Bowen Disease 

Bowen Disease – Introduction

• Squamous cell carcinoma (SCC) in situ^(1,3)
  •  nonmelanoma skin cancer of epithelial cell origin confined to the epidermis⁽¹⁾
  •  usually the result of damage due to chronic sun exposure, or other carcinogenic exposures such as human papillomavirus (HPV)⁽¹⁾
•  for squamous cell carcinoma in situ (SCCis) localized to the vulva, see Vulvar Intraepithelial Neoplasia (VIN)
• for penile lesions and the following clinical manifestations of penile carcinoma in situ, see Squamous Cell Carcinoma of Penis
  •  erythroplasia of Queyrat (EQ)
  •  Bowen’s disease of the penis (BDP)
  •  bowenoid papulosis (BP)
•  for anal lesions, see Anal Cancer

Also Called

•  squamous cell carcinoma in situ
•  Bowen’s disease

Definitions

• Fitzpatrick skin phototypes:
  • Type I:
    • always burns, never tans
    • characteristics typically include white skin, very fair skin, red or blond hair, blue eyes, freckles
  • Type II:
    • usually burns, then slight tan or tans with difficulty
    • characteristics typically include white or fair skin; red or blond hair; blue, hazel, or green eyes
  • Type III:
    • sometimes burns, gradually tans
    • characteristics include cream-white skin or fair skin with any eye or hair color
  • Type IV:
    • rarely burns, tans with ease
    • characteristics include olive to brown skin
  • Type V:
    • very rarely burns, tans very easily
    • characteristics include brown skin or dark brown skin
  • type VI
    • never burns, tans very easily
    • darkly pigmented
  • Reference – American Academy of Dermatology (AAD) and National Psoriasis Foundation (NPF) guidelines of care for the management and treatment of psoriasis with phototherapy (J Am Acad Dermatol 2019 Sep;81(3):775, Br J Dermatol 1977 Jan;96(1):1)

• field cancerization or field effect⁽³⁾
  •  describes an area or “field” of chronically actinic damaged skin that is adjacent or surrounding a neoplastic skin lesion
  •  the field may contain morphologically normal, but genetically altered clones with neoplastic potential
  •  both the tumor-directed and field-directed therapies should be considered in the treatment of epithelial cancers
•  field-directed therapies describe treatment modalities that target both clinically visible lesions and potential subclinical lesions on adjacent skin⁽³⁾

Epidemiology

Who Is Most Affected

• squamous cell carcinoma (SCC) in situ (Bowen disease) most commonly affects older, fair-skinned individuals, and those living in sunny climates, and near the equator⁽¹⁾
•  typically appears in patients ≥ 60 years old⁽¹⁾

Incidence/Prevalence

• annual incidence of Bowen disease
  •  in Canada 28 per 100,000 in men and 22 per 100,000 in women⁽¹⁾
  •  in White residents of Minnesota, 14.9 per 100,000⁽³⁾
  •  in White residents of Hawaii, 142 per 100,000 (62% in men and 38% in women) (J Am Acad Dermatol 1994 Oct;31(4):596)

Risk Factors

• exposure to ultraviolet (UV) and other types of radiation including^(1,3,4)
  •  natural sunlight
  •  indoor tanning devices
  •  ionizing or UV radiation therapy
  •  psoralen plus ultraviolet A (PUVA) treatments for psoriasis
• physical characteristics associated with increased risk include⁽¹⁾
  •  fair skin (Fitzpatrick skin types I and II)
  •  light-colored eyes
  •  light-colored, or red, hair
•  living near the equator⁽¹⁾
• immunosuppression, such as due to^(1,3,4)
  •  medical intervention or therapy (such as PUVA)
  •  therapeutic immunosuppression for organ transplants
  •  HIV/AIDS
  • non-Hodgkin lymphoma (NHL)
  •  chemotherapy
  • drugs, such as
    •  cyclosporine
    •  azathioprine
    •  systemic corticosteroids
• actinic keratosis (AK)⁽³⁾
  •  most AK lesions do not progress to squamous cell carcinoma (SCC); however, 60%-80% of cutaneous SCC begin as AK lesions
  •  controversy among dermatopathologists whether actinic keratosis should be reclassified as squamous cell carcinoma in situ
  •  multiple studies report rate of annual progression of individual AK lesions to SCC as 0.075% to 0.24%, however, reports range from 0% to 16%
  • predicted risk of progression of at least 1 AK lesion to SCC reported as
    •  1.5% over 2 years
    •  6.1% – 10.2% over 10 years for patients with mean 7.7 AK lesions
  •  Reference – Cutis 2011 Apr;87(4):201
• human papillomavirus (HPV)^(1,3)
  •  HPV DNA reported in about 5%-60% of extragenital lesions
  • HPV type 16
    •  reported in 60% of palmoplantar and periungual lesions
    •  strongly associated with anogenital lesions
  •  other HPV types associated with Bowen disease include types 18, 31, and 33 (Cancer 1999 Jul 15;86(2):282)
•  elemental or inorganic arsenic^(1,3)
• genetic-based disorders, such as⁽⁴⁾
  •  albinism
  • keratosis, ichthyosis, deafness (KID)
    •  patients develop invasive SCC
    •  associated with dysplastic lesions
  • xeroderma pigmentosum
    •  autosomal recessive condition with increased susceptibility to DNA damage
    •  associated with multiple childhood skin cancers
  • dystrophic epidermolysis bullosa
    •  autosomal recessive condition, caused by mutations in the collagen gene (COL7A1)
    •  associated with skin blistering
  • Fanconi anemia
    •  autosomal recessive condition with bone marrow failure and congenital malformations
    •  associated with development of SSC and other cancers
  • Rothmund-Thompson syndrome
    •  autosomal recessive condition
    •  associated with development of progressive poikiloderma with alopecia, dystrophic teeth and nails, and juvenile cataracts
  • Werner syndrome
    •  premature aging syndrome
    •  associated with very high risk of cancer
  • Muir-Torre syndrome
    •  autosomal dominant disease with germline mutations in DNA mismatch repair genes
    •  associated with sebaceous neoplasms and internal malignancies
  •  Li-Fraumeni syndrome
  •  hereditary nonpolyposis coli
  •  dyskeratosis congenita
  •  Huriez syndrome
  •  porokeratosis

Associated Conditions

•  chronic skin conditions caused by inflammation or injury, including lupus and seborrheic keratoses may be associated with Bowen disease⁽²⁾
• other nonmelanoma skin cancers, including basal cell carcinoma
  •  3-year overall risk of developing nonmelanoma skin cancer following Bowen disease or other nonmelanoma skin cancer estimated as 35%-60% (Arch Dermatol 2000 Dec;136(12):1524)
  •  increased risk of subsequent Bowen disease or other nonmelanoma skin cancers likely reflect a common etiology from solar ultraviolet (UV) radiation⁽⁴⁾

Etiology and Pathogenesis

Causes

•  usually caused by DNA damage due to chronic ultraviolet (UV) radiation exposure, but other carcinogenic agents are also implicated⁽¹⁾

Pathogenesis

•  DNA damage from ultraviolet (UV) exposure leads to neoplastic transformation of epidermal keratinocytes^(1,3)
• UVB and UVA radiation induce the generation of mutagenic photoproducts such as⁽⁴⁾
  •  cyclopyrimidine dimers and pyrimidine-pyrimidine (6-4) adducts (UVB radiation)⁽⁴⁾
  •  reactive oxygen species and DNA adducts (UVA radiation)⁽⁴⁾
•  may arise de novo or from within an existing lesion (such as, actinic keratosis or seborrheic keratoses)^(1,3)
• characteristic genetic alternations⁽³⁾
  • p53 inactivating mutations reported in approximately 90% of squamous cell carcinoma (SCC)^(3,4)
  • bcl2 inactivation⁽³⁾
• human papillomavirus (HPV) DNA reported in about 5%-60% of extragenital lesions^(1,3)
  •  HPV type 16 reported in 60% of palmoplantar and periungual lesions and strongly associated with anogenital lesions
  • HPV E6 protein targets p53 for proteasomal degradation
    •  DNA damage response, cell cycle arrest, and apoptosis are impaired
    •  leads to chromosomal instability, increasing risk of acquiring sufficient mutations to become malignant
  • HPV E7 protein targets pRb for proteasomal degradation
    •  promotes cell cycle advance through S-phase
    •  renders cells immune to normal cell cycle control mechanisms, promotes enhanced growth, and facilitates mutation acquisition
  •  Reference – Ecancermedicalscience 2015;9:526full-text

History

Chief Concern (CC)

• Bowen disease, also known as cutaneous squamous cell (SCC) in situ, typically presents as a nonhealing, erythematous skin lesion with a scaly or crusted surface (typically < 2 cm in diameter)^(1,3)
• Bowen disease is most commonly found on head, neck, arms, and legs in Whites^(1,3,4)
•  generally asymptomatic, although larger lesions may cause itchiness^(1,3)

History of Present Illness (HPI)

•  usually very slow-growing, but lesion may have enlarged over a period of months⁽¹⁾
•  periungual lesions may have been present for 3-5 years before diagnosis⁽¹⁾
• periungual lesions more common in men⁽¹⁾
  •  usually on the first 3 digits of left hand
  •  average age at presentation 55 years
• arsenic exposure from well water or proprietary medications have been associated with SCC in situ^(1,)
• characteristics of SCC in situ associated with arsenic exposure include:^(1,)
  •  multiple lesions
  •  macular hypopigmentation
  •  keratoses on palms and soles
  •  lesions in sun-protected area

Medication History

• ask about taking immunosuppressive drugs, such as^(1,3)
  •  cyclosporin, azathioprine, or other medications used following organ transplant
  •  systemic corticosteroids
  •  chemotherapy

Past Medical History (PMH)

• ask about history of any of the following exposures:^(1,3)
  •  other nonmelanoma skin cancer
  •  ionizing or ultraviolet (UV) radiation therapy for cancer
  •  psoralen plus ultraviolet A (PUVA) treatments

Social History (SH)

• ask about history of excessive exposure to UV radiation due to^(1,3)
  •  sunbathing
  •  indoor tanning devices
  •  living near the equator
  •  occupations with extended, habitual exposure to the sun
  •  history of PUVA treatment

Physical

Skin

• typical visual characteristics of lesions of Bowen disease (SCC in situ)^(1,3)
  •  flat, firm, and well-demarcated lesions with irregular borders
  •  erythematous, ranging from pink to bright, salmon red, with white, yellow, or rupial scaly surface, easily removed or firmly adherent
  •  may become nodular or wart-like over time
•  typically found on areas of skin chronically exposed to sunlight, especially the head, neck, arms, and legs^(1,3,4)
•  lesions more commonly found on head and neck in men and on lower limbs and cheeks in women⁽³⁾
• facial lesions⁽¹⁾
  •  can evolve from actinic keratoses or occur de novo
  •  bright red erythematous lesions with adherent, yellow, keratotic, scaly surface
• less common variants include
  • periungual and subungual lesions⁽¹⁾
    •  widely variable in appearance
    •  may present as flat, erythematous patches with little/no scale
    •  may present crusted, wart-like plaques associated with nail degeneration, onycholysis, and partial loss of nail plate
  • pigmented lesions (reported in 1.7%-5.5%), seen more frequently in:⁽²⁾
    • sun-protected areas (such as intertriginous regions and lower extremities)
    • males with darker skin tones
  • palmar lesions⁽¹⁾
    •  usually have expanding perimeter with fissures
    •  associated with frictional hypertrophy
  • perianal lesions⁽¹⁾
    •  often with a moist, macerated surface
    •  dull, erythematous background

Diagnosis

Making the Diagnosis

•  suspect Bowen disease (cutaneous squamous cell carcinoma [SCC] in situ) in older patients with nonhealing, chronic, flat or hyperkeratotic, erythematous lesion on sun-exposed skin^(1,3)
• the diagnosis of Bowen disease is made clinically, usually by visual examination, often aided by dermoscopy⁽³⁾
• diagnosis is confirmed by histopathologic findings on biopsy showing^(1,3)
  •  full-depth epidermal dysplasia^(1,3)
  •  intact dermoepidermal junction with no dermal penetration⁽¹⁾

Differential Diagnosis

• actinic keratosis
• invasive squamous cell carcinoma (SCC)
• psoriasis
•  eczema⁽¹⁾
• lichen simplex chronicus⁽¹⁾
• superficial basal cell carcinoma
•  fungal infection⁽¹⁾
• if periungual⁽¹⁾
  •  paronychia
  •  persistent warts
•  hidroacanthoma simplex (J Dermatol 2015 Oct;42(10):1002)
•  porokeratosis

Testing Overview

•  consider dermoscopy to identify high risk or equivocal lesions for biopsy, especially in patients with multiple lesions^(2,3)
• biopsy can be performed to confirm the diagnosis
• punch biopsy should include dermis and full-depth epidermis

Imaging Studies

Dermoscopy

•  reported to improve diagnostic accuracy and early diagnosis of nonmelanoma skin cancers compared to the unaided eye⁽³⁾
•  reported to improve accuracy of selecting lesions that require biopsy or treatment⁽³⁾
• dermoscopic criteria associated with Bowen disease lesions⁽³⁾
  •  punctate vessels – tiny, red, densely aligned, dotted vessels
  •  glomerular vessels – larger than punctate vessels with convoluted morphology, often in clusters
  •  yellow to light brown, amorphic, scaly or keratotic crust (does not cover large areas of lesion surface)
• dermoscopic criteria shared with Bowen lesions and with actinic keratosis or squamous cell carcinoma (SCC)⁽³⁾
  •  radial, structureless, red lines or hairpin vessels, surrounding a yellow or white scaly center (also associated with actinic keratoses)
  •  erosions and superficial hemorrhages – irregular distribution, color ranges from orange to red-brown, usually associated with yellow, opaque structures (also associated with SCC)

Biopsy and Pathology

• punch biopsy
  •  recommended for diagnostic skin biopsy or complete removal of lesions < 10 mm
  •  often provides better cosmetic result than shave biopsy
  •  suturing recommended for biopsies > 3 mm to avoid scarring
  •  Reference – J Gen Intern Med 1998 Jan;13(1):46full-text
• curette biopsy (including full thickness sample of epidermis and dermis) can exclude invasive squamous cell carcinoma, can be used for both diagnosis and treatment, and may be preferred to punch biopsy in some settings⁽²⁾
• perform histologic analysis prior to treatments such as laser therapy or radiation therapy⁽²⁾
• histologic and cytologic characteristics^(1,3)
  •  full-thickness epidermal dysplasia
  •  disordered architecture
  •  abnormal mitoses, resulting in giant cells with multiple nuclei
  •  dyskeratosis
  • prominent keratinization, often in swirled circular pattern (called “keratin pearls”)
  •  dermoepidermal junction intact
  •  no dermal penetration
•  invasive squamous cell carcinoma may be present in about 30% of patients with biopsy-proven Bowen disease
  •  based on prospective cohort study
  •  29 consecutive patients with biopsy-proven Bowen disease who had Mohs micrographic surgery had central specimens horizontally sectioned at 30-micrometer intervals
  •  9 lesions (31%) had invasive squamous cell carcinoma (SCC) on final histology after Mohs
  • invasive SCC associated with
    •  preoperative clinical findings of scales
    •  papular changes
    •  lesion diameter > 1.4 cm
  •  Reference – Dermatol Surg 2012 Sep;38(9):1456

Staging

• American Joint Committee on Cancer (AJCC) staging for cutaneous squamous cell carcinoma and other cutaneous carcinoma
  • Bowen disease classified as stage 0
    •  Tis – squamous cell carcinoma in situ
    •  N0 – no regional lymph node metastases
    •  M0 – no clinical or radiographic evidence of distant metastases (no pathologic M0; use clinical M to complete stage group)
  •  information, including clinical staging form and information on pathologic classification, can be found at AJCC PDF
  • Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer SBM, LLC.

Management

Management Overview

•  goal of treatment of Bowen disease (cutaneous squamous cell carcinoma [SCC] in situ) is complete removal or destruction of lesion to prevent invasive squamous cell carcinoma and metastases while achieving an acceptable cosmetic outcome⁽⁴⁾
• treatment choice is influenced by:^(1,2,4)
  •  size, number, and location of lesions
  •  effect on function and cosmesis
  •  accessibility to specialized treatment modalities
  •  immunocompetency status of patient
• for single or few, small lesions (< 2 cm) in areas that heal well
  • curettage generally considered as the treatment of choice
  • cryotherapy, surgical excision 5-fluorouracil (5-FU) are also commonly used
    • cryotherapy is associated with clearance rates of 65%-90%
    • 5-fluorouracil or cryotherapy may clear > 70% of Bowen lesions after 1 treatment cycle, but 5-fluorouracil associated with more adverse events (level 2 [mid-level] evidence)
    • excision reported to have lower risk of recurrence than less invasive treatment modalities in patients with Bowen disease (level 3 [lacking direct] evidence)
  • other options include
    • photodynamic therapy (PDT) (level 2 [mid-level] evidence)
    •  imiquimod 5% cream/day (level 2 [mid-level] evidence)
• for large, single lesions, or multiple lesions in areas that heal well
  • initial options include
    • 5-FU
    • photodynamic therapy with methyl aminolevulinate or 5-aminolevulinic acid, which may yield higher complete response rates after 1 treatment cycle than cryotherapy or 5-fluorouracil in patients with Bowen disease (level 2 [mid-level] evidence)
  • alternative options include imiquimod or cryotherapy
• for lesions in areas that heal poorly, consider
  • 5-FU or PDT
  •  if small lesions, consider also curettage, surgical excision or laser
  • curettage and electrocautery may induce faster healing, less pain, and fewer recurrences compared to cryotherapy in patients with Bowen disease on the lower leg (level 2 [mid-level] evidence)
  • alternative options include imiquimod or cryotherapy
  •  for slowly progressing, shallow lesions, especially on lower leg of patients with poor health, consider observation and topical emollient⁽²⁾
• consider Mohs micrographic surgery, particularly for high risk lesions and lesions in challenging sites, such as
  •  on central face, eyelids, eyebrows, periorbital, nose, lips, chin, mandible, preauricular and postauricular skin/sulci, temple, ears, genitalia, hands, or feet
  •  within a scar or chronic wound
  •  large, including > 10 mm on cheeks, forehead, scalp, neck, and pretibial sites, or > 20 mm on trunk or extremities
• for lesions that do not respond to monotherapy, consider combination therapies:⁽²⁾
  • cryotherapy followed by imiquimod or 5-FU
  •  imiquimod followed by CO₂ laser
  • laser and 5-FU
  • laser and photodynamic therapy (PDT)
  • simple shaving techniques followed by PDT
•  for patients aged ≥ 55 years old with larger lesions who are unwilling or unable to tolerate surgery, consider radiation therapy
•  for patients at high risk, such as organ transplant recipients, or patients with field cancerization, consider treatment with field-directed therapy using PDT or topical medication, such as 5-FU or imiquimod
• for treatment of genital lesions
  •  for squamous cell carcinoma in situ (SCCis) localized to the vulva, see also Vulvar Intraepithelial Neoplasia (VIN)
  •  for penile lesions, see also Squamous Cell Carcinoma of Penis
  •  for anal lesions, see also Anal Cancer

Medications

5-Fluorouracil (5-FU)

• dosing of 5% 5-fluorouracil for squamous cell carcinoma in situ (Bowen disease): once- or twice-daily for up to 4 weeks⁽²⁾
• National Comprehensive Cancer Network (NCCN) guidelines for squamous cell carcinoma (includes Bowen disease)⁽⁵⁾
  •  consider 5% topical 5-FU as an option for treatment of Bowen disease
  • topical 5-FU may have lower cure rate than excision
• British Association of Dermatologists’ 2022 treatment recommendations for 5-FU for squamous cell carcinoma in situ (Bowen disease)⁽²⁾
  • advise 5% 5-FU for:
    • small lesions (< 2 cm) in low-risk areas (trunk and limbs) (BAD Strong recommendation)
    • patients unable or unwilling to use other treatments (BAD Strong recommendation)
  • consider 5-FU for:
    • large, single lesions in low-risk areas and in patients unable or unwilling to use other treatments (BAD Good practice point)
    • large lesions in poor healing areas (for example, lower extremities) as alternative to other treatments (BAD Weak recommendation)
    • treatment of multiple and recurring lesions in patients with immunosuppression (BAD Good practice point)
•  consider 5-FU for field-directed therapy for patients with associated actinic keratosis⁽³⁾
•  reported recurrence of Bowen disease after topical 5-FU ranges 7%-42%⁽³⁾
• 5-fluorouracil or cryotherapy may clear > 70% of Bowen disease lesions after 1 treatment cycle, but 5-fluorouracil associated with more adverse events (level 2 [mid-level] evidence)
  •  based on Cochrane review of trials with methodologic limitations
  •  systematic review of 9 randomized trials evaluating interventions for cutaneous Bowen disease in 363 adults
  • all trials had ≥ 1 limitation including
    •  unclear allocation concealment
    •  blinding of outcome assessor not reported
  • comparing cryotherapy vs. 5-FU in analysis of 1 trial with 112 patients
    •  lesion clearance after first treatment cycle 71.4% vs. 72.2% (no significant difference)
    •  ≥ 1 adverse event, 48.8% vs. 76.7% risk ratio 0.64 (95% CI 0.47-0.86)
  •  Reference – Cochrane Database Syst Rev 2013 Jun 24;(6):CD007281

Imiquimod

• dosing of topical imiquimod for squamous cell carcinoma in situ (Bowen disease): apply imiquimod once daily 3 times each week for 4 weeks (up to 12 weeks may be needed)⁽²⁾
• NCCN guidelines for squamous cell carcinoma (includes Bowen disease)⁽⁵⁾
  •  consider imiquimod 5% topical cream topically as option for Bowen disease
  • imiquimod may have lower cure rate than excision
• British Association of Dermatologists’ 2022 treatment recommendations for imiquimod for Bowen disease⁽²⁾
  • consider topical imiquimod for squamous cell carcinoma in situ (Bowen disease) for:
    • low-risk sites if no other appropriate options (BAD Weak recommendation)
    • lesions on the lower extremities in patients who are unable to tolerate, or refractory to topical 5-fluorouracil (5%), photodynamic therapy, laser, curettage with cautery, or surgery (BAD Weak recommendation)
  • apply imiquimod once daily 3 times weekly for 4 weeks (up to 12 weeks may be needed)
•  consider imiquimod for field-directed therapy for patients with associated actinic keratosis⁽³⁾
• imiquimod 5% cream/day for 4 months may increase resolution of Bowen disease (level 2 [mid-level] evidence)
  •  based on randomized trial with blinding of outcome assessor not reported
  •  31 patients with biopsy-proven cutaneous Bowen disease randomized to imiquimod 5% cream/day vs. placebo for 16 weeks
  •  3 patients discontinued imiquimod of whom 1 was lost to follow-up, 1 had inflammatory reaction but did have complete resolution at 120 days, and 1 had localized bacterial infection and persistent dysplasia on histologic exam at 4 months
  • in intention-to-treat analysis assuming persistent disease in patient lost to follow-up
    •  10 of 15 (67%) imiquimod vs. 0 of 16 placebo patients had resolution of Bowen disease (NNT 2)
    •  3 imiquimod patients with resolution of Bowen disease continued to have mild epidermal dysplasia, so 47% vs. 0 had complete resolution of dysplasia
    •  among patients with resolution, no relapse over 9 months
    •  0 vs. 2 (12.5%) patients had progression to early invasive squamous cell carcinoma
  •  Reference – J Am Acad Dermatol 2006 Jun;54(6):1025
  •  no additional trials evaluating imiquimod for cutaneous Bowen disease found in Cochrane review (Cochrane Database Syst Rev 2013 Jun 24;(6):CD007281)

Photodynamic Therapy (PDT)

PDT

• recommendations from professional organizations on using photodynamic therapy (PDT) for Bowen disease (squamous cell carcinoma [SCC] in situ)
  • National Comprehensive Cancer Network (NCCN) guidelines for squamous cell carcinoma (includes Bowen disease)⁽⁵⁾
    •  consider PDT as option for treatment of Bowen disease
    •  may have lower cure rate than excision
  • European Association of Dermatology and Venereology 2019 recommendations for use of PDT
    • PDT is a strongly recommended treatment option for Bowen disease (squamous cell carcinoma in situ)
      • conventional methyl aminolevulinate (MAL-PDT) is approved in many countries for Bowen disease, but no formulation of aminolevulinic acid (ALA-PDT) is approved for this indication
      • although there are limited data to demonstrate that PDT is more effective, PDT may be associated with less pain and scarring than cryotherapy or topical 5-fluorouracil
      • PDT has been associated with faster rates of clearance achieved, but overall clearance over time similar to other therapies
      • combinations that are likely effective include
        • ALA-PDT combined with CO₂ laser (compared to laser alone)
        • ablative fractional laser-assisted MAL-PDT (compared to PDT alone)
      • therapeutic effect of PDT may be enhanced by pretreatment of lesions with topical imiquimod, although clinical data is limited
      • larger lesion size, severe atypia, older age, and incorrect application of PDT are among factors associated with increased risk of treatment failure following PDT
    • Reference – J Eur Acad Dermatol Venereol 2019 Dec;33(12):2225
  • British Association of Dermatologists’ 2022 treatment recommendations for Bowen disease⁽²⁾
    • offer conventional, red-light PDT as an option for treatment of squamous cell carcinoma in situ (Bowen disease), especially in sites with poor healing or cosmetically sensitive skin, and for multiple lesions and large-area lesions (BAD Strong recommendation)
    • consider conventional red-light PDT as a treatment especially for recurrent lesions in immunosuppressed patients (BAD Good practice point)
    • there is insufficient evidence to make a recommendation regarding daylight PDT for Bowen disease
•  reported recurrence of Bowen disease after PDT is 0%-31%⁽³⁾
•  consider PDT for field-directed therapy for patients with associated actinic keratosis⁽³⁾
• general information
  •  light-activated topical photosensitizer (5-aminolevulinic acid [ALA] or methyl aminolevulinate [MAL]) produces reactive oxygen species that damages membrane lipids, resulting in loss of membrane integrity and programmed cell death of target cells
  •  adverse effects may include significant pain at treatment site⁽¹⁾
•  photodynamic therapy with methyl aminolevulinate or 5-aminolevulinic acid may yield higher complete response rates after 1 treatment cycle than cryotherapy or 5-fluorouracil in patients with Bowen disease (level 2 [mid-level] evidence)
  •  based on Cochrane review of trials with methodologic limitations
  •  systematic review of 9 randomized trials evaluating interventions for cutaneous Bowen disease in 363 adults
  • all trials had ≥ 1 limitation including
    •  unclear allocation concealment
    •  blinding of outcome assessor not reported
  • comparing PDT to 5-FU
    •  PDT associated with increased lesion clearance (risk ratio [RR] 1.83, 95% CI 1.1-3.06 p < 0.05) in 1 trial with 40 adults and 66 lesions
    •  no significant difference in lesion clearance in 2 arms of 1 four-arm trial with 120 adults and 160 lesions
  • comparing PDT to cryotherapy
    •  PDT associated with increased clearance (RR 1.17, 95% CI 1.91-1.37 p < 0.05) in 2 arms of 1 four-arm trial with 178 adults and 215 lesions
    •  no significant difference in lesion clearance in 1 trial with 19 adults and 40 lesions
  •  Reference – Cochrane Database Syst Rev 2013 Jun 24;(6):CD007281
  •  similar results found in older systematic review with 7 of same trials in Health Technol Assess 2010 Jul;14(37):1PDF
• PDT reported to achieve clearance rate of 77% at 12-18 months and 66% at > 24 months in patients with Bowen disease (level 3 [lacking direct] evidence)
  •  based on noncomparative data in systematic review
  • systematic review of 9 randomized trials and 34 cohort studies evaluating PDT with mean or median follow-up of ≥ 1 year in patients with Bowen disease (1,943 lesions) or cutaneous squamous cell carcinoma (282 lesions) with no prior treatment
    • PDT used red light in 32 studies and laser in 9 studies
    • photosensitizer included aminolevulinic acid in 24 studies and methyl aminolevulinate in 18 studies
    • in patients with Bowen disease, lesions were mostly small (average diameter < 20 mm or surface area < 400 mm²) in 20 studies and mostly large in 9 studies
  • pooled clearance rate
    • in patients with Bowen disease
      • 76% (95% CI 71%-80%) overall in analysis of 39 studies (43 comparisons)
      • 77% (95% CI 70%-84%) at 12-18 months
      • 82% (95% CI 75%-88%) at 18-24 months
      • 66% (95% CI 56%-75%) at > 24 months
    • in patients with cutaneous squamous cell carcinoma
      • 51% (95% CI 35%-66%) overall in analysis of 10 studies (13 comparisons)
      • 51% (95% CI 20%-82%) at 12-18 months
      • 50% (95% CI 32%-68%) at 18-24 months
  • Reference – Dermatol Surg 2022 Apr 1;48(4):395
• single session of laser-assisted methyl aminolevulinate photodynamic therapy may increase clearance and reduce recurrence of lesions compared to 2 sessions of methyl aminolevulinate photodynamic therapy alone in patients with lower extremity Bowen disease (level 2 [mid-level] evidence)
  • based on randomized trial without statistical limitations
  • 60 adults (mean age 71 years) with Bowen disease on lower extremities were randomized to 1 session of ablative fractional laser-assisted methyl aminolevulinate photodynamic therapy (AFL-MAL-PDT) vs. 2 sessions of MAL-PDT and followed for 5 years
    • AFL-MAL-PDT group had single pulse of erbium:yttrium-argon-garnet ablative fractional laser (depth 550-600 mcm with level 1 coagulation, 22% treatment density) followed by topical methyl aminolevulinate 16% for 3 hours and PDT with red light-emitting diode (632 nm) with total dose 37 J/cm²
    • MAL-PDT had same methyl aminolevulinate and PDT protocol in 2 sessions spaced 1 week apart
  • complete response defined as disappearance of entire lesion without recurrence on the basis of inspection, photography, palpation, and histologic findings
  • 84 lesions were treated and included in analysis; analysis was not adjusted for correlations in patients with multiple lesions
  • comparing AFL-MAL-PDT vs. MAL-PDT in per-lesion analysis
    • complete response in 84.8% of lesions vs. 44.7% of lesions (p < 0.001)
    • recurrence in 9.3% vs. 41.4% (p = 0.003)
  • no significant difference in pain during PDT illumination or in common adverse events (erythema, crusting, hyperpigmentation, burning sensation, and itching all resolved within 7 days without complications)
  • Reference – J Am Acad Dermatol 2018 Nov;79(5):860

Surgery and Procedures

Cryotherapy

•  reported recurrence of Bowen disease after cryosurgery is 10%-35%⁽³⁾
• National Comprehensive Cancer Network (NCCN) guidelines for squamous cell carcinoma (SCC) (includes Bowen disease)⁽⁵⁾
  •  consider vigorous cryotherapy as option for treatment of Bowen disease
  •  may have lower cure rate than excision
• British Association of Dermatologists’ 2022 treatment recommendations for cryotherapy for Bowen disease⁽²⁾
  • advise cryotherapy as first-line option for small lesions (< 2 cm) (BAD Strong recommendation)
  • consider cryotherapy for any of the following: (BAD Good practice point)
    •  larger (≥ 2 cm) SCC in situ
    • lesions on the lower extremities
    •  immunocompromised patients
• general information
  • cryotherapy is simple, inexpensive, quick, and widely used treatment of SCC in situ⁽¹⁾
  • longer freezing times may be associated with increased effectiveness; common strategies include either of:⁽²⁾
    •  30-second freeze-thaw cycle (FTC)
    •  2 FTC of 10-20 seconds each with a thaw period
  •  leg lesions treated with cryotherapy have prolonged healing time, which may be problematic in elderly patients⁽¹⁾

Curettage With Cautery/Electrocautery

•  reported recurrence of Bowen disease after curettage with cautery/electrocautery ranges 12%-20%⁽³⁾
• NCCN guidelines for curettage for squamous cell carcinoma (includes Bowen disease)⁽⁵⁾
  •  consider curettage and electrodesiccation (C&E) as option for local, low risk cutaneous squamous cell carcinoma (NCCN Category 2A)
  •  if adipose reached on curettage, switch to excision
• British Association of Dermatologists’ 2022 treatment recommendations for curettage for Bowen disease⁽²⁾
  • advise curettage as an initial option for treatment of small SCC in situ (Bowen disease) (BAD Strong recommendation)
  • C&E is generally a good option to assess histologic diagnosis
  • consider curettage for larger SCC in situ (Bowen disease) (BAD Good practice point)
  • consider curettage for SCC in situ (Bowen disease) in immunosuppressed patients (BAD Good practice point)
• general information
  •  stroma of lesions appropriate for curettage are gelatinous compared to surrounding healthy dermis
  •  operator can differentiate between normal and cancerous tissue and precisely enucleate lesion using a curette
  •  recurrence reported in 6%-20%
  •  Reference – CCA/ACN 2008 Nov PDF
•  curettage and electrocautery may induce faster healing, less pain, and fewer recurrences compared to cryotherapy in patients with Bowen disease on the lower leg (level 2 [mid-level] evidence)
  •  based on prospective cohort study
  •  67 patients (mean age 74 years, 82% women) with 80 Bowen disease lesions had curettage and electrocautery or cryotherapy
  •  mean follow-up 22 months
  •  19 patients (21 lesions) were lost to follow-up
  •  pain assessed on visual analog scale (range 0-5, with higher numbers indicating increased pain)
  • comparing curettage and electrocautery vs. cryotherapy
    •  healing time for lower leg lesions 39 days vs. 90 days (p < 0.001)
    •  no pain at 24 hours in 68% vs. 25% (extrapolated from graph, no p value reported)
    •  recurrence 12% vs. 50% (p = 0.014)
  •  no patients reported severe pain
  •  in assessment of pain during treatment and subsequent 24 hours, curettage and electrocautery associated with reduced risk of reporting any pain (p < 0.001)
  •  Reference – Br J Dermatol 2000 Oct;143(4):759

Surgical Excision

•  reported recurrence of Bowen disease after surgical excision ranges 4%-20%⁽³⁾
• NCCN guidelines for squamous cell carcinoma [SCC} (includes Bowen disease)⁽⁵⁾
  •  consider surgical excision for local, low-risk lesions (NCCN Category 2A)
  • use standard excision with 4-6 mm margins and postoperative margin assessment (NCCN Category 2A)
• British Association of Dermatologists’ 2022 treatment recommendations for excision for Bowen disease⁽²⁾
  • advise surgical excision for SCC in situ if a histologic diagnosis is desired to rule out invasive SCC (BAD Strong recommendation)
  • advise surgical excision for SCC in situ for recurrent or refractory lesions when there is low risk for surgical morbidity (BAD Strong recommendation)
  • consider surgical excision for lesions in immunosuppressed patients (BAD Good practice point)
• general information
  • surgical excision is a simple, rapid treatment modality⁽¹⁾
  •  histological evaluation of excised lesion can verify diagnosis and conclusively rule out invasive SSC⁽¹⁾
• excision reported to have lower risk of recurrence than less invasive treatment modalities in patients with Bowen disease (level 3 [lacking direct] evidence)
  •  based on retrospective cohort study without direct statistical comparison between groups
  • 239 patients with 263 Bowen disease lesions received 1 of the following treatments and followed for about 8 years
    •  surgical excision
    •  cryotherapy
    •  photodynamic therapy
    •  laser ablation
    •  curettage with cautery
    •  radiotherapy
    •  topical 5-fluorouracil
    •  topical imiquimod
  •  recurrence in 6.5% overall
  • recurrence rates by treatment modality (no p values reported)
    •  0.8% with surgical excision
    •  4.7% with cryotherapy
    •  18% with photodynamic therapy
  •  Reference – Acta Derm Venereol 2016 Jan 20;96(1):64

Mohs Micrographic Surgery

• Mohs micrographic surgery involves removal of skin lesions with small margins of normal tissue and successive excision and examination of frozen tumor margins until no cancer cells remain⁽⁴⁾
•  reported recurrence of Bowen disease after Mohs micrographic surgery is about 6%⁽³⁾
• NCCN guidelines for Mohs surgery for squamous cell carcinoma (includes Bowen disease)⁽⁵⁾
  •  consider Mohs as an option (NCCN Category 2A)
  • also an option for lesions with positive margins after standard excision (NCCN Category 2A)
• American Academy of Dermatology/American College of Mohs Surgery/American Society for Dermatologic Surgery Association/American Society for Mohs Surgery (AAD/ACMS/ASDSA/ASMS) appropriate use clinical indications for Mohs surgery for squamous cell carcinoma in situ include
  •  primary lesion of any size if on mask areas of face, cheeks, forehead, scalp, neck, jaw line, genitalia, pretibial surface, hands, feet, nail units, and ankles, nipples, areola
  •  primary lesions > 2 cm if on trunk and extremities (excluding pretibial surface, hands, feet, nail units, and ankles)
  •  primary lesions ≥ 1.1 cm if on trunk and extremities (excluding pretibial surface, hands, feet, nail units, and ankles) in immunocompromised patients
  •  Reference – Dermatol Surg 2012 Oct;38(10):1582 or in J Am Acad Dermatol 2012 Oct;67(4):531, editorial can be found in Dermatol Surg 2012 Oct;38(10):1581
• British Association of Dermatologists’ 2022 treatment recommendations for Mohs surgery for Bowen disease ⁽²⁾
  • consider Mohs surgery as a good option to treat SCC in situ when tissue sparing is desired (for example, for lesions near the eyes or the nail unit) (BAD Weak recommendation)
• consider Mohs surgery as an option for
  •  periorificial lesions⁽¹⁾
  •  lesions located where wide surgical margins may be difficult to achieve without functional impairment⁽³⁾

Laser Therapy

• limited randomized control trial evidence to support laser therapy for Bowen disease (squamous cell carcinoma in situ) (Dermatol Surg 2017 May;43(5):615full-text)
• British Association of Dermatologists’ suggests to consider laser treatment if other treatments fail or are not appropriate (BAD Weak recommendation)⁽²⁾
• ablative CO₂ laser therapy may be more effective than nonablative neodymium:YAG laser therapy⁽²⁾
• laser-assisted photodynamic therapy may increase clearance and reduce recurrence of lesions compared to photodynamic therapy alone in patients with lower extremity Bowen disease

Radiation Therapy

•  reported recurrence of Bowen disease after radiation therapy is 0%-3%⁽³⁾
•  National Comprehensive Cancer Network (NCCN) guidelines for squamous cell carcinoma (includes Bowen disease) consider radiation as an option for lesions in nonsurgical candidates (NCCN Category 2A)⁽⁵⁾
• British Association of Dermatologists’ 2022 treatment recommendations for Bowen disease⁽²⁾
  • in immunocompetent patients
    • advise radiation therapy only when other treatments have failed, the lesion is recurrent or if surgery is not an option (BAD Strong recommendation)
    • consider brachytherapy for treatment of curved surfaces or regions of poor healing, for example the digits or lower legs (BAD Good practice point)
  • in immunosuppressed patients, reserve radiation therapy for those at risk of invasive disease or malignancy (BAD Good practice point)
• consider as radiation therapy as an option for⁽¹⁾
  •  lesions in nonsurgical candidates
  •  large or multiple lesions, particularly in elderly or infirm patients
  •  areas where surgical treatment modalities are difficult (for example, scalp)
• radiation therapy generally not recommended for
  •  patients < 55 years old because late effects of radiation (such as dyspigmentation, telangiectasia, and radiodystrophy) may be more cosmetically noticeable than surgical scar
  •  treatment sites with poor tolerance to radiation therapy (such as back of hand, abdominal wall, and lower limb)
  •  Reference – Br J Plast Surg 2003 Mar;56(2):85
• radiation therapy contraindicated in patients with⁽⁵⁾
  •  genetic conditions that increase risk of skin cancer, such as basal cell nevus syndrome and xeroderma pigmentosum
  •  connective tissue diseases including systemic sclerosis (scleroderma)

Follow-Up

•  follow-up check recommended at 6-12 months⁽³⁾
• longer term follow-up indicated for patients with any of the following⁽³⁾
  •  previous Bowen disease recurrence⁽³⁾
  •  previous or present skin cancer other than Bowen disease⁽³⁾
  •  perianal localization of lesion⁽³⁾
  •  immunosuppression⁽³⁾
•  dermoscopy may be considered for posttreatment response assessment, especially for pigmented Bowen disease⁽³⁾

Complications

• Bowen disease (squamous cell carcinoma in situ) may advance to invasive squamous cell carcinoma (SCC)⁽¹⁾

Prognosis

•  3%-5% of Bowen disease lesions are reported to progress to invasive squamous cell carcinoma (SCC)⁽¹⁾
•  older and/or immunosuppressed patients are more likely to have more aggressive lesions^(1,3)
• characteristics associated with high-risk disease, or increased risk of recurrence include⁽³⁾
  • size
    •  ≥ 6 mm diameter on mask areas of face (central face, eyelids, eyebrows, periorbital, nose, lips [cutaneous and vermilion], chin, mandible, preauricular and postauricular skin/sulci, temple, ear), genitalia, hands, and feet
    •  ≥ 10 mm diameter on cheeks, forehead, scalp, neck, and pretibial sites
    •  ≥ 20 mm diameter on trunk or extremities (except pretibia, hands, feet, nail units, and ankles)
  •  localization within a scar, chronic wound, or site of prior radiation therapy, thermal damage
  •  poorly defined borders
  •  recurrent lesion
  •  rapidly growing
  • patient-related factors
    •  impaired immune function
    •  current smoker
• factors associated with low-risk disease (less likely to recur or metastasize)⁽⁵⁾
  • size
    •  < 6 mm diameter on mask areas of face (central face, eyelids, eyebrows, periorbital, nose, lips [cutaneous and vermilion], chin, mandible, preauricular and postauricular skin/sulci, temple ear), genitalia, hands, and feet
    •  < 10 mm diameter on cheeks, forehead, scalp, neck, and pretibial sites
    •  < 20 mm diameter on trunk or extremities (except pretibia, hands, feet, nail units, and ankles)
  •  primary disease (not recurrent disease)
  •  well-defined border
  •  slow-growing
  •  not in site of prior radiation therapy or chronic inflammation
  •  no neurologic symptoms
  •  no history of organ transplant, other conditions of impaired immune function, or genetic conditions that increase risk of squamous cell carcinoma
• reported recurrence after different treatment options for Bowen disease⁽³⁾
  •  Mohs micrographic surgery 6%
  •  surgery/excision 4%-20%
  •  curettage with cautery/electrocautery 12%-20%
  •  cryosurgery 10%-35%
  •  radiation therapy 0%-3%
  •  topical 5-fluorouracil 7%-42%
  •  photodynamic therapy 0%-31%

Prevention

• suggestions to prevent ultraviolet (UV)-induced skin cancers⁽⁴⁾
  •  restrict time in midday sun
  •  monitor UV index (higher UV associated with increased damage)
  •  stay in the shade
  •  use topical sunscreens
  •  wear protective clothing
  •  avoid sunlamps and tanning beds

Screening

• Skin cancer screening:
  • United States Preventive Services Task Force (USPSTF) recommendations:
    • There is insufficient evidence to recommend for or against routine total-body skin cancer screening in asymptomatic adults (USPSTF Grade I).
    • Reference – JAMA 2023 Apr 18;329(15):1290full-text, supporting systematic review can be found in JAMA 2023 Apr 18;329(15):1296full-text
  • Cancer Council Australia 2019 recommendations:
    • Due to insufficient evidence, population-based screening for skin cancer is not recommended.
    • People should conduct skin self-examinations, including skin not exposed to sun, and consult a health care provider for any changes or new lesions.
    • People at high risk of developing skin cancer should have clinical skin exams every 6-12 months.
    • Smartphone applications to self-diagnose skin cancer are not recommended.
    • Reference – Screening and Early Detection of Skin Cancer 2019 Jan

Guidelines

United States Guidelines

• National Comprehensive Cancer Network (NCCN) statement on mitigating the impacts of anticancer drug shortages can be found at NCCN 2023 Jun 7 PDF
•  National Comprehensive Cancer Network (NCCN) guideline on squamous cell skin cancer can be found at NCCN website (free registration required)
• American Society of Clinical Oncology (ASCO) position on prioritization of antineoplastic agents in limited supply for first intervention can be found at ASCO, accessed 2023 Jun 13
•  College of American Pathologists/American Society for Colposcopy and Cervical Pathology (CAP/ASCCP) consensus recommendation on lower anogenital squamous terminology standardization project for HPV-associated lesions can be found in Arch Pathol Lab Med 2012 Oct;136(10):1266full-text, correction can be found in Arch Pathol Lab Med 2013 Jun;137(6):738
•  United States Preventive Services Task Force (USPSTF) recommendation statement on screening for skin cancer can be found in JAMA 2023 Apr 18;329(15):1290full-text, supporting systematic review can be found in JAMA 2023 Apr 18;329(15):1296full-text, summary for patients can be found in JAMA 2023 Apr 18;329(15):1324
•  United States Preventive Services Task Force (USPSTF) recommendation statement on behavioral counseling to prevent skin cancer can be found at USPSTF 2018 Mar 20 or in JAMA 2018 Mar 20;319(11):1134, editorial can be found in JAMA 2018 Mar 20;319(11):1101, commentary can be found in JAMA Intern Med 2018 May 1;178(5):609full-text
•  American Academy of Dermatology/American College of Mohs Surgery/American Society for Dermatologic Surgery Association/American Society for Mohs Surgery (AAD/ACMS/ASDSA/ASMS) appropriate use criteria on Mohs micrographic surgery can be found in Dermatol Surg 2012 Oct;38(10):1582 or in J Am Acad Dermatol 2012 Oct;67(4):531, editorial can be found in Dermatol Surg 2012 Oct;38(10):1581

United Kingdom Guidelines

• British Association of Dermatologists (BAD) guideline on management of people with cutaneous squamous cell carcinoma in situ (Bowen disease) 2022 can be found in Br J Dermatol 2023 Feb 10;188(2):186, editorial can be found in Br J Dermatol 2023 Feb 10;188(2):166

• British Association of Dermatologists/British Photodermatology Group (BAD/BPG) 2018 guideline on topical photodynamic therapy can be found in Br J Dermatol 2019 Apr;180(4):730.
• British Association of Dermatologists (BAD) consensus review on approach to management of adverse effects of topical photodynamic therapy can be found in Br J Dermatol 2019 Apr;180(4):715, editorial can be found in Br J Dermatol 2019 Apr;180(4):695.

European Guidelines

• European Dermatology Forum (EDF) guidelines on
  • topical photodynamic therapy (part 1): treatment delivery and established indications – actinic keratoses, Bowen disease and basal cell carcinomas can be found in J Eur Acad Dermatol Venereol 2019 Dec;33(12):2225
  • topical photodynamic therapy (part 2): emerging indications – field cancerization, photorejuvenation and inflammatory/infective dermatoses can be found inJ Eur Acad Dermatol Venereol 2020 Jan;34(1):17

Australian and New Zealand Guidelines

• Cancer Council Australia/Australian Government National Health and Medical Research Council (CCA/NHMRC) guideline on keratinocyte cancer: basal cell carcinoma, squamous cell carcinoma and related lesions can be found at CCA/NHMRC 2020 Jul 30PDF

Review Articles

• review of impact of skin cancer screening and secondary prevention campaigns on skin cancer incidence and mortality can be found in J Am Acad Dermatol 2017 Jan;76(1):129
•  review of radiation therapy for Bowen disease can be found in Rev Recent Clin Trials 2012 Feb;7(1):42
•  review of photosensitizers and light sources for photodynamic therapy for Bowen disease can be found in Arch Dermatol Res 2011 Apr;303(3):145
•  review of squamous cell carcinoma of the skin can be found in Int J Dermatol 2015 Feb;54(2):130
•  review of topical treatments for nonmelanoma skin cancer can be found in Clin Dermatol 2013 Nov-Dec;31(6):792
•  review of dermoscopy in diagnosis and management of nonmelanoma skin cancer can be found in Eur J Dermatol 2012 Jul-Aug;22(4):456
•  review of photoprotection can be found in Lancet 2007 Aug 11;370(9586):528, commentary can be found in Lancet 2007 Oct 27;370(9597):1481

MEDLINE Search

•  to search MEDLINE for (Bowen Disease) with targeted search (Clinical Queries), click therapy, diagnosis, or prognosis

Patient Information

• handouts from
  • British Association of Dermatologists PDF
  • National Organization for Rare Disorders
  • Patient UK PDF
• information on basal and squamous cell skin cancer from American Cancer Society or in Spanish
• information on squamous cell skin cancer from National Comprehensive Cancer NetworkPDF

References

1. Arlette JP, Trotter MJ. Squamous cell carcinoma in situ of the skin: history, presentation, biology and treatment. Australas J Dermatol. 2004 Feb;45(1):1-9.
2. Ashish S, Birnie AJ, Bordea C, Cheung ST, Mann J, Morton CA, et al. British Association of Dermatologists (BAD) guidelines for the management of people with cutaneous squamous cell carcinoma in situ (Bowen disease). Br J Dermatol 2023 Feb 10;188(2):186-194.
3. Lallas A, Argenziano G, Zendri E, et al. Update on non-melanoma skin cancer and the value of dermoscopy in its diagnosis and treatment monitoring. Expert Rev Anticancer Ther. 2013 May;13(5):541-58.
4. Madan V, Lear JT, Szeimies RM. Non-melanoma skin cancer. Lancet. 2010 Feb 20;375(9715):673-85, commentary can be found in Lancet 2010 Jul 17;376(9736):161 .
5. Schmults CD, Blitzblau R, Aasi SZ, et al. Squamous Cell Skin Cancer. Version 1.2023. In: National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. NCCN 2023 Mar from NCCN website (free registration required).