Melanoma pathophysiology: Difference between revisions

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Latest revision as of 22:50, 2 January 2019

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.; Serge Korjian M.D.

Overview

Malignant melanoma arises from the epidermal melanocytes, which are neural crest cells involved in the synthesis of melanin (a brown pigment with photoprotective properties). Development of melanoma is the result of multiple genetic mutations. The progression to melanoma usually involves the serine-threonine kinases of the MAPK/ERK pathway (mitogen-activated protein kinase) following mutation of either the N-RAS or BRAF oncogene. On gross pathology, the majority of melanomas appear as hyperkeratotic, black-brown, asymmetric nodules with irregular borders, but the morphology of the lesion mostly depends on the sub-type of melanoma. On microscopic histopathological analysis, each sub-type of melanoma has unique characteristic features.

Pathophysiology

Malignant melanoma arises from the epidermal melanocytes, which are neural crest cells involved in the synthesis of melanin (a brown pigment with photoprotective properties).

Genetics

The development of melanoma begins with the disruption of nevus growth control.^[1]
The progression to melanoma usually involves the serine-threonine kinases of the MAPK/ERK pathway (mitogen-activated protein kinase) following mutation of either the N-RAS or BRAF oncogene.
It is thought that the progression to melanoma requires multiple genetic mutations, where activation of the oncogene alone does not lead to the development of melanoma, and additional mutations (multiple hits), such as loss-of-function mutation of P53 tumor suppressor gene (or less commonly P16/CDKN2A or PTEN in familial cases) is required for the development of melanoma.^[1]
The development of melanoma may arise de novo or from pre-existing nevi. In both cases, mutations result in dysplasia and cytologic atypia that predispose to the malignant potential of the cells.
As more genes are mutated and the tumor grows, changes include the overexpression of N-cadherin, αVβ3 integrin, MMP2, MSH, cAMP, and survivin, and the loss of E-cadherin and TRMP1 proteins.^[1]
The following genes are involved in the pathogenesis of melanoma:^[1]

Tumor-suppressor genes:

P53
P16/CDK2NA
PTEN
RB
ARF

Proto-oncogenes:

N-RAS
BRAF
CCND1

Pathology

Characteristic features on gross pathology and microscopic analysis are variable depending on the melanoma sub-type.
The following table illustrates the findings on gross pathology and microscopic analysis of the sub-types of melanoma:^[2]^[3]

Melanoma Subtype	Features on Gross Pathology	Features on Histopathological Microscopic Analysis
Superficial spreading melanoma	Brown/black color, but may include reddish brown or white Hyperkeratotic, diffused borders with no distinct demarcation Irregular and elevated	Presence of intraepidermal lateral spread (most characteristic feature) Dermal invasion Desmoplasia Epidermal hyperplasia Appearance of epithelioid cells with occasional spindle cells
Nodular melanoma	Tan/reddish brown color Sharp borders Well-demarcated, dome-shaped papular/verrucous lesion	Sharp border differentiating malignant vs. normal tissue due to absence of intraepidermal lateral spread / no radial growth plate (most characteristic feature) Appearance of epithelioid cells with occasional spindle cells Melanocytes may have absent/minimal pigmentation
Acral lentiginous melanoma	Brown/black color, but may include reddish brown or white Hyperkeratotic, diffused borders with no distinct demarcation Irregular and elevated	Epidermal acanthosis and hyperkeratosis (most characteristic feature) Malignant melanocytes spread along the basal layer Cells arranged in lentiginous and dyscohesive pattern along the dermoepidermal junction May be any of round, epithelioid, spindle, or oval cells May have perineural or endoneural invasion
Lentigo maligna melanoma	Brown/black color, but may include reddish brown or white Hyperkeratotic, diffused borders with no distinct demarcation Irregular and elevated	Epidermal atrophy and flattening and prominent dermal invasion (most charactersitic feature) Large, pleomorphic cells Cells arranged in lentiginous and dyscohesive pattern along the dermoepidermal junction Preservation of retiform epidermis May be any of round, epithelioid, spindle, or oval cells Evidence of actinic damage of the dermal matrix May have perineural or endoneural invasion Positivity for CD133+ and CD34+
Non-cutaneous melanoma	Variable morphology depending on location of melanoma	Histopathologically similar to other sub-types of melanoma
Desmoplastic/Spindle cell melanoma	Skin colored and morphologically resembles scar tissue	Dermal, fibrotic nodule Ill-defined, variable spindle cells with irregular contours and stromal desmoplasia Highly infiltrative pattern Appearance of sclerotic collagen fibers Nuclear hyperchromasia Appearance of lymphoid aggregates Solar elastosis Involvement of endoneurium and perineurium (neurotropism) Possibly evidence of other melanoma sub-types (co-existing tumors, especially lentiginous melanoma)
Nevoid melanoma	Morphologically similar to a melanocytic nevus	Dermal mitosis Hypercellular and monomorphous-appearing dermal melanocytes that have a characteristic sheet-like appearance Evidence of cytologic atypia (nuclear enlargement, pleomorphism, irregular nuclear membrane, hyperchromasia) Irregular basal infiltration Evidence of angiotropism
Spitzoid melanocytic neoplasm	Morphologically similar to a Spitz nevus	Appearance of melanocytic proliferation along with features of Spitz tumors (small diameter, well-demarcated, symmetric lesion with no ulceration, epidermal effacement, dermal mitosis, or involvement of the subcutaneous fat) May have features that are not typically characteristic of Spitz tumors (ulceration, poor demarcation) Vertically oriented spindled melanocytes Clefts between junctional melanocytes
Angiotropic melanoma	No gross morphological features that distinguish angiotropic melanoma from other sub-types of melanoma	Melanoma cells in close proximity to abluminal surfaces of blood and/or lymphatic channels No invasion within the vascular lamina itself
Blue nevus-like melanoma	Morphologically similar to a blue nevus	Asymmetric nodular/multinodular appearance Aggregates of melaninized, atypical spindle cells
Composite melanoma	Features of more than one sub-type on gross pathology	Features of more than one sub-type on microscopic analysis May be characterized by one of the following: Collision tumor: Collision of melanoma and another nearby malignant tumor Colonization: Colonization of melanocytes in a tumor Combined: Two distinct tumors appear to have mixed features of the melanoma and the other tumor Biphenotypic: One tumor that simultaneously has features of melanoma and another epithelial malignancy

References

↑ ^1.0 ^1.1 ^1.2 ^1.3 Miller AJ, Mihm MC (2006). "Melanoma". N Engl J Med. 355 (1): 51–65. doi:10.1056/NEJMra052166. PMID 16822996.
↑ Schanderdorf D, Kochs C, Livingstone E (2013). Handbook of Cutaneous Melanoma: A Guide to Diagnosis and Treatment. Springer.
↑ Mooi W, Krausz T (2007). Pathology of Melanocytic Disorders 2nd Ed. CRC Press.

[pmid16822996-1] 1.0 ^1.1 ^1.2 ^1.3 Miller AJ, Mihm MC (2006). "Melanoma". N Engl J Med. 355 (1): 51–65. doi:10.1056/NEJMra052166. PMID 16822996.

[book1-2] Schanderdorf D, Kochs C, Livingstone E (2013). Handbook of Cutaneous Melanoma: A Guide to Diagnosis and Treatment. Springer.

[book2-3] Mooi W, Krausz T (2007). Pathology of Melanocytic Disorders 2nd Ed. CRC Press.

[1]

[2]

[3]

@@ Line 1: / Line 1: @@
-{{CMG}}
+__NOTOC__
+{{CMG}} {{AE}} {{YD}}; {{SSK}}
 {{Melanoma}}
 ==Overview==
+[[Malignant]] [[melanoma]] arises from the [[Epidermis (skin)|epidermal]] [[Melanocyte|melanocytes]], which are [[neural crest]] [[Cell (biology)|cells]] involved in the [[Chemical synthesis|synthesis]] of [[melanin]] (a brown [[pigment]] with photoprotective properties). Development of [[melanoma]] is the result of multiple [[Mutation|genetic mutations]]. The progression to [[melanoma]] usually involves the [[Serine/threonine-specific protein kinase|serine-threonine kinases]] of the [[MAPK/ERK pathway]] ([[mitogen-activated protein kinase]]) following [[mutation]] of either the ''[[Ras|N-RAS]]'' or ''[[BRAF]]'' [[oncogene]]. On [[gross pathology]], the majority of [[Melanoma|melanomas]] appear as [[Hyperkeratosis|hyperkeratotic]], black-brown, asymmetric [[nodule]]s with irregular borders, but the [[morphology]] of the [[lesion]] mostly depends on the sub-type of [[melanoma]]. On [[microscopic]] [[Histopathology|histopathological]] analysis, each sub-type of [[melanoma]] has unique characteristic features.
 ==Pathophysiology==
+[[Malignant]] [[melanoma]] arises from the [[Epidermis (skin)|epidermal]] [[Melanocyte|melanocytes]], which are [[neural crest]] [[Cell (biology)|cells]] involved in the [[Chemical synthesis|synthesis]] of [[melanin]] (a brown pigment with photoprotective properties).
+===Genetics===
+*The development of [[melanoma]] begins with the disruption of [[nevus]] growth control.<ref name="pmid16822996">{{cite journal| author=Miller AJ, Mihm MC| title=Melanoma. | journal=N Engl J Med | year= 2006 | volume= 355 | issue= 1 | pages= 51-65 | pmid=16822996 | doi=10.1056/NEJMra052166 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16822996  }} </ref>
+*The progression to [[melanoma]] usually involves the [[Serine/threonine-specific protein kinase|serine-threonine kinases]] of the [[MAPK/ERK pathway]] [[Mitogen-activated protein kinase|(mitogen-activated protein kinase)]] following [[mutation]] of either the ''[[Ras|N-RAS]]'' or ''[[BRAF]]'' [[oncogene]].
+*It is thought that the progression to [[melanoma]] requires multiple [[Mutation|genetic mutations]], where activation of the [[oncogene]] alone does not lead to the development of [[melanoma]], and additional [[Mutation|mutations]] (multiple hits), such as loss-of-function [[mutation]] of [[P53|''P53'' tumor suppressor gene]] (or less commonly ''[[P16 (gene)|P16/CDKN2A]]'' or ''[[PTEN]]'' in familial cases) is required for the development of [[melanoma]].<ref name="pmid16822996">{{cite journal| author=Miller AJ, Mihm MC| title=Melanoma. | journal=N Engl J Med | year= 2006 | volume= 355 | issue= 1 | pages= 51-65 | pmid=16822996 | doi=10.1056/NEJMra052166 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16822996  }} </ref>
+*The development of [[melanoma]] may arise [[de novo]] or from pre-existing [[nevus|nevi]]. In both cases, [[Mutation|mutations]] result in [[dysplasia]] and [[Atypia|cytologic atypia]] that predispose to the [[malignant]] potential of the [[Cell (biology)|cells]].
+*As more [[Gene|genes]] are [[Mutation|mutated]] and the [[tumor]] grows, changes include the [[Gene expression|overexpression]] of [[Cadherin|N-cadherin]], [[Integrin|αVβ3 integrin]], [[MMP2]], [[MSH]], [[cAMP]], and [[survivin]], and the loss of [[E-cadherin]] and TRMP1 [[Protein|proteins]].<ref name="pmid16822996">{{cite journal| author=Miller AJ, Mihm MC| title=Melanoma. | journal=N Engl J Med | year= 2006 | volume= 355 | issue= 1 | pages= 51-65 | pmid=16822996 | doi=10.1056/NEJMra052166 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16822996  }} </ref>
+*The following [[Gene|genes]] are involved in the [[pathogenesis]] of [[melanoma]]:<ref name="pmid16822996">{{cite journal| author=Miller AJ, Mihm MC| title=Melanoma. | journal=N Engl J Med | year= 2006 | volume= 355 | issue= 1 | pages= 51-65 | pmid=16822996 | doi=10.1056/NEJMra052166 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16822996  }} </ref>
+:*[[Tumor suppressor gene|Tumor-suppressor genes]]:
+::*''[[P53]]''
+::*''[[P16 (gene)|P16/CDK2NA]]''
+::*''[[PTEN]]''
+::*''[[RB]]''
+::*''[[ARF]]''
+:*[[Proto oncogenes|Proto-oncogenes]]:
+::*''[[Ras|N-RAS]]''
+::*''[[BRAF]]''
+::*''[[CCND1]]''
-==Genetics==
+==Pathology==
-Familial melanoma is genetically heterogeneous,<ref>{{cite journal | author = Greene MH. | title = The genetics of hereditary melanoma and nevi. | journal = Cancer | volume = 86 | issue = 11 | pages = 2464-2477 | year = 1998 | id = PMID 10630172}}</ref> and loci for familial melanoma have been identified on the chromosome arms 1p, 9p and 12q. Multiple genetic events have been related to the pathogenesis of melanoma.<ref>{{cite journal | author = Halachmi S, Gilchrest BA. | title = Update on genetic events in the pathogenesis of melanoma. | journal = Curr Opin Oncol | volume = 13 | issue = 2 | pages = 129-136 | year = 2001 | id = PMID 11224711}}</ref> The multiple [[Tumor suppressor gene|tumor suppressor]] 1 (CDKN2A/MTS1) gene encodes p16INK4a - a low-molecular weight protein inhibitor of [[cyclin-dependent kinase|cyclin-dependent protein kinases]] (CDKs) - which has been localised to the p21 region of [[Chromosome 9 (human)|human chromosome 9]].<ref>[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=full_report&list_uids=1029 CDKN2A cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4)] from Entrez Gene</ref>
+*Characteristic features on [[gross pathology]] and [[microscopic]] analysis are variable depending on the [[melanoma]] sub-type.
-<p>Today, melanomas are diagnosed only after they become visible on the skin.  In the future, however, physicians will hopefully be able detect melanomas based on a patient’s [[genotype]], not just his or her [[phenotype]].  Recent genetic advances promise to help doctors to identify people with high-risk genotypes and to determine which of a person’s lesions have the greatest chance of becoming cancerous.
+*The following table illustrates the findings on [[gross pathology]] and [[microscopic]] analysis of the sub-types of melanoma:<ref name="book1">{{cite book|last=Schanderdorf D, Kochs C, Livingstone E |date=2013 |title=Handbook of Cutaneous Melanoma: A Guide to Diagnosis and Treatment |publisher=Springer }}</ref><ref name="book2">{{cite book|last=Mooi W, Krausz T|date=2007 |title=Pathology of Melanocytic Disorders 2nd Ed. |publisher=CRC Press}}</ref>
-<p>A number of rare mutations, which often run in families, are known to greatly increase one’s susceptibility to melanoma.  One class of mutations affects the gene [[CDKN2A]].  An alternative reading frame mutation in this gene leads to the destabilization of [[p53]], a [[transcription factor]] involved in [[apoptosis]] and in fifty percent of human cancers.  Another mutation in the same gene results in a non-functional inhibitor of [[CDK4]], a [cyclin-dependent kinase] that promotes cell division.  Mutations that cause the skin condition [[Xeroderma Pigmentosum]] (XP) also seriously predispose one to melanoma.  Scattered throughout the genome, these mutations reduce a cell’s ability to repair DNA.  Both CDKN2A and XP mutations are highly penetrant.
+{| {{table}} cellpadding="4" cellspacing="0" style="border:#c9c9c9 1px solid; margin: 1em 1em 1em 0; border-collapse: collapse;"
-<p>Other mutations confer lower risk but are more prevalent in the population.  People with mutations in the MC1R gene, for example, are two to four times more likely to develop melanoma than those with two wild-type copies of the gene.   [[MC1R]] mutations are very common; in fact, all people with red hair have a mutated copy of the gene.
+| align="center" style="background: #4479BA;" | {{fontcolor|#FFF|'''Melanoma Subtype'''}}
-Two-gene models of melanoma risk have already been created, and in the future, researchers hope to create genome-scale models that will allow them to predict a patient’s risk of developing melanoma based on his or her genotype.
+| align="center" style="background: #4479BA;" | {{fontcolor|#FFF|'''Features on Gross Pathology'''}}
+| align="center" style="background: #4479BA;" | {{fontcolor|#FFF|'''Features on Histopathological Microscopic Analysis'''}}
+|-
+| [[Superficial (human anatomy)|Superficial]] spreading [[melanoma]]||
+*Brown/black color, but may include reddish brown or white
+*[[Hyperkeratosis|Hyperkeratotic]], diffused borders with no distinct demarcation
+*Irregular and elevated
+|
+*Presence of [[Epidermis (skin)|intraepidermal]] lateral spread (most characteristic feature)
+* [[Dermis|Dermal]] invasion
+* [[Desmoplasia]]
+* [[Epidermis (skin)|Epidermal]] [[hyperplasia]]
+*Appearance of [[epithelioid]] [[Cell (biology)|cells]] with occasional [[spindle cells]]
+|-
+| [[Nodular melanoma]]||
+*Tan/reddish brown color
+*Sharp borders
+*Well-demarcated, dome-shaped [[Papule|papular]]/verrucous [[lesion]]
+|
+*Sharp border differentiating [[malignant]] vs. normal [[Tissue (biology)|tissue]] due to absence of [[Epidermis (skin)|intraepidermal]] lateral spread / no radial growth plate (most characteristic feature)
+*Appearance of [[epithelioid]] [[Cell (biology)|cells]] with occasional [[spindle cells]]
+*[[Melanocyte|Melanocytes]] may have absent/minimal [[Biological pigment|pigmentation]]
+|-
+| [[Acral lentiginous melanoma]]||
+*Brown/black color, but may include reddish brown or white
+*[[Hyperkeratosis|Hyperkeratotic]], diffused borders with no distinct demarcation
+*Irregular and elevated
+|
+*[[Epidermis (skin)|Epidermal]] [[Acanthosis nigricans|acanthosis]] and [[hyperkeratosis]] (most characteristic feature)
+*[[Malignant]] [[Melanocyte|melanocytes]] spread along the [[Skin|basal layer]]
+*[[Cell (biology)|Cells]] arranged in [[Lentiginous melanoma|lentiginous]] and dyscohesive pattern along the dermoepidermal junction
+*May be any of round, [[epithelioid]], spindle, or oval [[Cell (biology)|cells]]
+*May have [[Perineurium|perineural]] or [[Endoneurium|endoneural]] invasion
+|-
+| [[Melanoma|Lentigo maligna melanoma]]||
+*Brown/black color, but may include reddish brown or white
+*[[Hyperkeratosis|Hyperkeratotic]], diffused borders with no distinct demarcation
+*Irregular and elevated
+|
+*[[Epidermis (skin)|Epidermal]] [[atrophy]] and flattening and prominent [[Dermis|dermal]] invasion (most charactersitic feature)
+*Large, [[Pleomorphism|pleomorphic]] [[Cell (biology)|cells]]
+*[[Cell (biology)|Cells]] arranged in lentiginous and dyscohesive pattern along the dermoepidermal junction
+*Preservation of retiform [[Epidermis (skin)|epidermis]]
+*May be any of round, [[epithelioid]], spindle, or oval [[Cell (biology)|cells]]
+*Evidence of [[actinic]] damage of the [[Dermis|dermal]] [[matrix]]
+*May have [[Perineurium|perineural]] or [[Endoneurium|endoneural]] invasion
+*Positivity for [[CD133|CD133+]] and [[CD34|CD34+]]
+|-
+| Non-[[Skin|cutaneous]] [[melanoma]]||
+*Variable [[morphology]] depending on location of [[melanoma]]
+|
+*[[Histopathology|Histopathologically]] similar to other sub-types of [[melanoma]]
+|-
+| [[Desmoplasia|Desmoplastic]]/Spindle [[Cell (biology)|cell]] [[melanoma]]||
+*[[Skin]] colored and [[Morphology|morphologically]] resembles [[scar tissue]]
+|
+*[[Dermis|Dermal]], [[Fibrosis|fibrotic]] [[Nodule (medicine)|nodule]]
+*Ill-defined, variable spindle cells with irregular contours and [[stromal]] [[desmoplasia]]
+*Highly infiltrative pattern
+*Appearance of [[Sclerosis|sclerotic]] [[collagen]] fibers
+*[[Cell nucleus|Nuclear]] [[Hyperchromicity|hyperchromasia]]
+*Appearance of [[Lymphatic system|lymphoid]] aggregates
+*Solar elastosis
+*Involvement of [[endoneurium]] and [[perineurium]] (neurotropism)
+*Possibly evidence of other [[melanoma]] sub-types (co-existing [[Tumor|tumors]], especially lentiginous [[melanoma]])
+|-
+| [[Melanoma|Nevoid melanoma]]
+|
+*[[Morphology|Morphologically]] similar to a [[melanocytic nevus]]
+|
+*[[Dermis|Dermal]] [[mitosis]]
+*Hypercellular and monomorphous-appearing [[Dermis|dermal]] [[Melanocyte|melanocytes]] that have a characteristic sheet-like appearance
+*Evidence of [[Cell biology|cytologic]] [[atypia]] ([[Cell nucleus|nuclear]] enlargement, [[pleomorphism]], irregular [[Cell nucleus|nuclear]] [[membrane]], [[Hyperchromicity|hyperchromasia]])
+*Irregular basal infiltration
+*Evidence of angiotropism
+|-
+| Spitzoid [[Melanoma|melanocytic]] [[neoplasm]]
+|
+*[[Morphology|Morphologically]] similar to a Spitz [[nevus]]
+|
+*Appearance of [[Melanoma|melanocytic]] proliferation along with features of Spitz [[Tumor|tumors]] (small [[diameter]], well-demarcated, symmetric [[lesion]] with no [[Ulcer|ulceration]], [[Epidermis (skin)|epidermal]] effacement, [[Dermis|dermal]] [[mitosis]], or involvement of the [[subcutaneous fat]])
+*May have features that are not typically characteristic of Spitz [[Tumor|tumors]] ([[Ulcer|ulceration]], poor demarcation)
+*Vertically oriented spindled [[Melanocyte|melanocytes]]
+*Clefts between junctional [[Melanocyte|melanocytes]]
+|-
+| Angiotropic [[melanoma]]
+|
+*No [[Gross examination|gross]] [[Morphology|morphological]] features that distinguish angiotropic [[melanoma]] from other sub-types of [[melanoma]]
+|
+*[[Melanoma]] [[Cell (biology)|cells]] in close proximity to abluminal surfaces of [[blood]] and/or [[Lymphatic system|lymphatic]] channels
+*No invasion within the [[vascular]] [[lamina]] itself
+|-
+| [[Blue nevus]]-like [[melanoma]]
+|
+*[[Morphology|Morphologically]] similar to a [[blue nevus]]
+|
+*Asymmetric [[Nodule (medicine)|nodular]]/[[Nodule|multinodular]] appearance
+*Aggregates of [[Melanin|melaninized]], atypical spindle [[Cell (biology)|cells]]
+|-
+| Composite [[melanoma]]
+|
+Features of more than one sub-type on [[gross pathology]]
+|
+*Features of more than one sub-type on [[microscopic]] analysis
+*May be characterized by one of the following:
+:*Collision [[tumor]]: Collision of [[melanoma]] and another nearby [[malignant]] [[tumor]]
+:*Colonization: Colonization of [[Melanocyte|melanocytes]] in a [[tumor]]
+:*Combined: Two distinct [[Tumor|tumors]] appear to have mixed features of the [[melanoma]] and the other [[tumor]]
+:*[[Phenotype|Biphenotypic]]: One [[tumor]] that simultaneously has features of [[melanoma]] and another [[Epithelium|epithelial]] [[Cancer|malignancy]]
+|}
 ==References==
 {{Reflist|2}}
+ [[Category:Up-To-Date]]
+[[Category:Oncology]]
+[[Category:Medicine]]
+[[Category:Dermatology]]
+[[Category:Surgery]]