Skin Cancer Notes: Basal Cell Carcinoma and Squamous Cell Carcinoma

Overview and Classification

• Learning objective: describe the risk factors, pathophysiology, and clinical manifestations of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC).
• Skin cancers are broadly classified as melanoma and non-m melanoma cancers; BCC and SCC are collectively referred to as non-melanoma skin cancers (NMSC).
• Proportions among NMSC: $70\%$ are basal cell carcinomas (BCC) and $30\%$ are squamous cell carcinomas (SCC).
• All three major skin cancers share a common risk factor: high ultraviolet (UV) exposure, but other etiologies differ by cancer type.
  • Basal cell carcinoma: additional risk factors include chemical exposure.
  • Squamous cell carcinoma: additional risk factors include infection with certain strains of human papillomavirus (HPV).
  • Melanoma: associated with familial gene mutations (inherited predisposition).
• Cellular origin (cell types affected):
  • BCC arises from DNA mutations in basal layer stem cells (stratum basale).
  • SCC arises from DNA mutations in epidermal keratinocytes (stratum spinosum).
  • Melanoma arises from melanocytes (often in/near the same region of the epidermis).
• Common pathway: disordered replication leading to DNA mutations (dysplasia) and progression to neoplasia.
• Important distinction: BCC and SCC differ markedly in aggressiveness and metastatic potential.
  • BCC: generally very slow-growing and rarely metastasizes.
  • SCC: more aggressive than BCC and can metastasize (to regional lymph nodes); prognosis worsens if metastasis occurs.
• Three main skin cancers originate in different epidermal cells, but all can present as a skin lesion and require biopsy for definitive diagnosis.
• Relative aggressiveness sequence (from least to most aggressive): BCC < SCC < malignant melanoma.

Skin anatomy refresher (where cancers arise)

• Epidermis layers (outer to deep):
  • Stratum corneum: dead keratinocytes; outermost layer.
  • Stratum lucidum (not always discussed in all texts).
  • Stratum granulosum.
  • Stratum spinosum: keratinocytes; origin site for SCC.
  • Stratum basale: deepest epidermal layer; contains basal cells; origin site for BCC.
• Dermis lies beneath the epidermis.
• Melanocytes reside in the epidermis (often near basal layer) and give pigment; they are the cell of origin for melanoma.

Basal Cell Carcinoma (BCC)

Epidemiology and risk factors

• Most common skin tumor; roughly $70\%$ of NMSC.
• Typical location: sun-exposed skin, especially on the head and neck; can occur elsewhere.
• More common in older individuals.
• Major risk factors:
  • Light skin phenotype: light skin color, red hair, blue eyes, freckles.
  • Ultraviolet (UV) radiation exposure (sun exposure).
  • Additional risk factors: arsenic exposure, chemical exposure, and oils.

Pathophysiology

• Initiation involves UV-induced DNA damage in pluripotent (undifferentiated) stem cells of the epidermis.
• Tumor suppressor gene mutations play a key role; estimated to be involved in about $50\%$ of BCCs.
• Mechanism: tumor suppressor genes fail to repair DNA or to promote apoptosis, leading to disordered cell replication and dysplasia that progresses to neoplasia.
• A notable point from the transcript: BCCs have disordered replication but are unlikely to shed malignant cells in a way that causes widespread metastasis; metastasis to distant sites is extremely uncommon.

Clinical features and presentation

• Typical lesion: elevated nodule with a central depression; may appear as a rodent ulcer (tussy, ulcer-like lesion).
• Appearance can vary by subtype; several growth patterns exist:
  • Superficial: erythematous, red, defined, macular, sometimes scaly, pearly color.
  • Nodular: translucent papule or nodule; may have small dilated vessels; borders may be slightly rolled.
  • Morpheaform (sclerotic): pale, scar-like, waxy or white/yellowish; typically more aggressive and may invade deeper tissues.
• Most lesions grow slowly and metastasis is rare.
• Diagnosis: primarily clinical observation; biopsy is used to confirm and exclude SCC or melanoma; specialized skin checks improve diagnostic accuracy.

Diagnosis and differential

• Diagnosis by history and physical examination followed by biopsy for confirmation.
• Differential diagnosis includes SCC and melanoma; biopsy ensures correct classification and margins.

Management

• Standard treatment: surgical excision with clear margins.
• Morphed/morpheaform BCCs can be more challenging due to indistinct borders and deeper invasion, sometimes requiring more aggressive treatment approaches.
• Recurrence risk can be higher in morphic (morpheaform) lesions due to indistinct clinical margins.

Squamous Cell Carcinoma (SCC)

Epidemiology and risk factors

• Arises from epidermal keratinocytes in the stratum spinosum; commonly occurs on sun-exposed skin; may be preceded by actinic keratosis (AK).
• Major risk factor: UV radiation exposure.
• Other risk factors/etologies:
  • HPV infection (certain strains) contributing to carcinogenesis.
  • Immunosuppression.
  • Vitamin D deficiency.
  • Light skin phenotype (as with BCC): pale skin, red hair, blue eyes, freckles (risk factors overlap with BCC).
  • Actinic keratosis (AK) is both a risk factor and an etiologic precursor for some SCCs (AK can progress to SCC but not all AKs become SCC).
• Genetic/ Molecular contributors:
  • Tumor suppressor gene mutations, notably p53 (TP53) mutations, present in roughly $50\%$ of SCCs.
  • Other mutations: NOTCH1, NOTCH2, and RAS family mutations.
  • HPV infection (~$25\%$ of SCCs) can promote carcinogenesis by inhibiting DNA repair and preventing apoptosis.

Pathophysiology

• UV exposure causes DNA damage and oxidative stress in keratinocytes, leading to dysregulated signaling and mutations.
• HPV can inhibit DNA repair and apoptosis, facilitating progression toward SCC in infected cells.
• The cumulative effect is disordered replication, dysplasia, and progression to invasive carcinoma.

Clinical features and presentation

• Common clinical manifestations:
  • Persistent non-healing ulcer.
  • Scaly crust and hyperkeratosis at the lesion.
  • May present as a papule that bleeds or ulcerates.
  • Local invasion into surrounding tissues is possible.
• Metastasis:
  • Can metastasize to regional lymph nodes in some cases, but this occurs in only about $2\%$ or fewer cases with a poor prognosis if metastasis occurs.
  • Most SCCs remain locally invasive rather than distant metastatic.

Diagnosis and differential

• Diagnosis via biopsy to determine cellular origin and invasion depth; helps distinguish SCC from BCC and melanoma and confirms clear margins.

Management

• Primary treatment: surgical excision with adequate margins.
• Outpatient basis: many cutaneous SCCs can be excised in a general practice or dermatology setting.
• Additional treatments depending on size, location, history, and risk factors:
  • Radiation therapy or chemotherapy may be considered for larger tumors, high-risk locations, prior cancers, or nodal involvement.
• Prognosis and follow-up: prognosis worsens with lymph node metastasis; regular follow-up for new lesions or recurrences is important.

Key differences and integrated takeaways

• Cells of origin:
  • BCC: stratum basale (basal cells) of the epidermis.
  • SCC: keratinocytes in the stratum spinosum.
  • Melanoma: melanocytes (contextual reference).
• Aggressiveness and metastasis:
  • BCC: least aggressive, very low metastasis risk.
  • SCC: more aggressive than BCC, can metastasize (to regional lymph nodes) in a minority of cases.
  • Melanoma: most aggressive among the three.
• Common etiologies and risk factors:
  • UV exposure is a common factor across BCC and SCC (and melanoma).
  • BCC additional risk: chemical exposure (e.g., arsenic; other chemicals/oils).
  • SCC additional risk: HPV infection, immunosuppression, AK as an antecedent lesion.
• Diagnostic and treatment approaches:
  • Both BCC and SCC are primarily diagnosed by biopsy and managed with surgical excision; SCC may require adjuvant therapy in selected cases.
  • The precise management plan depends on tumor type, size, location, histology (morphology for BCC), and patient history.
• Pathophysiology emphasis:
  • UV-induced DNA damage and mutations in tumor suppressor pathways drive initiation in both BCC and SCC.
  • p53 (TP53) mutations are notably implicated in SCC; ~50% of SCCs involve tumor suppressor gene mutations.
  • Notch and RAS mutations can contribute to SCC pathogenesis.
  • HPV contributes to SCC by impairing DNA repair and evading apoptosis in infected cells.

Practical and clinical implications

• Early detection and regular skin checks are important, especially for older adults and individuals with high-risk phenotypes (light skin, hair/eye color, freckles).
• Clinicians should differentiate BCC from SCC (and melanoma) via biopsy due to differences in prognosis and treatment.
• Patient education on sun protection and avoidance of carcinogenic exposures is a key preventive strategy.
• Actinic keratosis should be monitored and managed, given its potential to progress to SCC in some cases.

Connections to foundational principles

• UV radiation as a mutagen links to general cancer biology: DNA damage, replication error, and tumor suppressor gene failure leading to uncontrolled cell growth.
• The concept of clonal evolution: mutations in keratinocytes lead to clonal expansion, dysplasia, and neoplasia with potential local invasion or metastasis.
• The role of HPV illustrates how viral oncogenesis can disrupt normal cell cycle control and DNA repair mechanisms.
• Tissue-specificity: cancers arise from specific epidermal layers, explaining why BCC, SCC, and melanoma have distinct clinical and histopathological features.

Summary points for exam preparation

• Non-melanoma skin cancers comprise BCC (~70%) and SCC (~30%); UV exposure is a unifying risk factor.
• BCC: arises from basal cells (stratum basale), head/neck common, very low metastasis, three growth patterns (superficial, nodular, morpheaform), management mainly by excision; risk factors include light skin phenotype and chemical exposures; ~50% of BCCs involve tumor suppressor gene mutations.
• SCC: arises from keratinocytes (stratum spinosum), may follow actinic keratosis, HPV involvement, p53/NOTCH/RAS mutations, can metastasize (~2% cases), management mainly by excision with possible adjuvant therapy depending on size/location/history.
• Distinguishing clinical features and biopsy confirmation are critical for appropriate management and prognosis.