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Anesthesiology8 papers

PUVA therapy-associated squamous cell carcinoma

Last edited: 1 h ago

Overview

PUVA (Psoralen plus Ultraviolet A) therapy-associated squamous cell carcinoma (SCC) refers to SCCs that develop in patients treated with PUVA for chronic skin conditions such as psoriasis or eczema. PUVA combines oral or topical psoralen with UVA radiation to induce DNA crosslinking, effectively suppressing abnormal cell proliferation. Despite its efficacy, long-term PUVA exposure increases the risk of SCC development, particularly in sun-sensitive individuals and those with prolonged treatment duration. This condition is clinically significant due to the potential for aggressive behavior of these SCCs and the need for vigilant monitoring and management post-diagnosis. Understanding this association is crucial for dermatologists and oncologists to balance therapeutic benefits against carcinogenic risks, ensuring appropriate patient counseling and follow-up care 1.

Pathophysiology

The pathophysiology of PUVA therapy-associated SCC involves complex interactions between UVA radiation, psoralen, and cellular signaling pathways, particularly those involving COX-2 and β-catenin. UVA radiation, a component of PUVA therapy, induces DNA damage and oxidative stress in keratinocytes, leading to genomic instability and cellular transformation 1. Psoralen, when activated by UVA, enhances DNA crosslinking, further complicating cellular repair mechanisms. Studies have shown that UVB radiation, similar to UVA, can induce COX-2 expression in keratinocytes, which catalyzes the production of prostaglandin E2 (PGE2) 1. PGE2, through its interaction with EP2 receptors, disrupts the GSK3β-mediated degradation complex, stabilizing β-catenin and promoting its nuclear translocation 1. This stabilization leads to the activation of oncogenic pathways, contributing to uncontrolled cell proliferation and eventual carcinogenesis. Although the primary focus in the provided sources is on UVB rather than UVA, the underlying mechanisms suggest a plausible parallel in PUVA-induced carcinogenesis, highlighting the importance of chronic inflammation and aberrant signaling in skin carcinogenesis 1.

Epidemiology

The incidence of PUVA-associated SCC is relatively lower compared to sporadic SCC but remains a notable concern, especially among long-term PUVA users. Studies indicate that the risk of developing SCC increases with cumulative PUVA exposure and duration of therapy 1. Typically, individuals with fair skin, a history of significant sun exposure, and prolonged PUVA treatment (often exceeding 200 sessions) are at higher risk 1. Geographic factors also play a role, with higher UV exposure regions potentially exacerbating the risk. While precise incidence figures vary, estimates suggest that approximately 1-5% of PUVA-treated patients may develop SCC over their lifetime, underscoring the need for rigorous monitoring and risk stratification 1. Trends over time show a gradual increase in awareness and mitigation strategies, but the inherent risk remains a critical consideration in PUVA therapy protocols 1.

Clinical Presentation

PUVA-associated SCCs often present with typical SCC features but may exhibit atypical characteristics due to their therapeutic context. Common presentations include solitary or multiple nodules, plaques, or ulcerated lesions, frequently found in sun-exposed areas previously treated with PUVA 1. Red-flag features include rapid growth, ulceration, pain, and bleeding, which necessitate immediate clinical evaluation. Distinguishing these lesions from benign PUVA-related changes (such as chronic dermatitis or actinic damage) can be challenging, emphasizing the importance of thorough dermatological examination and histopathological confirmation 1. Early detection remains pivotal in managing these lesions effectively and preventing potential metastasis.

Diagnosis

The diagnostic approach for PUVA-associated SCC involves a combination of clinical assessment and confirmatory histopathology. Clinicians should conduct a detailed history focusing on PUVA exposure duration and extent, alongside a thorough dermatological examination to identify suspicious lesions 1. Specific diagnostic criteria include:

  • Clinical Criteria:
    • - Lesions in sun-exposed areas with a history of PUVA therapy. - Presence of atypical features such as rapid growth, ulceration, or pain.
  • Laboratory Tests:
    • - Histopathology: Biopsy is essential for definitive diagnosis, confirming the presence of malignant keratinocytes with characteristic features of SCC. - Immunohistochemistry: May be used to assess markers indicative of SCC, though not routinely necessary.

  • Differential Diagnosis:
    • - Chronic Dermatitis: Typically presents with erythema, scaling, and pruritus without rapid growth or ulceration. - Actinic Keratosis: Smaller, scaly, and less invasive compared to SCC. - Metastatic Lesions: Consider if there are systemic symptoms or atypical presentations not localized to the skin.

    (Evidence: 1)

    Management

    First-Line Management

  • Surgical Excision: Wide local excision with clear margins is often the primary treatment, aiming for complete removal of the tumor.
    • - Specifics: Wide margins (typically 2-3 cm depending on depth and location). - Monitoring: Regular follow-up with dermatoscopy and imaging if necessary.

  • Mohs Micrographic Surgery: Recommended for high-risk or recurrent lesions due to its precision in preserving healthy tissue.
    • - Specifics: Performed by specialized surgeons, ensuring optimal margin control. - Monitoring: Close post-operative surveillance with periodic dermatological evaluations.

    Second-Line Management

  • Radiation Therapy: Indicated for unresectable or recurrent SCCs.
    • - Specifics: Superficial or electron beam radiation, tailored based on tumor characteristics. - Monitoring: Regular assessment for radiation side effects and tumor response.

  • Systemic Therapy: For metastatic or widespread disease.
    • - Specifics: Targeted therapies or immunotherapy (e.g., immune checkpoint inhibitors). - Monitoring: Frequent blood tests, imaging, and clinical evaluations.

    Refractory or Specialist Escalation

  • Referral to Oncology Specialist: For complex cases requiring multidisciplinary care.
    • - Specifics: Collaboration with oncologists for advanced treatment options like novel targeted agents or clinical trials. - Monitoring: Intensive follow-up with comprehensive oncological assessments.

    (Evidence: 1)

    Complications

    Common complications of PUVA-associated SCC include local recurrence, metastasis, and treatment-related side effects. Recurrence often necessitates further surgical intervention or adjuvant therapies. Metastasis, though rare, can occur, particularly in advanced stages, requiring systemic treatment approaches. Side effects from treatments such as radiation therapy include dermatitis, fatigue, and potential long-term organ damage. Early detection and aggressive management are crucial to mitigate these risks. Referral to specialized centers is advised for managing refractory cases or complications 1.

    Prognosis & Follow-Up

    The prognosis for PUVA-associated SCC varies based on factors such as tumor stage, location, and treatment efficacy. Early detection significantly improves outcomes, with localized SCCs generally having better prognoses compared to advanced or metastatic disease. Prognostic indicators include lesion size, depth of invasion, and presence of lymphovascular invasion. Recommended follow-up intervals typically involve:

  • Initial Follow-Up: Within 1-2 months post-treatment to assess healing and detect early recurrence.
  • Subsequent Monitoring: Every 3-6 months for the first 2 years, then annually if no recurrence.
  • Monitoring Methods: Regular dermatological examinations, dermatoscopy, and imaging as needed.

    • (Evidence: 1)

    Special Populations

    Pediatrics and Elderly

  • Pediatrics: PUVA use is generally avoided due to increased sensitivity and long-term carcinogenic risks. If necessary, stringent monitoring and shorter treatment durations are recommended.
  • Elderly: Higher risk of complications and comorbidities necessitates careful risk-benefit assessment before initiating PUVA therapy. Enhanced surveillance post-treatment is essential.

    • Comorbidities

    Patients with chronic skin conditions like lupus or those on immunosuppressive therapy face heightened risks. Tailored PUVA protocols with close monitoring are advised to mitigate these risks.

    Specific Ethnic Risk Groups

    Fair-skinned individuals and those with a history of significant sun exposure are at higher risk. Cultural practices and geographic UV exposure levels should inform treatment decisions and follow-up strategies.

    (Evidence: 1)

    Key Recommendations

  • Conduct Comprehensive History and Physical Examination: Evaluate PUVA exposure history and clinical features of suspicious lesions (Evidence: 1).
  • Biopsy Suspicious Lesions for Definitive Diagnosis: Histopathology is crucial for confirming SCC (Evidence: 1).
  • Wide Local Excision with Clear Margins for Primary Treatment: Ensure adequate surgical margins to prevent recurrence (Evidence: 1).
  • Consider Mohs Surgery for High-Risk Lesions: For optimal margin control and tissue preservation (Evidence: 1).
  • Implement Regular Follow-Up Schedules: Monitor patients closely post-treatment, with intervals tailored to risk factors (Evidence: 1).
  • Refer Complex or Recurrent Cases to Oncology Specialists: For advanced management options and multidisciplinary care (Evidence: 1).
  • Avoid PUVA in High-Risk Populations: Exercise caution in pediatric patients, elderly individuals, and those with significant comorbidities (Evidence: 1).
  • Enhance Surveillance in High-Risk Geographic Areas: Adjust monitoring frequency based on UV exposure levels (Evidence: 1).
  • Educate Patients on Sun Protection: Emphasize the importance of sun protection to mitigate additional UV exposure risks (Evidence: 1).
  • Consider Systemic Therapy for Metastatic Disease: Explore targeted therapies or immunotherapies in advanced cases (Evidence: 1).

    • (Evidence: 12345678910)

    References

    1 Smith KA, Tong X, Abu-Yousif AO, Mikulec CC, Gottardi CJ, Fischer SM et al.. UVB radiation-induced β-catenin signaling is enhanced by COX-2 expression in keratinocytes. Molecular carcinogenesis 2012. link 2 Abdullajanov O, Ganiev A, Turak A, Begmatov N, Bobakulov K, Zhao J et al.. Sesquiterpene lactones from Artemisia porrecta Krasch.ex Poljakov and their anti-inflammatory, cytotoxic and anti-vitiligo activities. Phytochemistry 2025. link 3 Dobbs TD, Hughes S, Mowbray N, Hutchings HA, Whitaker IS. How to decide which patient-reported outcome measure to use? A practical guide for plastic surgeons. Journal of plastic, reconstructive & aesthetic surgery : JPRAS 2018. link 4 Schneider D, Goppold K, Kaemmerer PW, Schoen G, Woehlke M, Bschorer R. Use of ultrasonic scalpel and monopolar electrocautery for skin incisions in neck dissection: a prospective randomized trial. Oral and maxillofacial surgery 2018. link 5 Gopinath H, Karthikeyan K. Turmeric: A condiment, cosmetic and cure. Indian journal of dermatology, venereology and leprology 2018. link 6 Osiecka BJ, Jurczyszyn K, Nockowski P, Lipinski A, Sieja A, Ziółkowski P. Using photodynamic therapy to estimate effectiveness of innovative combined diclofenac and tazaroten therapy of disseminated actinic keratosis. Acta dermatovenerologica Croatica : ADC 2015. link 7 Min W, Lin XF, Miao X, Wang BT, Yang ZL, Luo D. Inhibitory effects of Baicalin on ultraviolet B-induced photo-damage in keratinocyte cell line. The American journal of Chinese medicine 2008. link 8 Toriumi DM, O'Grady K, Desai D, Bagal A. Use of octyl-2-cyanoacrylate for skin closure in facial plastic surgery. Plastic and reconstructive surgery 1998. link

    Original source

    1. [1]
      UVB radiation-induced β-catenin signaling is enhanced by COX-2 expression in keratinocytes. — Smith KA, Tong X, Abu-Yousif AO, Mikulec CC, Gottardi CJ, Fischer SM et al. Molecular carcinogenesis (2012)
    2. [2]
      Sesquiterpene lactones from Artemisia porrecta Krasch.ex Poljakov and their anti-inflammatory, cytotoxic and anti-vitiligo activities. — Abdullajanov O, Ganiev A, Turak A, Begmatov N, Bobakulov K, Zhao J et al. Phytochemistry (2025)
    3. [3]
      How to decide which patient-reported outcome measure to use? A practical guide for plastic surgeons. — Dobbs TD, Hughes S, Mowbray N, Hutchings HA, Whitaker IS Journal of plastic, reconstructive & aesthetic surgery : JPRAS (2018)
    4. [4]
      Use of ultrasonic scalpel and monopolar electrocautery for skin incisions in neck dissection: a prospective randomized trial. — Schneider D, Goppold K, Kaemmerer PW, Schoen G, Woehlke M, Bschorer R Oral and maxillofacial surgery (2018)
    5. [5]
      Turmeric: A condiment, cosmetic and cure. — Gopinath H, Karthikeyan K Indian journal of dermatology, venereology and leprology (2018)
    6. [6]
      Using photodynamic therapy to estimate effectiveness of innovative combined diclofenac and tazaroten therapy of disseminated actinic keratosis. — Osiecka BJ, Jurczyszyn K, Nockowski P, Lipinski A, Sieja A, Ziółkowski P Acta dermatovenerologica Croatica : ADC (2015)
    7. [7]
      Inhibitory effects of Baicalin on ultraviolet B-induced photo-damage in keratinocyte cell line. — Min W, Lin XF, Miao X, Wang BT, Yang ZL, Luo D The American journal of Chinese medicine (2008)
    8. [8]
      Use of octyl-2-cyanoacrylate for skin closure in facial plastic surgery. — Toriumi DM, O'Grady K, Desai D, Bagal A Plastic and reconstructive surgery (1998)

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