Basal Cell Carcinoma

Basal cell carcinoma is the most common skin malignancy. This cancer arises from the basal layer of the epidermis. The lesions most commonly appear on the face as pearly nodules, often with telangiectatic blood vessels and ulceration in elderly individuals. Diagnosis is established by tissue biopsy. Despite having low metastatic potential, basal cell carcinoma should be treated adequately because it is locally aggressive and destructive to tissues. Complete surgical excision is the main treatment method. Long-term prognosis is excellent with adequate management.

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Overview

Definition

Basal cell carcinoma is a skin cancer arising from the basal layer of epidermis and its appendages.

Epidemiology

  • Most common cancer worldwide
  • Most common skin malignancy
  • Age-adjusted incidence in the United States is 226 per 100,000 person-years.
  • > 1 million basal cell carcinomas are treated annually in the United States.
  • Men > women
  • Incidence increases with age.

Risk factors

  • Ultraviolet (UV) light exposure:
    • Sun exposure (outdoor workers)
    • Tanning beds
    • Phototherapy for psoriasis
  • Advanced age
  • Arsenic exposure (e.g., contaminated drinking water, contaminated seafood)
  • Ionizing radiation
  • Chronic immunosuppression 
  • Genetics: 
    • Fair complexion
    • Personal and family history of basal cell carcinoma
    • Genetic syndromes:
      • Gorlin syndrome (characterized by developmental anomalies and multiple basal cell carcinomas)
      • Xeroderma pigmentosum (mutation in repair of UV-induced DNA damage)
      • Bazex–Dupré–Christol syndrome (milia, hypotrichosis, multiple basal cell carcinomas)
      • Oculocutaneous albinism (disorder in melanin synthesis)

Locally aggressive basal cell carcinoma in a 75-year-old man

Image: “Basalioma” by Klaus D. Peter. License: CC BY 3.0

Pathophysiology and Clinical Presentation

Pathogenesis

  • UV radiation:
    • Most significant factor
    • UVA and UVB light → DNA damage
    • Genes most damaged by UV light involve the hedgehog signaling pathway.
  • Common mutations:
    • Patched homolog 1 (PTCH1) mutations (found in majority of basal cell carcinoma cases):
      • PTCH1 encodes a protein in the hedgehog pathway.
      • In the resting state, patched homolog 1 (PTCH1) protein normally inhibits smoothened homolog (SMO).
      • When the sonic hedgehog protein binds PTCH1 protein → PTCH1 is degraded → SMO is released
      • This process leads to a series of interacting proteins → GLI transcription factors activated → cell proliferation
      • General effect of PTCH1 gene mutations: unbound SMO allows unregulated cell growth
    • TP53 mutations also seen in 20%–60% of sporadic basal cell carcinomas:
      • TP53 normally involved in apoptosis and DNA repair
      • Mutations → cell proliferation and defective DNA
    • Other genes: SMO, SUFU

Clinical and histologic features

  • Disease characteristics: 
    • Lesion can be a papule, patch, or plaque.
    • Most remain localized but can become aggressive
    • Rarely metastasize (< 0.05%)
    • Slow-growing
  • Basal cell carcinoma distribution:
    • Face: 70% (nose, cheeks, forehead, nasolabial folds, and eyelids)
    • Trunk: 15%
    • Remaining body parts: 15%
  • Histopathology:
    • Cells of tumor islands with palisading arrangement at the periphery
    • Cellular apoptosis
    • Scattered mitotic activity in the dermis
  • Histologic types:
    • Nodular basal cell carcinoma
    • Superficial basal cell carcinoma
    • Morpheaphorm (sclerosing) basal cell carcinoma
    • Other, more rare, types:
      • Basosquamous cell carcinoma
      • Pigmented basal cell carcinoma
Histologic features and clinical presentation of major basal cell carcinoma types
TypeFrequencyHistologyClinical presentation
Nodular basal cell carcinoma80%
  • Nests of basaloid cells in the dermis
  • Peripheral palisading of malignant keratinocytes
  • Appearance of “clefts” between tumor stroma and dermis
    • Most common on the face
    • Pink or flesh-colored papule
    • Pearly, translucent
    • Rolled border (more raised than the middle)
    • Telangiectatic vessel
    • “Rodent ulcer”: ulcerated nodular basal cell carcinoma
      Superficial basal cell carcinoma15%Atypical basaloid tumors arise as buds from the epidermis
      • Higher incidence in males
      • Most common on the trunk
      • Scaly macule, patch, or plaque
      • Pink or red
      • Center may appear atrophic
      • Scattered dark pigment (may resemble melanoma)
      • +/– Telangiectasias
        Morpheaform basal cell carcinoma5%–10%
        • Thin cords of basaloid cells penetrating surrounding collagen
        • Collagen may appear sclerotic, resembling a scar.
          • Smooth papule or plaque
          • Light pink or flesh-colored
          • Firm, indurated
          • Ill-defined border

            Diagnosis and Staging

            Diagnosis

            History:

            • Family history of genetic diseases
            • Personal history of previous skin cancers
            • History of excessive sun exposure
            • HIV-positive status or other forms of immunocompromise

            Physical exam:

            • Thorough skin examination should be performed.
            • Assess for palpable lymphadenopathy.

            Dermoscopy:

            • Arborizing vessels
            • Blue-gray ovoid nests
            • Ulceration
            • Lack of pigmented network (unlike melanocytic lesions)

            Biopsy:

            • Establishes definitive diagnosis
            • Shave, punch, or excisional technique can be used.

            Staging

            • Basal cell carcinoma metastasis is rare and is thus not usually staged.
            • Often, the cancer is treated before it spreads.
            • Sites of metastasis:
              • Regional lymph nodes
              • Lungs
              • Bones
              • Liver
              • Skin
            • Imaging: CT or MRI used for evaluation of metastasis
            • Staging follows that for cutaneous squamous cell carcinoma but is applicable only to head and neck lesions (American Joint Committee on Cancer, 8th edition).
            • Stages:
              • Stage 0: cancer involves only the epidermis (in situ)
              • Stage I: 
                • Cancer is not large (≤ 2 cm).
                • No spread to the lymph nodes or other organs
              • Stage II: 
                • Cancer is large (>2 cm but ≤ 4 cm). 
                • No spread to lymph nodes or other organs
              • Stage III: 
                • Cancer > 4 cm or cancer of any size with deep, perineural or minor bone invasion and/or spread to 1 ipsilateral lymph node (no extranodal extension)
                • No spread to other organs
              • Stage IV: lesions of any size; spread to other organs (distant metastasis)

            Management and Prognosis

            Treatment approach

            Assess risk of recurrence:

            • Helps determine treatment of choice
            • Inadequate treatment of high-risk lesions can result in recurrence and complications (e.g., deformities).
            • High-risk features:
              • Location: face, ears, hands, and feet
              • Size:
                • ≥ 10 mm on head, neck, and pretibia
                • ≥ 20 mm in other areas
              • Aggressive variants: morpheaform, basosquamous, micronodular
              • Recurrent lesions
              • Perineural invasion
              • Poorly defined borders
              • Basal cell carcinomas in previous radiation sites
              • Immunocompromised patient

            Surgery:

            • Standard surgical excision: 
              • 1st-line treatment for low-risk lesions
              • Margins: 4–5 mm
            • Mohs micrographic surgery:
              • 1st-line treatment for high-risk lesions
              • For facial lesions/cosmetically sensitive areas (less normal tissue resected)

            Alternative therapies: 

            • Options for patients who are poor surgical candidates or who prefer not to have surgery:
              • Topical chemotherapy (e.g., imiquimod or fluorouracil):
                • Low-risk sites
                • 6-week treatment
                • Skin irritation is a side effect.
              • Electrodesiccation and curettage:
                • Can be used for small low-risk basal cell carcinomas
                • Risk of incomplete tumor removal
              • Cryosurgery:
                • Not for high-risk lesions
                • Can result in scarring and hypopigmentation
              • Radiotherapy: for high-risk lesions in poor surgical candidates

            Therapy for advanced disease: 

            • For metastasis or locally advanced basal cell carcinoma that is not amenable to radiotherapy or surgery
            • Inhibitor of sonic hedgehog pathway: vismodegib, sonidegib

            Prognosis

            • Overall prognosis is excellent.
            • Metastatic potential: 0.05%–0.1%.
            • Population-based case mortality: 0.05%.

            Differential Diagnosis

            • Squamous cell carcinoma: second most common skin cancer: Squamous cell carcinoma usually presents as a firm, erythematous, keratotic plaque or papule. Diagnosis is through biopsy. Histopathologic examination confirms the diagnosis by showing findings such as atypical keratinocytes infiltrating into the dermis.
            • Dermatofibroma: a common mesenchymal growth of the skin where skin fibroblasts are the major constituents: Dermatofibroma usually presents as a firm, indurated, mobile nodule measuring about 0.5–1 cm. Upon lateral compression, a dimple-like depression in the overlying skin appears (“buttonhole” sign). 
            • Melanoma: skin malignancy arising from melanocytes: Melanoma presents as irregular pigmented lesions and can resemble pigmented variants of basal cell carcinoma. Diagnosis is confirmed by biopsy. This condition carries a significantly worse prognosis than basal cell carcinoma.
            • Actinic keratosis: benign keratinocytic lesion considered a precursor to squamous cell carcinoma: Lesions of actinic keratosis present as scaly erythematous macules. Diagnosis is established by biopsy.
            • Inflammatory skin conditions: Psoriasis and eczema can present with erythematous papules and plaques and clinically resemble superficial basal cell carcinoma. Diagnosis is made with a thorough exam, dermoscopy, and biopsy.

            References

            1. Aasi SZ. (2020). Treatment and prognosis of basal cell carcinoma at low risk of recurrence. Retrieved January 19, 2021, from https://www.uptodate.com/contents/treatment-and-prognosis-of-basal-cell-carcinoma-at-low-risk-of-recurrence
            2. Aasi SZ. (2020). Treatment of basal cell carcinomas at high risk for recurrence. Retrieved January 19, 2021, from https://www.uptodate.com/contents/treatment-of-basal-cell-carcinomas-at-high-risk-for-recurrence
            3. Bader R. (2020). Basal cell carcinoma. Medscape. Retrieved February 3, 2021, from https://emedicine.medscape.com/article/276624-overview
            4. Curti BD, Leachman S, Urba WJ. (2018). Cancer of the skin. Jameson J., et al. (Eds.). Harrison’s Principles of Internal Medicine, 20th ed. McGraw-Hill.
            5. Lazar A. (2020). The skin. In Kumar V, et al. (Eds.). Pathologic Basis of Disease (10th ed.). Elsevier.
            6.  Wu PA. (2019). Epidemiology, pathogenesis, and clinical features of basal cell carcinoma. Retrieved January 19, 2021, from https://www.uptodate.com/contents/epidemiology-pathogenesis-and-clinical-features-of-basal-cell-carcinoma

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