epithelial and neuroendocrine markers in alveolar rhabdomyosarcoma: a potentially serious diagnostic pitfall.". Mod Pathol 21 (7): 795-806. doi:10.1038/modpathol.2008.86. PMID 18487991.
  9. ↑ 9.0 9.1 9.2 Bing, Z.; Zhang, PJ. (2011). "Adult urinary bladder tumors with rhabdomyosarcomatous differentiation: clinical, pathological and immunohistochemical studies.". Diagn Pathol 6: 66. doi:10.1186/1746-1596-6-66. PMID 21762516.
  10. ↑ Makawita S, Ho M, Durbin AD, Thorner PS, Malkin D, Somers GR (2009). "Expression of insulin-like growth factor pathway proteins in rhabdomyosarcoma: IGF-2 expression is associated with translocation-negative tumors". Pediatr. Dev. Pathol. 12 (2): 127–35. doi:10.2350/08-05-0477.1. PMID 18788888.
  11. ↑ Wachtel M, Runge T, Leuschner I, et al. (February 2006). "Subtype and prognostic classification of rhabdomyosarcoma by immunohistochemistry". J. Clin. Oncol. 24 (5): 816–22. doi:10.1200/JCO.2005.03.4934. PMID 16391296.
  12. ↑ URL: http://www.ncbi.nlm.nih.gov/omim/606597. Accessed on: 18 August 2010.
  13. ↑ Gallego Melcón, S.; Sánchez de Toledo Codina, J. (Jul 2007). "Molecular biology of rhabdomyosarcoma.". Clin Transl Oncol 9 (7): 415-9. PMID 17652054.
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