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A. Classification navigator

  1. Malignant skin tumors account for ~50% of all cancers in USA
  2. Neoplastic Keratinocytes
    1. Basal cell carcinoma (Ca)
    2. Squamous cell Ca
  3. Neoplastic melanocytes: Malignant Melanoma
  4. Kaposi Sarcoma
    1. Tumor of vascular endothelium
    2. Caused by HHV-8, usually in immunosuppressed patients
  5. Connective Tissue Tumors
  6. Tumors of immune cells
    1. Cutaneous T cell lymphoma: mycosis fungoides, Scezary Syndrome
    2. Langerhans' Cell Histiocytosis
  7. Very rare tumors of neuronal cells in skin (such as Merkel Cells; see below)
  8. Squamous and basal cell Ca in solid-organ transplant patients [2]

B. Basal Cell CA (BCC) [1,8] navigator

  1. Clinical Features
    1. Most common malignant tumor and most common (80% of) skin cancer
    2. Over 1 million new cases per year in USA
    3. Usually occurs in older people on chronically sun-damaged skin
    4. <1% metastatic diseases
    5. Significant disfiguration can occur if left untreated
  2. Risk Factors
    1. Blond or red hair
    2. Blue or green eyes
    3. Light skin color
    4. Ultraviolet (UV) light
    5. Use of tanning bed
    6. Smoking
    7. Ionizing radiation
    8. Toxins: arsenic, coal tar
    9. Solid organ transplant
    10. Genetic disorders: albinism, xeroderma pigmentosum, Rombo syndrome, Nevoid basal cell carcinoma (Gorlin's) syndrome, Bazex-Dupre-Chrisol Syndrome
  3. Appearance
    1. ~80% are found on head and neck; 15% on trunk
    2. Mainly in sun exposed areas
    3. Pearly papule or nodule, often with telangiectasias and rolled border
    4. Hypopigmentation or Hyperpigmentation may occur
    5. Superficial BCC present as scaly erythematous patch or plaque
    6. Tumors may ulcerate
  4. Pathology
    1. Proliferation of basaloid epidermal cells downward into dermis
    2. Cells may be arranged in a variety of patterns (usually not significant)
    3. Sclerosing (Infiltrating) and morpheaform types are most aggressive
    4. Loss of function mutations in tumor suppressor protein patched homologue 1 (PTCH1) found in ~35% of sporadic BCC and in Rolin's syndrome
    5. Mutations in other hedgehog pathway
  5. Risk Factors for Metastasis and Recurrence
    1. Tumor diameter >2cm
    2. Location on central part of face or ears
    3. Long-standing duration
    4. incomplete excision
    5. Aggressive histologic pattern of growth: perineural or perivascular involvement
    6. indistinct borders
    7. Metastasis usually to regional lymph nodes, then bone, lung, liver
  6. Treatment Overview
    1. Because of low risk of metastasis, focus is on local control
    2. Surgical excision - all types of skin cancers
    3. Cryosurgery - nodular and superficial forms only
    4. Electrodesiccation - superficial BCC only
    5. Mohs micrographic surgery
    6. Radiation therapy
    7. Photodynamic Therapy
    8. Imiquimod 5% cream
    9. 5 year cure rates of >95% possible with most BCC
  7. Mohs Micrographic Surgery (MMS)
    1. Morpheaform types of BCC
    2. Recurrent BCC - best treatment
    3. Those found in areas of high recurrence rates
    4. Those found near crucial structure (such as those near eyes)
    5. Large tumors
    6. MMS has non-significantly lower recurrence than surgical excision [7]
    7. In-office examination of horizontal frozen-section specimens to 100% of margins
    8. If any part of margins shows tumor, then additional thin surgical sections are taken
    9. Has lowest 5-year recurrence of any treatment (1% for primary, 5.6% for recurrent BCC)
  8. Radiation Therapy
    1. Especially for large lesions (usually with surgery) or bone invasion
    2. Difficult to treat locations
    3. Not recommended for patients <60 years due to risk of carcinogenesis and cosmetics
    4. Surgery generally superior to radiation therapy for lesions of the face
  9. Photodynamic Therapy
    1. Topical 5-aminolevulinic acid followed by red-light irradiation
    2. Effective or non-hypertrophic actinic keratosis and basal cell carcinomas
  10. Imiquimod 5% Cream (Aldera®) [3]
    1. Immune response modifier, stimulates innate and adaptive immunity
    2. Approved for biopsy-proven, <2cm primary lesions on trunk, neck, arms, legs of adults
    3. Response rate for once daily 5days/week x 6 weeks was 83% at week 12
    4. Twice daily application often limited by occurrence of local cutaneous reactions
  11. Daily sunscreen (15 SPF) use for 4.5 years did not reduce the incidence of first BCC or the total number of BCC in a study of 1383 persons [4]
  12. Gorlin (Nevoid-BCC) Syndrome
    1. Autosomal dominant
    2. BCC, palmar and plantar pits, cysts of the jaw, bifid ribs, hypertelorism
    3. BCCs becgin in early childhood but generally good prognosis

B. Squamous Cell Cancer [8] navigator

  1. Epidemiology
    1. Middle aged to elderly individuals, Men > Women
    2. Over 250,000 cases per year (incidence has been increasing)
    3. Incidence in whites is 100-150 per 100,000 persons per year
    4. Lifetime risk ~12% in men, ~7% in women
    5. Full body skin screning should be performed every 18-24 months in normal persons
    6. In persons with a history of nonmelanomatous skin cancer, screen every 6 months
    7. All organ transplant recipients should be screened at least twice a year
  2. Clinical Features
    1. Usually appears on chronically exposed skin
    2. History of exposure to sunlight during childhood, especially with history of sunburns
    3. Rarely develops in children and blacks
    4. May arise de novo
    5. May arise from actinic keratosis, which is the precursor lesion
    6. Appears as crusted papule, plaque or nodule
    7. May be skin colored, pink or brown
  3. Major and Moderate Risk Factors
    1. Exposure to ultraviolet radiation (UVB > UVA)
    2. Long-term psoralen (methoxsalen) - UVA treatment (PUVA)
    3. Addition of cyclosporin to PUVA increases squamous cell cancer risk ~7X [5]
    4. Exposure to ionizing radiation
    5. Infection with human papillomavirus (especially types 6,11,16,18)
    6. Immunosuppressed patients: transplantation, HIV, chemotherapy
    7. Leukemia and lymphoma
    8. Three-fold increased risk in cockpit crews flying >5000 hours [6]
    9. Increased in Xeroderma pigmentosum, albinism
    10. Chronically injured or diseased skin, skin ulcers, sinus tracts
    11. Chronic skin inflammation: dystrophic epidermolysis bullosa, discoid lupus, lichen planus
    12. Osteomyelitis
    13. Radiation dermatitis
    14. Actinic keratosis is the precursor lesion
    15. Arsenic exposure
  4. Pathogenesis
    1. UV induced damage to skin normally causes apoptosis of keratinocytes
    2. DNA damage can lead to cells with dysfunctional (two mutant) p53 genes
    3. UV damage to cells with dysfunctional p53 stimulates growth of abnormal clone
    4. Abnormal clone forms an actinic keratosis (a kind of carcinoma in situ)
    5. Actinic keratosis continues to grow and may form frank SCC
    6. UVA (and UVB) damage to skin, particularly with azathioprine treatment, increases risk [9]
  5. Histopathology
    1. Atypical keratinocytes extending from epidermis into the dermis
    2. Tend to form irregular lobules with focal areas of keratinization = eddies or pearls
    3. Variants include spindle cells, adenoid, and verrucous squamous cell cancers
    4. SCC which do not cross basement membrane are called Bowen's Disease (in situ)
    5. Verrucous carcinomas are less common, indolent, cauliflower-shaped variants of SCC
    6. Depth of >4mm, involvement of reticular dermis or deeper layers are risk for recurrence and metastasis
  6. Treatment
    1. Invasive SCC has the potential to recur and metastasize
    2. Recurrence is 8% and metastatic rate is 5% at 5 years
    3. Invasive SCC should be treated; a variety of modalities are available
    4. Electrodessication and curettage, excision, Mohs micrographic surgery, cryotherapy
    5. Radiation therapy may be offerred in selected cases
    6. In situ SSC can be treated with above modalities or curettage, cryotherapy, or laser
    7. Topical chemotherapy - usually 5-fluorouracil (cream or lotion)
  7. Radiation Therapy
    1. Both SCC and BCC are sensitive to radiation therapy
    2. No pain, hospitalization, or surgery is involved when used alone
    3. No disfigurement (except for some large lesions)
    4. May cause alopecia
    5. Large lesions and those involving bone may be best treated with this modality
  8. Daily use of sunscreen (15 SPF) reduces the number of number of SCC but not the incidence of first SCC with use over 4.5 years [4]

D. Malignant Melanoma navigator

  1. Clinical Features
    1. 1% of all cancers in US with increasing incidence over past 40 years
    2. 27,000 cases per year (1989) USA with ~25% fatality rate.
    3. Occurs primarily during productive years of life (ages 20-60)
  2. Etiologic Risk Factors
    1. History of change in pigmentation in a lesion - most reliable predictor
    2. Light eyes and light colored hair
    3. History of severe sunburns
    4. Fair complexioned skin
    5. Proximity of Residence to equator
    6. Xeroderma pigmentosum
    7. Family history of melanoma or dysplastic nevi
  3. Appearance
    1. Asymmetric, Irregular Border
    2. Surface varies from macular to papular or nodular
    3. Irregular color, 2 or more shades of brown, gray or black
    4. Occasional pale areas
    5. Erythema due to inflammation
    6. Diameter usually >6mm
  4. Clinical Presentation - location of lesions varies with race and sex
  5. Classification
    1. Superficial spreading melanoma - most common type
    2. Lentigo maligna melanoma
    3. Nodular melanoma
    4. Acrolentiginous melanoma
  6. Histopathology
    1. Atypical melanocytic cells in the dermis
    2. Spindle or epitheliod shaped
    3. Often pleomorphic with frequent mitoses
    4. Cytoplasm often dusty pink-tan due to melanin granules
    5. May have upward spread of cells into the epidermis
    6. Assessment of level and depth of invasion
    7. Ulceration and inflammation may occur
  7. Prognosis
    1. Dependent on type and location of tumor
    2. Depth of invasion is currently the best overall prognostic indicator
    3. The majority of melanoma (<0.75 mm) have excellent prognosis
    4. Age and male sex are poor prognostic indicators
    5. Uneven lesion good; pedunculated poor
    6. Diameter: <20mm diameter better prognosis than >20mm

E. Merckel Cell Carcinoma [10] navigator

  1. Uncommon skin cancer derived from Merkel cells (neuroendocrine cell type)
  2. Merkel cells are mechanoreceptors in basal cell alyer of skin and outer root sheath of hair follicle
  3. Risk Factors
    1. Long term exposure to sun
    2. Ultraviolet A (UVA) treatment for psoriasis
    3. Immunosuppression: 40X increased risk in solid organ transplant, 13X increased in HIV+
    4. May occur in association with other skin tumors
  4. Usually presents as small (<2cm) painless, firm nodule on sun-exposed area of head or neck
  5. Immunohistochemical studies generally required for diagnosis
    1. Small cells with salt-and-pepper chromatin and scanty cytoplasm
    2. Cytokeratin 20 positive in perinuclear dot-like pattern
    3. Neurofilament and neuron-specific enolase positive
    4. Negative for cytokeratin 7, thyroid transcription factor 1, S100, leukocyte common antigen
    5. Biological features similar to small cell lung cancer (SCLC, another neuroendocrine tumor)
  6. Translocation t(1;17) and and trisomy 6 in some cases
  7. A novel polyomavirus may be involved in pathogenesis
  8. Treatment
    1. Wide excision of primary site, with margins >2cm and preferably 3cm
    2. On head area, Mohs surgery is usually used, but recurrence rates up to 40%
    3. If high risk of recurrence, post-operative radiation therapy is recommended
    4. Many experts consider this a variant of SCLC, and should be treated as an aggressive tumor
    5. Lymph node (LN) dissection is generally required to assess extend, and as therapy
    6. If LN are involved, relatively high dose (>45 Gy) necessary to reduce recurrence risk
    7. High risk and recurrent tumors treated with combination chemotherapy
    8. SCLC regimens are usually used, including carboplatin + etoposide
    9. Complete remissions >40% after 4 cycles (usually combined with radiotherapy)

References navigator

  1. Rubin AI, Chen EH, Ratner D. 2005. NEJM. 353(21):2262 abstract
  2. Euvrard S, Kanitakis J, Claudy A. 2003. NEJM. 348(17):1681 abstract
  3. Beutner KR, Geisse JK, Helman D, et al. 1999. J Am Acad Dermatol. 41:1002 abstract
  4. Green A, Williams G, Neale R, et al. 1999. Lancet. 354(9080):723
  5. Marcil I and Stern RS. 2001. Lancet. 358(9287):1042 abstract
  6. Gundestrup M and Storm HH. 1999. Lancet. 354(9195):2029 abstract
  7. Smeets NWJ, Krekels GAM, Ostertag JU, et al. 2004. Lancet. 364(9447):1766
  8. Alam M and Ratner D. 2001. NEJM. 344(13):975 abstract
  9. Parrish JA. 2005. NEJM. 353(25):2712 abstract
  10. Busse PM, Clark JR, Muse VV, Liu V. 2008. 2008. NEJM. 358(25):2717 (Case Record) abstract