Difference between revisions of "Fibroblastic/myofibroblastic tumours"

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*[[Extravasated RBCs]].
*[[Extravasated RBCs]].
*Inflammation.
*Inflammation.
*+/-Giant cells.
*+/-[[Giant cell]]s.


Notes:
Notes:

Revision as of 03:19, 1 December 2012

This article covers fibroblastic/myofibroblastic tumours. These tumours fit into the larger category of soft tissue lesions.

List of tumours

Benign

WHO classification:[1]

  • Fibrous hamartoma of infancy.
  • Juvenile hyaline fibromatosis.
  • Desmoplastic fibroblastoma.
  • Mammary-type myofibroblastoma.

Locally aggressive

WHO classification:[1]

Occasionally metastasizing

WHO classification:[2]

Malignant

WHO classification:[2]

Non-malignant

Proliferative fasciitis

General

  • Benign.
  • May mimic a sarcoma.[3]

Clinical:

  • Solid subcutaneous nodule.
  • Rapid growth.
  • May be painful.

Gross

  • Classically upper and lower extremities.[3]
  • Poorly demarcated.

Microscopic

Features:[4]

  • Large polygonal (ganglion-like) and/or spindled cells with:
    • Vesicular (clear) nuclei.
    • Prominent nucleoli.
  • +/-Binucleation.
  • Loose myxoid stroma.
  • Frequent typical mitoses.
    • No atypical mitoses.

DDx:

Images:

Proliferative myositis

General

  • Benign.
  • Possible arise from pericytes.[6]

Microscopic

Features:[6][7]

  • Large ganglion-like cells.
    • Cells have single prominent nucleolus.
  • Spindle cells.
  • +/-Binucleation.
  • Mitotic activity.
    • No atypical mitoses.

Image:

IHC

Features:[6]

  • Vimentin +ve.
  • SMA +ve.
  • Desmin +ve/-ve.

Others:[6]

  • Factor XIIIa -ve.
  • S100 -ve.
  • CAM5.2 -ve.
  • NSE -ve.

Elastofibroma

General

  • Benign.
  • Classically, subscapular in elderly women.[8][9]

Gross

Features:

  • Yellow-white, moderate demarcation to surrounding tissue.[10]

Microscopic

Features:

  • Thick bundles of collagen.
  • Elastin fibres.

Image:

Nodular fasciitis

Not to be confused with necrotizing fasciitis.

General

  • Benign.
  • All age groups.
  • Associated with trauma.

Microscopic

Features:[11][12]

  • Usu. well-circumscribed.
  • Clusters of (non-pleomorphic) spindle cells.
  • Inflammation (lymphocytes).
  • Microcysts in cellular regions - uncommon - discriminatory.
  • Mitoses - common.
  • Extravasated RBCs.

The BD feature list:[13][14]

  • Tissue culture-like/CNS-like morphology.
  • Thick (keloid-like) collagen bundles - key feature.
  • Extravasated RBCs.
  • Inflammation.
  • +/-Giant cells.

Notes:

  • No significant nuclear atypia.
  • No atypical mitoses.
  • May be cellular.

DDx:[15]

Images:

IHC

Routine spindle cell panel:

  • CD34 -ve.
  • Desmin -ve.
  • SMA -ve.
  • S100 -ve.
  • AE1/AE3 -ve.

Others:

  • H-caldesmon -ve.
  • EMA -ve.
  • Vimentin +ve.

Molecular

  • Evolving - case reports.
    • t(15;15)(q13;q25).[16]

Desmoid-type fibromatosis

  • AKA desmoid tumour.
  • AKA desmoid fibromatosis.

General

Microscopic

Features:[18][19]

  • "Sweeping fascicles"/bundles.
  • Spindle cells with:
    • Small slender nuclei.
    • Solid dark eosinophilic cytoplasm.
  • +/-Mitoses - may be abundant.
  • Long thin-walled vessels - parallel to one another - important feature.

Notes:

Images:

IHC

Features:[18]

  • Beta-catenin +ve - important.
  • SMA +ve ~50% of lesions.

Lipofibromatosis

  • AKA infantile subcutaneous fibromatosis.

General

  • Childhood.

Microscopic

Features:[18]

  • Fibroblastic cells surrounding adipocytes.

Image:

IHC

Features:[18]

  • CD34 +ve.
  • BCL2 +ve.
  • S100 +ve.
  • CD99 +ve.
  • Actin +ve.
  • EMA +ve.

Desmoplastic fibroblastoma

General

  • Benign lesion.
  • Classically found in shoulder region.

Epidemiology:

  • May be on the lip.

Microscopic

Features:[22][23]

  • Acellular stroma with abundant collagen.

Notes:

  • No nuclear atypia.

IHC

Calcifying fibrous tumour

General

  • Rare.
  • Benign.

Microscopic

Features:[25]

  • Submucosal circumscribed fibrocollagenous nodule.
  • Psammomatous calcifications.
  • Focal plasma cells at the periphery.

Myofibroma

General

  • Benign.
  • Often < 2 years old; however, may be seen in adults.
  • Not common.[26]

Gross

  • Classically (oral) locations: tongue, buccal mucosa, lip.[26]

Microscopic

Features:[26]

  • Spindle cells with:
    • Tapering nuclei.
    • Eosinophilic cytoplasm.

Note:

DDx:

IHC

Features:[26]

  • Vimentin +ve.
  • SMA +ve.
  • S-100 -ve,

Cellular angiofibroma

General

Gross

Features:[28]

  • Superficial.
  • Well-circumscribed.

Classic location:

Microscopic

Features:[28]

  • Spindle cell lesion.
  • Many small-to-medium blood vessls.

IHC

Features:[28]

  • CD34 ~50% of cases.
  • SMA ~41% of cases.
  • CD99 -ve.
  • EMA -ve.

Occasionally metastasizing

Inflammatory myofibroblastic tumour

  • AKA inflammatory pseudotumour, AKA inflammatory fibrosarcoma,[29] AKA plasma cell granuloma.[30][31]

General

  • Mostly benign.
  • Children & young adults.
  • Classically located in mesentery of ileocolic region or small bowel.[29]

Microscopic

Features:[29]

  • Inflammation:
  • Spindle cells without atypia.
  • +/-Fasciular architecture.
  • Mitoses -- though none atypical.
  • +/-Necrosis.
  • +/-Hemorrhage.
  • Calcifications.

DDx:

Notes:

  • Some consider this a wastebasket diagnosis... for benign appearing spindle cell lesions.[33]

Images:

IHC

Features - dependent on site:

  • SMA +ve.[34]
  • Vimentin +ve.

Variable staining with:

Negative:[34]

  • S100, CD117, CD68.

Molecular

  • ALK rearrangements.[32]

Low-grade myofibroblastic sarcoma

General

  • Rare ~ 100 cases in the literature.
  • Usu. oral cavity or extremities.[36]

Microscopic

Features:

  • Spindle cells in the storiform pattern[36] or in fasicles.
  • Rare mitoses.

Images:

DDx:

IHC

  • SMA +ve.
  • CD34 -ve.
  • CD117 -ve.[36]
  • H-caldesmon -ve.[36]


Congenital-infantile fibrosarcoma

Should not be confused with adult fibrosarcoma.

General

  • Locally aggressive.

Microscopic

Features:[37]

  • Spindle cell lesion.

Molecular

Characteristic translocation:[38]

Solitary fibrous tumour

  • Abbreviated SFT.

General

  • Grouped with hemangiopericytoma in the WHO classification - as it is thought to be the same tumour.[18]
  • May be benign or malignant; more commonly benign.[39][40]
  • May be associated with hypoglycemia.
    • Known as Doege-Potter syndrome.[41]

Gross

Microscopic

Features - benign:

  • Spindle cells in a patternless pattern.
  • Hemangiopericytoma-like area (staghorn vessels).
  • Keloid-like collagen bundles - key feature.
  • Usually well-circumscribed.

Criteria for malignancy:[18]

  • Necrosis.
  • Mitoses >4/10 HPF -- definition suffers from HPFitis.
  • Increased cellularity.
  • Marked nuclear atypia.
  • Infiltrative margin.

Images:

IHC

  • CD34 ~90% +ve.
  • CD99 ~70% +ve.
  • BCL2 ~50% +ve.

Hemangiopericytoma

General

  • Grouped with solitary fibrous tumour in the WHO classification; possibly the same tumour (?).[18]
  • Arises from the pericyte, a connective tissue cell of small vessels that is thought to be involved in flow regulation.
  • Hematologic spread most common - to lungs.[42]
  • Oncogenic osteomalacia - assoc. with hemangiopericytoma.[42]

Presentation

  • Usually painless mass, slow enlargement.

Radiology

  • Intramedullary lytic mass.
  • May be well-circumscribed.
  • +/-Periosteal reaction.
  • +/-Sclerotic border.

May be worked-up with angiography to distinguish from a vascular malformation.[43]

Location

  • Usually extremities - femur or proximal tibial.[42]

Microscopic

Features:[43]

  • Hypervascular lesion - key diagnostic feature.[44]
    • Abundant thin-walled branching small vessels of variable size.
      • May be described as "staghorn vessels" or "antler-like" vasculature.
      • Cells may "onion-skin" around thin blood vessels.
  • Spindle or ovoid shaped cells in nests or sheets.

DDx:

IHC

Features:[18][44]

  • Vimentin +ve (usually).
  • Desmin -ve (typical).
  • Factor VIII -ve (marks endothelium).
  • CD34 +ve.
    • CD34 usu. -ve in synovial sarcoma.
  • CD31 -ve (marks benign endothelium).
  • vWF (von Willebrand factor) -ve.

May be in the DDx for meningioma:[45]

  • EMA -ve.
  • S100 -ve.

Malignant

Low-grade fibromyxoid sarcoma

  • AKA hyalinizing spindle cell tumour.
  • Should not be confused with myxofibrosarcoma.
  • Abbreviated LGFMS.

General

  • Deep soft tissue.
  • Related to hyalinizing spindle cell tumour with giant collagen rosettes.[46]

Microscopic

Features:[47]

  • Myxoid stroma alternating with fibrogenic areas - key feature.
  • Low cellularity.
  • Spindle cells.
  • +/-Rosette of collagen with central hyaline core.[48]

Notes:

  • Few/absent mitoses.

DDx:

Images:

IHC

Features:[48]

  • EMA +ve.
  • CD99 +ve.
  • BCL2 +ve.

Others:[48]

  • SMA -ve.
  • S100 -ve.
  • Desmin -ve.

Molecular pathology

Adult fibrosarcoma

General

  • Malignant.
  • Older adults.
  • Locations: head & neck, extremities.

Microscopic

Feature:[48]

  • Spindle cell lesion.
  • Herring bone pattern - key feature.
  • Mitoses.

DDx (herring bone):

  • MPNST.
  • Synovial sarcoma.
  • Fibrosarcoma.

DDx:

Images:

IHC

Features:[48]

  • Vimentin.
  • SMA.

Myxofibrosarcoma

General

  • Malignant.
  • Usu. older people, superficial (skin/dermis) and extremities (arm, legs).[51][52]

Microscopic

Features:[51]

  • Discontinuous fibrous septae.
  • Myxoid background.
  • Variable cellularity and nuclear pleomorphism.
  • Spindle cells or epithelioid cells.[52]
  • Curvilinear vessels.[52]

DDx:

Image:

IHC

  • Vimentin +ve -- otherwise non-distinctive.[51]

See also

References

  1. ↑ 1.0 1.1 Humphrey, Peter A; Dehner, Louis P; Pfeifer, John D (2008). The Washington Manual of Surgical Pathology (1st ed.). Lippincott Williams & Wilkins. pp. 601. ISBN 978-0781765275.
  2. ↑ 2.0 2.1 Humphrey, Peter A; Dehner, Louis P; Pfeifer, John D (2008). The Washington Manual of Surgical Pathology (1st ed.). Lippincott Williams & Wilkins. pp. 602. ISBN 978-0781765275.
  3. ↑ 3.0 3.1 Chung, EB.; Enzinger, FM. (Oct 1975). "Proliferative fasciitis.". Cancer 36 (4): 1450-8. PMID 1058047.
  4. ↑ Meis, JM.; Enzinger, FM. (Apr 1992). "Proliferative fasciitis and myositis of childhood.". Am J Surg Pathol 16 (4): 364-72. PMID 1566969.
  5. ↑ Gleason, BC.; Hornick, JL. (Apr 2008). "Inflammatory myofibroblastic tumours: where are we now?". J Clin Pathol 61 (4): 428-37. doi:10.1136/jcp.2007.049387. PMID 17938159.
  6. ↑ 6.0 6.1 6.2 6.3 el-Jabbour, JN.; Bennett, MH.; Burke, MM.; Lessells, A.; O'Halloran, A. (Jul 1991). "Proliferative myositis. An immunohistochemical and ultrastructural study.". Am J Surg Pathol 15 (7): 654-9. PMID 2058761.
  7. ↑ Lundgren, L.; Kindblom, LG.; Willems, J.; Falkmer, U.; Angervall, L. (May 1992). "Proliferative myositis and fasciitis. A light and electron microscopic, cytologic, DNA-cytometric and immunohistochemical study.". APMIS 100 (5): 437-48. PMID 1586481.
  8. ↑ URL: http://emedicine.medscape.com/article/1057113-overview. Accessed on: 26 October 2011.
  9. ↑ Ben Hassouna, J.; Hamdi, N.; Ben Bachouche, W.; Bouzid, T.; Dhiab, T.; Rahal, K. (Oct 2010). "Elastofibroma dorsi.". Orthop Traumatol Surg Res 96 (6): 717-20. doi:10.1016/j.otsr.2010.03.019. PMID 20708994.
  10. ↑ Rose, Alan G. (2008). Atlas of Gross Pathology with Histologic Correlation (1st ed.). Cambridge University Press. pp. 592. ISBN 978-0521868792.
  11. ↑ Humphrey, Peter A; Dehner, Louis P; Pfeifer, John D (2008). The Washington Manual of Surgical Pathology (1st ed.). Lippincott Williams & Wilkins. pp. 606. ISBN 978-0781765275.
  12. ↑ de Feraudy S, Fletcher CD (September 2010). "Intradermal nodular fasciitis: a rare lesion analyzed in a series of 24 cases". Am. J. Surg. Pathol. 34 (9): 1377–81. doi:10.1097/PAS.0b013e3181ed7374. PMID 20716998.
  13. ↑ Dickson, B. 26 April 2011.
  14. ↑ URL: http://anvita.info/wiki/Nodular_Fasciitis. Accessed on: 11 November 2011.
  15. ↑ URL: http://www.mckeedermpath.com/SPOT%20DIAGNOSIS%20CASE%20268.html. Accessed on: 11 November 2011.
  16. ↑ Velagaleti GV, Tapper JK, Panova NE, Miettinen M, Gatalica Z (March 2003). "Cytogenetic findings in a case of nodular fasciitis of subclavicular region". Cancer Genet. Cytogenet. 141 (2): 160–3. PMID 12606136.
  17. ↑ URL: http://www.dtrf.org/dtrf_aboutdesmoids.htm. Accessed on: 15 April 2011.
  18. ↑ 18.0 18.1 18.2 18.3 18.4 18.5 18.6 18.7 Humphrey, Peter A; Dehner, Louis P; Pfeifer, John D (2008). The Washington Manual of Surgical Pathology (1st ed.). Lippincott Williams & Wilkins. pp. 609. ISBN 978-0781765275.
  19. ↑ URL: http://www.surgicalpathologyatlas.com/glfusion/mediagallery/media.php?f=0&sort=0&s=20090717111548196. Accessed on: 4 October 2011.
  20. ↑ URL: http://www.cheapmedicinechest.com/abdominal-pain-and-colonic-obstruction-from-an-intra-abdominal-desmoid-tumor.html. Accessed on: 4 October 2011.
  21. ↑ Watanabe, H.; Ishida, Y.; Nagashima, K.; Makino, T.; Norisugi, O.; Shimizu, T. (Feb 2008). "Desmoplastic fibroblastoma (collagenous fibroma).". J Dermatol 35 (2): 93-7. doi:10.1111/j.1346-8138.2008.00421.x. PMID 18271804.
  22. ↑ URL: http://www.dermatologyoutlines.com/dermskintumornonmelanocytic.html#collagenousfibroma. Accessed on: 19 March
  23. ↑ 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. 161. ISBN 978-0781740517.
  24. ↑ Takahara, M.; Ichikawa, R.; Oda, Y.; Uchi, H.; Takeuchi, S.; Moroi, Y.; Kiryu, H.; Furue, M. (Oct 2008). "Desmoplastic fibroblastoma: a case presenting as a protruding nodule in the dermis.". J Cutan Pathol 35 Suppl 1: 70-3. doi:10.1111/j.1600-0560.2007.00964.x. PMID 18544056.
  25. ↑ Attila T, Chen D, Gardiner GW, Ptak TW, Marcon NE (July 2006). "Gastric calcifying fibrous tumor". Can. J. Gastroenterol. 20 (7): 487–9. PMC 2659917. PMID 16858502. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2659917/.
  26. ↑ 26.0 26.1 26.2 26.3 Brasileiro, BF.; Martins-Filho, PR.; Piva, MR.; da Silva, LC.; Nonaka, CF.; Miguel, MC. (Jul 2010). "Myofibroma of the oral cavity. A rare spindle cell neoplasm.". Med Oral Patol Oral Cir Bucal 15 (4): e596-600. PMID 20038894. http://www.medicinaoral.com/pubmed/medoralv15_i4_p596.pdf.
  27. ↑ Dray MS, McCarthy SW, Palmer AA, et al. (January 2006). "Myopericytoma: a unifying term for a spectrum of tumours that show overlapping features with myofibroma. A review of 14 cases". J. Clin. Pathol. 59 (1): 67–73. doi:10.1136/jcp.2005.028704. PMC 1860256. PMID 16394283. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1860256/.
  28. ↑ 28.0 28.1 28.2 28.3 28.4 Flucke, U.; van Krieken, JH.; Mentzel, T. (Jan 2011). "Cellular angiofibroma: analysis of 25 cases emphasizing its relationship to spindle cell lipoma and mammary-type myofibroblastoma.". Mod Pathol 24 (1): 82-9. doi:10.1038/modpathol.2010.170. PMID 20852591.
  29. ↑ 29.0 29.1 29.2 Humphrey, Peter A; Dehner, Louis P; Pfeifer, John D (2008). The Washington Manual of Surgical Pathology (1st ed.). Lippincott Williams & Wilkins. pp. 610. ISBN 978-0781765275.
  30. ↑ URL: http://www.uptodate.com/contents/inflammatory-myofibroblastic-tumor-plasma-cell-granuloma-of-the-lung. Accessed on: 27 November 2011.
  31. ↑ Manohar, B.; Bhuvaneshwari, S. (Jan 2011). "Plasma cell granuloma of gingiva.". J Indian Soc Periodontol 15 (1): 64-6. doi:10.4103/0972-124X.82275. PMID 21772725.
  32. ↑ 32.0 32.1 Saab, ST.; Hornick, JL.; Fletcher, CD.; Olson, SJ.; Coffin, CM. (Apr 2011). "IgG4 plasma cells in inflammatory myofibroblastic tumor: inflammatory marker or pathogenic link?". Mod Pathol 24 (4): 606-12. doi:10.1038/modpathol.2010.226. PMID 21297584.
  33. ↑ URL: http://www.pathconsultddx.com/pathCon/diagnosis?pii=S1559-8675%2806%2970283-2. Accessed on: 10 May 2011.
  34. ↑ 34.0 34.1 34.2 Shi, H.; Li, Y.; Wei, L.; Sun, L. (Apr 2010). "Primary colorectal inflammatory myofibroblastic tumour: a clinicopathological and immunohistochemical study of seven cases.". Pathology 42 (3): 235-41. doi:10.3109/00313021003631312. PMID 20350216. Cite error: Invalid <ref> tag; name "pmid20350216" defined multiple times with different content
  35. ↑ Miyamoto, H.; Montgomery, EA.; Epstein, JI. (Apr 2010). "Paratesticular fibrous pseudotumor: a morphologic and immunohistochemical study of 13 cases.". Am J Surg Pathol 34 (4): 569-74. doi:10.1097/PAS.0b013e3181d438cb. PMID 20216379.
  36. ↑ 36.0 36.1 36.2 36.3 Miyazawa, M.; Naritaka, Y.; Miyaki, A.; Asaka, S.; Isohata, N.; Yamaguchi, K.; Murayama, M.; Shimakawa, T. et al. (Sep 2011). "A low-grade myofibroblastic sarcoma in the abdominal cavity.". Anticancer Res 31 (9): 2989-94.
  37. ↑ Corsi, A.; Boldrini, R.; Bosman, C. (Oct 1994). "Congenital-infantile fibrosarcoma: study of two cases and review of the literature.". Tumori 80 (5): 392-400. PMID 7839472.
  38. ↑ Sheng, WQ.; Hisaoka, M.; Okamoto, S.; Tanaka, A.; Meis-Kindblom, JM.; Kindblom, LG.; Ishida, T.; Nojima, T. et al. (Mar 2001). "Congenital-infantile fibrosarcoma. A clinicopathologic study of 10 cases and molecular detection of the ETV6-NTRK3 fusion transcripts using paraffin-embedded tissues.". Am J Clin Pathol 115 (3): 348-55. doi:10.1309/3H24-E7T7-V37G-AKKQ. PMID 11242790.
  39. ↑ URL: http://www.pathconsultddx.com/pathCon/diagnosis?pii=S1559-8675%2806%2970528-9. Accessed on: 25 June 2010.
  40. ↑ URL: http://wjso.com/content/6/1/86. Accessed on: 25 June 2010.
  41. ↑ Roy, TM.; Burns, MV.; Overly, DJ.; Curd, BT. (Nov 1992). "Solitary fibrous tumor of the pleura with hypoglycemia: the Doege-Potter syndrome.". J Ky Med Assoc 90 (11): 557-60. PMID 1474302.
  42. ↑ 42.0 42.1 42.2 URL: http://emedicine.medscape.com/article/1255879-overview. Accessed on: 2 May 2010.
  43. ↑ 43.0 43.1 URL: http://emedicine.medscape.com/article/1255879-diagnosis. Accessed on: 2 May 2010.
  44. ↑ 44.0 44.1 Enzinger & Weiss's Soft Tissue Tumors. 4th Ed. PP.1007-13. ISBN 0-323-01200-0.
  45. ↑ Croul, SE. 8 November 2010.
  46. ↑ Ramaswamy, AS.; Chatura, KR.. "Hyalinizing spindle cell tumor with giant rosettes.". Ann Saudi Med 31 (1): 83-6. PMC 3101732. PMID 20864787. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3101732/.
  47. ↑ Vernon SE, Bejarano PA (September 2006). "Low-grade fibromyxoid sarcoma: a brief review". Arch. Pathol. Lab. Med. 130 (9): 1358–60. PMID 16948525.
  48. ↑ 48.0 48.1 48.2 48.3 48.4 48.5 Humphrey, Peter A; Dehner, Louis P; Pfeifer, John D (2008). The Washington Manual of Surgical Pathology (1st ed.). Lippincott Williams & Wilkins. pp. 611. ISBN 978-0781765275.
  49. ↑ Panagopoulos I, Storlazzi CT, Fletcher CD, et al. (July 2004). "The chimeric FUS/CREB3l2 gene is specific for low-grade fibromyxoid sarcoma". Genes Chromosomes Cancer 40 (3): 218–28. doi:10.1002/gcc.20037. PMID 15139001.
  50. ↑ 50.0 50.1 Mentzel, T.; Katenkamp, D.; Fletcher, CD. (Mar 1996). "[Low malignancy myxofibrosarcoma versus low malignancy fibromyxoid sarcoma. Distinct entities with similar names but different clinical course].". Pathologe 17 (2): 116-21. PMID 8650138.
  51. ↑ 51.0 51.1 51.2 Humphrey, Peter A; Dehner, Louis P; Pfeifer, John D (2008). The Washington Manual of Surgical Pathology (1st ed.). Lippincott Williams & Wilkins. pp. 612-3. ISBN 978-0781765275.
  52. ↑ 52.0 52.1 52.2 Nascimento, AF.; Bertoni, F.; Fletcher, CD. (Jan 2007). "Epithelioid variant of myxofibrosarcoma: expanding the clinicomorphologic spectrum of myxofibrosarcoma in a series of 17 cases.". Am J Surg Pathol 31 (1): 99-105. doi:10.1097/01.pas.0000213379.94547.e7. PMID 17197925.
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