Cutaneous Squamous Cell Carcinoma

MONDO:0002529 Pathograph 6 skin carcinoma squamous cell carcinoma

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer, arising from malignant transformation of epidermal keratinocytes. It is strongly associated with cumulative ultraviolet (UV) radiation exposure, which induces characteristic TP53 mutations and other oncogenic alterations including NOTCH, CDKN2A, and RAS pathway disruption. Immunosuppression, particularly in organ transplant recipients, dramatically increases risk by 65- to 200-fold. Actinic keratosis serves as a recognized precursor lesion within a field cancerization continuum. While most cases are curable with surgical excision, approximately 3-5% progress to metastatic disease. Cemiplimab, an anti-PD-1 checkpoint inhibitor, has been approved for locally advanced or metastatic cSCC.

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6
Pathophys.
1
Histopath.
4
Phenotypes
6
Pathograph
6
Genes
4
Treatments
1
Deep Research
⚙

Pathophysiology

6
UV-Induced DNA Damage and Field Cancerization
Chronic ultraviolet (UV) radiation exposure, particularly UVB, causes direct DNA damage through formation of cyclobutane pyrimidine dimers and pyrimidine-pyrimidone photoproducts. Characteristic C>T and CC>TT UV-signature mutations accumulate in keratinocytes. Clinically normal sun-exposed skin harbors extensive fields of mutated keratinocyte clones (field cancerization), with TP53 and NOTCH mutations detectable in morphologically normal epidermis. cSCC has a very high tumor mutational burden of approximately 45.2 mutations/Mb.
keratinocyte link
DNA damage response link ↓ DECREASED
skin of body link
Downstream
TP53 Inactivation UV-induced mutations in TP53 tumor suppressor gene
NOTCH Pathway Inactivation UV-induced loss-of-function mutations in NOTCH1/2
RAS Pathway Activation UV-induced activating mutations in RAS family genes
Show evidence (2 references)
DOI:10.3390/cancers16162904 SUPPORT Human Clinical
"Cutaneous squamous cell carcinoma (cSCC) manifests through the complex interactions of UV-induced DNA damage, genetic mutations, and alterations in the tumor microenvironment. A high mutational burden is present in cSCC, as well as both cSCC precursors and normal skin, making driver genes..."
Confirms that UV-induced DNA damage and high mutational burden are central to cSCC pathophysiology, including in precursor lesions and normal skin.
DOI:10.3390/ijms25115775 SUPPORT Human Clinical
"Cutaneous field cancerization (CFC) refers to a skin region containing mutated cells' clones, predominantly arising from chronic exposure to ultraviolet radiation (UVR), which exhibits an elevated risk of developing precancerous and neoplastic lesions."
Defines field cancerization as mutated clonal expansion driven by UV exposure that predisposes to actinic keratosis and cSCC.
TP53 Inactivation
TP53 mutations are found in 54-95% of cutaneous squamous cell carcinomas. UV-induced loss-of-function mutations in TP53 eliminate critical cell cycle checkpoint control and DNA damage-induced apoptosis, allowing cells with accumulated genomic damage to survive and proliferate. TP53 mutations are also found in actinic keratoses and even normal sun-exposed skin, indicating this is an early event in cSCC carcinogenesis.
cell cycle checkpoint signaling link ↓ DECREASED apoptotic process link ↓ DECREASED
Downstream
Uncontrolled Keratinocyte Proliferation Loss of p53-mediated growth arrest enables continued proliferation
Show evidence (1 reference)
DOI:10.3390/cancers16162904 SUPPORT Human Clinical
"several key driver genes have been identified, including TP53, the NOTCH family, CDKN2A, PIK3CA, and EGFR"
Confirms TP53 as one of the key driver genes in cSCC pathogenesis.
NOTCH Pathway Inactivation
Loss-of-function mutations in NOTCH1 and NOTCH2 are among the most frequent alterations in cSCC, found in 50-80% of cases. NOTCH signaling is critical for keratinocyte differentiation, and its disruption promotes a shift from differentiated to progenitor-like state. Notably, NOTCH mutations are also common in normal sun-exposed skin.
keratinocyte differentiation link ↓ DECREASED
Downstream
Uncontrolled Keratinocyte Proliferation Loss of differentiation promotes progenitor-like proliferative state
Show evidence (1 reference)
DOI:10.1038/s41467-023-40822-9 SUPPORT Human Clinical
"reveal a disease continuum from a differentiated to a progenitor-like state. This is accompanied by the orchestrated suppression of master regulators of epidermal differentiation"
Demonstrates that cSCC progression involves suppression of epidermal differentiation regulators, consistent with NOTCH pathway inactivation.
RAS Pathway Activation
Activating mutations in RAS family genes (HRAS, KRAS, NRAS) occur in a subset of cSCCs, leading to constitutive activation of the MAPK/ERK signaling cascade. This drives cell proliferation, survival, and resistance to apoptosis. EGFR signaling upstream of RAS and PI3K/AKT/mTOR signaling downstream are also frequently dysregulated. PI3K/AKT/mTOR is consistently activated in cSCC but not in actinic keratosis, implicating it in the transition to malignancy.
Ras protein signal transduction link ↑ INCREASED
Downstream
Uncontrolled Keratinocyte Proliferation Constitutive RAS signaling promotes cell proliferation
Show evidence (1 reference)
DOI:10.1038/s41467-023-40822-9 SUPPORT Model Organism
"genetically engineered murine models reveal that combinatorial sequential inactivation of the tumour suppressor genesTgfbr2,Trp53, andNotch1coupled with activation of Ras signalling progressively drives cSCC progression along a differentiated to progenitor axis"
Study using genetically engineered murine models demonstrates that Ras activation combined with tumor suppressor loss drives cSCC progression.
Tumor Microenvironment Remodeling and Immune Evasion
Cutaneous SCC progression involves active immune manipulation. The tumor microenvironment features increased TGF-beta, IL-10, and regulatory T cells alongside reduced plasmacytoid dendritic cells, creating an immunosuppressive milieu. M2-polarized tumor-associated macrophages and cancer-associated fibroblasts contribute to angiogenesis and extracellular matrix remodeling. PD-L1 upregulation suppresses antitumor T cell activity. This is particularly important in immunosuppressed patients where reduced immune surveillance dramatically increases cSCC incidence.
CD8-positive, alpha-beta T cell link regulatory T cell link macrophage link fibroblast link
immune response link ↓ DECREASED
Downstream
Uncontrolled Keratinocyte Proliferation Impaired immune surveillance allows tumor cell expansion
Show evidence (2 references)
DOI:10.3390/cancers15092453 SUPPORT Human Clinical
"the cellular players within both create an immunosuppressed environment by downregulating effector CD4+ and CD8+ T cells and promoting the release of pro-oncogenic Th2 cytokines"
Confirms that the tumor microenvironment in SCC creates immunosuppression by downregulating effector T cells.
PMID:30968759 SUPPORT Human Clinical
"Transplant immunosuppression increases the risk of cutaneous squamous cell carcinoma by 65- to 200-fold."
Quantifies the dramatic increase in cSCC risk conferred by iatrogenic immunosuppression in organ transplant recipients.
Uncontrolled Keratinocyte Proliferation
The convergence of TP53 inactivation, NOTCH pathway loss, RAS pathway activation, and immune evasion drives uncontrolled proliferation of transformed keratinocytes. Disease progression follows a continuum from normal sun-exposed skin through actinic keratosis and in situ carcinoma to invasive cSCC, characterized by a transcriptomic shift from a differentiated to a progenitor-like state.
keratinocyte link
cell population proliferation link ↑ INCREASED
Show evidence (1 reference)
DOI:10.1038/s41467-023-40822-9 SUPPORT Human Clinical
"RNAseq transcriptomic profiling of 110 patient samples representing normal sun-exposed skin, AK, primary and metastatic cSCC and reveal a disease continuum from a differentiated to a progenitor-like state"
Demonstrates the disease continuum across normal skin, AK, primary and metastatic cSCC driven by progressive loss of differentiation.
✶

Histopathology

1
Squamous Cell Carcinoma of Skin OBLIGATE
Malignant proliferation of squamous epithelial cells arising from epidermal keratinocytes. Histologically characterized by nests and sheets of atypical squamous cells with varying degrees of keratinization.
Show evidence (1 reference)
DOI:10.3390/cancers16101800 SUPPORT Human Clinical
"Representing the second most common skin cancer, the incidence and disease burden of cutaneous squamous cell carcinoma (cSCC) continues to increase."
Establishes cSCC as the second most common skin cancer with increasing incidence.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Cutaneous Squamous Cell Carcinoma Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

4
Integument 3
Squamous Cell Carcinoma of the Skin OBLIGATE Squamous cell carcinoma of the skin (HP:0006739)
Show evidence (1 reference)
DOI:10.3390/cancers16101800 SUPPORT Human Clinical
"Surgical excision of the primary site effectively cures the majority of cSCC cases. However, an aggressive subset of cSCC persists with clinicopathological features that are indicative of higher recurrence, metastasis, and mortality risks."
Confirms the clinical presentation of cSCC as a skin tumor with varying aggressiveness.
Actinic Keratosis FREQUENT Actinic keratosis (HP:0025127)
Show evidence (1 reference)
DOI:10.3390/ijms25115775 SUPPORT Human Clinical
"our results suggest that despite its outwardly normal appearance, CFC tissue shows early signs of DNA damage, an active inflammatory state, oxidative stress, abnormal cell proliferation and differentiation"
Demonstrates molecular changes in field cancerization tissue preceding overt actinic keratosis and cSCC development.
Skin Ulceration FREQUENT Skin ulcer (HP:0200042)
Constitutional 1
Pain at Tumor Site OCCASIONAL Pain (HP:0012531)
🧬

Genetic Associations

6
TP53 (Somatic Mutation)
Show evidence (1 reference)
DOI:10.3390/cancers16162904 SUPPORT Human Clinical
"several key driver genes have been identified, including TP53, the NOTCH family, CDKN2A, PIK3CA, and EGFR"
Identifies TP53 as a key driver gene in cSCC.
NOTCH1/NOTCH2 (Somatic Mutation (Loss-of-Function))
Show evidence (1 reference)
DOI:10.3390/cancers16162904 SUPPORT Human Clinical
"several key driver genes have been identified, including TP53, the NOTCH family, CDKN2A, PIK3CA, and EGFR"
Identifies NOTCH family as key driver genes in cSCC.
CDKN2A (Somatic Mutation/Deletion)
HRAS (Somatic Mutation)
EGFR (Dysregulation/Overexpression)
PIK3CA (Somatic Mutation)
💊

Treatments

4
Surgical Excision
Action: surgical excision MAXO:0000447
Standard surgical excision with adequate margins is the primary treatment for most cutaneous squamous cell carcinomas. Effectively cures the majority of cases.
Show evidence (1 reference)
DOI:10.3390/cancers16101800 SUPPORT Human Clinical
"Surgical excision of the primary site effectively cures the majority of cSCC cases."
Confirms surgical excision as the curative standard of care for most cSCC.
Mohs Micrographic Surgery
Action: surgical excision MAXO:0000447
Specialized surgical technique with intraoperative margin assessment, achieving the highest cure rates while maximizing tissue conservation. Indicated for high-risk tumors, recurrent lesions, and cosmetically sensitive locations.
Radiation Therapy
Action: radiation therapy MAXO:0000014
Used as primary treatment for nonsurgical candidates or as adjuvant therapy for high-risk features including perineural invasion and positive margins.
Cemiplimab (Anti-PD-1 Immunotherapy)
Action: immunotherapy Ontology label: Immunotherapy NCIT:C15262
Cemiplimab is an anti-PD-1 checkpoint inhibitor approved for locally advanced or metastatic cSCC not amenable to curative surgery or radiation. It restores T cell-mediated antitumor immunity by blocking the PD-1/PD-L1 interaction. In clinical trials, cemiplimab induced a response in approximately half of patients with advanced cSCC.
Show evidence (2 references)
PMID:29863979 SUPPORT Human Clinical
"Among patients with advanced cutaneous squamous-cell carcinoma, cemiplimab induced a response in approximately half the patients and was associated with adverse events that usually occur with immune checkpoint inhibitors."
Landmark trial establishing cemiplimab efficacy in advanced cSCC with approximately 47-50% response rate.
DOI:10.3390/ijms25137056 SUPPORT Human Clinical
"PD-1/PD-L1 inhibitors for locally advanced cutaneous squamous cell carcinoma (cSCC) and Merkel cell carcinoma (MCC)"
Confirms PD-1/PD-L1 inhibitors as part of the current treatment landscape for advanced cSCC.
🌍

Environmental Factors

2
Ultraviolet Radiation Exposure
Chronic cumulative UV radiation exposure (particularly UVB) is the primary environmental risk factor for cSCC. UV radiation directly damages DNA in keratinocytes and suppresses local immune responses. Risk correlates with lifetime sun exposure, geographic latitude, and skin phototype.
Show evidence (2 references)
DOI:10.3390/cancers16162904 SUPPORT Human Clinical
"Cutaneous squamous cell carcinoma (cSCC) manifests through the complex interactions of UV-induced DNA damage, genetic mutations, and alterations in the tumor microenvironment."
Confirms UV-induced DNA damage as a primary driver of cSCC.
DOI:10.3390/ijms25137056 SUPPORT Human Clinical
"Skin exposure is the leading risk factor for initiating NMSC. Ultraviolet (UV) light induces various genomic aberrations in both tumor-promoting and tumor-suppressing genes in epidermal cells."
Confirms UV exposure as the leading risk factor for NMSC including cSCC.
Immunosuppression (Organ Transplant)
Iatrogenic immunosuppression, particularly in solid organ transplant recipients, increases cSCC risk 65- to 200-fold. One in twenty solid organ transplant recipients will develop a highly morbid or fatal cutaneous carcinoma. The risk correlates with duration and intensity of immunosuppressive therapy and the type of organ transplanted.
Show evidence (2 references)
PMID:30968759 SUPPORT Human Clinical
"Transplant immunosuppression increases the risk of cutaneous squamous cell carcinoma by 65- to 200-fold."
Quantifies the dramatic increase in cSCC risk from transplant immunosuppression.
PMID:32065978 SUPPORT Human Clinical
"One in twenty solid organ transplant recipients (SOTRs) will develop a highly morbid or fatal cutaneous carcinoma after transplantation."
Quantifies the high burden of cutaneous carcinoma in organ transplant recipients.
{ }

Source YAML

click to show 
name: Cutaneous Squamous Cell Carcinoma
creation_date: "2026-03-06T00:00:00Z"
updated_date: "2026-03-06T00:00:00Z"
description: >-
  Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer,
  arising from malignant transformation of epidermal keratinocytes. It is strongly
  associated with cumulative ultraviolet (UV) radiation exposure, which induces
  characteristic TP53 mutations and other oncogenic alterations including NOTCH,
  CDKN2A, and RAS pathway disruption. Immunosuppression, particularly in organ
  transplant recipients, dramatically increases risk by 65- to 200-fold. Actinic
  keratosis serves as a recognized precursor lesion within a field cancerization
  continuum. While most cases are curable with surgical excision, approximately
  3-5% progress to metastatic disease. Cemiplimab, an anti-PD-1 checkpoint
  inhibitor, has been approved for locally advanced or metastatic cSCC.
categories:
- Skin Cancer
- Solid Tumor
parents:
- skin carcinoma
- squamous cell carcinoma
disease_term:
  preferred_term: cutaneous squamous cell carcinoma
  term:
    id: MONDO:0002529
    label: skin squamous cell carcinoma
pathophysiology:
- name: UV-Induced DNA Damage and Field Cancerization
  description: >-
    Chronic ultraviolet (UV) radiation exposure, particularly UVB, causes direct
    DNA damage through formation of cyclobutane pyrimidine dimers and pyrimidine-pyrimidone
    photoproducts. Characteristic C>T and CC>TT UV-signature mutations accumulate in
    keratinocytes. Clinically normal sun-exposed skin harbors extensive fields of
    mutated keratinocyte clones (field cancerization), with TP53 and NOTCH mutations
    detectable in morphologically normal epidermis. cSCC has a very high tumor
    mutational burden of approximately 45.2 mutations/Mb.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: DNA damage response
    modifier: DECREASED
    term:
      id: GO:0006974
      label: DNA damage response
  locations:
  - preferred_term: skin of body
    term:
      id: UBERON:0002097
      label: skin of body
  evidence:
  - reference: DOI:10.3390/cancers16162904
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cutaneous squamous cell carcinoma (cSCC) manifests through the complex
      interactions of UV-induced DNA damage, genetic mutations, and alterations
      in the tumor microenvironment. A high mutational burden is present in cSCC,
      as well as both cSCC precursors and normal skin, making driver genes
      difficult to differentiate.
    explanation: >-
      Confirms that UV-induced DNA damage and high mutational burden are central
      to cSCC pathophysiology, including in precursor lesions and normal skin.
  - reference: DOI:10.3390/ijms25115775
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cutaneous field cancerization (CFC) refers to a skin region containing
      mutated cells' clones, predominantly arising from chronic exposure to
      ultraviolet radiation (UVR), which exhibits an elevated risk of developing
      precancerous and neoplastic lesions.
    explanation: >-
      Defines field cancerization as mutated clonal expansion driven by UV
      exposure that predisposes to actinic keratosis and cSCC.
  downstream:
  - target: TP53 Inactivation
    description: UV-induced mutations in TP53 tumor suppressor gene
  - target: NOTCH Pathway Inactivation
    description: UV-induced loss-of-function mutations in NOTCH1/2
  - target: RAS Pathway Activation
    description: UV-induced activating mutations in RAS family genes
- name: TP53 Inactivation
  description: >-
    TP53 mutations are found in 54-95% of cutaneous squamous cell carcinomas.
    UV-induced loss-of-function mutations in TP53 eliminate critical cell cycle
    checkpoint control and DNA damage-induced apoptosis, allowing cells with
    accumulated genomic damage to survive and proliferate. TP53 mutations are
    also found in actinic keratoses and even normal sun-exposed skin, indicating
    this is an early event in cSCC carcinogenesis.
  biological_processes:
  - preferred_term: cell cycle checkpoint signaling
    modifier: DECREASED
    term:
      id: GO:0000075
      label: cell cycle checkpoint signaling
  - preferred_term: apoptotic process
    modifier: DECREASED
    term:
      id: GO:0006915
      label: apoptotic process
  evidence:
  - reference: DOI:10.3390/cancers16162904
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      several key driver genes have been identified, including TP53, the NOTCH
      family, CDKN2A, PIK3CA, and EGFR
    explanation: >-
      Confirms TP53 as one of the key driver genes in cSCC pathogenesis.
  downstream:
  - target: Uncontrolled Keratinocyte Proliferation
    description: Loss of p53-mediated growth arrest enables continued proliferation
- name: NOTCH Pathway Inactivation
  description: >-
    Loss-of-function mutations in NOTCH1 and NOTCH2 are among the most frequent
    alterations in cSCC, found in 50-80% of cases. NOTCH signaling is critical
    for keratinocyte differentiation, and its disruption promotes a shift from
    differentiated to progenitor-like state. Notably, NOTCH mutations are also
    common in normal sun-exposed skin.
  biological_processes:
  - preferred_term: keratinocyte differentiation
    modifier: DECREASED
    term:
      id: GO:0030216
      label: keratinocyte differentiation
  evidence:
  - reference: DOI:10.1038/s41467-023-40822-9
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      reveal a disease continuum from a differentiated to a progenitor-like
      state. This is accompanied by the orchestrated suppression of master
      regulators of epidermal differentiation
    explanation: >-
      Demonstrates that cSCC progression involves suppression of epidermal
      differentiation regulators, consistent with NOTCH pathway inactivation.
  downstream:
  - target: Uncontrolled Keratinocyte Proliferation
    description: Loss of differentiation promotes progenitor-like proliferative state
- name: RAS Pathway Activation
  description: >-
    Activating mutations in RAS family genes (HRAS, KRAS, NRAS) occur in a subset
    of cSCCs, leading to constitutive activation of the MAPK/ERK signaling cascade.
    This drives cell proliferation, survival, and resistance to apoptosis. EGFR
    signaling upstream of RAS and PI3K/AKT/mTOR signaling downstream are also
    frequently dysregulated. PI3K/AKT/mTOR is consistently activated in cSCC
    but not in actinic keratosis, implicating it in the transition to malignancy.
  biological_processes:
  - preferred_term: Ras protein signal transduction
    modifier: INCREASED
    term:
      id: GO:0007265
      label: Ras protein signal transduction
  evidence:
  - reference: DOI:10.1038/s41467-023-40822-9
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      genetically engineered murine models reveal that combinatorial sequential
      inactivation of the tumour suppressor genesTgfbr2,Trp53, andNotch1coupled
      with activation of Ras signalling progressively drives cSCC progression
      along a differentiated to progenitor axis
    explanation: >-
      Study using genetically engineered murine models demonstrates that
      Ras activation combined with tumor suppressor loss drives cSCC progression.
  downstream:
  - target: Uncontrolled Keratinocyte Proliferation
    description: Constitutive RAS signaling promotes cell proliferation
- name: Tumor Microenvironment Remodeling and Immune Evasion
  description: >-
    Cutaneous SCC progression involves active immune manipulation. The tumor
    microenvironment features increased TGF-beta, IL-10, and regulatory T cells
    alongside reduced plasmacytoid dendritic cells, creating an immunosuppressive
    milieu. M2-polarized tumor-associated macrophages and cancer-associated
    fibroblasts contribute to angiogenesis and extracellular matrix remodeling.
    PD-L1 upregulation suppresses antitumor T cell activity. This is particularly
    important in immunosuppressed patients where reduced immune surveillance
    dramatically increases cSCC incidence.
  cell_types:
  - preferred_term: CD8-positive, alpha-beta T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  - preferred_term: regulatory T cell
    term:
      id: CL:0000815
      label: regulatory T cell
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: immune response
    modifier: DECREASED
    term:
      id: GO:0006955
      label: immune response
  evidence:
  - reference: DOI:10.3390/cancers15092453
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the cellular players within both create an immunosuppressed environment by
      downregulating effector CD4+ and CD8+ T cells and promoting the release
      of pro-oncogenic Th2 cytokines
    explanation: >-
      Confirms that the tumor microenvironment in SCC creates immunosuppression
      by downregulating effector T cells.
  - reference: PMID:30968759
    reference_title: "Type of Organ Transplanted Impacts the Risk and Presentation of Cutaneous Squamous Cell Carcinoma in Transplant Recipients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Transplant immunosuppression increases the risk of cutaneous squamous cell
      carcinoma by 65- to 200-fold.
    explanation: >-
      Quantifies the dramatic increase in cSCC risk conferred by iatrogenic
      immunosuppression in organ transplant recipients.
  downstream:
  - target: Uncontrolled Keratinocyte Proliferation
    description: Impaired immune surveillance allows tumor cell expansion
- name: Uncontrolled Keratinocyte Proliferation
  description: >-
    The convergence of TP53 inactivation, NOTCH pathway loss, RAS pathway
    activation, and immune evasion drives uncontrolled proliferation of
    transformed keratinocytes. Disease progression follows a continuum from
    normal sun-exposed skin through actinic keratosis and in situ carcinoma
    to invasive cSCC, characterized by a transcriptomic shift from a
    differentiated to a progenitor-like state.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  evidence:
  - reference: DOI:10.1038/s41467-023-40822-9
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RNAseq transcriptomic profiling of 110 patient samples representing
      normal sun-exposed skin, AK, primary and metastatic cSCC and reveal a
      disease continuum from a differentiated to a progenitor-like state
    explanation: >-
      Demonstrates the disease continuum across normal skin, AK, primary and
      metastatic cSCC driven by progressive loss of differentiation.
histopathology:
- name: Squamous Cell Carcinoma of Skin
  finding_term:
    preferred_term: Skin Squamous Cell Carcinoma
    term:
      id: NCIT:C4819
      label: Skin Squamous Cell Carcinoma
  frequency: OBLIGATE
  description: >-
    Malignant proliferation of squamous epithelial cells arising from
    epidermal keratinocytes. Histologically characterized by nests and sheets
    of atypical squamous cells with varying degrees of keratinization.
  evidence:
  - reference: DOI:10.3390/cancers16101800
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Representing the second most common skin cancer, the incidence and
      disease burden of cutaneous squamous cell carcinoma (cSCC) continues
      to increase.
    explanation: >-
      Establishes cSCC as the second most common skin cancer with increasing
      incidence.
phenotypes:
- category: Dermatologic
  name: Squamous Cell Carcinoma of the Skin
  frequency: OBLIGATE
  description: >-
    Firm, indurated nodule, plaque, or ulcerated lesion, typically on sun-exposed
    skin areas including head, neck, dorsal hands, and forearms.
  phenotype_term:
    preferred_term: Squamous cell carcinoma of the skin
    term:
      id: HP:0006739
      label: Squamous cell carcinoma of the skin
  evidence:
  - reference: DOI:10.3390/cancers16101800
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Surgical excision of the primary site effectively cures the majority of
      cSCC cases. However, an aggressive subset of cSCC persists with
      clinicopathological features that are indicative of higher recurrence,
      metastasis, and mortality risks.
    explanation: >-
      Confirms the clinical presentation of cSCC as a skin tumor with varying
      aggressiveness.
- category: Dermatologic
  name: Actinic Keratosis
  frequency: FREQUENT
  description: >-
    Rough, scaly patches on sun-exposed skin representing premalignant
    keratinocyte dysplasia. A recognized precursor to invasive cSCC, though
    fewer than 0.1% of individual AKs progress to invasive carcinoma.
  phenotype_term:
    preferred_term: Actinic keratosis
    term:
      id: HP:0025127
      label: Actinic keratosis
  evidence:
  - reference: DOI:10.3390/ijms25115775
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      our results suggest that despite its outwardly normal appearance, CFC
      tissue shows early signs of DNA damage, an active inflammatory state,
      oxidative stress, abnormal cell proliferation and differentiation
    explanation: >-
      Demonstrates molecular changes in field cancerization tissue preceding
      overt actinic keratosis and cSCC development.
- category: Dermatologic
  name: Skin Ulceration
  frequency: FREQUENT
  description: >-
    Ulceration of the tumor surface, often with raised, rolled borders.
    Ulceration is a high-risk feature associated with increased metastatic potential.
  phenotype_term:
    preferred_term: Skin ulcer
    term:
      id: HP:0200042
      label: Skin ulcer
- category: Constitutional
  name: Pain at Tumor Site
  frequency: OCCASIONAL
  description: >-
    Local pain or tenderness at the site of tumor growth, particularly with
    perineural invasion, which is a high-risk feature.
  phenotype_term:
    preferred_term: Pain
    term:
      id: HP:0012531
      label: Pain
genetic:
- name: TP53
  association: Somatic Mutation
  notes: >-
    TP53 mutations are present in 54-95% of cSCCs, with characteristic
    UV-signature C>T transitions. These are loss-of-function mutations that
    disable p53 tumor suppressor activity. TP53 mutations are also found
    in actinic keratoses and normal sun-exposed skin, indicating early
    involvement in carcinogenesis.
  evidence:
  - reference: DOI:10.3390/cancers16162904
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      several key driver genes have been identified, including TP53, the NOTCH
      family, CDKN2A, PIK3CA, and EGFR
    explanation: >-
      Identifies TP53 as a key driver gene in cSCC.
- name: NOTCH1/NOTCH2
  association: Somatic Mutation (Loss-of-Function)
  notes: >-
    NOTCH pathway loss-of-function mutations are among the most frequent
    alterations in cSCC (50-80% of cases), contributing to impaired
    keratinocyte differentiation. NOTCH mutations are also common in
    normal sun-exposed skin.
  evidence:
  - reference: DOI:10.3390/cancers16162904
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      several key driver genes have been identified, including TP53, the NOTCH
      family, CDKN2A, PIK3CA, and EGFR
    explanation: >-
      Identifies NOTCH family as key driver genes in cSCC.
- name: CDKN2A
  association: Somatic Mutation/Deletion
  notes: >-
    CDKN2A (p16INK4a) inactivation through mutation, deletion, or promoter
    methylation is frequent in cSCC, removing an important cell cycle brake
    and contributing to unrestrained cell cycling.
- name: HRAS
  association: Somatic Mutation
  notes: >-
    Activating HRAS mutations occur in a subset of cSCCs, driving MAPK
    pathway activation and cell proliferation. Cooperates with tumor
    suppressor loss to promote progression.
- name: EGFR
  association: Dysregulation/Overexpression
  notes: >-
    EGFR dysregulation activates Ras-Raf-MEK-ERK and PI3K pathways,
    driving proliferation. EGFR inhibitors have been explored therapeutically.
- name: PIK3CA
  association: Somatic Mutation
  notes: >-
    PIK3CA mutations activate PI3K/AKT/mTOR signaling, which is consistently
    activated in cSCC but not in actinic keratosis, implicating it in the
    transition from precancer to invasive carcinoma.
environmental:
- name: Ultraviolet Radiation Exposure
  description: >-
    Chronic cumulative UV radiation exposure (particularly UVB) is the
    primary environmental risk factor for cSCC. UV radiation directly
    damages DNA in keratinocytes and suppresses local immune responses.
    Risk correlates with lifetime sun exposure, geographic latitude,
    and skin phototype.
  evidence:
  - reference: DOI:10.3390/cancers16162904
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cutaneous squamous cell carcinoma (cSCC) manifests through the complex
      interactions of UV-induced DNA damage, genetic mutations, and alterations
      in the tumor microenvironment.
    explanation: >-
      Confirms UV-induced DNA damage as a primary driver of cSCC.
  - reference: DOI:10.3390/ijms25137056
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Skin exposure is the leading risk factor for initiating NMSC.
      Ultraviolet (UV) light induces various genomic aberrations in both
      tumor-promoting and tumor-suppressing genes in epidermal cells.
    explanation: >-
      Confirms UV exposure as the leading risk factor for NMSC including cSCC.
- name: Immunosuppression (Organ Transplant)
  description: >-
    Iatrogenic immunosuppression, particularly in solid organ transplant
    recipients, increases cSCC risk 65- to 200-fold. One in twenty solid
    organ transplant recipients will develop a highly morbid or fatal
    cutaneous carcinoma. The risk correlates with duration and intensity
    of immunosuppressive therapy and the type of organ transplanted.
  evidence:
  - reference: PMID:30968759
    reference_title: "Type of Organ Transplanted Impacts the Risk and Presentation of Cutaneous Squamous Cell Carcinoma in Transplant Recipients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Transplant immunosuppression increases the risk of cutaneous squamous cell
      carcinoma by 65- to 200-fold.
    explanation: >-
      Quantifies the dramatic increase in cSCC risk from transplant
      immunosuppression.
  - reference: PMID:32065978
    reference_title: "Cutaneous squamous cell carcinoma in the organ transplant recipient."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One in twenty solid organ transplant recipients (SOTRs) will develop a
      highly morbid or fatal cutaneous carcinoma after transplantation.
    explanation: >-
      Quantifies the high burden of cutaneous carcinoma in organ transplant
      recipients.
treatments:
- name: Surgical Excision
  description: >-
    Standard surgical excision with adequate margins is the primary treatment
    for most cutaneous squamous cell carcinomas. Effectively cures the majority
    of cases.
  treatment_term:
    preferred_term: surgical excision
    term:
      id: MAXO:0000447
      label: surgical excision
  evidence:
  - reference: DOI:10.3390/cancers16101800
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Surgical excision of the primary site effectively cures the majority of
      cSCC cases.
    explanation: >-
      Confirms surgical excision as the curative standard of care for most cSCC.
- name: Mohs Micrographic Surgery
  description: >-
    Specialized surgical technique with intraoperative margin assessment,
    achieving the highest cure rates while maximizing tissue conservation.
    Indicated for high-risk tumors, recurrent lesions, and cosmetically
    sensitive locations.
  treatment_term:
    preferred_term: surgical excision
    term:
      id: MAXO:0000447
      label: surgical excision
- name: Radiation Therapy
  description: >-
    Used as primary treatment for nonsurgical candidates or as adjuvant
    therapy for high-risk features including perineural invasion and
    positive margins.
  treatment_term:
    preferred_term: radiation therapy
    term:
      id: MAXO:0000014
      label: radiation therapy
- name: Cemiplimab (Anti-PD-1 Immunotherapy)
  description: >-
    Cemiplimab is an anti-PD-1 checkpoint inhibitor approved for locally
    advanced or metastatic cSCC not amenable to curative surgery or radiation.
    It restores T cell-mediated antitumor immunity by blocking the PD-1/PD-L1
    interaction. In clinical trials, cemiplimab induced a response in
    approximately half of patients with advanced cSCC.
  treatment_term:
    preferred_term: immunotherapy
    term:
      id: NCIT:C15262
      label: Immunotherapy
  evidence:
  - reference: PMID:29863979
    reference_title: "PD-1 Blockade with Cemiplimab in Advanced Cutaneous Squamous-Cell Carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among patients with advanced cutaneous squamous-cell carcinoma,
      cemiplimab induced a response in approximately half the patients and was
      associated with adverse events that usually occur with immune checkpoint
      inhibitors.
    explanation: >-
      Landmark trial establishing cemiplimab efficacy in advanced cSCC with
      approximately 47-50% response rate.
  - reference: DOI:10.3390/ijms25137056
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PD-1/PD-L1 inhibitors for locally advanced cutaneous squamous cell
      carcinoma (cSCC) and Merkel cell carcinoma (MCC)
    explanation: >-
      Confirms PD-1/PD-L1 inhibitors as part of the current treatment
      landscape for advanced cSCC.
datasets:
📚

References & Deep Research

Deep Research

1
Falcon ▸
Disease Pathophysiology Research Template
Edison Scientific Literature 25 citations 2026-03-06T03:47:46.241824

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Pathophysiology Research Template

Target Disease

  • Disease Name: Cutaneous Squamous Cell Carcinoma
  • MONDO ID: (if available)
  • Category:

Research Objectives

Please provide a comprehensive research report on the pathophysiology of Cutaneous Squamous Cell Carcinoma. Focus on the molecular and cellular mechanisms underlying disease progression.

Required Information

1. Core Pathophysiology

  • What are the primary pathophysiological mechanisms?
  • What molecular pathways are dysregulated?
  • What cellular processes are affected?

2. Key Molecular Players

  • Genes/Proteins: Which genes are causally involved or implicated?
  • Chemical Entities: What metabolites, drugs, or small molecules are relevant?
  • Cell Types: Which cell types are primarily affected?
  • Anatomical Locations: Which tissues/organs are involved?

3. Biological Processes (for GO annotation)

  • What biological processes (GO terms) are disrupted?
  • Consider: signaling pathways, metabolic processes, cellular responses, transport, etc.

4. Cellular Components

  • Where in the cell do key processes occur?
  • Consider: organelles, membrane compartments, extracellular space, etc.

5. Disease Progression

  • What is the sequence of events from initial trigger to clinical manifestation?
  • Are there distinct stages or phases?

6. Phenotypic Manifestations

  • What are the key clinical phenotypes?
  • How do they relate to the underlying mechanisms?

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes where possible to support key statements

Output Format

Structure your response as a narrative that could be used to populate a disease knowledge base entry with: - Pathophysiology description - Gene/protein annotations with ontology terms (HGNC, GO) - Phenotype associations (HP terms) - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Evidence items with PMIDs

Cutaneous Squamous Cell Carcinoma (cSCC): Pathophysiology Research Report (molecular/cellular mechanisms)

Disease identifiers and scope

  • Disease name: Cutaneous squamous cell carcinoma (cSCC)
  • Ontology IDs: EFO: EFO_1001927 (cutaneous squamous cell carcinoma); related broader term MONDO: MONDO_0002529 (skin squamous cell carcinoma) (ontology linkage noted via Open Targets disease listing; mechanistic content below focuses on cSCC in skin). (hosseini2024themutationaland pages 1-2)
  • Category: Keratinocyte-derived non-melanoma skin cancer (NMSC). cSCC is described as the “second most common subtype of non-melanoma skin cancer” and responsible for ~20% of skin cancers. (hosseini2024themutationaland pages 1-2)

1) Key concepts and definitions (current understanding)

1.1 Definition and cellular origin

cSCC arises from malignant proliferation of epidermal keratinocytes, with a strong association to chronic sun exposure/UV radiation as a leading preventable risk factor. (corchadocobos2023cutaneoussquamouscell pages 1-3, hosseini2024themutationaland pages 1-2)

1.2 Field cancerization (foundational concept)

Field cancerization in skin refers to a region that can appear clinically/morphologically normal while harboring mutated keratinocyte clones that expand under chronic UV exposure, creating a “field” predisposed to multiple actinic keratoses (AK) and cSCC. (camillo2024exvivoanalysis pages 1-2)

A 2024 ex vivo study frames this explicitly as: “cutaneously field cancerization (CFC) refers to a skin region containing mutated cells’ clones… arising from chronic exposure to ultraviolet radiation (UVR)” and associated with increased risk for AK and cSCC. (camillo2024exvivoanalysis pages 1-2)

1.3 Disease continuum / progression state shift

Recent transcriptomic profiling supports a continuum across: normal sun-exposed skin → AK → primary cSCC → metastasis, characterized by a shift “from a differentiated to a progenitor-like state,” with suppression of epidermal differentiation regulators, remodeling of immune landscape, and increased tumor-specific keratinocytes. (bailey2023drivergenecombinations pages 1-2, bailey2023drivergenecombinations media 6aac691f, bailey2023drivergenecombinations media 983dee4c)

2) Core pathophysiology (primary mechanisms, pathways, processes)

2.1 UV-driven DNA damage and mutational signatures

UVB exposure is repeatedly emphasized as the central preventable etiologic driver, inducing characteristic UV mutational patterns in keratinocytes and precursors. (hosseini2024themutationaland pages 1-2)

Mechanistically: - UV causes DNA mutations (often repaired by nucleotide excision repair (NER)); defective repair can contribute to tumorigenesis. (hosseini2024themutationaland pages 1-2) - Reported UV signatures include C>T substitutions at dipyrimidine sites and CC>TT dinucleotide substitutions; newer work also identifies frequent T>C substitutions with specific sequence motifs. (hosseini2024themutationaland pages 1-2)

Clinical/biological implication: cSCC has a very high tumor mutational burden; one 2024 review reports median ~45.2 mutations/Mb for cSCC, consistent with UV etiopathogenesis and immunogenicity. (sol2024therapeuticapproachesfor pages 2-3)

2.2 Early driver events + altered epidermal homeostasis

A 2024 review describes cSCC tumorigenesis as a “disruption of epidermal homeostasis” driven by UV-induced DNA damage, gene mutations, and tumor microenvironment changes. (hosseini2024themutationaland pages 1-2)

Key early events include TP53 and NOTCH pathway disruption: - TP53 is repeatedly cited as among the most frequently mutated drivers; importantly, TP53 mutations also appear in AK and even normal sun-exposed skin, supporting field cancerization and complicating “driver vs passenger” assignment. (hosseini2024themutationaland pages 4-6, hosseini2024themutationaland pages 1-2) - NOTCH family genes (NOTCH1/2/3) show frequent mutations in normal sun-exposed skin; one review quantifies NOTCH alterations averaging 83 driver mutations/cm² in normal skin, and TP53 ~9.5 driver mutations/cm². (hosseini2024themutationaland pages 1-2)

2.3 AK→cSCC transition: pathway activation and selection

Although AK and normal sun-exposed skin share many mutations, progression is associated with coordinated transcriptomic and microenvironmental changes, including: - suppression of epidermal differentiation programs and induction of progenitor-like programs (differentiated→progenitor axis). (bailey2023drivergenecombinations pages 1-2, bailey2023drivergenecombinations media 6aac691f) - evidence that PI3K/AKT/mTOR signaling is “consistently activated in cSCC but not in AK,” implicating it as a transition-associated pathway (e.g., PTEN loss, PIK3CA activation). (hosseini2024themutationaland pages 4-6)

2.4 Tumor microenvironment (TME) and immune evasion

Multiple 2023–2024 sources emphasize that cSCC progression involves active immune manipulation and immune-evasive TMEs: - Advanced cSCC TMEs have increased TGF-β, IL-10, and regulatory T cells (Tregs) and reduced plasmacytoid dendritic cells (pDCs), consistent with suppression of anti-tumor immunity. (jiang2024cutaneoussquamouscell pages 1-2) - A TME-focused review details pro-tumor immune cell polarization and stromal remodeling: M2 tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) contribute to angiogenesis/ECM remodeling and immunosuppression, including CAF secretion of MMPs, VEGF, and IL-6, and TAM secretion of MMP-9/11 with increased lymphatic density. (chiang2023reviewofthe pages 6-8)

2.5 Inflammation, oxidative stress, and DNA damage in precancer fields

Cutaneous field cancerization can exhibit measurable molecular changes prior to overt tumor: - UVR can cause DNA damage directly and indirectly via ROS, inducing oxidative lesions such as 8-hydroxy-2′-deoxyguanosine (8-OHdG), and can upregulate iNOS and inflammatory responses. (camillo2024exvivoanalysis pages 1-2) - Ex vivo analyses report downregulation of p53, increased proliferation markers (Ki67, p16), altered keratinocyte differentiation markers, increased iNOS, IL-6, IL-8, and “early signs of DNA damage… oxidative stress… abnormal cell proliferation and differentiation” in CFC tissue. (camillo2024exvivoanalysis pages 1-2)

3) Key molecular players (genes/proteins, pathways, cell types, anatomy, chemicals)

Category Item Mechanistic Role in cSCC Example Evidence Statement Evidence Type PMID(s) Publication URL Citation ID
Driver Gene TP53 Defective apoptosis and unchecked proliferation of DNA-damaged keratinocytes; early event. "TP53 is one of the most frequently mutated driver genes in cSCC... 54–95% of cases" Review Not in excerpt Hosseini et al. (2024) Link (hosseini2024themutationaland pages 4-6)
Driver Gene NOTCH1/2 Loss-of-function disrupts differentiation; found in normal skin fields. "Loss-of-function mutated in cSCC (around 50–80%)... NOTCH1 is commonly mutated in normal skin (~20% of cells)" Review Not in excerpt Hosseini et al. (2024) Link (hosseini2024themutationaland pages 4-6)
Driver Gene CDKN2A Altered cell-cycle control; inactivation leads to unrestrained growth. "Altered early and, when co-mutated with TP53, associates with worse outcomes and metastasis risk" Review Not in excerpt Hosseini et al. (2024) Link (hosseini2024themutationaland pages 4-6)
Driver Gene RAS/HRAS Oncogenic activation drives proliferation; cooperates with tumor suppressor loss. "Combinatorial sequential inactivation of... Tgfbr2, Trp53 and Notch1 coupled with activation of Ras signalling" Primary Not in excerpt Bailey et al. (2023) Link (bailey2023drivergenecombinations pages 1-2)
Driver Gene EGFR Dysregulation activates Ras-Raf-MEK-ERK and PI3K pathways driving proliferation. "EGFR dysregulation activates Ras-Raf-MEK-ERK and PI3K pathways, driving proliferation" Review Not in excerpt Sol et al. (2024) Link (sol2024therapeuticapproachesfor pages 2-3)
Pathway PI3K/AKT/mTOR Consistently activated in cSCC but not AK; mediates growth/survival. "Consistently activated in cSCC but not in AK, implicating it in the AK→cSCC transition" Review Not in excerpt Hosseini et al. (2024) Link (hosseini2024themutationaland pages 4-6)
Pathway TGF-β/TGFBR2 Tumor suppressor loss promotes progression; expression promotes immune evasion. "Increased TGF-β... attenuat[ing] anti-tumor immune responses" Review Not in excerpt Jiang et al. (2024) Link (jiang2024cutaneoussquamouscell pages 1-2)
Driver Gene FAT1 Loss promotes epithelial-mesenchymal transition (EMT), stemness, and metastasis. "FAT1 loss promotes EMT, increasing invasion, stemness, and metastatic potential" Review Not in excerpt Jiang et al. (2024) Link (jiang2024cutaneoussquamouscell pages 1-2)
Driver Gene COL11A1 Mutations alter extracellular matrix architecture to promote invasion. "COL11A1 mutations alter extracellular matrix to promote invasion" Review Not in excerpt Jiang et al. (2024) Link (jiang2024cutaneoussquamouscell pages 1-2)
Field Marker iNOS, IL-6, IL-8 Inflammatory mediators upregulated in field cancerization. "Increased expression of iNOS and proinflammatory cytokines IL-6 and IL-8" Primary Not in excerpt Camillo et al. (2024) Link (camillo2024exvivoanalysis pages 1-2)
TME Factor Tregs Create immunosuppressive milieu; suppress effector T cells. "Create an immunosuppressive environment by downregulating effector CD4+ and CD8+ T cells" Review Not in excerpt Chiang et al. (2023) Link (chiang2023reviewofthe pages 6-8)
TME Factor pDCs Plasmacytoid dendritic cells; reduced in cSCC, impairing anti-tumor immunity. "Reduced plasmacytoid dendritic cells, favoring immune evasion" Review Not in excerpt Jiang et al. (2024) Link (jiang2024cutaneoussquamouscell pages 1-2)
TME Factor M2 TAMs / CAFs M2 Macs stimulate angiogenesis; CAFs secrete MMPs/VEGF. "CAFs secrete MMPs, VEGF, and IL-6; TAMs secrete MMP-9/11" Review Not in excerpt Chiang et al. (2023) Link (pqac-000011)
Mechanism UV Signatures Specific mutations (C>T, CC>TT) caused by UVB exposure. "C>T substitution mutations... CC>TT dinucleotide substitutions... frequent T>C substitutions" Review Not in excerpt Hosseini et al. (2024) Link (hosseini2024themutationaland pages 1-2)
Mechanism Field Cancerization Morphologically normal skin containing mutated clones (e.g. TP53, NOTCH1). "Skin regions appearing morphologically normal but containing clones of mutated cells" Primary Not in excerpt Camillo et al. (2024) Link (camillo2024exvivoanalysis pages 1-2)
Statistic Mutational Burden High burden reflects UV etiology. "Median mutations/Mb: cSCC 45.2" Review Not in excerpt Sol et al. (2024) Link (sol2024therapeuticapproachesfor pages 2-3)
Statistic AK Progression Rate of individual AKs becoming invasive cSCC. "Fewer than 0.1% of individual AKs progress to cSCC" Primary Not in excerpt Bailey et al. (2023) Link (bailey2023drivergenecombinations pages 1-2)
Statistic Metastasis Rate Overall metastatic risk for primary cSCC. "3–5% of primary cSCC may progress to life-threatening metastatic disease" Primary Not in excerpt Bailey et al. (2023) Link (bailey2023drivergenecombinations pages 1-2)
Statistic Nodal Metastasis Risk in high-stage tumors (BWH T2b/T3). "BWH staging notes T2b and T3 have >20% risk of nodal metastases" Review Not in excerpt Jiang et al. (2024) Link (jiang2024cutaneoussquamouscell pages 4-5)

Table: This table aggregates critical genes (e.g., TP53, NOTCH1), pathways, tumor microenvironment (TME) components, and clinical statistics defining cSCC pathophysiology, derived from 2023-2024 literature.

3.1 Genes/proteins (HGNC symbols; representative roles)

  • TP53: DNA damage response/apoptosis; loss enables proliferation of damaged keratinocytes; frequently mutated in cSCC and present in fields/AK. (hosseini2024themutationaland pages 4-6, corchadocobos2023cutaneoussquamouscell pages 1-3)
  • NOTCH1/NOTCH2: differentiation/tumor suppressor roles; frequently mutated; also found in normal sun-exposed skin. (hosseini2024themutationaland pages 4-6, hosseini2024themutationaland pages 1-2, corchadocobos2023cutaneoussquamouscell pages 1-3)
  • CDKN2A: cell-cycle control; alterations contribute to “unrestrained cell cycling and uncontrolled cell growth.” (corchadocobos2023cutaneoussquamouscell pages 1-3)
  • RAS (incl. HRAS): proliferative signaling; progression can be driven by Ras activation with sequential tumor suppressor inactivation (TGFβ/TP53/NOTCH). (bailey2023drivergenecombinations pages 1-2)
  • EGFR: downstream activation of MAPK and PI3K signaling cascades. (sol2024therapeuticapproachesfor pages 2-3)
  • PIK3CA/PTEN; AKT/mTOR: implicated in AK→cSCC transition and growth/survival programs. (hosseini2024themutationaland pages 4-6)
  • FAT1 and COL11A1: invasion/EMT and ECM remodeling signals in aggressive disease. (jiang2024cutaneoussquamouscell pages 1-2)

3.2 Cell types (CL terms; primary involvement)

Representative cell types implicated by the TME literature include: - Keratinocytes (tumor cells; CL: keratinocyte) - Regulatory T cells (Tregs) (CL: regulatory T cell) - CD8+ T cells (CL: CD8-positive, alpha-beta T cell) - Plasmacytoid dendritic cells (pDCs) (CL: plasmacytoid dendritic cell) - Langerhans cells / dendritic cells (CL: Langerhans cell; dendritic cell) - Tumor-associated macrophages (M2-like TAMs) (CL: macrophage) - Tumor-associated neutrophils (TANs) (CL: neutrophil) - Cancer-associated fibroblasts (CAFs) (CL: fibroblast)

These are reported as functionally shaping immunosuppression, angiogenesis, ECM remodeling, and metastatic potential. (chiang2023reviewofthe pages 6-8, jiang2024cutaneoussquamouscell pages 1-2)

3.3 Anatomical locations (UBERON)

  • Skin / epidermis (UBERON: skin; epidermis): primary site; sun-exposed epidermis is the initiating compartment for UV mutagenesis and field cancerization. (hosseini2024themutationaland pages 1-2, camillo2024exvivoanalysis pages 1-2)

3.4 Chemical entities (CHEBI; representative)

  • Reactive oxygen species (ROS) (CHEBI: reactive oxygen species) and oxidative DNA lesions such as 8-OHdG are implicated in UV-mediated field effects and carcinogenesis. (camillo2024exvivoanalysis pages 1-2)
  • Cytokines (not CHEBI; protein entities) relevant to inflammatory TME states include TGF-β, IL-6, IL-8, IL-10. (chiang2023reviewofthe pages 6-8, jiang2024cutaneoussquamouscell pages 1-2, camillo2024exvivoanalysis pages 1-2)

4) Biological processes disrupted (GO-oriented)

Representative disrupted biological processes supported by cited evidence include: - DNA damage response / DNA repair (UV damage; NER involvement). (hosseini2024themutationaland pages 1-2) - Keratinocyte differentiation / epidermis development: suppression of differentiation programs across the continuum and shift to progenitor-like state. (bailey2023drivergenecombinations pages 1-2, bailey2023drivergenecombinations media 6aac691f) - Cell proliferation / cell-cycle progression: p53 dysregulation, Ki67 upregulation in fields, CDKN2A pathway disruption. (camillo2024exvivoanalysis pages 1-2, corchadocobos2023cutaneoussquamouscell pages 1-3) - Inflammatory response and cytokine-mediated signaling (IL-6/IL-8/iNOS; TGF-β-driven immune polarization). (camillo2024exvivoanalysis pages 1-2, chiang2023reviewofthe pages 6-8) - Extracellular matrix organization and remodeling (CAFs, MMPs; COL11A1 effects). (chiang2023reviewofthe pages 6-8, jiang2024cutaneoussquamouscell pages 1-2) - Immune evasion / negative regulation of anti-tumor immunity (Tregs, reduced antigen-presenting/DC populations, TGF-β/IL-10). (chiang2023reviewofthe pages 6-8, jiang2024cutaneoussquamouscell pages 1-2)

5) Cellular components (where key processes occur)

Evidence-supported cellular/anatomical compartments include: - Epidermal layers and keratinocyte compartments where differentiation proceeds and is progressively disrupted along the cSCC continuum. (bailey2023drivergenecombinations pages 1-2) - Extracellular space / ECM where CAF-derived MMPs/VEGF and COL11A1-linked matrix changes contribute to invasion. (chiang2023reviewofthe pages 6-8, jiang2024cutaneoussquamouscell pages 1-2) - Nuclear DNA as the substrate for UV-induced mutations and oxidative DNA lesions. (hosseini2024themutationaland pages 1-2, camillo2024exvivoanalysis pages 1-2)

6) Disease progression model (sequence of events)

  1. Chronic UV exposure induces DNA damage, UV-signature mutations, and oxidative stress/inflammation in sun-exposed epidermis; many mutated clones persist in clinically normal skin (field cancerization). (hosseini2024themutationaland pages 1-2, camillo2024exvivoanalysis pages 1-2)
  2. Precancer lesions (AK; SCC in situ) arise within mutated fields; early driver events include TP53 and NOTCH alterations, with widespread clonal expansion. (bailey2023drivergenecombinations pages 1-2, hosseini2024themutationaland pages 4-6, camillo2024exvivoanalysis pages 1-2)
  3. Invasive primary cSCC emerges through additional pathway activation and state shifts (loss of differentiation, acquisition of progenitor-like programs), including PI3K/AKT/mTOR activation relative to AK. (bailey2023drivergenecombinations pages 1-2, hosseini2024themutationaland pages 4-6)
  4. Advanced/metastatic progression is accompanied by immune landscape remodeling and immune evasion; clinically, only a minority progress to metastasis. (bailey2023drivergenecombinations pages 1-2, hosseini2024themutationaland pages 1-2)

7) Phenotypic manifestations and clinicopathologic correlates

  • cSCC is often curable by excision, but a subset becomes locally advanced or metastatic. (hosseini2024themutationaland pages 1-2, bailey2023drivergenecombinations pages 1-2)
  • High-risk clinicopathologic features correlate with recurrence/metastasis and can be conceptualized as downstream manifestations of invasive programs and TME remodeling (e.g., deep invasion, perineural invasion, immunosuppression-associated aggressiveness). (jiang2024cutaneoussquamouscell pages 4-5, chiang2023reviewofthe pages 6-8)

8) Recent developments (prioritizing 2023–2024)

8.1 2023 primary multi-stage transcriptomics (disease continuum)

A 2023 Nature Communications study provides a high-resolution continuum map across normal sun-exposed skin, AK, primary and metastatic cSCC and experimentally supports progression driven by combinatorial sequential inactivation of tumor suppressors (Tgfbr2, Trp53, Notch1) plus Ras activation, aligning mechanistic events with observed transcriptomic state change. (bailey2023drivergenecombinations pages 1-2)

Figures summarizing this continuum and driver patterns are shown in the study’s Figure 1 and Figure 4 (progression signatures and oncoprint of drivers). (bailey2023drivergenecombinations media 6aac691f, bailey2023drivergenecombinations media 983dee4c)

8.2 2024 emphasis on “mutations in normal skin” and driver detection limits

A 2024 review emphasizes that many key drivers in cSCC are also common in normal sun-exposed skin, complicating driver identification; it provides quantitative mutation densities for NOTCH and TP53 in normal skin. (hosseini2024themutationaland pages 1-2)

8.3 2024 ex vivo evidence for molecularly abnormal but clinically normal fields

The 2024 field cancerization ex vivo study provides measurable biomarker changes (p53, Ki67, p16; iNOS; IL-6/IL-8; oxidative DNA damage) supporting the concept that preclinical fields contain actionable pathophysiology. (camillo2024exvivoanalysis pages 1-2)

9) Current applications and real-world implementations

  • Standard of care: surgery and/or radiotherapy for most primary cSCC; systemic therapies are used for locally advanced/metastatic disease. (bailey2023drivergenecombinations pages 1-2, hosseini2024themutationaland pages 1-2)
  • Immunotherapy: anti-PD1 checkpoint therapy is described as first-line in advanced disease, but “50% of individuals fail to respond,” underscoring the need for predictive biomarkers and combination strategies. (bailey2023drivergenecombinations pages 1-2)
  • Targeted therapy: EGFR pathway dysregulation supports use of EGFR inhibitors, though responses may be limited. (bailey2023drivergenecombinations pages 1-2, sol2024therapeuticapproachesfor pages 2-3)
  • Field cancerization challenge: therapies aimed at AK/SCC lesions may not eradicate mutated clones within the field, enabling recurrence and de novo lesions, motivating field-directed prevention strategies. (camillo2024exvivoanalysis pages 1-2)

10) Relevant statistics and data (recent sources, with context)

  • Metastatic cSCC frequency: ~5% of cases, per a 2024 review. (hosseini2024themutationaland pages 1-2)
  • AK progression to cSCC: “fewer than 0.1% of individual AKs will progress to cSCC,” per the 2023 Nature Communications study (reflecting current estimates). (bailey2023drivergenecombinations pages 1-2)
  • Primary cSCC to life-threatening metastasis: estimated 3–5%. (bailey2023drivergenecombinations pages 1-2)
  • Mutational burden: median ~45.2 mutations/Mb (reported for cSCC in a 2024 review). (sol2024therapeuticapproachesfor pages 2-3)
  • Nodal metastasis and mortality (historical clinical summary within a seminal review): lymph node metastases ~4% and mortality ~2% are reported in an established review excerpt used here for mechanistic framing. (corchadocobos2023cutaneoussquamouscell pages 1-3)
  • High-risk staging statistic: BWH T2b/T3 associated with >20% risk of nodal metastases. (jiang2024cutaneoussquamouscell pages 4-5)

11) Expert opinions / authoritative analysis (from cited sources)

  • The cSCC literature increasingly frames disease biology as an interplay of UV mutagenesis and microenvironmental/immune factors, not solely tumor-intrinsic mutations. (hosseini2024themutationaland pages 1-2)
  • The “differentiated-to-progenitor-like” axis provides an organizing principle linking keratinocyte state, inflammation, and immune escape across progression. (bailey2023drivergenecombinations pages 1-2, bailey2023drivergenecombinations pages 10-11)

12) Evidence items with PMIDs (limitations)

Important limitation of this tool-based evidence set: the retrieved full-text excerpts used here (mostly open-access reviews and one primary paper) do not display PubMed IDs in the captured passages, so PMIDs cannot be reliably attached to many mechanistic statements from the excerpts without introducing uncited external lookup. Accordingly, PMIDs are marked “not in excerpt” in the structured table. (sol2024therapeuticapproachesfor pages 2-3, hosseini2024themutationaland pages 1-2, jiang2024cutaneoussquamouscell pages 1-2, bailey2023drivergenecombinations pages 1-2)

Appendix: Curated source list (URLs + publication dates)

  • Bailey P. et al. Driver gene combinations dictate cutaneous squamous cell carcinoma disease continuum progression. Nature Communications (Accepted 2023-08-08; published 2023). https://doi.org/10.1038/s41467-023-40822-9 (bailey2023drivergenecombinations pages 1-2)
  • Hosseini TM. et al. The Mutational and Microenvironmental Landscape of Cutaneous Squamous Cell Carcinoma: A Review. Cancers (Published 2024-08-21). https://doi.org/10.3390/cancers16162904 (hosseini2024themutationaland pages 1-2)
  • Jiang R. et al. Cutaneous Squamous Cell Carcinoma: An Updated Review. Cancers (Published 2024-05; issue 10). https://doi.org/10.3390/cancers16101800 (jiang2024cutaneoussquamouscell pages 1-2)
  • Camillo L. et al. Ex Vivo Analysis of Cell Differentiation, Oxidative Stress, Inflammation, and DNA Damage on Cutaneous Field Cancerization. Int. J. Mol. Sci. (Published 2024-05-26). https://doi.org/10.3390/ijms25115775 (camillo2024exvivoanalysis pages 1-2)
  • Sol S. et al. Therapeutic Approaches for Non-Melanoma Skin Cancer: Standard of Care and Emerging Modalities. Int. J. Mol. Sci. (Published 2024-06). https://doi.org/10.3390/ijms25137056 (sol2024therapeuticapproachesfor pages 2-3)
  • Chiang E. et al. Review of the Tumor Microenvironment in Basal and Squamous Cell Carcinoma. Cancers (Published 2023-04). https://doi.org/10.3390/cancers15092453 (chiang2023reviewofthe pages 6-8)

References

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  2. (corchadocobos2023cutaneoussquamouscell pages 1-3): Roberto Corchado-Cobos, Natalia García-Sancha, Rogelio González-Sarmiento, Jesús Pérez-Losada, and Javier Cañueto. Cutaneous squamous cell carcinoma: from biology to therapy. International Journal of Molecular Sciences, 21:2956, Apr 2023. URL: https://doi.org/10.3390/ijms21082956, doi:10.3390/ijms21082956. This article has 270 citations.

  3. (camillo2024exvivoanalysis pages 1-2): Lara Camillo, Elisa Zavattaro, Federica Veronese, Laura Cristina Gironi, Ottavio Cremona, and Paola Savoia. Ex vivo analysis of cell differentiation, oxidative stress, inflammation, and dna damage on cutaneous field cancerization. International Journal of Molecular Sciences, 25:5775, May 2024. URL: https://doi.org/10.3390/ijms25115775, doi:10.3390/ijms25115775. This article has 3 citations.

  4. (bailey2023drivergenecombinations pages 1-2): Peter Bailey, Rachel A. Ridgway, Patrizia Cammareri, Mairi Treanor-Taylor, Ulla-Maja Bailey, Christina Schoenherr, Max Bone, Daniel Schreyer, Karin Purdie, Jason Thomson, William Rickaby, Rene Jackstadt, Andrew D. Campbell, Emmanouil Dimonitsas, Alexander J. Stratigos, Sarah T. Arron, Jun Wang, Karen Blyth, Charlotte M. Proby, Catherine A. Harwood, Owen J. Sansom, Irene M. Leigh, and Gareth J. Inman. Driver gene combinations dictate cutaneous squamous cell carcinoma disease continuum progression. Nature Communications, Aug 2023. URL: https://doi.org/10.1038/s41467-023-40822-9, doi:10.1038/s41467-023-40822-9. This article has 42 citations and is from a highest quality peer-reviewed journal.

  5. (bailey2023drivergenecombinations media 6aac691f): Peter Bailey, Rachel A. Ridgway, Patrizia Cammareri, Mairi Treanor-Taylor, Ulla-Maja Bailey, Christina Schoenherr, Max Bone, Daniel Schreyer, Karin Purdie, Jason Thomson, William Rickaby, Rene Jackstadt, Andrew D. Campbell, Emmanouil Dimonitsas, Alexander J. Stratigos, Sarah T. Arron, Jun Wang, Karen Blyth, Charlotte M. Proby, Catherine A. Harwood, Owen J. Sansom, Irene M. Leigh, and Gareth J. Inman. Driver gene combinations dictate cutaneous squamous cell carcinoma disease continuum progression. Nature Communications, Aug 2023. URL: https://doi.org/10.1038/s41467-023-40822-9, doi:10.1038/s41467-023-40822-9. This article has 42 citations and is from a highest quality peer-reviewed journal.

  6. (bailey2023drivergenecombinations media 983dee4c): Peter Bailey, Rachel A. Ridgway, Patrizia Cammareri, Mairi Treanor-Taylor, Ulla-Maja Bailey, Christina Schoenherr, Max Bone, Daniel Schreyer, Karin Purdie, Jason Thomson, William Rickaby, Rene Jackstadt, Andrew D. Campbell, Emmanouil Dimonitsas, Alexander J. Stratigos, Sarah T. Arron, Jun Wang, Karen Blyth, Charlotte M. Proby, Catherine A. Harwood, Owen J. Sansom, Irene M. Leigh, and Gareth J. Inman. Driver gene combinations dictate cutaneous squamous cell carcinoma disease continuum progression. Nature Communications, Aug 2023. URL: https://doi.org/10.1038/s41467-023-40822-9, doi:10.1038/s41467-023-40822-9. This article has 42 citations and is from a highest quality peer-reviewed journal.

  7. (sol2024therapeuticapproachesfor pages 2-3): Stefano Sol, Fabiana Boncimino, Kristina Todorova, Sarah Elizabeth Waszyn, and Anna Mandinova. Therapeutic approaches for non-melanoma skin cancer: standard of care and emerging modalities. International Journal of Molecular Sciences, 25:7056, Jun 2024. URL: https://doi.org/10.3390/ijms25137056, doi:10.3390/ijms25137056. This article has 35 citations.

  8. (hosseini2024themutationaland pages 4-6): Tara M. Hosseini, Soo J. Park, and Theresa W Guo. The mutational and microenvironmental landscape of cutaneous squamous cell carcinoma: a review. Cancers, 16:2904, Aug 2024. URL: https://doi.org/10.3390/cancers16162904, doi:10.3390/cancers16162904. This article has 16 citations.

  9. (jiang2024cutaneoussquamouscell pages 1-2): Rina Jiang, Mike Fritz, and Syril Keena T. Que. Cutaneous squamous cell carcinoma: an updated review. Cancers, 16:1800, May 2024. URL: https://doi.org/10.3390/cancers16101800, doi:10.3390/cancers16101800. This article has 53 citations.

  10. (chiang2023reviewofthe pages 6-8): Elizabeth Chiang, Haleigh Stafford, Jane Buell, Uma Ramesh, Moran Amit, Priyadharsini Nagarajan, Michael Migden, and Dan Yaniv. Review of the tumor microenvironment in basal and squamous cell carcinoma. Cancers, 15:2453, Apr 2023. URL: https://doi.org/10.3390/cancers15092453, doi:10.3390/cancers15092453. This article has 32 citations.

  11. (jiang2024cutaneoussquamouscell pages 4-5): Rina Jiang, Mike Fritz, and Syril Keena T. Que. Cutaneous squamous cell carcinoma: an updated review. Cancers, 16:1800, May 2024. URL: https://doi.org/10.3390/cancers16101800, doi:10.3390/cancers16101800. This article has 53 citations.

  12. (bailey2023drivergenecombinations pages 10-11): Peter Bailey, Rachel A. Ridgway, Patrizia Cammareri, Mairi Treanor-Taylor, Ulla-Maja Bailey, Christina Schoenherr, Max Bone, Daniel Schreyer, Karin Purdie, Jason Thomson, William Rickaby, Rene Jackstadt, Andrew D. Campbell, Emmanouil Dimonitsas, Alexander J. Stratigos, Sarah T. Arron, Jun Wang, Karen Blyth, Charlotte M. Proby, Catherine A. Harwood, Owen J. Sansom, Irene M. Leigh, and Gareth J. Inman. Driver gene combinations dictate cutaneous squamous cell carcinoma disease continuum progression. Nature Communications, Aug 2023. URL: https://doi.org/10.1038/s41467-023-40822-9, doi:10.1038/s41467-023-40822-9. This article has 42 citations and is from a highest quality peer-reviewed journal.