Basal Cell Carcinoma (BCC)

Malignant Diseases of the Skin

Basal Cell Carcinoma (BCC)

• BCC is the most common type of skin cancer, accounting for roughly 60% of all skin cancers.

Etiologic Factors for BCC

• Chronic sun exposure is a major etiologic factor.
• Radiation can contribute to the development of BCC.
• Exposure to arsenic is an etiologic factor
• Burns and scars can be etiologic factors.
• Genetic disorders such as xeroderma pigmentosa, basal cell nevus syndrome, and albinism can increase BCC risk.
• Nevus sebaceous, present at birth on the scalp or face, becomes BCC in approximately 10% of cases.

Clinical Presentations of BCC

• Superficial BCC accounts for 30% of cases.
  • Superficial BCC is flush with the skin, erythematous, and scaly.
  • Shallow ulcers, crusting, or atrophic scarring may be exhibited.
  • Superficial BCC can be confused with eczema or fungal infection.
• Nodular BCC accounts for 60% of cases.
  • Nodular BCC presents as a flesh-colored nodule with small telangiectatic vessels.
  • Larger lesions often develop a central depression that may ulcerate and form a peripheral rolled border.
  • The rolled border is sometimes referred to as a "rodent ulcer".
• Pigmented BCC is distinguished by its brown pigmentation and is otherwise similar to nodular BCC.
• Morpheaform or sclerosing BCC accounts for 5-10% of cases.
  • Morpheaform BCC appears as a firm white or yellowish plaque with an ill-defined border and induration.
  • Ulceration practically never occurs
  • Patients describe it as an "enlarging scar", representing an "aggressive growth" BCC.
• Merkel cell carcinoma is a relatively new entity that resembles BCC histologically and may occur as a single tumor in older people.
• Adnexal carcinoma arises from sebaceous sweat glands.

Recurrence of BCC

• Lesions with a low likelihood of recurrence have specific characteristics
  • Less than 6 mm in diameter in high-risk areas (central face, nose, lips, eyelids, eyebrows, periorbital skin, chin, mandible, ears, preauricular and postauricular areas, temples, hands, feet).
  • Less than 10 mm in diameter in other areas of the head and neck.
  • Less than 20 mm in diameter in all other areas (excluding hands and feet).
  • Nodular or superficial histopathologic growth pattern.
  • Well-defined clinical borders.
• Approximately 40% of patients who have had one BCC will develop another lesion within 5 years.
• Surgical excision with 4 to 5 mm margins has shown 5-year cure rates 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 in low-risk sites (neck, trunk, and extremities) had a 3 percent recurrence rate.
  • BCCs less than 6 mm in diameter in high-risk sites (nose, paranasal, nasolabial groove, ear, chin, mandibular, perioral, periocular areas) had a 5 percent failure rate.
  • Tumors greater than 6 mm had a recurrence rate of 18 percent.

Molecular Pathogenesis of BCC

• PTCH1 is a tumor suppressor gene located on chromosome 9.
  • The pathogenesis is similar to retinoblastoma.
    • Two somatic hits in the same cell are required for sporadic cases.
    • One somatic hit plus the inheritance of a defective allele are required in familial cases (basal cell nevus syndrome, xeroderma pigmentosum).
• PTCH proteins, along with smoothened (SMO), make up the receptor for the hedgehog (HH) protein, which 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 in cutaneous squamous cell cancers.

Squamous Cell Carcinoma (SCC)

• Squamous Cell Carcinoma (SCC) accounts for roughly 30% of skin cancers.

Etiologic Factors for SCC

• Radiation injury is an etiologic factor.
• Chronic sun exposure is an etiologic factor.
• Chronic chemical exposure to hydrocarbons and arsenic is an etiologic factor.
• Burns are an etiologic factor.
• Unstable scars (Marjolin's ulcer) are an etiologic factor.
• Actinic Keratosis is an etiologic factor.
• Leukoplakia is an etiologic factor.
• Chronic ulcers are an etiologic factor.
• Chronic draining sinus tracts are an etiologic factor.

Clinical Presentations of SCC

• Common sites of SCC include ears, lips, temples, upper parts of the face, and dorsum of hands.
• Early tumors appear much like actinic keratosis except scaling is raised in a skin colored papule.
• More advanced lesions may ulcerate and have a horny, crusted appearance.
• Nodular Squamous Cell Carcinoma presents as a dome-shaped, skin-colored papule that is usually ulcerated.
  • These lesions are more apt toward outward growth patterns, hemispherical shape, and sharp margination.
  • May or may not occur on sun-damaged skin.
  • Is most commonly located on lower lips, ears, and dorsum of hand.
• Keratoacanthoma
  • It is a rapidly growing lesion with a tendency for spontaneous resolution.
  • Histological and clinical appearance are very similar to nodular squamous cell carcinoma.

Marjolin's Ulcer

• Marjolin's ulcer results from chronic unstable burns scars or chronic draining osteomyelitis that cause premalignant changes leading to squamous cell carcinoma
  • Appear at margins of ulcers present for usually 5 or more years.
    • Typically slow-growing at first, but tend to recur and metastasize rapidly after resection.
    • Treatment consists of wide local excision followed by regional node dissection 2-4 weeks later after wound has healed primarily.

Radiation-Induced SCC

• Occurs as a firm, poorly marginated ulcer at the site of previously administered radiation therapy.
• Develops very slowly, usually 15 years or more after radiation.

Bowen's Disease (SCC)

• Has a characteristic appearance of a slowly enlarging erythematous patch with a fairly sharp, irregular outline.
  • Areas of superficial scaling and small areas of crusting within the tumor
  • Color varies from red to tan, causing confusion with BCC.
  • Recommended treatment is surgical excision.

Pathogenesis of SCC

• All types of SCC appear from moderately well differentiated epithelial cells.
• Low grade SCC show considerable evidence of Keratinization and have relatively few mitotic per high powered field.
• More aggressive lesions show evidence of Keratinization and have greatly increased mitotic rates.

Course and Prognosis of SCC

• Untreated squamous cell carcinomas will destroy and invade surrounding tissue more aggressively than basal cell carcinoma.
• Metastatic Rate actinically induced squamous cell carcinomas is less than 1-2%.
• Nodular squamous cell carcinomas have approximately a 10% metastatic rate.
• Keratoacanthomas do not metastasize.
• The recurrence rate is 10% following initial treatment.
  • Re-treatment leads to an ultimate cure rate of 98%.
• Five-year cure rates are 90-95%.

Treatment of SCC

• Small (less than 2 cm) actinically induced squamous cell carcinomas may utilize the same treatment modalities as those discussed for basal cell carcinomas.
• For more aggressive, larger lesions, excision with frozen section pathologic diagnosis is preferred.

New Treatment Concepts for Skin Cancer

• Imiquimod™
• Matristem™
• ACELL™

Basal Cell Variant: Merkel Cell Cancer

• There is increased interest and incidence on the rise.
  • Journal American Medical Association, July 3, 2018, volume 320, #1, page 18-20.
• Although rare, incidents are on the rise.
  • Merkel cell cancer is linked to a virus – a previously unknown polyomavirus.
  • 80% of Merkel cell cancers are linked to Merkel Polyomavirus, 20% to UV exposure.
  • More aggressive than melanoma.
• Merkel Cell Tumor presents with the acronym AEIOU:
  • A- Asymptomatic
  • E- Expanding rapidly
  • I- Immunosuppressive
  • O- Older patients usually older than 70 years old
  • U- UV exposure
  • 90% of Merkel cell carcinomas have 3+ of these features

Treatment for Merkel Cell Cancer

• Excisional surgery with possible sentinel node
• Radiation therapy
• Immunotherapy is showing promise, with AVELUMAB seemingly becoming standard of care for all metastatic Merkel cell patients.

Melanoma

• Melanoma arises from melanocytes, which are the pigment-producing cells of the skin.

Suspicious Signs of Melanoma

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

Epidemiology of Melanoma

• Malignant melanoma accounts for 1% of all cancers.
• 20%-30% arise in the head and neck area.
• Occurs predominantly in whites and commonly occurs between ages 30-60.
• Approximately 50% of malignant melanomas arise from junctional or compound nevi, and 50% arise anew.
• 14,000 new cases are diagnosed in the United States each year.

Clinical Presentations of Melanoma

• Superficial Spreading Melanoma accounts for roughly 70% of cases.
  • Presents as a relatively flat-topped, slow-growing pigmented papule or plaque with; irregular borders, irregular pigmentation, black, red, white, or blue color.
  • The lesion is almost always wider than it is tall.
  • Larger lesions may appear "bumpy" and lobulated.
  • May be pigmented spread to adjacent normal tissue.
  • The back is most common area in men, whereas the legs are most common in women.
• Nodular Melanoma accounts for less 15% of melanomas.
  • They appear as dome-shaped, darkly pigmented papules or nodules.
  • Grow faster and develop deeper color than superficial spreading type.
  • More evenly pigmented and are usually as tall as they are wide.
• Lentigo Maligna Melanoma
  • It is a least common type.
  • Found almost exclusively on the face.
  • Arise from pre-existing lentigo appearing as one or more small, darkly pigmented papules superimposed on a flat, light brown patch. -"Hutchinsons' freckle"
• Acrolentiginous Melanoma
  • It is accounts for 10% of Melanomas.
  • It is the most common type of melanoma occurring on the digits, palms, and soles.
  • Appears as one or more dark, smooth papules against a background of gray or black macular, uneven pigmentation.

Predisposing Factors for Melanoma

• Sun exposure is strongly correlated with the number and severity of individual sunburns.
• Genetics
  • 10% of patients have a positive family history.
• Congenital nevi
  • Patients with congenital hairy nevi are at a higher risk for malignant transformation (15-40% incidence).
• Immune response
  • Patients with compromised immune systems, whether innate or iatrogenic, are at increased risk.

Staging and Diagnosis of Melanoma

• Clark's classification assesses the level of invasion.
  • Level 1: Tumor confined to epidermis
  • Level 2: Tumor invades papillary dermis
  • Level 3: Tumor fills papillary dermis but does not invade reticular dermis
  • Level 4: Tumor invades reticular dermis
  • Level 5: Tumor invades subcutaneous fat
• Breslow Classification measures the depth of invasion in millimeters.
  • Incidence of regional metastasis correlates with tumor thickness.
    • Up to .75 mm deep- 0%
    • 0.76mm- 1.5mm – 25%
    • 1.51mm to 3.99mm – 51%
    • Greater than 4.0mm- 62%
• To complete staging, a patient must undergo a thorough history, a physical exam, a complete blood count, Chem-12, urinalysis, and chest x-ray.

Melanoma Staging

• Primary Tumor (T) assessed by tumor thickness, ulceration, and mitotic rate.
  • T1: ≤1 mm
  • T2: 1.01 to 2 mm
  • T3: 2.01 to 4 mm
  • T4: >4 mm
  • "a" or "b" based on the presence or absence of ulcerations
  • 10-year survival decreases progressively from 96% with primary lesions <0.5 mm thick to 54% with lesions 4.01 to 6 mm thick.
• Lymphatic Involvement (N)
  • N0 – No regional lymphatic metastases.
  • N1 – One involved lymph node. N1 disease is subdivided into N1a (micrometastases) and N1b (macrometastases).
  • N2 – N2a and N2b are defined by the presence of two or three involved nodes.
  • N3 – four or more positive nodes.
  • Patients with nodal disease limited to micrometastases
    • The most important factor affecting prognosis was the number of nodes involved. Five-year survival rates with one, two, or three positive lymph nodes were 71, 65, and 61%, respectively.
    • Patients with macrometastases in the regional nodes, the number of nodes was significantly associated with prognosis Five-year survival rates for one, two, or three positive lymph nodes were 50, 43, and 40%, respectively.
• Distant Metastases (M) are subclassified according to the site of disease involvement and serum LDH level.
  • M0 - No distant metastases
  • M1a – Metastases to distant skin, subcutaneous, or lymph node sites, with a normal serum LDH, has the best prognosis
  • M1b – Lung metastases in patients with a normal serum LDH
  • M1c - Metastases to other visceral sites with a normal serum LDH, or any metastasis associated with an elevated serum LDH, has the worst prognosis.
• Stage grouping
  • Stage I melanoma is limited to patients with low-risk primary melanomas (T1a through T2a)
    • There is no evidence of regional or distant metastases.
  • Stage II disease includes primary tumors that are at higher risk of recurrence (T2b through T4b).
    • There is no evidence of lymphatic disease or distant metastases
  • Stage III disease includes patients with pathologically documented involvement of regional lymph nodes or the presence of in transit or satellite metastases (N1-N3).
  • Stage IV is defined by the presence of distant metastases (M1a-M1c).

Melanoma Mets and Treatment

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

Treatment of Melanoma

• Depended on the depth of invasion and tumor level.
• Excision
  • Excision alone, with a cuff of normal tissue, is required for Clark's level 1 lesions.
    • Usually a .5-1cm margins.
  • Excision with a wide margin and possibly underlying fascia is required for Clark's level 2-5.
    • An exception are lesion on the face where lesser margins are adequate.
• Node resection is necessary if they are Clinically involved regional lymph nodes with Clark's level 2-5 lesions.
  • Prophylactic resection of lymph nodes is controversial.
  • It recommended for patients with level 5 disease, or if a tumor overlies a lymph node area.
  • Others recommend resection if depth is greater than 0.75mm, or Clark's level is 3 to aid in staging and enhance survival.
• Adjuvent Therapy
  • Regional hyperthermic perfusion involves isolating the blood supply of a limb with a pump or oxygenator.
    • High doses of chemotherapy at elevated temperatures (40c) are delivered to the limb without systemic toxicity.
  • Chemotherapy has been found to significantly alter the course of disease.
  • Immunotherapy is useful to control cutaneous and not visceral Metastases.
  • Radiotherapy is strictly palliative and used for brain and bone metastases.

Prognosis of Melanoma

• If the disease is confined to the primary site, the 5-year survival rate approaches 80-90%.
• If regional lymph nodes are involved, the 5-year survival drops to 30-50%.
• Patients with distant or Visceral Metastases usually do not live more than 12 months.