Difference between revisions of "Chondro-osseous tumours"

From Libre Pathology
Jump to navigation Jump to search
(→‎Microscopic: fix ref)
Line 599: Line 599:
*Foam cells.
*Foam cells.


DDx - general for site:<ref name=pmid17031677>{{Cite journal  | last1 = Krenn | first1 = V. | last2 = Morawietz | first2 = L. | last3 = König | first3 = A. | last4 = Haeupl | first4 = T. | title = [Differential diagnosis of chronic synovitis]. | journal = Pathologe | volume = 27 | issue = 6 | pages = 402-8 | month = Nov | year = 2006 | doi = 10.1007/s00292-006-0866-6 | PMID = 17031677 }}</ref>
DDx - general for the site:<ref name=pmid17031677>{{Cite journal  | last1 = Krenn | first1 = V. | last2 = Morawietz | first2 = L. | last3 = König | first3 = A. | last4 = Haeupl | first4 = T. | title = [Differential diagnosis of chronic synovitis]. | journal = Pathologe | volume = 27 | issue = 6 | pages = 402-8 | month = Nov | year = 2006 | doi = 10.1007/s00292-006-0866-6 | PMID = 17031677 }}</ref>
*[[Synovial chondromatosis]].
*[[Synovial chondromatosis]].
*[[Gout]].
*[[Gout]].

Revision as of 02:26, 29 November 2013

Chondro-osseous tumours occasionally cross the desk of the pathologist. They are grouped together as bone may develop from cartilage.

Primary bone tumours are rare; the most common bone tumour is metastases.[1]

Bone tumours occasionally are lumped with soft tissue tumours. Soft tissue tumours are dealt with in the soft tissue lesions article. An introduction to bone is found in the bone article. An introduction to cartilage is found in the cartilage article.

General

  • Diagnosis of a primary bone tumour should not be made without radiologic & clinical information!
  • Metastasis:primary bone tumours = >20:1.[1]

Common malignant

Epidemiology:[2]

  • Osteosarcoma -> 2nd decade.
  • Ewing's ->5-20 yrs.
  • Chondrosarcoma -> from enchondroma or osteochrondroma -- patients over 40 yrs.
  • Multiple myeloma -> most common primary bone tumour in adults.

Malignant bone tumours by age

Most common by age:[2]

Benign aggressive bone tumours

Ref.:[3][4]

Summary tables

Bone tumours

Entity Key feature Other features Radiology / gross Clinical Stains / other Image
Osteoma normal bone (???) other features (???) radiology / gross (???) ? no stains / may be assoc. with FAP Image (???)
Osteoid osteoma osteoblastic rimming anastomosing bony trabeculae <= 1.5 cm, metaphysis painful, NSAIDs remove pain, young IHC / other
Osteoid osteoma. (WC)
Osteoblastoma osteoblastic rimming anastomosing bony trabeculae > 1.5 cm, metaphysis not painful IHC / other
Osteoblastoma. (WC)
Ewing sarcoma small round blue cell tumour cytoplasmic clearing (due to glycogen) usu. diaphysis pediatric, typically 1-10 years PAS+, PASD-, chromosomal translocations (usually t(11;22)(q24;q12))
Ewing sarcoma. PAS stain. (WC)
Osteosarcoma osteoid +/-hemorrhage, +/-cartilage distal femur, prox. tibia, prox. humerous typically 10-30 years, pain, swelling no stains; many subtypes
Osteosarcoma. (WC)
Giant cell tumour of bone abundant giant cells nuclei of surrounding cells similar to those in giant cells growth plate of long bones 20-45 years old, +/-joint pain, +/-immobility IHC / other
Giant cell tumour. (WC)

Cartilage tumours

Entity Key feature Other features Radiology / gross Clinical Stains / other Image
Chondroma ctyologically benign cells equally spaced nests usu. diaphysis benign / DDx: chondroma, well-diff. chondrosarcoma IHC / bone marrow cavity chondroma = enchondroma
Enchondroma. (WC)
Chondroblastoma abundant extracellular material, abundant eosinophilic cytoplasm calcifications surround cells nests ("chickenwire" appearance) - classic epiphysis DDx: giant cell tumour of bone S100+ve, vimentin +ve
Chondroblastoma. (WC)
Chondrosarcoma cartilaginous appearance +/- nuclear atypia lack osteoid, if present -> osteosarcoma usu. diaphysis, classically hip; almost never distal extremity >40 years old IHC / may be histologically benign looking
Chondrosarcoma. (WC)

Other

Entity Key feature Other features Radiology / gross Clinical Stains / other Image
Osteochondroma benign bone and cartilage Other features metaphyseal lesions Clinical IHC / other Image
Adamantinoma bisphasic - stroma & epithelium Other features tibia, fibula, intracortical, radiolucent Clinical IHC / other
Adamantinoma. (WC)
Diffuse tenosynovial giant-cell tumour (AKA PVNS) pigmented giant cells nodules Radiology / gross Clinical IHC / other
PVNS. (WC)
Brown tumour fibrosis, +/-giant cells unaffected bone incr. osteoblasts and osteoclasts Radiology / gross due to hypercalcemia; not a neoplasm IHC / other
Brown tumour. (WC)

Radiology

Radiologic features
Features Benign Malignant
Bone changes sclerotic rim tumour perforation
Circumscription pushing margins ill-defined/moth-eaten
Soft tissue involvement no common
Periosteal reaction no "hair-on-end" or "sunburst",
"onion skin", Codman's triangle
Location
Diagnosis Epiphysis Metaphysis Diaphysis Type of lesion
Aneurysmal bone cyst common most common rare bone
Chondroblastoma most common rare extremely rare cartilage
Chondrosarcoma uncommon common most common cartilage
Chondromyxoid fibroma rare most common common other
Enchondroma rare common common cartilage
Ewing sarcoma rare common most common bone
Giant cell tumour most common rare extremely rare bone
Metastatic carcinoma rare common most common other
Non-ossifying fibroma extremely rare most common common other
Osteoblastoma rare most common uncommon bone
Osteochondroma extremely rare[citation needed] most common common bone/cartilage
Osteoid osteoma uncommon common common[5] bone
Osteosarcoma rare most common uncommon bone

How to remember the primary bone lesions:

  1. Ewing sarcoma is the only malignant primary bone tumour of the diaphysis.
  2. Giant cell tumour of bone is the only primary bone lesion of the epiphysis.
  3. The rest of the primary bone lesions are metaphyseal.
    • Osteochondroma is bone first and cartilage second. It behaves like most primary bone lesions; it is usually metaphyseal.

How to remember the primary cartilaginous lesions:

  1. Chondroblastoma is epiphyseal. The chicken wire goes around the chicken coop.
  2. The others are diaphyseal.

Cartilage

Chondroma

General

  • Benign thingy.
  • Usual legs and feet.
  • May be difficult to separate from chondrosarcoma.
  • Multiple chondromas = enchondromatosis; three distinct syndromes:[6]
  • Enchondroma = chondroma in the marrow space.

Clinical:[6]

  • Pain.

Radiology

Features:[6]

  • Lytic lesion.
  • Usual close to a growth plate.

Microscopic

Features:

  • Ctyologically benign cells is spaced nests.

Images

Chondroblastoma

General

  • Growth plate lesion.
  • Sclerotic margin.
  • "Young" = growth plates open.
  • Typically painful.[8]

Gross

  • Well-defined lesion.

Image:

Microscopic

Features:[9]

  • Abundant extracellular material - pink on H&E stain - looks vaguely like cartilage.
  • Chondroblasts:
    • Nuclear morphology variable: ovoid, folded or grooved.
    • Moderate-abundant eosinophilic cytoplasm.
  • +/-Calcification surrounds the cell nests ("chickenwire" appearance) - classic feature.
    • Cell nests have a thin pale blue rimming.
  • +/-Giant cells.

DDx:

Images

www:

IHC

Features:[9]

  • S100 +ve.
  • Vimentin +ve.[10]

Chondromyxoid fibroma

General

  • Benign.
  • Teenagers or young adults.

Gross

  • Metaphyseal lesion.
  • Well-circumscribed.

Microscopic

Features:[12]

  • Spindle cells or stellate cells in a myxoid or chondroid stroma.

Images:

Chondrosarcoma

General

  • Usually a good prognosis.

Clinical/epidemiologic features:[13]

  • Usually arise in a (benign) abnormality of cartilage (e.g. osteochondroma, enchondroma).
  • May be associated with a syndrome:
    • Olier disease (multiple enchondromatosis).
    • Maffucci syndrome (multiple enchondromas and hemangiomas).

Notes:

  • Review article (from oncology perspective): PMID 17545802.

Subtypes

Several subtypes exist:

  • Chondrosarcoma not otherwise specified (NOS).
  • Juxtacortical chondrosarcoma.
  • Myxoid chondrosarcoma.
  • Mesenchymal chondrosarcoma.
  • Clear cell chondrosarcoma.
  • Dedifferentiated chondrosarcoma.

Microscopic

Features:[14][15]

  • "Abnormal cartilage":
    • +/-Nuclear atypia - high grade lesions.
      • High grade lesions:
        • Nuclear clearing.
        • Nucleoli.
        • Hyperchromasia.
      • Low/intermediate grade lesions:
        • Bi-nucleation.
        • Hypochromatic enlarged nuclei.
        • Infiltration of lamellar bone ("invasion") - not common - diagnostic.
    • Increased cellularity.
      • More cellular than cartilage... but relatively paucicellular compared to other sarcomas.
    • Irregular spacing of chondrocytes.

Notes:

  • Low grade chondrosarcoma are not cytologically malignant; the diagnosis rests mostly on radiologic findings.
    • The exception is infiltration of lamellar bone -- this is diagnostic of chondrosarcoma.[16]

DDx:

Images

Variants

Mesenchymal chondrosarcoma
  • Arise in soft tissue; this is where the name comes from.[17]
  • Rare variant of chondrosarcoma.

Microscopic: Features:

  • "White clouds in a blue sky".

Image:

Myxoid chondrosarcoma

Microscopic: Features:

  • Chordoma-like:
    • Myxoid background.
    • Small cells with eosinophilic cytoplasm.

DDx:

Extraskeletal myxoid chondrosarcoma
  • Originally thought to be a variant of myxoid chondrosarcoma of bone; however, may not be a chondrosarcoma at all.[19]
  • Characteristic chromosomal translocation: t(9;22) CHN-EWS.

DDx:

  • Chordoma.[19]
    • S-100 +ve (strong).
    • EMA +ve.

Image:

Dedifferentiated chondrosarcoma

Clinical:

  • Abysmal to poor prognosis.
    • In one series (22 patients) 5-year survival ~20%.[21]
    • All dead in two years in another series (25 patients).[22]

Features:[22]

  1. Poorly differentiated (mesenchymal) malignancy.
  2. Well-differentiated cartilaginous component.

Images:

Grading

Features:[23]

  • Grade I: mild-to-moderate increase of cellularity +/- binucleated cells.
  • Grade II: between Grade I and Grade III.
  • Grade III: nuclear pleomorphism, mitoses common.

IHC

  • S-100 -ve. (???)

Bone

Osteoma

General

Microscopic

Features:

  • Normal bone.

Osteoid osteoma

Osteoblastoma

Ewing sarcoma

Osteosarcoma

Giant cell tumour of bone

Other

This section collects stuff that doesn't neatly fit into the bone or cartilage category.

Osteochondroma

General

  • Benign.
  • Very common.
  • Abnormal outgrowth of bone and cartilage - associated with growth plate.
  • Usually present before age 20.[24]

Gross

Features:

  • Metasphyseal lesions.[25]
    • Often distal femur, proximal humerus or proximal tibia.[24]
    • Occasionally iliac mass.[26]
  • Mushroom-like shape - with broad or narrow base.

Note:

  • Very unusual in craniofacial bones.[24]

Microscopic

Features:[24]

  • Bone - forms base of "mushroom".
  • Cartilage - layer usu. thinner in older individuals.
    • Lobular arrangement[27] - clusters of 3-12 lacunae (separated by stroma).
    • May have mild atypia.
    • Nuclear enlargement - up to 5x normal.
  • Perichondrium - covers the cartilage.
    • Thin layer of cells - higher cellular density than cartilage.
      • Bland spindle cells in a fibrous (eosinophilic) stroma.

Notes:

  • Benign cartilage - one chondrocyte per lacuna, small and round nucleus, no binucleation.

DDx:

Images:

Diffuse tenosynovial giant-cell tumour

  • AKA tenosynovial giant-cell tumour, diffuse type.
  • Previously known as pigmented villonodular synovitis (PVNS).[28]

General

Gross

  • Typically knee or hip.[33]
  • May be extra-articular.[31]

Microscopic

Features:[34]

  • Subsynovial nodules composed of cells with:
    • Abundant cytoplasm.
    • Pale nuclei.
  • Multinucleated giant cells.
  • Hemosiderin-laden macrophages.
  • Foam cells.

DDx - general for the site:[35]

Images

www:

Molecular

Sign out

RIGHT FEMORAL HEAD AND JOINT CAPSULE, EXCISION:
- DEGENERATIVE JOINT DISEASE.
- DIFFUSE TENOSYNOVIAL GIANT-CELL TUMOUR (PIGMENTED VILLONODULAR SYNOVITIS).

Micro

The soft tissue sections show nodules with abundant hemosiderin-laden macrophages and multinucleated giant cells. Nuclear atypia is not identified. Mitotic activity is not apparent.

Giant cell tumour of tendon sheath

  • Abbreviated GCT of tendon sheath.

General

Gross

Features:[38]

  • Circumscribed mass - yellow-brown to tan.

Note:

  • May be associated with bony erosions in larger lesions.[38]

Image:

Microscopic

Features:[37]

  • Foam cells.
    • Cells with moderate to abundant foamy-appearing cytoplasm.
  • Multinucleated giant cells - may be scarce.
  • +/-Tendon.
    • Dense connective tissue.
  • +/-Hemosiderin-laden macrophages.

Note:

  • Features of malignancy: nuclear pleomorphism,[40] abnormal mitoses, >10 mitoses/HPF, tumour necrosis lack of maturation to superficial part (nuclei shrink, cytoplasm lipid-ified).[37]

DDx:

Images

www:

Sign out

LESION, RIGHT INDEX FINGER, EXCISION:
- GIANT CELL TUMOUR OF THE TENDON SHEATH.

Micro

The sections show histiocytes and rare multinucleated giant cells on a background of dense connective tissue compatible with tendon. No nuclear atypia is apparent. Rare mitotic activity is identified. No atypical mitoses are apparent.

Alternate

The sections show histiocytes and rare multinucleated giant cells on a background of dense connective tissue compatible with tendon. Hemosiderin-laden macrophages are present. No nuclear atypia is apparent. No mitotic activity is apparent.

Adamantinoma

Brown tumour

General

  • Not a true neoplasm.[42]
    • If tumour is understood as a synonym for neoplasm, the name is a misnomer.
    • May (clinically) mimic a true neoplasm.
  • Due to hyperparathyroidism - usually parathyroid adenoma.
    • Usually secondary to chronic renal failure.

Hypercalcemia DDx

Mnemonic GRIMED:[43]

Microscopic

Features:

  • Fibrosis.
  • +/-Giant cells with round to oval nuclei and nucleoli.[44]
  • Bone unaffected by tumour - increased numbers of the following:
    • Multinucleated cells (osteoclasts).
    • Mononuclear cells around the bony trabeculae (osteoblasts).

DDx:

Images

www:

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. 632. ISBN 978-0781765275.
  2. 2.0 2.1 Yeung, J.C.; Leonard, Blair J. N. (2005). The Toronto Notes 2005 - Review for the MCCQE and Comprehensive Medical Reference (2005 ed.). The Toronto Notes Inc. for Medical Students Inc.. pp. OR42. ISBN 978-0968592854.
  3. Yeung, J.C.; Leonard, Blair J. N. (2005). The Toronto Notes 2005 - Review for the MCCQE and Comprehensive Medical Reference (2005 ed.). The Toronto Notes Inc. for Medical Students Inc.. pp. OR41. ISBN 978-0968592854.
  4. URL: http://www.emedicine.com/RADIO/topic494.htm.
  5. URL: http://www.wheelessonline.com/ortho/osteoid_osteoma. Accessed on: 7 May 2012
  6. 6.0 6.1 6.2 URL: http://emedicine.medscape.com/article/389224-overview. Accessed on: 25 December 2010.
  7. Online 'Mendelian Inheritance in Man' (OMIM) 166000
  8. Mitchell, Richard; Kumar, Vinay; Fausto, Nelson; Abbas, Abul K.; Aster, Jon (2011). Pocket Companion to Robbins & Cotran Pathologic Basis of Disease (8th ed.). Elsevier Saunders. pp. 625. ISBN 978-1416054542.
  9. 9.0 9.1 Humphrey, Peter A; Dehner, Louis P; Pfeifer, John D (2008). The Washington Manual of Surgical Pathology (1st ed.). Lippincott Williams & Wilkins. pp. 642. ISBN 978-0781765275.
  10. 10.0 10.1 10.2 URL: http://emedicine.medscape.com/article/1254949-diagnosis. Accessed on: 31 December 2010.
  11. URL: http://path.upmc.edu/cases/case494.html. Accessed on: 24 January 2012.
  12. Humphrey, Peter A; Dehner, Louis P; Pfeifer, John D (2008). The Washington Manual of Surgical Pathology (1st ed.). Lippincott Williams & Wilkins. pp. 642. ISBN 978-0781765275.
  13. Skubitz KM, D'Adamo DR (November 2007). "Sarcoma". Mayo Clin. Proc. 82 (11): 1409–32. PMID 17976362. http://www.mayoclinicproceedings.com/content/82/11/1409.long.
  14. IAV. 26 February 2009.
  15. Klatt, Edward C. (2006). Robbins and Cotran Atlas of Pathology (1st ed.). Saunders. pp. 417. ISBN 978-1416002741.
  16. Dickson, B. 28 April 2011.
  17. Dowling EA (June 1964). "Mesenchymal chondrosarcoma". J Bone Joint Surg Am 46: 747–54. PMID 14161087. http://www.ejbjs.org/cgi/reprint/46/4/747.pdf.
  18. Fisher C (May 2000). "Parachordoma exists--but what is it?". Adv Anat Pathol 7 (3): 141–8. PMID 10809219.
  19. 19.0 19.1 Aigner, T.; Oliveira, AM.; Nascimento, AG. (Feb 2004). "Extraskeletal myxoid chondrosarcomas do not show a chondrocytic phenotype.". Mod Pathol 17 (2): 214-21. doi:10.1038/modpathol.3800036. PMID 14657948.
  20. URL: http://www.cttr.org/cms/?p=736. Accessed on: 1 May 2011.
  21. Mitchell, AD.; Ayoub, K.; Mangham, DC.; Grimer, RJ.; Carter, SR.; Tillman, RM. (Jan 2000). "Experience in the treatment of dedifferentiated chondrosarcoma.". J Bone Joint Surg Br 82 (1): 55-61. PMID 10697315.
  22. 22.0 22.1 Sopta, J.; Dordević, A.; Tulić, G.; Mijucić, V. (Feb 2008). "Dedifferentiated chondrosarcoma: our clinico-pathological experience and dilemmas in 25 cases.". J Cancer Res Clin Oncol 134 (2): 147-52. doi:10.1007/s00432-007-0262-5. PMID 17653766.
  23. Humphrey, Peter A; Dehner, Louis P; Pfeifer, John D (2008). The Washington Manual of Surgical Pathology (1st ed.). Lippincott Williams & Wilkins. pp. 643. ISBN 978-0781765275.
  24. 24.0 24.1 24.2 24.3 Parkin, B.; Bennett, JC.; Zaher, A. (Aug 2003). "Pathologic quiz case: an iliac mass in a 25-year-old woman. Osteochondroma.". Arch Pathol Lab Med 127 (8): e355-6. doi:10.1043/1543-2165(2003)127e355:PQCAIM2.0.CO;2. PMID 12873205.
  25. URL: http://www.medpath.info/MainContent/Skeletal/Bone_07.html. Accessed on: 18 September 2012.
  26. Kokavec, M.; Gajdoš, M.; Džupa, V. (2011). "[Osteochondroma of the iliac crest: case report].". Acta Chir Orthop Traumatol Cech 78 (6): 583-5. PMID 22217414.
  27. 27.0 27.1 URL: http://path.upmc.edu/cases/case341/dx.html. Accessed on: 19 September 2012.
  28. Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; Aster, Jon (2009). Robbins and Cotran pathologic basis of disease (8th ed.). Elsevier Saunders. pp. 1247. ISBN 978-1416031215.
  29. Kondo, R.; Akiba, J.; Hiraoka, K.; Hisaoka, M.; Hashimoto, H.; Kage, M.; Yano, H. (Aug 2012). "Malignant diffuse-type tenosynovial giant cell tumor of the buttock.". Pathol Int 62 (8): 559-64. doi:10.1111/j.1440-1827.2012.02838.x. PMID 22827766.
  30. Li, CF.; Wang, JW.; Huang, WW.; Hou, CC.; Chou, SC.; Eng, HL.; Lin, CN.; Yu, SC. et al. (Apr 2008). "Malignant diffuse-type tenosynovial giant cell tumors: a series of 7 cases comparing with 24 benign lesions with review of the literature.". Am J Surg Pathol 32 (4): 587-99. doi:10.1097/PAS.0b013e318158428f. PMID 18301053.
  31. 31.0 31.1 Somerhausen, NS.; Fletcher, CD. (Apr 2000). "Diffuse-type giant cell tumor: clinicopathologic and immunohistochemical analysis of 50 cases with extraarticular disease.". Am J Surg Pathol 24 (4): 479-92. PMID 10757395.
  32. URL: http://emedicine.medscape.com/article/1253223-overview. Accessed on: 6 January 2011.
  33. Frassica, FJ.; Bhimani, MA.; McCarthy, EF.; Wenz, J. (Oct 1999). "Pigmented villonodular synovitis of the hip and knee.". Am Fam Physician 60 (5): 1404-10; discussion 1415. PMID 10524485.
  34. URL: http://www.wheelessonline.com/ortho/pigmented_villonodular_synovitis.
  35. Krenn, V.; Morawietz, L.; König, A.; Haeupl, T. (Nov 2006). "[Differential diagnosis of chronic synovitis].". Pathologe 27 (6): 402-8. doi:10.1007/s00292-006-0866-6. PMID 17031677.
  36. Lucas, DR. (Aug 2012). "Tenosynovial giant cell tumor: case report and review.". Arch Pathol Lab Med 136 (8): 901-6. doi:10.5858/arpa.2012-0165-CR. PMID 22849738.
  37. 37.0 37.1 37.2 Tadrous, Paul.J. Diagnostic Criteria Handbook in Histopathology: A Surgical Pathology Vade Mecum (1st ed.). Wiley. pp. 341. ISBN 978-0470519035. Cite error: Invalid <ref> tag; name "Ref_DCHH341" defined multiple times with different content Cite error: Invalid <ref> tag; name "Ref_DCHH341" defined multiple times with different content
  38. 38.0 38.1 38.2 Humphrey, Peter A; Dehner, Louis P; Pfeifer, John D (2008). The Washington Manual of Surgical Pathology (1st ed.). Lippincott Williams & Wilkins. pp. 612. ISBN 978-0781765275.
  39. Pan, YW.; Huang, XY.; You, JF.; Tian, GL.; Li, C. (Nov 2008). "[Malignant giant cell tumor of the tendon sheaths in the hand].". Zhonghua Wai Ke Za Zhi 46 (21): 1645-8. PMID 19094761.
  40. 40.0 40.1 Shinjo, K.; Miyake, N.; Takahashi, Y. (Oct 1993). "Malignant giant cell tumor of the tendon sheath: an autopsy report and review of the literature.". Jpn J Clin Oncol 23 (5): 317-24. PMID 8230758.
  41. Suresh, SS.; Zaki, H. (Dec 2010). "Giant cell tumor of tendon sheath: case series and review of literature.". J Hand Microsurg 2 (2): 67-71. doi:10.1007/s12593-010-0020-9. PMID 22282671.
  42. Meydan N, Barutca S, Guney E, et al. (June 2006). "Brown tumors mimicking bone metastases". J Natl Med Assoc 98 (6): 950–3. PMC 2569361. PMID 16775919. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2569361/?page=1.
  43. Shiau, Carolyn; Toren, Andrew (2006). Toronto Notes 2006: Comprehensive Medical Reference (Review for MCCQE 1 and USMLE Step 2) (22nd edition (2006) ed.). Toronto Notes for Medical Students, Inc.. pp. Emerg.. ISBN 978-0968592861.
  44. URL: http://path.upmc.edu/cases/case139/micro.html. Accessed on: 6 January 2012.

External links