Difference between revisions of "Dermatopathology"

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| <ref>URL: [http://dermnetnz.org/pathology/pathology-glossary.html http://dermnetnz.org/pathology/pathology-glossary.html]. Accessed on: 8 August 2012.</ref>  
| <ref>URL: [http://dermnetnz.org/pathology/pathology-glossary.html http://dermnetnz.org/pathology/pathology-glossary.html]. Accessed on: 8 August 2012.</ref>  
|-
|-
|Epidermotropism
|Epidermotropism †
| intraepithelial lymphocytes in [[CTCL]]; how to remember: epidermotropis''m'' = ''m''alignant
| intraepithelial lymphocytes in [[CTCL]]; how to remember: epidermotropis''m'' = ''m''alignant
| <ref name=pmid20132423>{{Cite journal  | last1 = Fung | first1 = MA. | title = 'Epidermotropism' vs. 'exocytosis' of lymphocytes 101: definition of terms. | journal = J Cutan Pathol | volume = 37 | issue = 5 | pages = 525-9 | month = May | year = 2010 | doi = 10.1111/j.1600-0560.2010.01515.x | PMID = 20132423 }}</ref>
| <ref name=pmid20132423>{{Cite journal  | last1 = Fung | first1 = MA. | title = 'Epidermotropism' vs. 'exocytosis' of lymphocytes 101: definition of terms. | journal = J Cutan Pathol | volume = 37 | issue = 5 | pages = 525-9 | month = May | year = 2010 | doi = 10.1111/j.1600-0560.2010.01515.x | PMID = 20132423 }}</ref>
|-
|-
|Exocytosis
|Exocytosis †
| intraepithelial lymphocytes in benign conditions
| intraepithelial lymphocytes in benign conditions
| <ref name=pmid20132423>{{Cite journal  | last1 = Fung | first1 = MA. | title = 'Epidermotropism' vs. 'exocytosis' of lymphocytes 101: definition of terms. | journal = J Cutan Pathol | volume = 37 | issue = 5 | pages = 525-9 | month = May | year = 2010 | doi = 10.1111/j.1600-0560.2010.01515.x | PMID = 20132423 }}</ref>
| <ref name=pmid20132423>{{Cite journal  | last1 = Fung | first1 = MA. | title = 'Epidermotropism' vs. 'exocytosis' of lymphocytes 101: definition of terms. | journal = J Cutan Pathol | volume = 37 | issue = 5 | pages = 525-9 | month = May | year = 2010 | doi = 10.1111/j.1600-0560.2010.01515.x | PMID = 20132423 }}</ref>
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| <ref>URL: [http://www.medilexicon.com/medicaldictionary.php?t=63448 http://www.medilexicon.com/medicaldictionary.php?t=63448]. Accessed on: 13 March 2013.</ref><ref>URL: [http://dictionary.reference.com/browse/ortho- http://dictionary.reference.com/browse/ortho-]. Accessed on: 13 March 2013.</ref>
| <ref>URL: [http://www.medilexicon.com/medicaldictionary.php?t=63448 http://www.medilexicon.com/medicaldictionary.php?t=63448]. Accessed on: 13 March 2013.</ref><ref>URL: [http://dictionary.reference.com/browse/ortho- http://dictionary.reference.com/browse/ortho-]. Accessed on: 13 March 2013.</ref>
|}  
|}  
Note:
* † These definitions are not universally accepted. ''Epidermotropism'' is sometimes used in the context of benign disease.<ref name=pmid9537476>{{Cite journal  | last1 = Fung | first1 = MA. | last2 = LeBoit | first2 = PE. | title = Light microscopic criteria for the diagnosis of early vulvar lichen sclerosus: a comparison with lichen planus. | journal = Am J Surg Pathol | volume = 22 | issue = 4 | pages = 473-8 | month = Apr | year = 1998 | doi =  | PMID = 9537476 }}</ref>


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Revision as of 14:39, 14 March 2013

Dermatopathology is the pathology of skin.

Pathology is a significant part of dermatology and dermatologists spend five years in residency. So, it is a huge area.

Specimens

  • Shave biopsy = done for what is presumed to be benign disease - classically exophytic lesions, e.g. seborrheic keratosis.
  • Saucerization = scooped shave biopsy.[1]
  • Punch biopsy = cylindrical piece of skin, usu. epidermis and dermis - suspicious lesions/malignant lesions, e.g. basal cell carcinoma.
  • Incisional biopsy = a piece of the lesion for pathologic assessment; lesion not completely removed.
  • Excision = lesion cut-out with intent for complete removal - usual has a generous margin, e.g. malignant melanoma excision.
  • Re-excision = done to get a wider margin or remove part of a lesion that was incompletely removed in a prior excision.
    • Conservative re-excision = cut-out more with a minimal rim of normal tissue.[2]
  • Sentinel lymph node removal = a special type of lymphadenectomy usu. done for staging, esp. malignant melanoma.

Histology

Layers of the skin

  • Epidermis - outer most layer, avascular, separated from dermis by a basement membrane, epithelial tissue.
  • Dermis - below the epidermis, vascular, separated from the epidermis by a basement membrane, connective tissue.
  • Subdermis - below the dermis, connective tissue.

Epidermis

Layers of the epidermis

Epidermis layers - from the surface to epidermal-dermal junction:

  • Stratum corneum.
  • Stratum lucidum.
    • Present only in "thick" skin.[3]
  • Stratum granulosum.
  • Stratum spinosum (aka prickle layer).
  • Stratum basale (germinativum).

Mnemonic: Corn Lovers Grow Several Bales.

Cells of the epidermis

  • Keratinocytes.
    • Usually eosinophilic cytoplasm - important feature.
    • May have clear perinuclear halo (glycogenated keratinocytes).
    • Intercellular bridges (high power) - key feature.
  • Melanocytes.
    • Usuallly basal location.
    • Epithelioid or dentritic morphology.
    • Pericellular clearing - key feature.
    • Clear cytoplasm.
    • +/-Pigmentation.
  • Other:
    • Toker cell.
    • Neutrophils.
      • Trilobated nuclei - 2-3 little dots - key feature.
    • Lymphocytes.
      • Small (round) nucleus.
      • Scant/indistinct cytoplasm.
    • Other foreign cells:
      • Paget disease: large cells with clear cytoplasm, may cluster, above basal layer.

Normal histology

Features:

  • Keratinocytes:
    • Basal ~ 2x RBC.
      • May palisade focally ~ 1:2 = width: height.
  • Melanocytes < 25 melanocytes / 0.5 mm of basal layer.[4]
  • Basket weave stratum corneum (non-acral skin).

Dermis

Subdivided into layers:

  1. Papillary dermis.
    • Location: superficial - opposed to the deep aspect of the epidermis.
    • Appearance: dense, thick collagen bundles.
  2. Reticular dermis.
    • Location: deep - between papillary dermis and subdermis.
    • Appearance: loose connective tissue.

Images:

Adnexal structures

The top five structures of the skin:[7]

Structure / Attribute Histomorphology Function IHC Other Image
Eccrine gland clusters of tubular structures, pale cytoplasm thermoregulation (cooling) - produce sweat CK7+, CEA+, CAM5.2+, EMA+ ? ?
Apocrine gland apical snouts, tubular structures ear wax, body odor ? ? ?
Sebaceous gland clusters of cells side-by-side, pale fluffy cytoplasm grease hair, sexual lubrication ? assoc. with hair follicle ?
Hair follicle linear structure keep individual warm ? assoc. with sebaceous glands ?
Nail epidermal structure weapon (claw-like), look pretty? ? ? (osumc.edu)

Ducts vs. glands:[8]

  • Eccrine glands - spindle-shaped myoepithelial cells surround luminal cells.
  • Eccrine ducts - cuboidal type subepithelial cells.

Common terms

Clinical descriptors

There are multitude of clinical descriptors - common ones are:[9]

Name Size † Description Other Image
Macule <= 10 mm flat + change of colour if > 10 mm --> patch Macule (WC)
Patch > 10 mm flat + change of colour if <= 10 mm --> macule Patch (WC)
Papule <= 10 mm raised if > 10 mm --> nodule Papule (WC)
Nodule > 10 mm raised if <= 10 mm --> papule Nodule (WC)
Plaque > 10 mm raised, flat-top plateau-like Plaque (WC)
Vesicle <= 10 mm raised, fluid filled if > 10 mm --> bulla Vesicle (WC)
Bulla > 10 mm raised, fluid filled if <= 10 mm --> vesicle Bulla (WC)

Note:

  • † Definitions vary -- some authors use a 5 mm cut-off.

Histologic descriptors

Dermatopathology doesn't have intuitive terms, e.g. thickening of the stratum spinosum isn't spinosum hyperplasia. The terms have to committed to memory.

Common terms in a table

Term Meaning Reference
Acanthosis thickening of the prickle layer (stratum spinosum) of epidermis [10]
Acantholysis loss of intercellular connections in the epidermis
Dyskeratosis abnormal keratinization, often refers to keratinization below the stratum granulosum; keratinization above may be abnormal (dependent on body site)
Parakeratosis retention of nuclei in the stratum corneum, normal in mucous membranes
Spongiosis epidermal intercellular edema; cells appear to have a clear halo around 'em [11]
Basket weave stratum corneum appearance of the normal stratum corneum; presence in the context of pathology suggests an acute process
Compact hyperkeratosis stratum corneum layer is dense and thickened; this suggests a chronic process [12]
Epidermotropism † intraepithelial lymphocytes in CTCL; how to remember: epidermotropism = malignant [13]
Exocytosis † intraepithelial lymphocytes in benign conditions [13]
Orthokeratosis anuclear keratin layer is present (stratum corneum) - seen in normal skin; ortho- means correct [14][15]

Note:

  • † These definitions are not universally accepted. Epidermotropism is sometimes used in the context of benign disease.[16]

Image:

Others terms

  • Crust = epithelial elements, blood.

Image:

Skin diseases

Neoplasms

Main article: Dermatologic neoplasms

Malignant

Skin cancer is very common. The basic DDx of a malignant skin lesion is:

Non-malignant disease

Main article: Non-malignant skin disease

Non-malignant skin disease is common. It is the domain of dermatologists. It can be scary for general anatomical pathologists because the differential diagnosis is often broad, and, it's generally not something the general anatomical pathologist sees a lot of.

Subarticles

Common entities in tables

Non-malignant non-cystic - very common

Entity Key histologic feature Other features Clinical Stains/IHC DDx Other Image
Seborrheic keratosis (SK) horn cysts (intraepidermal collections of keratin) hyperkeratosis, brown granular material at the DE junction, sharply demarcated stuck on appearance none fibroepithelial polyp Leser–Trélat sign = many SKs in malignancy (WC)
Dermatofibroma fibrous bundles esp. at edge of lesion "dirty fingers" = acanthosis + basal keratinocyte hyperpigmentation +/-trauma Hx CD34-, Factor XIIIa+ DFSP very common (pacificderm.org)
Fibroepithelial polyp (skin tag) on a stalk (epithelium on 3+ sides) no horn nests, no hyperkeratosis raised lesion none seborrheic keratosis very common (dermatlas.med.jhmi.edu)
Lipoma mature adipocytes - uniform size var. of size may be seen, should prompt search for lipoblasts mobile subcutaneous mass S100 (???) liposarcoma variants: angiolipoma (blood vessels), myolipoma (muscle) (ahajournals.org)
Cicatrix (dermal scar) dense collagen bundles running parallel to DE junction, loss of dermal papillae loss of adnexal structures, +/-giant cells, +/-foreign material, +/-inflammatory cells site of previous trauma/surgery usu. none; S-100 (to exclude melanoma) residual disease, hypertrophic scar, (desmoplastic) melanoma (WC).

Non-malignant non-cystic - common

Entity Key histologic feature Other features Clinical Stains/IHC DDx Other Image
Neurofibroma bland spindle cells mast cells, mixed with collagen, assoc. with a nerve may be associated with neurofibromatosis, esp. plexiform type S100+, GFAP+ neurotized melanocytic nevus may develop into MPNST (WC)
Keratoacanthoma keratin plug, glassy pink cytoplasm, pushing downward growth minimal/no nuclear atypia grow rapidly then involute none squamous cell carcinoma some don't believe in the entity (WC)
Molluscum contagiosum suprabasilar cells with abundant granular eosinophilic cytoplasm small peripheral nucleus polypoid lesion; mushroom-like (?) none (?) DDx (?) favourite exam case (WC)
Verruca vulgaris hypergranulosis (thick granular layer) + keratohyaline granules hyperkeratosis (thick s. corneum), acanthosis (thick s. spinosum), rete ridges lengthened (~7-10x normal), large vessels at DE junction, koilocytic change (???) raised lesions, classically on hand none (p16+?) squamous cell carcinoma caused by HPV (WC)
Condyloma acuminatum koilocytes parakeratosis, long folded rete ridges (papillomatosis) - pseudopapillary look genital lesion none (p16+) fibroepithelial polyp caused by HPV (WC)
Granuloma annulare dermal palisading granuloma around necrotic collagen mucin in centre of lesion, (peripheral) lymphocytes, usu. more superficial than necrobiosis lipoidica benign, self-limited none (CD68?) necrobiosis lipoidica, rheumatoid nodule, epithelioid sarcoma Other ? (WC), (WC)
Necrobiosis lipoidica dermal palisading granuloma around necrotic collagen, plasma cells mucin in centre of lesion, (peripheral) chronic inflammatory cells may be assoc. diabetes mellitus none (CD68?) granuloma annulare, rheumatoid nodule histology identical to necrobiosis lipoidica diabeticorum (drmihm.com)
Angiofibroma fibrotic dermis, dilated capillaries enlarged (stellate fibroblasts) dome-shaped - face, boys & nosebleeds (nasopharyngeal angiofibroma) Stains/IHC DDx may be associated with tuberous sclerosis Angiofibroma (drdittmar.lu)
Keloid thick collagen bundles - surrounded by paler staining fibroblasts replaces adnexal structures site of previous trauma, esp. in blacks none dermatofibroma (???) hypertrophic scar (ucsf.edu).
Eccrine poroma abundant basaloid cells with (small) ductal structures incloses islands of sclerotic stroma with edema erythematous lesions Stains/IHC ? DDx ? Other ? (flickr.com), (flickr.com)
Syringoma bilayered ducts, occasionally tadpole like shape usu. close to eyelid Stains/IHC ? DDx ? Other ? (cdlib.org)
Chondroid syringoma (mixed tumour of skin) chondromyxoid stroma, epithelial component epithelial component in nests with eosinophilic cytoplasm, round/ovoid nuclei with nucleoli Clinical ? Stains/IHC ? DDx ? related to pleomorphic adenoma (???) Image ?
Angiokeratoma ectatic superficial dermal vessels + overlying hyperkeratosis - may be seen in Fabry disease Stains/IHC ? venous lake Other ? (WC)

Non-malignant non-cystic - children

Entity Key histologic feature Other features Clinical Stains/IHC DDx Other Image
Pilomatricoma anucleate squamous cells (ghost cells), giant cells bland basaloid cells common in children none squamous cell carcinoma mutations of CTNNB1 gene (WC)
Juvenile xanthogranuloma (JXG) Touton giant cells - multi-nucleated cells where nuclei are distributed around the cell periphery forming a ring abundant cytoplasm children CD68+, CD1a-, CD207- Langerhans cell histiocytosis may be seen in adults, known as adult xanthogranuloma (WC)

Non-malignant cystic

Entity Key histologic feature Other features Clinical Stains/IHC DDx Other Image
Epidermal cyst cyst lined by squamous epithelium with a granular layer keratinous debris, no skin adnexal structures cyst none pilar cyst, dermoid cyst Other? (ucsf.edu)
Pilar cyst cyst lined by squamous epithelium without a granular layer keratinous debris cyst none epidermal cyst Other? (WC)
Steatocystoma cyst lined by squamous epithelium with a corrugated eosinophilic lining epidermis has no granular layer cyst none dermoid cyst, follicular cyst Other? (WC)
Dermoid cyst cyst lined by keratinizing squamous epithelium with adnexal structures adnexal structure = hair, sebaceous gland, sweat glands cyst none epidermal cyst may be seen in the ovary (uiowa.edu)

Pre-malignant

Entity Key histologic feature Other features Clinical Stains/IHC DDx Other Image
Actinic keratosis epidermal atypia, esp. (basal) nuclear enlargement var. of nuclear size, shape and staining, parakeratosis (important in early lesions); does not involves adnexal epithelium and follicular epithelium yellow-brown scaly none squamous carcinoma, Bowen disease seen with solar elastosis (WC)
Bowen disease (squamous cell carcinoma in situ) epidermal atypia, esp. suprabasal nuclear enlargement var. of nuclear size, shape and staining; usually full thickness involvement; involve adnexal epithelium and follicular epithelium none squamous carcinoma, actinic keratosis typically seen with solar elastosis (WC)

Common malignant

Entity Key histologic feature Other features Clinical Stains/IHC DDx Other Image
Basal cell carcinoma (BCC) basaloid cells with peripheral palisading, artificial cleft myxoid stroma raised, pearly, telangiectasia usu. none req., CK5/6+ trichoepithelioma, basaloid squamous cell carcinoma assoc. nevoid basal cell carcinoma syndrome, Bazex syndrome (ucsf.edu)
Squamous cell carcinoma (SCC) nuclear enlargement, eosinophilic cytoplasm, central nucleus small nucleolus, intercellular bridges flaky appearance usu. none req., p63+, HMWK+ keratoacanthoma, Paget disease (EMPD & PDB), malignant melanoma, Toker cell hyperplasia Other (WC)
Malignant melanoma spindle and/or epithelioid morphology +/-nuclear atypia (esp. nucleoli) mitoses (esp. deep), +/-pigment, +/-nested arch., asymmetry, upward spread (into epidermis), epithelioid m. deep, +/-single cells, +/-sheets of cells ABCD = Asymmetry, Borders poor demarc., Colour dark, Diameter large S100+, Melan A+, HMB-45+, microphthalmia+, tyrosinase+ melanocytic lesions esp. Spitz nevus, Bowen's disease may be familial, dysplastic nevus (WC)

Less common malignant

Entity Key histologic feature Other features Clinical Stains/IHC DDx Other Image
Kaposi sarcoma vascular spindle cell lesion hyaline globules (intracytoplasmic) often HIV/AIDS HHV-8 Masson's hemangioma, angiosarcoma, Kaposiform hemangioendothelioma stages: patch stage, plaque stage, nodular stage, exophytic, infiltrative, lymphadenopathic (WC)
Cutaneous T-cell lymphoma (includes mycosis fungoides) single lymphocytes in epidermis ("lymphocyte exocytosis") lymphocyte nests in the epidermis ("Pautrier microabscesses"), short arrays of lymphocytes along the basal layer of the epidermis ("epidermotropism") Clinical CD45, CD4 B cell lymphoma (?) Other (WC)
Atypical fibroxanthoma dermal lesion with marked nuclear atypia multinucleated cells, mitoses, vacuolated cytoplasm old men, head and neck p63-, 34betaE12-, S100-, desmin- sarcomatoid squamous carcinoma, melanoma, leiomyosarcoma some classify this as benign; thought to be related to undifferentiated pleomorphic sarcoma (cdlib.org)[18]
Merkel cell carcinoma neuroendocrine nuclear features (stippled chromatin, no nucleolus), scant cytoplasm +/-nuclear moulding, usu. intermediate cell size Merkel cell polyomavirus associated, usu. head & neck or extremities CK20+, EMA+ cutaneous Ewing sarcoma, basal cell carcinoma, (dermal) lymphoma, metastatic small cell carcinoma (e.g. lung) rare, aggressive (bccancer.bc.ca), (WC)
Dermatofibrosarcoma protuberans (DFSP) spindle cell tumour with storiform pattern, tumour often contains adipocytes dermal tumour with preserved adnexal structures locally aggressive CD34+, factor XIIIa- dermatofibroma, solitary fibrous tumour (usu. deeper) rarely metastases, characteristic translocation: t(17;22)(q22;q15) COLA1/PDGFB; may transform to fibrosarcoma (WC)

Presentations

Leukoplakia

Main article: Leukoplakia

DDx:[19]

Skin disease and systemic conditions

Tabular list

Entity Disease/syndrome Key histologic feature Image
Acanthosis nigricans diabetes mellitus, malignancy basal cell hyperpigmentation, hyperkeratosis, prominent rete ridges (cdlib.org)
Trichilemmoma Cowden disease "hyperkeratosis" (cancer.gov)[20]
Angiokeratoma Fabry disease hyperkeratosis + vessels in superficial dermis (WC)
Dermatitis herpetiformis Celiac disease subepidermal bullous disease, papillary abscesses (lampyris101.com)
Angiofibroma tuberous sclerosis fibrotic dermis + dilated blood vessels (drdittmar.lu)
Sebaceous adenoma Muir-Torre syndrome abundant sebaceous glands with abn. arch. (WC)
Seborrheic keratosis, multiple with explosive onset Leser–Trélat sign (malignancy) horn cysts, hyperkeratosis gross (WC), micro. (WC)

Acanthosis nigricans

General

Associated with:

Microscopic

Features (memory device BPH):[22]

  • Basal cell hyperpigmentation.
  • Prominent rete ridges.
  • Hyperkeratosis.

Images:

Others

References

  1. ↑ Elston, D. (Jul 2012). "Practical advice regarding problematic pigmented lesions.". J Am Acad Dermatol 67 (1): 148-55. doi:10.1016/j.jaad.2012.04.006. PMID 22703907.
  2. ↑ URL: http://www.nedermatology.com/skin-cancer-treatments.php. Accessed on: 26 February 2013.
  3. ↑ Busam, Klaus J. (2009). Dermatopathology: A Volume in the Foundations in Diagnostic Pathology Series (1st ed.). Saunders. pp. 1. ISBN 978-0443066542.
  4. ↑ Trotter, MJ. (Jun 2011). "Melanoma margin assessment.". Clin Lab Med 31 (2): 289-300. doi:10.1016/j.cll.2011.03.006. PMID 21549242.
  5. ↑ URL: http://www.biology-online.org/articles/fibroblast_heterogeneity_skin_deep/figures.html. Accessed on: 29 March 2012.
  6. ↑ URL: http://melanoma.blogsome.com/category/skin-structure/. Accessed on: 29 March 2012.
  7. ↑ Busam, Klaus J. (2009). Dermatopathology: A Volume in the Foundations in Diagnostic Pathology Series (1st ed.). Saunders. pp. 4-8. ISBN 978-0443066542.
  8. ↑ HJ. 27 Feb 2009.
  9. ↑ URL: http://www.pediatrics.wisc.edu/education/derm/text.html. Accessed on: 18 September 2012.
  10. ↑ http://dictionary.reference.com/browse/acanthosis
  11. ↑ 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. 1230. ISBN 0-7216-0187-1.
  12. ↑ URL: http://dermnetnz.org/pathology/pathology-glossary.html. Accessed on: 8 August 2012.
  13. ↑ 13.0 13.1 Fung, MA. (May 2010). "'Epidermotropism' vs. 'exocytosis' of lymphocytes 101: definition of terms.". J Cutan Pathol 37 (5): 525-9. doi:10.1111/j.1600-0560.2010.01515.x. PMID 20132423.
  14. ↑ URL: http://www.medilexicon.com/medicaldictionary.php?t=63448. Accessed on: 13 March 2013.
  15. ↑ URL: http://dictionary.reference.com/browse/ortho-. Accessed on: 13 March 2013.
  16. ↑ Fung, MA.; LeBoit, PE. (Apr 1998). "Light microscopic criteria for the diagnosis of early vulvar lichen sclerosus: a comparison with lichen planus.". Am J Surg Pathol 22 (4): 473-8. PMID 9537476.
  17. ↑ URL: http://www.eplasty.com/index.php?option=com_content&view=article&id=492&catid=171:volume-10-eplasty-2010&Itemid=121. Accessed on: 16 October 2012.
  18. ↑ Vandergriff, TW.; Reed, JA.; Orengo, IF. (2008). "An unusual presentation of atypical fibroxanthoma.". Dermatol Online J 14 (1): 6. PMID 18319023.
  19. ↑ 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. 1065. ISBN 0-7216-0187-1.
  20. ↑ URL: http://ccr.cancer.gov/staff/gallery.asp?profileid=12822. Accessed on: 14 December 2011.
  21. ↑ URL: http://www.emedicine.com/derm/topic1.htm, URL: [1].
  22. ↑ 22.0 22.1 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. 596. ISBN 978-1416054542.
  23. ↑ 23.0 23.1 Greenwald, J.; Heng, M. (2007). Toronto Notes for Medical Students 2007 (2007 ed.). The Toronto Notes Inc. for Medical Students Inc.. pp. D23. ISBN 978-0968592878.
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