Premalignant Skin Conditions

Actinic keratoses: Erythematous scaly lesions on sun-damaged skin & considered “precancerous” lesions that have the potential to progress into invasive SCC.

Bowen’s disease: SCC in situ It has the potential to progress to invasive SCC.

Leukoplakia: Leukoplakia refers to a white patch or plaque on the oral mucosa that cannot be wiped off and cannot be characterized clinically or pathologically as any other disease.

1. PREMALIGNANT SKIN LESIONS www.facebook.com/groups/dermatologycourseonline

2. PREMALIGNANT SKIN CONDITIONS PRE-MALIGNANT LESIONS: Actinic keratoses  SCC Bowen’s disease  SCC Leukoplakia  SCC Sebaceous nevus  BCC Dysplastic nevi  Melanoma Lentigo maligna  LMM VERY HIGH RISK: Xeroderma Pigmentosum  melanoma, BCC, SCC Immunosuppression (e.g. organ transplant)

3. ACTINIC KERATOSES (AK s )

4. ACTINIC KERATOSES (AK s /SOLAR KERATOSES) Erythematous scaly lesions on sun-damaged skin. AKs are considered “ precancerous ” lesions that have the potential to progress into invasive SCC . The risk of squamous cell carcinoma occurring in a patient with more than ten actinic keratoses is about 10 to 15% . The atypical keratinocytes are confined to the lower portion of the epidermis .

5. ACTINIC KERATOSES (AK s /SOLAR KERATOSES) They are especially common in middle-aged to older fair-skinned persons or those who have worked outdoors for long periods without skin protection .

6. Multiple AKs on the face of an elderly woman with fair complexion, blue eyes, and moderate to severe photodamage; the AKs vary in size from a few millimeters to more than 1 cm. On the left forehead, the red nodule with slight scale-crust represents a well-differentiated SCC.

7. Multiple hypertrophic AKs on the bald scalp with hypopigmentation at sites of previous treatment. Pink-colored atrophic AK with minimal scale on the forehead.

8. Multiple, large hypertrophic AKs on the shin of an elderly woman; note the thick scale.

9. Inflamed AK tend to have white circles on a pink background. The circles have 4 white dots in them called rosettes

10. Lesions are said to have a strawberry-like appearance. The arrow denotes one of the many 'pips'. These findings will only be evident in lesions with little scale, or where the scale has been lifted off

11. C/P OF AK s The patient may complain of uncomfortable and disfigurement . Multiple circumscribed flat or thickened , scaly or warty lesion may be skin colored or erythematous . The associated scale is usually white to yellow in color and feels rough . Diagnosis usually made by visual inspection and palpation ; because of the rough texture , it is sometimes easier to detect lesions via touch.

12. C/P OF AK s Occur primarily in sites that have received the greatest amount of cumulative sun exposure (e.g. scalp in bald individuals , face most often affecting the cheeks , temples and forehead , nose , ears also neck , dorsal forearms and hands , shins ).

13. C/P OF AK s AK may develop into a cutaneous horn .

14. C/P OF AK s AKs have the potential to persist , spontaneously regress , or progress to SCC , but clinically it is difficult to predict which course a given AK will take.

15. C/P OF AK s Clinical clues to progression to invasive SCC and need for biopsy: Tenderness Volume (particularly thickness ) Ulceration Bleeding Inflammation Failure to respond to appropriate therapy

16. CLINICAL VARIANTS OF AK s

17. A hyperkeratotic actinic keratosis This patient had a number of AK. One of the lesions was hyperkeratotic (red arrow) - it is important to remove the scale if there is any uncertainty about the diagnosis  

18. Actinic cheilitis: Dry, whitish–gray, scaly plaques with possible erythema, erosion, or ulceration Due to chronic sun exposure; also may be associated with smoking and chronic irritation

19. ACTINIC CHEILITIS (SOLAR CHEILITIS) Pre-malignant changes on the lip due to chronic sun exposure and tends to be more severe in smokers . Invasive squamous cell carcinoma should be suspected if a persistent ulcer or nodule develops .

20. ACTINIC CHEILITIS (SOLAR CHEILITIS) Actinic cheilitis most commonly results in the following features: Dry lips Thinned skin of the lips Scaly patches Less common features of actinic cheilitis include: Swelling of the lip Redness and soreness Ulceration and crusting Loss of demarcation between the vermilion border of the lip and its adjacent skin Prominent folds and lip lines White thickened patches (leukokeratosis) Discolored skin with pale or yellow areas

21. DD x OF AK s SCC in situ Invasive SCC in case of thicker lesions (e.g. HAK) BCC lichen planus-like keratosis (LPLK) Irritated seborrheic keratosis (SK) Verruca vulgaris Amelanotic melanoma Actinic porokeratosis

22. HISTOPATHOLOGY OF AK s Hyperkera tosis . Focal parakera tosis overlying atypical keratinocytes ( mainly basal) that show  mi tosis . Dyskera tosis may be seen. Loss of granular layer . Sparing adnexae and acrosyringium . The dermis : perivascular/lichenoid lymphocytic infiltrate ; solar elas tosis .

23. HYPERKERATOTIC AK with alternating pink and blue colors in the cornified layer; the pink-colored parakeratotic columns within the stratum corneum are located above the atypical keratinocytes in the spinous layer, while the blue-colored columns of orthohyperkeratosis are above the acrosyringia . Atypical epidermal keratinocytes also display a pinkish color that contrasts with the color of the basophilic, normal keratinocytes of the acrosyringia

24. Hypertrophic actinic keratosis

25. PIGMENTED ACTINIC KERATOSIS with increased melanin pigmentation within the basal layer. Note the solar elastosis in the dermis

26. ACTINIC CHEILITIS: Alternating orthokeratosis and parakeratosis; disordered maturation of epidermal cells with increased mitosis and atypia; prominent solar elastosis; moderate infiltrate (including plasma cells below ulcerations)

27. R x OF AK s Lesion-targeted treatments are best for an isolated or limited number of lesions while field treatments are best for more numerous or larger lesions . It is not practical to remove all Aks in those with very extensive sun damage ; in such cases it is important to get rid of thickened or tender lesions as these are the ones at greatest risk of progressing to skin cancer.

28. COMMON TREATMENT OPTIONS FOR ACTINIC KERATOSES LOCALIZED/LESION-TARGETED TREATMENTS Lesion-Targeted Treatment Helpful Hints 1. Liquid nitrogen cryosurgery Blistering & shedding of the sun damaged skin 99% cure rate No cutting or anesthesia necessary 10- to 14-day healing period Risk of hypopigmentation 2. Curettage & electro- desiccation Preferred with thicker keratoses Requires local anesthesia Crust forms which heals over few weeks Risk of hypopigmentation and scarring (less so if curettage alone) 3. Excision (Shave excision or excisional biopsy) Requires local anesthesia Usually the surgical wound is sutured Risk of scarring

29. TOPICAL FIELD TREATMENTS Topical Agent Dosing Helpful Hints 1. 5-Fluorouracil 0.5% cream apply at bedtime × 4 weeks 1.0% or 5.0% cream apply twice /d for 2–4 wk. 2.0% and 5.0% solutions apply twice a day for 2–4 weeks When treating extensor extremities, pretreatment with a topical retinoid for 1–2 weeks may be required When there are many lesions on the face Warn of photosensitivity, which can be severe Optimal results occur if treatment continues until there is significant inflammation or superficial erosions Healing usually occurs within 2 weeks of stopping treatment 2. Imiquimod 2.5% or 3.75% cream – apply at bedtime for 2 weeks; take a 2-week break, and then repeat 2-week application cycle 5% cream – apply twice a week for 16 consecutive weeks Recommended treatment area is 25 cm 2 It is an immune response modifier It causes an inflammatory reaction May cause systemic flu-like symptoms Not recommended if patient has an underlying autoimmune condition May cause hypopigmentation at the treated site 3. Diclofenac 3% gel – apply twice a day for 90 days A maximum amount of 8 g daily should not be exceeded It is well tolerated Do not use if patient is allergic to non-steroidal anti-inflammatory drugs (NSAIDs) It has less severe cutaneous reaction but poor compliance ( longer application period) 4. Ingenol mebutate 0.015% gel – apply at bedtime for 3 consecutive nights (face and scalp) 0.05% gel – apply at bedtime for 2 consecutive nights (trunk and extremities) About half of all lesions resolve after two to three days of treatment Was approved by the FDA in 2012 Rapid onset of action; typically within 24 hours of application, patient will experience erythema and burning Healing occurs within 10–14 days Supposedly does not cause hypopigmentation

30. Actinic keratoses with field change on the right forehead Same patient after 4 weeks of Efudix cream Same patient 8 weeks after treatment had finished. The skin has responded very well and healed nicely

31. Actinic keratoses treated with 5-FU

32. Actinic keratoses treated with imiquimod

33. PROCEDURAL FIELD TREATMENTS Procedure Helpful Hints 1. Photodynamic therapy (PDT) (e.g. 5-ALA + blue light) Involves applying a photosensitizer to the affected area prior to exposing it to a source of visible light (including daylight). Can be painful Requires 48 hours of no outdoor exposure post-treatment Relatively quick recovery over 1–2 weeks 2. Chemical peels (e.g. trichloracetic acid) May require local anesthesia May cause significant irritation and temporary discoloration Healing typically over 7 days 3. Ablative laser techniques (e.g. ablative fractional lasers, erbium:YAG laser) Requires local anesthesia Depending on the technique, recovery period varies Hypopigmentation a potential complication

34. Prevention of AK Prevention is possible with broad-spectrum sunscreens and sun avoidance measures .

35. R x OF ACTINIC CHEILITIS IN ADDITION TO THE ABOVE MENTIONED MEASURES: Smoking should be stopped . Men can consider growing a moustache . Using a lip balm contains sunscreen is recommended . Vermilionectomy ( surgical removal of the lip ).

36. BOWEN’S DISEASE (SCC IN SITU/intraepidermal SCC)

37. BOWEN’S DISEASE Keratinocyte atypia is seen throughout the entire epidermis ( full-thickness ). It has the potential to progress to invasive SCC , with an estimated risk of ~ 3–5% if untreated. Bowen’s disease may arise de novo or from a pre-existing AK .

38. Etiology OF BOWEN’S DISEASE SUN EXPOSURE: most often found on sun exposed sites of fair skinned individuals. This is because UVR damages the DNA  a mutant clone of the gene p53  of uncontrolled growth of the keratinocytes. UVR also suppresses the immune response preventing recovery from this damage. ARSENIC INGESTION : this may result in multiple areas of intraepidermal SCC on the trunk and limbs years after exposure . IONIZING RADIATION : intraepidermal SCC was common on the hands of radiologists early in the 20th century. HUMAN PAPILLOMAVIRUS INFECTION ( oncogenic strains HPV-16 or - 18 ): rarely causes intraepidermal SCC. However, HPV infecting genital sites is the cause of vulval and penile intraepithelial neoplasia or mucosal SCC in situ .

39. Scaly red plaque on the chest with skip areas.

40. Bright-red, well-demarcated plaque on the proximal nail fold with associated horizontal nail ridging; the possibility of HPV infection needs to be considered

41. Extensive involvement of the finger, which is often misdiagnosed clinically as psoriasis or chronic eczema and therefore treated for years with corticosteroid creams (as was this patient).

42. C/P OF BOWEN’S DISEASE The most common presentation of SCC in situ is an erythematous scaly patch or slightly elevated plaque . The development of a induration , ulceration or bleeding may indicate progression into invasive SCC .

43. C/P OF BOWEN’S DISEASE It usually presents as an asymptomatic , well-defined erythematous patch or thin plaque with scales and irregular border that expands centrifugally .

44. C/P OF BOWEN’S DISEASE Although it may arise on any area of skin , the lesions are most often diagnosed on sun exposed sites such as the head (ears , face) and neck , followed by the extremities and trunk .

45. C/P OF BOWEN’S DISEASE Less common sites ( non-sunexposed sites): Related to HPV infection : Beard area. Periungual and subungual may results in a red streak ( erythronychia ) that later may destroy the nail plate . Anogenital (now referred to as intraepithelial neoplasia/IEN ). Related to arsenic exposure .

46. C/P OF BOWEN’S DISEASE MAJOR CLINICAL VARIANTS: Pigmented variant Penile intraepithelial neoplasia (PIN).

47. Squamous cell carcinoma, in situ, of the penis, also known as penile intraepithelial neoplasia (PIN ). Formerly called SCC in situ, erythroplasia of Queyrat type. Large eroded erythematous plaque with welldemarcated borders. The lesion began on the shaft of the penis.

48. PENILE INTRAEPITHELIAL NEOPLASIA (PIN) Synonyms: Bowen’s disease of the penis Erythroplasia of Queyrat SCC-in-situ of the penis 10-30 % progress to invasive SCC . Usually affecting uncircumcised males over 50 years of age. The diagnosis is often delayed as it may resemble other forms of chronic balanitis . Skin biopsy should be performed to confirm the diagnosis, and to rule out invasive SCC , which requires more aggressive treatment.

49. Etiology of pin CHRONIC INFECTION WITH HUMAN PAPILLOMA VIRUS (HPV): HPV-16 is the most common type identified . Partners of patients with PIN should be screened for other forms of intraepithelial neoplasia caused by HPV in the genital area. Many national immunization programs now include a vaccine against the causative HPV-16 and 18. Vaccination of boys and young men should be included, to  the risk of developing PIN in the future. CHRONIC SKIN DISEASE: especially lichen sclerosus & lichen planus. SMOKING IMMUNE SUPPRESSION: by medications or disease. CHRONIC IRRITATION: by urine, friction or injury to the penile area .

50. c/p of PIN Circumscribed , asymptomatic , bright red , shiny plaque on the glans of penis or inner aspect of the foreskin . It may have a smooth , velvety , moist , scaly , eroded or warty surface . The following signs and symptoms may occur : Redness and inflammation Itching Pain Crusting or scaling Ulcers Bleeding In the late stages, discharge from penis, phimosis or dysuria

51. DD x OF BOWEN’S DISEASE AK Invasive SCC Superficial BCC LPLK Irritated SK Amelanotic melanoma Occasionally may be misdiagnosed as an isolated lesion of psoriasis or nummular eczema, but a clue is its lack of response to appropriate therapy

52. HISTOPATHOLOGY OF BOWEN’S DISEASE Atypical keratinocytes involving full thickness of epidermis that shows acanthosis . Loss of granular layer . Hyperkeratosis and diffuse confluent parakeratosis . “ Wind-blown epidermis ” (loss of orderly maturation). “ Flip sign ” (superficial epidermis appears like deeper epidermis instead of normal superficial epidermis with larger, mature, eosinophilic cells). Atypical keratinocytes more commonly extend down the adnexa than in an AK. Perivascular infiltrate . Pigmented variant , in which there is abundant melanin in the epidermis. The “ pagetoid ” variant ( the presence of desmosomal spines can be helpful in Dx). PIN shows the same histopathology .

53. R x OF BOWEN’S DISEASE Surgical: Shave excision with curettage Curettage and electrodesiccation (especially for smaller lesions) Liquid nitrogen cryotherapy Photodynamic therapy Surgical excision Laser ablation Mohs micrographic surgery (e.g. head and neck, acrogenital ) especially in severe or recurrent cases Medical: Imiquimod cream Topical 5% fluorouracil (twice daily for a longer period, e.g. 8 weeks) may be used when a surgical approach would prove difficult to perform because of location or extent. Superficial radiotherapy

54. Leukoplakia

55. Leukoplakia Leukoplakia refers to a white patch or plaque on the oral mucosa that cannot be wiped off and cannot be characterized clinically or pathologically as any other disease . Typically occurs in middle-aged and older adults ( men > women ). It is the most common premalignant condition of the oral mucosa as longstanding lesions may transform to SCC in ~5% of cases .

56. ERYTHROPLAKIA Similarly , ERYTHROPLAKIA is defined as a red intraoral patch or slightly elevated , velvety plaque that cannot be diagnosed as a particular disease .

57. Leukoplakia LEUKOPLAKIA IS ASSOCIATED WITH : Smoking (six times more common in smokers than non-smokers). Alcohol intake. Chronic persistent irritants such as jagged teeth, ill-fitting dentures.

58. Intra-oral photograph showing white patch, with crack mud appearance on the left buccal mucosa, suggestive of homogenous leukoplakia

59. Erythroplakia

60. Erythroleukoplakia

61. Leukoplakia . Sharply demarcated, white plaque involving the ventral surface of the tongue and floor of the mouth.

62. Erythroleukoplakia ("speckled leukoplakia"), left commissure. Biopsy showed mild epithelial dysplasia and candida infection. Antifungal medication may turn this type of lesion into a homogenous leukoplakia (i.e. the red areas would disappear)

63. Nodular leukoplakia

64. Nodular leukoplakia in right commissure. Biopsy showed severe dysplasia

65. Exophytic leukoplakia on the buccal mucosa

66. Leukoplakia of the soft palate

67. The lower mandibular gingiva exhibits multifocal corrugated leukoplakia affecting the marginal and attached gingiva between teeth #21 and #26. Multiple biopsies revealed a histologic diagnosis ranging from verrucous hyperplasia to mild epithelial dysplasia.

68. Proliferative Verrucous Leukoplakia (tends to occur in women without traditional risk factors, is characterized by multifocal red and white patches that eventually develop a verrucous surface; difficult to treat and associated with high risk of transformation to SCC).

69. Verrucous proliferative leukoplakia of the oral cavity . The lesions have focally progressed to invasive squamous cell carcinoma; HPV DNA was not detectable by PCR.

70. c/p of Leukoplakia THE SITES AFFECTED: Buccal mucosa Alveolar mucosa Inner aspect of lower lip Floor of mouth Lateral or ventral tongue Soft palate

71. Clinical types of Leukoplakia

72. c/p of Leukoplakia Homogeneous Non-homogeneous Refers to homogeneous uniform colour AND texture Refers to irregularity of either the colour OR the texture Uniform white colour Predominantly white or white-red speckled (erythroleukoplakia) Uniform flat, thin appearance The surface may become leathery – smooth, wrinkled, corrugated or with shallow cracks. Irregular texture which can be flat, nodular, exophytic, verrucous (including proliferative verrucous) This form is usually asymptomatic. This form may be associated with mild discomfort or localized pain.

73. c/p of Leukoplakia The following signs suggesting malignant transformation; Ulceration Induration Bleeding Outgrowth The presence of dysplasia , carcinoma in-situ and invasive carcinoma cannot always be predicted clinically .

74. D x of Leukoplakia Oral leukoplakia is a clinical diagnosis of exclusion . Toluidine blue supravital staining: Areas of significant dysplasia or carcinoma have a strong affinity for the dye & contain intracellular wider canals that may facilitate penetration of the dye whereas the normal mucosa does not. This response permits detection of small and early lesions and also permits their surface delineation . Biopsy: to rule out malignancy .

75. SEVERITY OF DYSPLASIA

76. Histopathological photomicrograph showing area of increased epithelial thickness together with hyperkeratosis, suggestive of mild dysplasia

77. Histopathological photomicrograph showing squamous hyperparakeratosis blunt and elongated epithelial ridges and cytonuclear atypia confined to the lower epithelial half, suggestive of moderate dysplasia.

78. Histopathological photomicrograph showing epithelial alterations involving nearly the entire epithelial thickness, suggestive of severe dysplasia

79. The Phases of Leukoplakia and Dysplasia

80. Histopathology of Leukoplakia Biopsies should be taken from either a symptomatic area , or if asymptomatic then from red or indurated areas . The histopathology of oral leukoplakia is not diagnostic .

81. Histopathology of Leukoplakia Hyperkeratosis is seen most frequently . Epithelial changes range from atrophy to acanthosis . Dysplasia may be mild , moderate , severe , carcinoma in situ or invasive carcinoma. Erythroplakia generally shows more advanced dysplastic features, with 90% of lesions demonstrating severe epithelial dysplasia , carcinoma in situ or invasive carcinoma at the time of biopsy.

82. Histopathology of Leukoplakia FACTORS INFLUENCES RISK OF TRANSFORMATION TO SCC; The degree of histologic epithelial dysplasia . Nonhomogeneous leukoplakia particularly erythroplakia . Lesions located on the floor of the mouth or lateral/ventral tongue also have higher malignant potential.

83. R x of leukoplakia

84. R x of leukoplakia AVOIDANCE OF AGGRAVATING FACTORS: Quit smoking Stopping alcohol consumption Avoid irritation/ trauma After elimination of possible causative factors for 2–6 weeks , persistent lesions should be biopsied .

85. R x of leukoplakia MEDICAL Rx: Topical imiquimod . Systemic retinoids ( acitretin or isotretinoin).

86. R x of leukoplakia SURGICAL Rx: For leukoplakia with moderate to severe dysplasia or in high-risk sites and for erythroplakia often require complete removal and continued monitoring ( lifelong follow-up ) and should avoid carcinogenic habits. Options include : Surgical excision CO 2 laser ablation Electrofulguration  Cryosurgery Photodynamic therapy

87. REFERENCES Dermatology essentials. Google images. http://dermoscopymadesimple.blogspot.com http://www.dermnetnz.org http://www.pcds.org.uk Recognition & Treatment of Pre-Malignant & Malignant skin lesions by Bruce Philp St . Andrews Centre Broomfield Hospital (Presentation) www.facebook.com/groups/dermatologycourseonline /