L-16 Basal Cell Carcinoma: Types and Causes

Malignant Diseases of the Skin

• Basal cell carcinoma makes up roughly 60% of skin cancers.

Etiologic Factors for Basal Cell Carcinoma

• Chronic sun exposure
• Radiation
• Arsenic
• Burns and scars
• Genetic disorders such as xeroderma pigmentosa, basal cell nevus syndrome, and albinism
• Nevus sebaceous, present at birth on the scalp or face, has approximately 10% chance of becoming BCC

Common Clinical Presentations of Basal Cell Carcinoma

• Superficial Basal Cell Carcinoma (30%) presents with skin flush, is erythematous and scaly, with or without shallow ulcers or crusting, and atrophic scarring, is often confused with eczema or fungal infection
• Nodular Basal Cell Carcinoma (60%) present as a flesh-colored nodule featuring telangiectatic vessels, and larger lesions form a peripheral rolled border, also known as a "rodent ulcer"
• Pigmented Basal Cell Carcinoma is distinguished by its brown pigmentation, and is otherwise similar to nodular BCC
• Morpheafarm or Sclerosing Basal Cell Carcinoma (5-10%) presents as a firm white or yellowish plaque with an ill-defined border
  • Induration is always present.
  • Ulceration rarely occurs.
  • Patients frequently describe the presentation as an "enlarging scar".
• Merkel Cell Carcinoma is a relatively new entity that resembles BCC histologically and commonly occurs as a single tumor in elderly individuals
• Adnexal carcinoma arises from sebaceous sweat glands

Basal Cell Carcinoma Recurrence

• Lesions with a low likelihood of recurrence are less than 6 mm in diameter in high-risk areas like the central face, nose, lips, eyelids, eyebrows, periorbital skin, chin, mandible, ears, preauricular and postauricular areas, temples, hands and feet
• Lesions with a low likelihood of recurrence are less than 10 mm in diameter in other areas of the head and neck or less than 20 mm in diameter anywhere excluding hands and feet
• Nodular or superficial histopathologic growth patterns have low likelihood of recurrence
• Well-defined clinical borders have low likelihood of recurrence
• 40% of patients with one BCC will develop another lesion within 5 years
• Surgical excision with 4 to 5 mm margins has a five year cure rate exceeding 95%
• Surgical excision is used for lesions with low and high risk of recurrence
• Electrodesiccation and curettage (ED&C) is most appropriate for low-risk superficial or nodular BCCs on the trunk or extremities
• BCCs occurring in low-risk sites have a three percent recurrence rate
• BCCs less than 6 mm in diameter in high-risk sites have a 5 percent failure rate
• Tumors greater than 6 mm have a recurrence rate of 18 percent

Molecular Pathogenesis of Basal Cell Carcinoma

• PTCH1 is a tumor suppressor gene on chromosome 9
• Similar to retinoblastoma's "two hit" hypothesis
  • Two hits to the same cell are needed for sporadic cases
  • One somatic hit plus inheritance of a defective allele is needed for familial cases of basal cell nevus syndrome or xeroderma pigmentosum)
• PTCH proteins, along with SMO, are receptors for the hedgehog (HH) protein that activates the Sonic Hedgehog signaling pathway
• PTCH-induced repression of SMO limits the effects of the SHH signal
• Inactivating mutations of the PTCH gene lead to overexpression of the SHH signal
• P53 mutations are less frequent in BCCs than cutaneous squamous cell cancers

Squamous Cell Carcinoma

• Squamous cell carcinoma represents roughly 30% of all skin cancers.

Etiologic Factors

• Radiation injury
• Chronic sun exposure
• Chronic chemical exposure (hydrocarbons, arsenic)
• Burns
• Unstable scars, such as Marjolin's ulcer
• Actinic Keratosis
• Leukoplakia
• Chronic ulcers
• Chronic draining sinus tracts

Clinical Presentation

• Common sites include ears, lips, temples, upper face, and dorsum of hands
• Early tumors appear like actinic keratosis except scaling is raised in a skin-colored papule
• Advanced lesions may ulcerate, presenting a horny and crusted appearance
• Nodular Squamous Cell Carcinoma is a dome-shaped, skin-colored papule that is usually ulcerated
  • These appear to grow outward, a hemispherical shape with sharp margins
  • May or may not occur on sun-damaged skin
  • Most commonly located on the lower lips, ears, and dorsum of hands.
• Keratoacanthoma
  • Is rapidly growing
  • Features a tendency for spontaneous resolution
  • Has a histological and clinical appearance similar to nodular squamous cell carcinoma

Marjolin's Ulcer

• Chronic unstable burn scars or chronic draining osteomyelitis can cause premalignant changes leading to squamous cell carcinoma
• Present on the margins of ulcers for 5 or more years
• Typically slow-growing, but tend to recur and metastasize rapidly after resection
• Treatment entails wide local excision followed by regional node dissection two to four weeks after the wound has healed

Radiation-Induced Malignancy

• Occurs as a firm, poorly marginated ulcer at previously radiated sites
• Lesions are very slow to develop over 15 or more years after radiation

Bowen's Disease:

• Presents with a characteristic appearance of a slowly growing, erythematous patch with fine scaling and small crusted areas
• Characteristics
  • A fairly sharp, irregular outer border.
  • The color varies from red to tan.
• Surgical excision is the recommended treatment.

Squamous Cell Carcinoma Pathogenesis

• SCC appears from moderately well-differentiated epithelial cells
• Low grade SCC shows evidence of keratinization and has few mitotic figures per high powered field
• More aggressive lesions display increased keratinization and have increased mitotic rate

Squamous Cell Carcinoma Course and Prognosis

• Untreated squamous cell carcinoma will invade and destroy skin much more aggressively than basal cell carcinoma
• Actinic induced squamous cell carcinomas display a less than 1-2% metastatic rate
• Nodular squamous cell carcinomas display an approximate 10% rate
• Keratoacanthomas usually do not metastasize
• Recurrence occurs 10% of the time following initial treatment, but re-treatment leads to a 98% cure rate.
• Five year cure rates for SCC range from 90-95%.

Current Squamous Cell Carcinoma Treatments

• Treatment options for small (less than 2 cm) actinically induced squamous cell carcinomas include same modalities as basal cell carcinomas
• More aggressive, larger lesions, excision with frozen section pathologic diagnosis is preferred

New Treatment Concepts

• Imiquimod™
• Matristem™
• ACeLL™

Basal Cell Varients

• Merkel Cell Cancer demonstrates rising interest and incidence
• Journal American Medical Association, July 3, 2018, volume 320, #1, pages 18-20
  • Rare, but on the rise
  • 80% of Merkel cell cancers are due to Merkel polyomavirus while 20% are due to UV exposure
  • More aggressive than melanoma
• Merkel Cell Tumor, AEIOU, significant acronym
  • A - Asymptomatic
  • E - Expanding rapidly
  • I - Immunosuppressive
  • O - Older patients, usually over 70 years of age
  • U - UV exposure
  • 90% of Merkel cell carcinomas have three or more of these features

Merkel Cell Treatment

• Excisional surgery, possible sentinel node
• Radiotherapy
• Immunotherapy has shown promise
• Avelumab appears to be the standard of care for all metastatic Merkel cell patients

Melanoma

• Arises from melanocytes, the pigment producing cells of the skin

Melanoma: Suspicious Signs

• Irregular borders
• Variegated color (red, white, blue shades)
• Increase in size, or change in color.
• Scaliness, erosion, oozing, crusting, bleeding, or development of satellite lesions

Melanoma Epidemiology

• Represents 1% of all cancers
• 20-30% arise in the head and neck area
• Occurs predominantly in caucasian patients
• Patients between the ages of 30 and 60 are commonly affected
• Approximately 50% of malignant melanomas are from junctional or compound nevi, and 50% arise anew
• 14,000 new cases are diagnosed yearly in the U.S.

Melanoma Clinical Presentations

• Superficial spreading melanoma: 70% of melanomas

  • Presents as a relatively flat topped, slow growing pigmented papule or plaque
  • Characterized by Irregular borders, irregular pigmentation and black, red, white, or blue color
  • Lesion is frequently wider than it is tall and larger lesions can appear bumpy or lobulated, and may spread pigmentation to adjacent tissue
  • In men, the back is the most common occurence, while in women, occurence is most common on the legs

• Nodular Melanoma, 15% of melanomas

  • Appears as dome shaped, darkly pigmented papules or nodules
  • Grows faster and develops a deeper color than the superficial spreading type
  • More evenly pigmented, usually as tall as they are wide

• Lentigo Maligna Melanoma is the least common type

  • Found almost exclusively on the face
  • Arises from pre-existing lentigo, apperaing as one or more small, darkly pigmented papules on a flat, light brown patch, called "Hutchinsons' freckle"

• Acrolentiginous Melanoma, accounts for 10% of melanomas

  • Most common type of melanoma occurs on digits, palms, and soles, and most often among African Americans
  • One or more dark smooth papules stand against a background of gray or black macular with uneven pigmentation

Melanoma: Predisposing Factors

• Sun exposure, more closely tied to number and severity of individual sunburns, rather than lifetime sun exposure
• Ten percent of patients have positive family histories relating to genetics
• Patients with congenital hairy nevi are at higher risk for malignant transformation and these have a 15-40 percent incidence.
• Patients with compromised Inate or iatrogenic immune systems also increase risk

Melanoma: Staging and Diagnosis

• Clark's classification assess level of invasion
  • Level 1: Tumor confined to the epidermis
  • Level 2: Tumor invades papillary dermis
  • Level 3: Tumor fills papillary dermis, but not reticular dermis
  • Level 4: Tumor invades reticular dermis
  • Level 5: Tumor invades subcutaneous fat
• Breslow Classification, measures depth of invasion in millimeters, correlating with the incidence of regional metastasis
  • Lesions up to 0.75 mm depth have 0% incidence of regional metastasis
  • Lesions measuring 0.76-1.5 mm depth have a 25% incidence of regional metastasis
  • Lesions between 1.51 and 3.99 mm depth have a 51% incidence of regional metastasis -Lesions greater than 4.0 mm have a 62% incidence of regional metastasis.
• To complete the staging, patients must have a thorough history and physical review as well as a complete blood count with SMA-12, urinalysis, and chest X-ray

Melanoma: Metastases

• Melanoma can metastasize through the lymphatic system and bloodstream to any organ of the body
• Patients with Clark's level 1, 2 or 3 lesions and a depth less than 0.76 mml are at low risk of metastasis
• Patients with Clark's level 4 or 5 lesions and a depth over 1.5 mm are at high risk of metastasis

Melanoma Treatment

• Determined by the depth of invasion and tumor level
• Excision is required for Clark's level 1 Lesions
  • Only a cuff of normal tissue is required (usually .5-1c mm margins)
• Excision is required for Clark's level 2-5
  • A wide margin and underlying fascia is required, unless Lesions occur on the face where lesser margins are adequate

Melanoma treatment: Node Resection

• Clinically involved regional lymph nodes with Clark's level 2-5 lesions should be retreated
• Prophylactic resection of lymph nodes: controversial among experts, though some say that it can be performed on patients with level 5 disease or if a tumor overlies a lymph node area.
• Lymph node resection is recommended if the depth of the lesion is greater than 0.75mm or Clark's level 3.
• It is intended to aid in staging and enhance survival

Melanoma Adjuvent Therapy

• A. Regional hyperthermic perfusion involves isolating the blood supply of a limb with a pump/oxygenator, enabling high doses of chemotherapy at elevated temperatures of to be delivered to the limb without side effects of systemic toxicity
• B. Chemotherapy has been found to significantly alter the course of disease
• C. Immunotherapy is useful to control cutaneous metastases
  • However is not effective against visceral metastases
• D. Radiotherapy is strictly palliative and is used for brain and bone metastases

Melanoma Prognosis

• If the disease is confined to the primary site, a five year survival rate approaches 80-90%
• If regional lymph nodes are involved, the five year survival rate drops to 30-50%
• Patients with distant or visceral metastases usually live no more than 12 months

Melanoma Staging

• Tumor thickness, ulceration, and mitotic rate are key qualities to note when staging Melanoma

• Primary Tumor (T): tumor thickness, ulceration and mitotic rate

  • T1: ≤1mm
  • T2: 1.01 to 2 mm
  • T3: 2.01 to 4 mm
  • T4: >4 mm
  • "a" or "b" note the presence or abcense of ulcerations

• 10-year survival decreases with progressively increased tumor thickness

  • Decreases from 96 percent for primary lesions less than 0.5 mm to 54 percent for lesions measuring 4.01 to 6 mm thick