Melanoma pathophysiology: Difference between revisions

	Melanoma Microchapters
Home
Patient Information
Overview
Historical Perspective
Classification
Pathophysiology
Causes
Differentiating Melanoma from other Diseases
Epidemiology and Demographics
Risk Factors
Screening
Natural History, Complications and Prognosis
Diagnosis
Diagnostic Study of Choice
History and Symptoms
Physical Examination
Laboratory Findings
Electrocardiogram
X-ray
Echocardiography and Ultrasound
CT scan
MRI
Other Imaging Findings
Other Diagnostic Studies
Treatment
Medical Therapy
Surgery
Primary Prevention
Secondary Prevention
Cost-Effectiveness of Therapy
Future or Investigational Therapies
Case Studies
Case #1
Melanoma pathophysiology On the Web
Most recent articles
Most cited articles
Review articles
CME Programs
Powerpoint slides
Images
American Roentgen Ray Society Images of Melanoma pathophysiology All Images X-rays Echo & Ultrasound CT Images MRI
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
NICE Guidance
FDA on Melanoma pathophysiology
CDC on Melanoma pathophysiology
Melanoma pathophysiology in the news
Blogs on Melanoma pathophysiology
Directions to Hospitals Treating Melanoma
Risk calculators and risk factors for Melanoma pathophysiology

VisualWikitext

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==
-[[Image:Malignant melanoma.jpg|left|thumb|240px|Nodular melanoma on the leg of an elderly woman.]]
+[[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).
-Generally, an individual's risk for developing melanoma depends on two groups of factors: intrinsic and environmental.<ref>[http://www.skincarephysicians.com/skincancernet/who_is_most.html  Who is Most at Risk for Melanoma?]</ref> "Intrinsic" factors are generally an individual's family history and inherited [[genotype]], while the most relevant environmental factor is sun exposure.
-[[Epidemiologic]] studies suggest that exposure to [[ultraviolet]] radiation (UVA<ref name="uva">{{cite journal | author = Wang S, Setlow R, Berwick M, Polsky D, Marghoob A, Kopf A, Bart R | title = Ultraviolet A and melanoma: a review. | journal = J Am Acad Dermatol | volume = 44 | issue = 5 | pages = 837-46 | year = 2001 | id = PMID 11312434}}</ref> and UVB) is one of the major contributors to the development of melanoma. UV radiation causes [[DNA damage|damage]] to the [[DNA]] of cells, typically thymine dimerization, which when unrepaired can create [[mutation]]s in the cell's [[gene]]s. When the cell [[cell division|divides]], these mutations are propagated to new generations of cells. If the mutations occur in [[oncogene]]s or [[tumor suppressor gene]]s, the rate of [[mitosis]] in the mutation-bearing cells can become uncontrolled, leading to the formation of a [[tumor]]. Occasional extreme sun exposure (resulting in "[[sunburn]]") is causally related to melanoma.<ref>{{cite journal | author = Oliveria S, Saraiya M, Geller A, Heneghan M, Jorgensen C | title = Sun exposure and risk of melanoma. | journal = Arch Dis Child | volume = 91 | issue = 2 | pages = 131-8 | year = 2006 | id = PMID 16326797}}</ref> Those with more chronic long term exposure (outdoor workers) may develop protective mechanisms. Melanoma is most common on the back in men and on legs in women (areas of intermittent sun exposure) and is more common in indoor workers than outdoor workers (in a British study<ref>{{cite journal | author = Lee J, Strickland D | title = Malignant melanoma: social status and outdoor work. | journal = Br J Cancer | volume = 41 | issue = 5 | pages = 757-63 | year = 1980 | id = PMID 7426301}}</ref>). Other factors are [[mutation]]s in or total loss of [[tumor suppressor gene]]s.  Use of sunbeds (with deeply penetrating UVA rays) has been linked to the development of skin cancers, including melanoma.
-===[[Superficial spreading melanoma]]===
 ===Genetics===
-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>
+*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>
-<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 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]].
-<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.
+*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>
-<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.
+*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]].
-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.
+*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]]''
 ==Pathology==
-===Gross Pathology===
+*Characteristic features on [[gross pathology]] and [[microscopic]] analysis are variable depending on the [[melanoma]] sub-type.
-===Histopathological Analysis===
+*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>
+{| {{table}} cellpadding="4" cellspacing="0" style="border:#c9c9c9 1px solid; margin: 1em 1em 1em 0; border-collapse: collapse;"
-The microscopic hallmarks of nodular melanoma are:
+| align="center" style="background: #4479BA;" | {{fontcolor|#FFF|'''Melanoma Subtype'''}}
-* Dome-shaped at low power
+| align="center" style="background: #4479BA;" | {{fontcolor|#FFF|'''Features on Gross Pathology'''}}
-* Epidermis thin or normal
+| align="center" style="background: #4479BA;" | {{fontcolor|#FFF|'''Features on Histopathological Microscopic Analysis'''}}
-* Dermal nodule of melanocytes with a 'pushing' growth pattern
+|-
-* No "radial growth phase"
+| [[Superficial (human anatomy)|Superficial]] spreading [[melanoma]]||
+*Brown/black color, but may include reddish brown or white
+*[[Hyperkeratosis|Hyperkeratotic]], diffused borders with no distinct demarcation
-'''The microscopic hallmarks of acral lentiginous melanoma are:'''
+*Irregular and elevated
-* Atypical [[melanocyte]]s in junctional nests
+|
-* [[Dermis|dermal]] invasion
+*Presence of [[Epidermis (skin)|intraepidermal]] lateral spread (most characteristic feature)
+* [[Dermis|Dermal]] invasion
 * [[Desmoplasia]]
-* [[Hyperplastic]] [[Epidermis (skin)|epidermis]]
+* [[Epidermis (skin)|Epidermal]] [[hyperplasia]]
+*Appearance of [[epithelioid]] [[Cell (biology)|cells]] with occasional [[spindle cells]]
-===Superficial spreading melanoma===
+|-
-*Presence of intraepidermal lateral spread (most characteristic feature)
+| [[Nodular melanoma]]||
-*Appearance of epithelioid cells with occasional spindle cells
+*Tan/reddish brown color
+*Sharp borders
-===Nodular Melanoma===
+*Well-demarcated, dome-shaped [[Papule|papular]]/verrucous [[lesion]]
-*Sharp border differentiating malignant vs. normal tissue due to absence of intraepidermal lateral spread (most characteristic feature)
+|
-*Appearance of epithelioid cells with occasional spindle cells
+*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)
-*Melanocytes may have absent/minimal pigmentation
+*Appearance of [[epithelioid]] [[Cell (biology)|cells]] with occasional [[spindle cells]]
+*[[Melanocyte|Melanocytes]] may have absent/minimal [[Biological pigment|pigmentation]]
-===Acral Lentiginous Melanoma===
+|-
-*Epidermal acanthosis and hyperkeratosis (mmost characteristic feature)
+| [[Acral lentiginous melanoma]]||
-*Malignant melanocytes spread along the basal layer
+*Brown/black color, but may include reddish brown or white
-*Cells arranged in lentiginous and dycohesive pattern along the dermoepidermal junction
+*[[Hyperkeratosis|Hyperkeratotic]], diffused borders with no distinct demarcation
-*May be any of round, epithelioid, spindle, or oval cells
+*Irregular and elevated
-*May have perineural or endoneural invasion
+|
+*[[Epidermis (skin)|Epidermal]] [[Acanthosis nigricans|acanthosis]] and [[hyperkeratosis]] (most characteristic feature)
-===Lentigo Maligna Melanoma====
+*[[Malignant]] [[Melanocyte|melanocytes]] spread along the [[Skin|basal layer]]
-*Epidermal atrophy and flattening (most charactersitic feature)
+*[[Cell (biology)|Cells]] arranged in [[Lentiginous melanoma|lentiginous]] and dyscohesive pattern along the dermoepidermal junction
-*Large, pleomorphic cells
+*May be any of round, [[epithelioid]], spindle, or oval [[Cell (biology)|cells]]
-*Malignant melanocytes spread along the basal layer
+*May have [[Perineurium|perineural]] or [[Endoneurium|endoneural]] invasion
-*Cells arranged in lentiginous and dycohesive pattern along the dermoepidermal junction
+|-
-*May be any of round, epithelioid, spindle, or oval cells
+| [[Melanoma|Lentigo maligna melanoma]]||
-*Evidence of actinic damage of the dermal matrix
+*Brown/black color, but may include reddish brown or white
-*May have perineural or endoneural invasion
+*[[Hyperkeratosis|Hyperkeratotic]], diffused borders with no distinct demarcation
+*Irregular and elevated
-===Desmoplastic melanoma===
+|
-*Dermal, fibrotic nodule
+*[[Epidermis (skin)|Epidermal]] [[atrophy]] and flattening and prominent [[Dermis|dermal]] invasion (most charactersitic feature)
-*Ill-defined, variable spindle cells with irregular contours and stromal desmoplasia
+*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 sclerotic collagen fibers
+*Appearance of [[Sclerosis|sclerotic]] [[collagen]] fibers
-*Nuclear hyperchromasia
+*[[Cell nucleus|Nuclear]] [[Hyperchromicity|hyperchromasia]]
-*Appearance of lymphoid aggregates
+*Appearance of [[Lymphatic system|lymphoid]] aggregates
 *Solar elastosis
-*Involvement of endoneurium and perineurium (neurotropism)
+*Involvement of [[endoneurium]] and [[perineurium]] (neurotropism)
-*Possibly evidence of other melanoma subtypes (co-existing tumors, especially lentiginous melanoma)
+*Possibly evidence of other [[melanoma]] sub-types (co-existing [[Tumor|tumors]], especially lentiginous [[melanoma]])
+|-
-===Nevoid melanoma===
+| [[Melanoma|Nevoid melanoma]]
-*Dermal mitosis
+|
-*Hypercellular and monomorphous-appearing dermal melanocytes that have a characteristic sheet-like appearance
+*[[Morphology|Morphologically]] similar to a [[melanocytic nevus]]
-*Evidence of cytologic atypia (nuclear enlargement, pleomorphism, irregular nuclear membrane, hyperchromasia)
+|
+*[[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===
+| Spitzoid [[Melanoma|melanocytic]] [[neoplasm]]
-*Appearance of melanocytic proliferation along with features of Spitz tumors (small diametes, 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)
+*[[Morphology|Morphologically]] similar to a Spitz [[nevus]]
-*Vertically oriented spindled melanocytes
+|
-*Clefts between junctional melanocytes
+*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)
-===Angiotropic melanoma===
+*Vertically oriented spindled [[Melanocyte|melanocytes]]
-*Melanoma cells in close proximity to abluminal surfaces of blood and/or lymphatic channels
+*Clefts between junctional [[Melanocyte|melanocytes]]
-*No invasion within the vascular lamina itself
+|-
+| Angiotropic [[melanoma]]
-===Blue nevus-like melanoma===
+|
-*Asymmetric nodular/multinodular appearance
+*No [[Gross examination|gross]] [[Morphology|morphological]] features that distinguish angiotropic [[melanoma]] from other sub-types of [[melanoma]]
-*Aggregates of melaninized, atpical spindle cells
+|
-*
+*[[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
-===Future thought===
+|-
-<p>One important pathway in [[melanin]] synthesis involves the transcription factor [[MITF]].  The MITF gene is highly conserved and is found in people, mice, birds, and even fish.  MITF production is regulated via a fairly straightforward pathway.  [[UV radiation]] causes increased expression of transcription factor [[p53]] in [[keratinocytes]], and p53 causes these cells to produce melanoctye stimulating hormone ([[MSH]]), which binds to [[MC1R]] receptors on [[melanocytes]].  Ligand-binding at MC1R receptors activates [[adenyl cyclases]], which produce [[cAMP]], which activates [[CREB]], which promotes [[MITF]] expression.  The targets of MITF include [[p16]] (a CDK inhibitor) and [[Bcl2]], a gene essential to [[melanocyte]] survival.  It is often difficult to design drugs that interfere with transcription factors, but perhaps new drugs will be discovered that can impede some reaction in the pathway upstream of MITF.
+| [[Blue nevus]]-like [[melanoma]]
-<p>Studies of [[chromatin]] structure also promise to shed light on transcriptional regulation in melanoma cells.  It has long been assumed that [[nucleosomes]] are positioned randomly on [[DNA]], but murine studies of genes involved in melanin production now suggest that nucleosomes are stereotypically positioned on DNA.   When a gene is undergoing transcription, its transcription start site is almost always nucleosome-free.  When the gene is silent, however, nucleosomes often block the transcriptional start site, suggesting the nucleosome position may play a role in gene regulation.
+|
-<p>Finally, given the fact that tanning helps protect skin cells from UV-induced damage, new melanoma prevention strategies could involve attempts to induce tanning in individuals who would otherwise get sunburns.  Redheads, for example, do not tan because they have MC1R mutations.  In mice, it has been shown that the melanin-production pathway can be rescued downstream of MC1R.   Perhaps such a strategy will eventually be used to protect humans from 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]]