Squamous cell carcinoma of the skin pathophysiology: Difference between revisions

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{{CMG}}; '''Associate Editor(s)-in-Chief:''' [[User:Aditya Govindavarjhulla|Aditya Govindavarjhulla, M.B.B.S.]] [mailto:agovi@wikidoc.org], [[User:Raviteja Reddy Guddeti|Raviteja Guddeti, M.B.B.S.]] [mailto:ravitheja.g@gmail.com]
{{CMG}}; '''Associate Editor(s)-in-Chief:''' [[User:Aditya Govindavarjhulla|Aditya Govindavarjhulla, M.B.B.S.]] [mailto:agovi@wikidoc.org], [[User:Raviteja Reddy Guddeti|Raviteja Guddeti, M.B.B.S.]] [mailto:ravitheja.g@gmail.com]
== Overview ==
== Overview ==
[[Squamous cell carcinoma]] (SCC) is type of [[non-melanoma skin cancer]]. The cancer arises as a result of uncontrolled growth of the squamous cells in the epidermis of the skin. Unlike it's counter part, the [[basal cell carcinoma]] which also belongs to the group of non-melanoma cancer, SCC is rapid growing and invasive. SCCs may occur on all areas of the body including the mucous membranes and genitals, but are most common in areas frequently exposed to the sun, such as the rim of the ear, lower lip, face, bald scalp, neck, hands, arms and legs. Wrinkling, changes in pigmentation, and loss of elasticity of the skin are often the telltale signs of sun damage
[[Squamous cell carcinoma]] (SCC) is type of non-[[melanoma]] [[skin cancer]]. The [[Cancer (medicine)|cancer]] arises as a result of uncontrolled [[growth]] of the [[Squamous cell|squamous cells]] in the [[epidermis]] of the [[Skin Changes|skin]]. Unlike it's counter part, the [[basal cell carcinoma]] which also belongs to the group of non-[[melanoma]] [[cancer]], [[squamous cell carcinoma]] is rapid growing and [[invasive]]. [[Squamous cell carcinoma|SCCs]] may occur on all areas of the [[body]] including the [[mucous membranes]] and [[genitals]], but are most common in areas frequently exposed to the [[Sun exposure|sun]], such as the rim of the [[ear]], [[Lip|lower lip]], [[face]], bald [[scalp]], [[neck]], [[hands]], [[Arm|arms]] and [[Leg|legs]]. Wrinkling, changes in [[pigmentation]], and loss of [[Elastic|elasticity]] of the [[skin]] are often the telltale [[signs]] of [[Sun exposure|sun]] damage.


== Pathophysiology ==
== Pathophysiology ==
[[Squamous cell carcinoma]] is a potentially invasive cancer that arises from the surface epithelium.The development of squamous cell carcinoma is frequently a multistep process. Early lesions tend to be either actinic keratoses, with atypia of the basal keratinocytic layer of the epidermis or squamous cell carcinoma in situ, in which keratinocytic atypia spans the full thickness epidermis.
*<nowiki/>Malignant transformation of normal epidermal keratinocytes is the hallmark of squamous cell carcinoma of the ski<nowiki/>n.
*<nowiki/>One cri<nowiki/>tical pathogenic event is the development of apoptotic resistance through functional loss of TP53, a well<nowiki/>-studied tumor<nowiki/> suppressor gene.
**<nowiki/>TP53 mutations are seen in over 90% of skin cancers diagnosed in the United States, as well as in most precursor<nowiki/> skin lesions,<nowiki/> suggesting that loss of TP53 is an early event in the development of cSCC.<ref name="pmid16712710">{{cite journal| author=Brash DE| title=Roles of the transcription factor p53 in keratinocyte carcinomas. | journal=Br J Dermatol | year= 2006 | volume= 154 Suppl 1 | issue=  | pages= 8-10 | pmid=16712710 | doi=10.1111/j.1365-2133.2006.07230.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16712710  }}</ref>
* UVR causes [[deoxyribonucleic acid]] ([[DNA]]) damage through the creation of [[pyrimidine]] dimers, a process known to result in the genetic mutation of ''TP53.''
* Upon subsequent UVR exposure, keratinocytes undergo clonal expansion, acquiring further genetic defects, ultimately leading to invasive cutaneous squamous cell carcinoma.
* Many other genetic abnormalities are believed to contribute to the pathogenesis of squamous cell carcinoma of the skin, including mutations of ''BCL2'' and ''RAS.''
* Likewise, alterations in intracellular signal transduction pathways, including the [[epidermal growth factor receptor]] (EGFR) and [[cyclooxygenase]] ([[COX]]), have been shown to play a role in the development of squamous cell carcinoma of the skin.
* Squamous cell [[carcinoma in situ]] (CIS), sometimes referred to as Bowen disease, is a precursor to invasive cSCC. Characteristics of this lesion include nuclear atypia, frequent mitoses, cellular pleomorphism, and dyskeratosis, parakeratosis, and hyperkeratosis.
*<nowiki/>[[p53]] is mutated commonly in [[Actinic keratosis]], demonstrating that [[Dysplastic change|dysplastic]] lesions have acquired the initial [[Genetic mutations|ge]]<nowiki/>[[Genetic mutations|netic mutation]]<nowiki/>s prior to becoming [[cutaneous squamous cell carcinoma]].<ref name="pmid11966728">{{cite journal |vauthors=Ortonne JP |title=From actinic keratosis to squamous cell carcinoma |journal=Br. J. Dermatol. |volume=146 Suppl 61 |issue= |pages=20–3 |date=April 2002 |pmid=11966728 |doi= |url=}}</ref><ref name="pmid15976832">{{cite journal |vauthors=Berner A |title=[Actinic keratosis and development of cutaneous squamous cell carcinoma] |language=Norwegian |journal=Tidsskr. Nor. Laegeforen. |volume=125 |issue=12 |pages=1653–4 |date=June 2005 |pmid=15976832 |doi= |url=}}</ref><ref name="pmid15468170">{{cite journal |vauthors=Tsai KY, Tsao H |title=The genetics of skin cancer |journal=Am J Med Genet C Semin Med Genet |volume=131C |issue=1 |pages=82–92 |date=November 2004 |pmid=15468170 |doi=10.1002/ajmg.c.30037 |url=}}</ref>
* The mechanism leading to genomic instability in [[keratinocytes]] likely results from [[UVB radiation|UVB-induced]] inactivation of [[P53 gene|p5]]<nowiki/>[[P53 gene|3]], since approximately 58% of [[cutaneous squamous cell carcinoma]] harbor [[UVB]] signature [[mutations]] such as CC→TT and C→T transitions.<ref name="pmid52880">{{cite journal |vauthors=Borelli D, Salas J |title=[The use of trypan blue instead of cotton blue in mycology] |language=Spanish; Castilian |journal=Rev. Latinoam. Microbiol. |volume=17 |issue=3 |pages=185–6 |date=1975 |pmid=52880 |doi= |url=}}</ref>
* Aberrant activation of [[EGFR]] and [[Fyn-related kinase|Fyn]], a Src-family tyrosine kinase (SFK), are seen in [[human]] [[cutaneous squamous cell carcinoma]].
* [[Kinases]] downregulate [[p53]] [[mRNA]] and [[protein]] levels through a [[C-Jun|c-Jun–dependent mechanism]] revealing another mechanism for controlling [[P53 gene|p53]] function<ref name="pmid2747621">{{cite journal |vauthors=Strabala TJ, Bednarek SY, Bertoni G, Amasino RM |title=Isolation and characterization of an ipt gene from the Ti plasmid Bo542 |journal=Mol. Gen. Genet. |volume=216 |issue=2-3 |pages=388–94 |date=April 1989 |pmid=2747621 |doi= |url=}}</ref>
* Amplification and activating [[mutations]] of the [[Ras oncogene]] have been found in [[squamous cell carcinoma]] and [[Actinic keratosis|actnic keratosis]]
* [[Ras gene|Ras]] is an upstream activator of the Raf/Mek/Erk1/Erk2 [[kinase pathway]], and activating [[mutations]] in [[Ras gene|Ras]] can promote [[cutaneous squamous cell carcinoma]].<ref name="pmid7611795">{{cite journal |vauthors=Spencer JM, Kahn SM, Jiang W, DeLeo VA, Weinstein IB |title=Activated ras genes occur in human actinic keratoses, premalignant precursors to squamous cell carcinomas |journal=Arch Dermatol |volume=131 |issue=7 |pages=796–800 |date=July 1995 |pmid=7611795 |doi= |url=}}</ref>
* Expression of β1-[[integrins]] and their [[ligands]] correlates with [[Tumor cell|tumor]] progression in [[human]] [[skin]].
* [[Ras gene|Ras]] family members of [[Proto-oncogene|proto-oncogenes]] transduce [[cellular]] growth and [[proliferation]] signals downstream of [[Cell membranes|cell membrane]]–bound [[receptor]] [[tyrosine kinases]] (RTKs). [[Ras gene|Ras]] can be activated by [[gene]] [[amplification]], activating [[mutations]], or overexpression of upstream RTKs. Aberrant [[Ras gene|Ras]] activation promotes several key tumorigenic [[phenotypes]] including [[mitogenesis]], [[resistance]] to [[apoptosis]], [[drug]] [[resistance]].<ref name="pmid16541145">{{cite journal |vauthors=Khavari PA |title=Modelling cancer in human skin tissue |journal=Nat. Rev. Cancer |volume=6 |issue=4 |pages=270–80 |date=April 2006 |pmid=16541145 |doi=10.1038/nrc1838 |url=}}</ref>
[[Squamous cell carcinoma]] is a potentially [[invasive]] [[cancer]] that arises from the surface [[epithelium]].The development of [[squamous cell carcinoma]] is frequently a multistep process. Early lesions tend to be either [[actinic keratoses]], with atypia of the basal [[Keratinocytes|keratinocytic]] layer of the [[epidermis]] or [[squamous cell carcinoma]] in situ, in which [[Keratinocytes|keratinocytic]] atypia spans the full thickness [[epidermis]].
   
   
These precursors are frequently present adjacent to invasive squamous cell carcinomas which invade the dermis as nests, islands, or cords squamous cells with or occasionally as individual cells. Several grading schemes have been developed for squamous cell carcinoma and incorporate the extent of keratinization (a form of differentiation) and nuclear atypia. A widely used scheme divides tumors into well, moderately, or poorly differentiated.
These precursors are frequently present adjacent to invasive [[squamous cell carcinomas]] which invade the [[dermis]] as nests, islands, or cords [[Squamous cell|squamous cells]] with or occasionally as individual [[Cells (biology)|cells]]. Several [[Grading (tumors)|grading]] schemes have been developed for [[squamous cell carcinoma]] and incorporate the extent of [[keratinization]] (a form of differentiation) and [[nuclear]] atypia. A widely used scheme divides [[tumors]] into well, moderately, or poorly [[Differentiate|differentiated]].


Although poorly differentiated tumors tend to behave more aggressively, well-differentiated tumors can also give rise to metastasis and result in death. Several histologic variants of squamous cell carcinoma have been documented, including verrucous, spindle cell and pseudovascular.
Although poorly differentiated [[tumors]] tend to behave more aggressively, well-differentiated [[tumors]] can also give rise to [[metastasis]] and result in death. Several [[histological]] variants of [[squamous cell carcinoma]] have been documented, including [[Verrucous carcinoma|verrucous]], [[Spindle cells|spindle cell]] and [[pseudovascular]].
== Microscopic Pathology ==
*
* Large [[lesions]] require a thorough sample that will adequately assess the entirety of the [[Lesions|lesion]].
* Findings [[Histopathological|Histopathological evaluation]] is important in determining the next step in the [[Grading (tumors)|grade]] and treatment of the [[Cancer (medicine)|cancer.]] The [[Neoplastic|neoplastic cells]] may demonstrate varying degrees of [[squamous]] [[differentiation]] and [[atypia]] uncder the [[Microscopes|microscope]].  


Frequently an actinic keratosis or squamous cell carcinoma overlies the invasive component and the two are focally contiguous. Occasionally squamous tumors arise rapidly, have a crater-form morphology and spontaneously regress. These tumors are known as keratoacanthomas. Some craterform squamous lesions do not regress, but continue to invade and grow and represent invasive squamous cell carcinomas.
*The most conspicuous finding under a [[Microscopes|microscope]] are [[Keratin|keratin pearls]](well formed [[Desmosomes|desmosome]] attachments and intracytoplasmic bundles of [[keratin]] tonofilaments).
 
*SCC can be graded up to [[Grading (tumors)|grade]] 3.
=== Microscopic Pathology ===
**[[Differentiation|Well differentiated]]: [[nuclei]] which are more normal, abundant [[cytoplasm]] & [[extracellular]] keratin pearls
Histopathological examination confirms diagnosis and aids in the staging of the disease. Histopathological evaluates in detail the following characteristics of the specimen;
**Poorly differentiated: High degree of [[nuclear]] [[atypia]], greater [[nuclear:cytoplasmic ratio]] and less [[keratinization]]. Due to poor [[differentiation]] it may mimic [[Mesenchymal|mesenchymal tumor]]<nowiki/>s. Poorly differentiated [[carcinoma]] has a higher rate of [[metastasis]] and high rates of [[invasion]] into surrounding [[tissues]].
*Invasion
**Moderately differentiated: Has an appearance that is midway between poorly [[differentiated]] and well [[differentiated]].
*Differentiation
**[[Squamous cell carcinoma in situ of skin|Squamous cell carcinoma in situ]] - has full thick atypia of [[Squamous cell|squamous cells]] (including surfaces) without [[invasion]] through the [[basement membrane]].
*Depth
 
The various types of biopsy that may be obtained includes shave, punch, and excisional biopsies. The sample may be obtained at a physician's office under local anesthesia. The type of biopsy method chosen is based upon the size of lesion.
*For smaller lesions in easy accessible region of the body, an excisional biopsy is preferred. This may be therapeutic as well as diagnostic.
*For lesions which are large and for which the cosmetic appearance may be of concern, a punch biopsy is advisable. Further treatment is based upon the results of histopathological evaluation.
*A shave biopsy is seldom recommended in cases where the lesion is suspected to be malignant.
 
Important principles to consider when taking a sample for biopsy.
* A full thickness biopsy should be taken to best evaluate the true depth of the lesion and extent of invasion. Depth of the lesion is an important determinant in the prognosis and staging of cancer.<ref>Brantsch KD, Meisner C, Schönfisch B, Trilling B, Wehner-Caroli J, Röcken M, et al. Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study. Lancet Oncol. Aug 2008;9(8):713-20</ref>
* The biopsy specimen should also include samples of normal tissue as a comparison.
* Large lesions require a thorough sample that will adequately assess the entirity of the lesion.
 
Toluidine Blue can be used for the early detection of the oral lesions of squamous cell carcinoma. It has high sensitivity, specificity and accuracy in detecting premalignant lesions. <ref>name="pmid22259809">{{cite journal |author=Rahman F, Tippu SR, Khandelwal S, Girish KL, Manjunath BC, Bhargava A |title=A study to evaluate the efficacy of toluidine blue and cytology in detecting oral cancer and dysplastic lesions |journal=Quintessence Int |volume=43 |issue=1 |pages=51–9 |year=2012 |month=January |pmid=22259809 |doi= |url=}}</ref> The basic principle surrounding the use of toluidine blue staining is that it doesn't stain the normal mucosa, however the dye is easily absorbed by the nuclei of malignant cells.
 
Patients found to have regional lymphadenopathy on physical exam, or in imaging studies, should undergo lymph node biopsy or fine needle aspiration biopsy.
 
'''<u>Histological Findings</u>'''
Histopathological evaluation is important in determining the next step in the grade and treatment of the cancer. The neoplastic cells may demonstrate varying degrees of squamous differentiation and atypia uncder the microscope.
*The most conspicuous finding under a microscope are keratin pearls(well formed desmosome attachments and intracytoplasmic bundles of keratin tonofilaments).
*SCC can be graded up to grade 3.
**Well differentiated: nuclei which are more normal, abundant cytoplasm & extracellular keratin pearls
**Poorly differentiated: High degree of nuclear atypia, greater nuclear:cytoplasmic ratio and less keratinization. Due to poor differentiation it may mimic mesenchymal tumors. Poorly differentiated carcinoma has a higher rate of metastasis and high rates of invasion into surrounding tissues.
**Moderately differentiated: Has an appearance that is midway between poorly differentiated and well differentiated.
**Squamous cell carcinoma in situ - has full thick atypia of squamous cells (including surfaces) without invasion through the basement membrane.
*Invasive carcinomas cause the most inflammation upon invasion of the surrounding tissues.
 
 
'''<u>Skin</u>'''
 
Persons who present with Squamous cell carcinoma of skin may have one of the following risk factors like
 
* significant sun exposure
* benign lesions like Chalazion
* chronic ulcers.
 
<div align="left">
<gallery heights="175" widths="175">
Image:squamous cell skin cancer.jpg|Squamous cell skin cancer.<ref>http://picasaweb.google.com/mcmumbi/USMLEIIImages</ref>
Image:Squamous cell carcinoma oral 003.jpg|Squamous cell carcinoma in oral cavity. <br> <small> [http://www.peir.net Image courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology] </small>
Image:AuricleMelanoma SqCC.jpg|This patient had two adjacent cancers.  The flat black lesion below the antitragus is a malignant melanoma.  The white elevated keratotic lesion is a squamous cell carcinoma <ref>http://www.ghorayeb.com</ref>.
</gallery>
</div>
 
<u>Presentation</u> : They usually notice plaque. Ulcers are commonly seen over the face causing disfiguration. At times they can be exophytic over the lips etc.
 
'''<u>Tongue and Esophagus</u>'''
 
Persons who present with Squamous cell carcinoma of tongue and esophagus are most likely to have following risk factor
 
* Tobacco chewing/smoking
* Alcohol Abuse
* Poor dental hygiene
 
<div align="left">
<gallery heights="175" widths="175">
Image:Squamous cell carcinoma oral 001.jpg|Squamous cell carcinoma in oral cavity. <br> <small> [http://www.peir.net Image courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology] </small>
Image:Squamous_cell_carcinoma.jpg|A large squamous cell carcinoma of the tongue<ref>http://picasaweb.google.com/mcmumbi/USMLEIIImages</ref>
</gallery>
</div>
 
<u>Presentation</u> : Its usually ulcerated in the lateral part of the tongue, pink - red color. Patient finds tough to eat or swallow. As it bleeds on touch or biting. They have dysphagia/ odynophagia when esophagus is involved. In later stages even liquids are tough to go thru. Swelling of lymph nodes is seen in advanced stages where we can find lumps in the neck
 
'''<u>Nasopharynx</u>'''
 
Persons who have SCC of this region seldom have any risk factors. It most of the times caused by EBV infection.
 
<u>Presentation</u> : Patient presents with symptoms from the mass effect of the tumour. They include nasal discharge, bleeding, obstruction; ear infection, deafness , tinnitus are complained. Other important complaints include headache and neck swelling due to lymph nodal spread.<ref>Sham JS, Poon YF, Wei WI, Choy D. Nasopharyngeal carcinoma in young patients. Cancer. Jun 1 1990;65(11):2606-10.</ref>
 
'''<u>Lungs</u>'''
 
Persons who have SCC of lungs usually have risk factors like
 
* Therapeutic radiation (PUVA for psoriais)
* Tobacco smoking
 
<div align="left">
<gallery heights="175" widths="175">
Image:Oral cancer (1) squamous cell carcinoma histopathology.jpg|[[Biopsy]] of a highly differentiated squamous cell carcinoma of the mouth.[[H&E stain|Haematoxylin & eosin stain]].
Image:Ca bronchus.jpg|Photograph of a squamous cell carcinoma. Tumour is on the left, obstructing the bronchus (lung). Beyond the tumour the bronchus is inflammed and contains mucus
</gallery>
</div>
 
<u>Presentation</u> : Persons who present with SCC of lungs doesn't present usually with any typical symptoms of pulmonary. But in few we may see persistent cough, hemoptysis when it is exophytic and occupies whole of the bronchi which can even lead to recurrent infections.
 
'''<u>Penis</u>'''
 
Persons who present with Squamous cell carcinoma of penis are most likely to have
 
* Pre-malignanat lesions ([[Bowen's disease]], [[Condyloma]] , [[Warts]])
* Smoking and tobacco chewing
 
<u>Presentation</u> : Unhealed lesions, subtle indurations may be the intial presentation. Often presentation to the clinic is delayed due to embarrassment most of the times. Warts can be a pre-disposing factor.Large warts lead to infections and necrosis leading to hemorrhages at times.
 
<u>'''Others'''</u>
 
<div align="left">
<gallery heights="175" widths="175">
Image:Head_oral_scc2.jpg|Squamous Cell Cancer of the Mouth: Cancer that began along the lower gum  line has spread to left submandibular lymph nodes.
Image:Head_oral_scc3.jpg|Squamous Cell Cancer of the Mouth: Cancer that began along the lower gum  line has spread to left submandibular lymph nodes.
</gallery>
</div>
 
<div align="left">
<gallery heights="175" widths="175">
Image:Auriclesqccastellateexcision.jpg|Recurrent squamous cell carcinoma of the auricle (far left) excised with a stellate incision across the antihelix.
Image:Auricle003.jpg|The final result of the excision.
</gallery>
</div>
 
<div align="left">
<gallery heights="175" widths="175">
Image:Squamous cell carcinoma of prostate.jpg|Prostate: Squamous cell carcinoma
Image:Squamous cell carcinoma of prostate 2.jpg|Prostate: Squamous cell carcinoma
</gallery>
</div>
 
<div align="left">
<gallery heights="175" widths="175">
Image:Head oral scc.jpg|Squamous Cell Cancer of the Mouth: Irregular, necrotic appearing tissue  on the inside of the mouth due to extensive squamous cell cancer. Patient has limited ability to open  his mouth (aka trismus) as a result of the infiltrating cancer.
Image:head_oral_scc1.jpg|Squamous Cell Cancer, Base of Tongue: Note white area with swelling, right  base of tongue.
 
Image:Squamous cell carcinoma oral 002.jpg|Squamous cell carcinoma in oral cavity. <br> <small> [http://www.peir.net Image courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology] </small>
</gallery>
</div>
 
=== Cervix: Squamous cell carcinoma===
 
{{#ev:youtube|zB47nE-i8dQ}}
 
{{#ev:youtube|J3kULzKGzws}}


==References==
==References==
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{{reflist|2}}
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Latest revision as of 14:15, 14 August 2020

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aditya Govindavarjhulla, M.B.B.S. [2], Raviteja Guddeti, M.B.B.S. [3]

Overview

Squamous cell carcinoma (SCC) is type of non-melanoma skin cancer. The cancer arises as a result of uncontrolled growth of the squamous cells in the epidermis of the skin. Unlike it's counter part, the basal cell carcinoma which also belongs to the group of non-melanoma cancer, squamous cell carcinoma is rapid growing and invasive. SCCs may occur on all areas of the body including the mucous membranes and genitals, but are most common in areas frequently exposed to the sun, such as the rim of the ear, lower lip, face, bald scalp, neck, hands, arms and legs. Wrinkling, changes in pigmentation, and loss of elasticity of the skin are often the telltale signs of sun damage.

Pathophysiology

Squamous cell carcinoma is a potentially invasive cancer that arises from the surface epithelium.The development of squamous cell carcinoma is frequently a multistep process. Early lesions tend to be either actinic keratoses, with atypia of the basal keratinocytic layer of the epidermis or squamous cell carcinoma in situ, in which keratinocytic atypia spans the full thickness epidermis.

These precursors are frequently present adjacent to invasive squamous cell carcinomas which invade the dermis as nests, islands, or cords squamous cells with or occasionally as individual cells. Several grading schemes have been developed for squamous cell carcinoma and incorporate the extent of keratinization (a form of differentiation) and nuclear atypia. A widely used scheme divides tumors into well, moderately, or poorly differentiated.

Although poorly differentiated tumors tend to behave more aggressively, well-differentiated tumors can also give rise to metastasis and result in death. Several histological variants of squamous cell carcinoma have been documented, including verrucous, spindle cell and pseudovascular.

Microscopic Pathology

References

  1. ↑ Brash DE (2006). "Roles of the transcription factor p53 in keratinocyte carcinomas". Br J Dermatol. 154 Suppl 1: 8–10. doi:10.1111/j.1365-2133.2006.07230.x. PMID 16712710.
  2. ↑ Ortonne JP (April 2002). "From actinic keratosis to squamous cell carcinoma". Br. J. Dermatol. 146 Suppl 61: 20–3. PMID 11966728.
  3. ↑ Berner A (June 2005). "[Actinic keratosis and development of cutaneous squamous cell carcinoma]". Tidsskr. Nor. Laegeforen. (in Norwegian). 125 (12): 1653–4. PMID 15976832.
  4. ↑ Tsai KY, Tsao H (November 2004). "The genetics of skin cancer". Am J Med Genet C Semin Med Genet. 131C (1): 82–92. doi:10.1002/ajmg.c.30037. PMID 15468170.
  5. ↑ Borelli D, Salas J (1975). "[The use of trypan blue instead of cotton blue in mycology]". Rev. Latinoam. Microbiol. (in Spanish; Castilian). 17 (3): 185–6. PMID 52880.
  6. ↑ Strabala TJ, Bednarek SY, Bertoni G, Amasino RM (April 1989). "Isolation and characterization of an ipt gene from the Ti plasmid Bo542". Mol. Gen. Genet. 216 (2–3): 388–94. PMID 2747621.
  7. ↑ Spencer JM, Kahn SM, Jiang W, DeLeo VA, Weinstein IB (July 1995). "Activated ras genes occur in human actinic keratoses, premalignant precursors to squamous cell carcinomas". Arch Dermatol. 131 (7): 796–800. PMID 7611795.
  8. ↑ Khavari PA (April 2006). "Modelling cancer in human skin tissue". Nat. Rev. Cancer. 6 (4): 270–80. doi:10.1038/nrc1838. PMID 16541145.


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