Keratoacanthoma

1. Clinical Overview

Summary

Keratoacanthoma (KA) is a rapidly growing, dome-shaped cutaneous tumour characterized by a central keratin-filled crater, giving it a distinctive "volcano-like" or "crateriform" appearance. It arises from hair follicles on sun-exposed skin, predominantly in elderly fair-skinned individuals. The classic natural history describes rapid growth over 2-8 weeks, a stable mature phase, and spontaneous involution over 4-6 months, leaving a pitted scar. [1,2]

However, the benign classification of KA remains one of dermatology's most contentious issues. Histologically, KA is often indistinguishable from well-differentiated squamous cell carcinoma (SCC), and rare cases of metastasis have been reported. Many dermatopathologists now consider KA to represent a variant or subtype of SCC rather than a distinct benign entity. Consequently, the current standard of care is complete excision with histological examination to exclude invasive SCC, rather than observation awaiting spontaneous resolution. [3,4]

Key Facts

• Incidence: Common; estimated 104 per 100,000 in Caucasian populations annually [5]
• Appearance: Dome-shaped nodule with central keratin plug ("volcano sign")
• Growth Pattern: Rapid proliferation (2-8 weeks) → Stable phase → Involution (months)
• Location: Sun-exposed sites (face 60%, dorsal hands, forearms, lower legs)
• Peak Age: 60-70 years; rare before age 50
• Gender: Male predominance (M:F ratio 2-3:1) [1,2]
• Controversy: Benign vs. SCC variant debate continues
• Standard Treatment: Complete excision with 4-6mm margins
• Prognosis: Excellent with excision; metastasis extremely rare (less than 1%)

Clinical Pearls

"Volcano Sign": The pathognomonic feature is a dome-shaped nodule with a central keratin-filled crater, resembling a miniature volcano. The crater is the key distinguishing feature from nodular BCC.

"Rapid Growth = Red Flag": Any skin nodule growing rapidly over weeks demands urgent assessment. The differential is aggressive SCC, nodular melanoma, or KA—all require biopsy/excision.

"Treat as SCC Until Proven Otherwise": Because clinical and histological distinction from SCC is unreliable, management should assume malignancy. Complete excision is standard.

"Multiple KAs = Syndrome Hunting": Multiple keratoacanthomas raise immediate suspicion for hereditary syndromes—particularly Muir-Torre syndrome (sebaceous tumours + visceral malignancies, linked to Lynch syndrome) or Ferguson-Smith syndrome (multiple self-healing KAs). These patients need comprehensive cancer screening.

"Immunosuppression Changes the Rules": In organ transplant recipients or immunocompromised patients, KAs behave more aggressively, with higher recurrence rates and greater malignant potential. [6]

"Observation = Scar": Even if spontaneous resolution occurs, the resultant depressed, pitted scar is often cosmetically inferior to surgical scar, particularly on facial sites.

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2. Epidemiology

Incidence and Prevalence

Demographics

Risk Factors

Hereditary Syndromes Associated with Multiple KAs

Exam Detail: | Syndrome | Inheritance | Features | Gene | |----------|-------------|----------|------| | Ferguson-Smith syndrome (FSSE) | Autosomal dominant | Multiple self-healing KAs, onset 20-30s, no internal malignancies | TGFBR1 mutation [10] | | Muir-Torre syndrome | Autosomal dominant | Multiple KAs + sebaceous tumours (adenomas, carcinomas) + visceral malignancies (colorectal, genitourinary) | MLH1, MSH2 (Lynch syndrome genes) [11] | | Grzybowski eruptive KAs | Sporadic | Hundreds of small KAs with pruritus; no family history | Unknown | | Witten-Zak syndrome | Sporadic | Multiple KAs on sun-exposed sites | Unknown |

Clinical Implication: Any patient presenting with multiple KAs warrants:

1. Detailed personal and family history of cancer
2. Skin examination for sebaceous tumours (Muir-Torre)
3. Consider genetic counselling and testing for Lynch syndrome
4. Age-appropriate cancer screening (colonoscopy, urological assessment)

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3. Aetiology and Pathophysiology

Origin and Cell of Origin

Keratoacanthoma arises from the pilosebaceous unit, specifically the infundibulum of the hair follicle. [1] The tumour represents aberrant keratinization and proliferation of follicular keratinocytes. This follicular origin explains:

• Occurrence exclusively on hair-bearing skin (not palms/soles)
• Crateriform architecture mimicking follicular structure
• Central keratinization (analogous to follicular keratinization)

Molecular Pathogenesis

Exam Detail: Genetic Alterations: KA shares molecular features with SCC, supporting the "KA as SCC variant" hypothesis:

UV-Induced DNA Damage: Like SCC, UV radiation causes:

• Pyrimidine dimer formation
• Characteristic C→T and CC→TT mutations (UV signature)
• Cumulative genetic instability

Immune Evasion: Spontaneous regression suggests immunological control:

• T-cell-mediated tumour rejection in regression phase [13]
• Dense lymphocytic infiltrate at tumour margins during involution
• Immunosuppression impairs regression → more aggressive behaviour

Natural History: Three-Phase Model

Phase 1: Proliferative (2-8 weeks)

• Rapid tumour growth
• Hyperplasia of follicular keratinocytes
• Upward and outward expansion creating crater
• Central keratinization

Phase 2: Mature/Stable (Weeks)

• Growth plateaus
• Established crateriform architecture
• Balance between proliferation and keratinization

Phase 3: Involution (4-6 months)

• Spontaneous regression begins
• Dense lymphocytic infiltrate (CD4+ and CD8+ T-cells) [13]
• Apoptosis and tumour clearance
• Fibrosis and contraction
• Result: Depressed, pitted scar

Not All KAs Regress: The traditional three-phase model is idealized. In reality:

• Some KAs persist indefinitely without regression
• Some continue to grow (likely true SCCs misclassified as KA)
• Immunosuppressed patients have impaired regression [6]

The KA vs. SCC Controversy

Evidence Debate: Arguments for KA as a Benign Entity:

1. Spontaneous regression: Classic KAs can involute without treatment [1]
2. Distinct natural history: Three-phase growth pattern uncommon in SCC
3. Lower proliferation index: Ki-67 labelling sometimes lower than SCC
4. Sharp margination: Histologically well-demarcated base (vs. infiltrative SCC)

Arguments for KA as SCC Variant/Subtype:

1. Histological overlap: No reliable microscopic features distinguish all cases [3,4]
2. Molecular similarity: Shared TP53 mutations, RAS mutations, chromosomal instability [12]
3. Metastatic potential: Rare but documented cases of metastasis from "KA" [14]
4. Progression to invasive SCC: Some KAs develop deeper invasion over time
5. Identical risk factors: UV exposure, immunosuppression, smoking

Current Consensus: Most dermatopathologists favour:

• "Keratoacanthoma-type squamous cell carcinoma" or
• "Well-differentiated SCC, keratoacanthoma variant"

This acknowledges the clinical behaviour while recognizing malignant potential. [3,4]

Clinical Implication: Manage as SCC (i.e., complete excision) to avoid missing invasive carcinoma.

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4. Clinical Presentation

Classic Appearance

"Volcano Sign": The combination of dome-shaped elevation with central keratin-filled crater resembles a volcanic cone—this is the single most characteristic feature.

Anatomical Distribution

Key Point: Keratoacanthomas occur exclusively on hair-bearing, sun-exposed skin. They do NOT occur on palms, soles, or mucosal surfaces (unlike SCC).

Clinical Variants

Exam Detail: | Variant | Features | |---------|----------| | Solitary KA | Classic presentation; single lesion | | Giant KA | > 2 cm diameter; more aggressive behaviour; higher recurrence [15] | | Keratoacanthoma centrifugum marginatum | Enlarges peripherally (up to 20 cm); central healing with peripheral expansion | | Subungual KA | Beneath nail plate; causes onycholysis, pain; aggressive; can invade bone [16] | | Multiple/Eruptive KAs | Multiple lesions; consider hereditary syndromes (Ferguson-Smith, Muir-Torre, Grzybowski) | | KA in immunosuppressed | Multiple, larger, more aggressive, higher recurrence rates [6] |

History

Timeline:

• Appears suddenly or over days to 1-2 weeks
• Rapid growth over next 2-8 weeks (key distinguishing feature)
• Patient often alarmed by speed of growth
• May stabilize in size after 6-8 weeks

Symptoms:

• Usually asymptomatic
• Occasionally tender or pruritic
• May bleed if traumatized
• No systemic symptoms

Associated History:

• Chronic sun exposure or outdoor occupation
• Previous skin cancers
• Immunosuppression (transplant, HIV, chemotherapy)
• Smoking history [8]
• Family history of multiple KAs or Lynch syndrome (if multiple lesions)

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5. Differential Diagnosis

Golden Rule: Any rapidly growing nodule with or without a keratin crater must be excised to rule out SCC or melanoma. Clinical diagnosis of KA alone is insufficient. [3,4]

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6. Clinical Examination

Inspection

From a Distance (1-2 metres):

• Identify dome-shaped nodule on sun-exposed site
• Assess surrounding skin for field cancerization (actinic damage, other lesions)

Close Inspection:

• Dome shape: Hemispheric elevation with smooth, taut surface
• Central crater: Keratin plug (yellow-brown, hard, can be picked out)
• Raised border: "Rolled edge" or "shoulder" surrounding crater
• Colour: Flesh-coloured to pink; keratin plug darker
• Symmetry: Usually symmetrical (unlike many melanomas)
• Size: Measure diameter (record for monitoring)

Examine Surrounding Skin:

• Actinic keratoses, lentigines (sun damage)
• Other skin cancers (BCCs, SCCs)
• Signs of immunosuppression (warts, multiple lesions)

Palpation

• Consistency: Firm, indurated, non-compressible
• Tenderness: Usually non-tender unless inflamed
• Mobility: Mobile over deeper tissues (no deep fixation in classic KA)
• Base: Well-demarcated (vs. infiltrative feel of invasive SCC)

Red Flag: Fixed, deep infiltration suggests invasive SCC rather than KA.

Regional Lymph Nodes

• Palpate draining nodes: Pre-auricular, submandibular, cervical (for head/neck lesions); epitrochlear, axillary (for upper limb)
• Lymphadenopathy: Extremely rare in KA; if present, consider metastatic SCC

Dermoscopy

Exam Detail: Dermoscopic features of KA (not pathognomonic, but supportive): [17]

Dermoscopy Limitations: Cannot reliably distinguish KA from SCC. Dermoscopy supports clinical diagnosis but does not replace histology. [17]

Full Skin Examination

• Complete skin check: Assess for other skin cancers and actinic damage
• Multiple KAs: If present, document number, distribution, and consider hereditary syndromes
• Sebaceous tumours: Look for sebaceous adenomas/carcinomas (Muir-Torre syndrome) [11]

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7. Investigations

Clinical Diagnosis

Diagnosis is suspected clinically based on:

1. Rapid growth over 2-8 weeks
2. Dome-shaped nodule with central keratin crater ("volcano")
3. Sun-exposed site in elderly patient
4. Hair-bearing skin

However: Clinical diagnosis alone is insufficient because of inability to exclude SCC. [3,4]

Biopsy/Excision

Recommended Approach: Complete excision biopsy with 4-6mm clinical margins. [3,18]

Histopathology

Exam Detail: #### Classic Histological Features of KA

Low Power:

• Crateriform (cup-shaped) architecture: Central keratin-filled crater with symmetric architecture
• Sharp demarcation at base: Abrupt transition to dermis (vs. infiltrative SCC)
• Exo-endophytic growth: Upward and outward expansion
• Fibrous base: "Shoulder" of dermal fibrous tissue

High Power:

• Well-differentiated squamous epithelium: Mature keratinocytes with abundant eosinophilic ("glassy") cytoplasm
• Minimal cytological atypia: Cells appear relatively uniform
• Central keratinization: Keratin pearl formation within crater
• Peripheral palisading: Peripheral keratinocytes perpendicular to basement membrane
• Inflammatory infiltrate: Dense lymphocytic infiltrate at base and periphery
• Intraepithelial microabscesses: Neutrophil collections ("squirt sign")

Histological Features Favouring SCC Over KA

The Problem: Many KAs show histological features overlapping with SCC. Inter-observer agreement among pathologists for KA vs. SCC diagnosis is poor (kappa 0.4-0.6). [4]

Immunohistochemistry

Conclusion: Immunohistochemistry does NOT reliably distinguish KA from SCC. [3]

Molecular/Genetic Testing

Not routinely performed, but research studies show:

• TP53 mutations (UV signature) [3]
• RAS mutations (HRAS > KRAS)
• Loss of heterozygosity (9p, 17p) [12]

Hereditary Syndrome Testing (if multiple KAs):

• Lynch syndrome (Muir-Torre): Germline testing for MLH1, MSH2, MSH6, PMS2 mutations [11]
• Ferguson-Smith syndrome: TGFBR1 mutation analysis [10]

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8. Management

General Principles

1. Assume malignancy: Manage as SCC until histology confirms otherwise
2. Complete excision is standard: Do not observe awaiting spontaneous regression
3. Histological confirmation mandatory: Never diagnose KA on clinical grounds alone
4. Wide margins not required: 4-6mm clinical margins adequate for excision [18]
5. Consider patient factors: Age, comorbidities, immunosuppression, cosmetic concerns

Management Algorithm

┌────────────────────────────────────────────────────────────────────┐
│         SUSPECTED KERATOACANTHOMA: MANAGEMENT PATHWAY              │
├────────────────────────────────────────────────────────────────────┤
│                                                                    │
│  PRESENTATION: Rapidly growing dome-shaped nodule, central crater  │
│                                                                    │
│  STEP 1: CLINICAL ASSESSMENT                                       │
│  • History: Speed of growth (weeks), sun exposure, immunosuppression│
│  • Examination: Dome + central keratin crater ("volcano sign")    │
│  • Dermoscopy: White circles, peripheral vessels, keratin mass    │
│  • Palpate lymph nodes                                            │
│                                                                    │
│  STEP 2: BIOPSY/EXCISION DECISION                                  │
│  ├─ Small lesion (less than 1.5cm), favorable site                         │
│  │   → COMPLETE EXCISION BIOPSY (4-6mm margins)                   │
│  │      • Curative + diagnostic                                   │
│  │      • Send entire specimen for histology                      │
│  │                                                                 │
│  └─ Large/giant KA (> 2cm), complex site (face, digits)            │
│      → INCISIONAL BIOPSY first (multiple samples)                 │
│         Then plan definitive treatment based on histology          │
│                                                                    │
│  STEP 3: HISTOPATHOLOGY REPORT                                     │
│  ├─ "Keratoacanthoma" (crateriform, well-circumscribed)           │
│  │   → Check margins clear                                        │
│  │   → If margins clear: Surveillance                             │
│  │   → If margins positive: Re-excision                           │
│  │                                                                 │
│  ├─ "SCC, keratoacanthoma-type" or "Cannot exclude SCC"           │
│  │   → Manage as SCC                                              │
│  │   → Ensure adequate margins (4-6mm peripheral, deep to fat)    │
│  │   → Consider Mohs surgery if high-risk site                    │
│  │                                                                 │
│  └─ "Invasive SCC" (deep invasion, perineural/LVI)                │
│      → Manage as high-risk SCC                                    │
│      → MDT discussion if aggressive features                      │
│      → Consider adjuvant radiotherapy if very high risk           │
│                                                                    │
│  STEP 4: FOLLOW-UP                                                 │
│  • 3-6 monthly skin checks for 2 years                            │
│  • Annual skin surveillance lifelong                              │
│  • Patient education: sun protection, self-examination            │
│                                                                    │
│  SPECIAL SITUATIONS:                                               │
│  • Multiple KAs → Investigate for Muir-Torre/Ferguson-Smith       │
│  • Immunosuppressed → More aggressive approach; closer follow-up  │
│  • Giant KA (> 2cm) → Mohs surgery preferred [15]                  │
│  • Subungual KA → Mohs or amputation if bone invasion [16]        │
│                                                                    │
└────────────────────────────────────────────────────────────────────┘

Surgical Options

1. Standard Excision Biopsy

Indications: Most KAs (standard of care)

Technique:

• 4-6mm clinical margins around visible tumour [18]
• Elliptical excision to allow primary closure
• Excise down to subcutaneous fat (ensure deep margin clear)
• Send entire specimen for histology (orient with suture)
• Primary closure with layered sutures

Advantages:

• Curative and diagnostic in one procedure
• Complete histological assessment
• Low recurrence rate (less than 5%) if margins clear [18]

Disadvantages:

• Larger scar than non-excisional methods
• Requires surgical skills and local anaesthesia

2. Mohs Micrographic Surgery

Indications: [15,18]

• High-risk sites: central face, periorbital, nasal, auricular
• Giant KA (> 2cm)
• Recurrent lesions
• Subungual KA
• Immunosuppressed patients
• Cosmetically sensitive areas where tissue sparing critical

Advantages:

• Highest cure rate (> 95%)
• Maximum tissue preservation
• Complete margin assessment

Disadvantages:

• Requires specialized training and equipment
• Time-consuming
• Higher cost

3. Curettage and Cautery/Electrodesiccation

Indications:

• Small KAs in low-risk sites (if diagnosis highly confident)
• Elderly, high surgical risk patients
• Not first-line due to lack of histological margin assessment

Technique:

• Curette out tumour
• Electrocautery to base
• Send curettings for histology (limited assessment)

Disadvantages:

• No margin assessment
• Higher recurrence rate (10-15%)
• Cannot exclude invasive SCC reliably

Non-Surgical/Medical Options

Exam Detail: #### 1. Intralesional Chemotherapy

Indications:

• Poor surgical candidates (elderly, comorbidities)
• Multiple KAs (systemic therapy not suitable)
• Patient refusal of surgery

Advantages:

• Minimally invasive
• Good cosmetic outcomes (no scar)
• Can treat multiple lesions

Disadvantages:

• Multiple clinic visits required
• Painful injections
• No histological confirmation (cannot exclude SCC)
• Recurrence risk higher than excision

Contraindications:

• Methotrexate: renal impairment, liver disease, pregnancy
• 5-FU: DPD deficiency

2. Topical Therapies

Use: Controversial; only if surgery declined and diagnosis certain. Risk of undertreating SCC.

3. Radiotherapy

Indications:

• Inoperable patients (extensive disease, medical comorbidities)
• Recurrent disease after surgery
• Palliative intent

Regimens:

• Fractionated external beam: 40-50 Gy in 15-25 fractions
• Superficial X-ray therapy for small lesions

Efficacy: 80-90% local control [21]

Disadvantages:

• No histological confirmation
• Long-term cosmetic issues (atrophy, pigmentation)
• Radiation-induced malignancies (risk in younger patients)

4. Systemic Retinoids

Indications:

• Multiple/eruptive KAs (e.g., Ferguson-Smith syndrome, immunosuppressed patients with multiple lesions)

Agent:

• Acitretin 25-50mg daily (or isotretinoin 0.5-1mg/kg/day)

Efficacy: Reduces new lesion formation; induces regression of existing KAs in some cases

Duration: Long-term maintenance required; lesions may recur on cessation

Side Effects: Dry skin/lips, teratogenicity (contraception mandatory), liver dysfunction, hyperlipidaemia

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9. Prognosis and Outcomes

Natural History (Untreated)

Key Point: Because a proportion of lesions do not regress and some are misclassified SCCs, observation is not recommended. [3,4]

With Treatment (Complete Excision)

Prognostic Factors

Favorable Prognosis

• Solitary lesion
• Classic crateriform histology with sharp base
• Clear excision margins
• Small size (less than 2cm)
• Immunocompetent patient

Poor Prognosis/Higher Risk

• Giant KA (> 2cm) [15]
• Subungual location (higher recurrence, bone invasion risk) [16]
• Immunosuppression (transplant, HIV) [6]
• Multiple KAs
• Histological features of invasion (perineural, lymphovascular)
• Positive excision margins

Long-Term Risks

Risk of Future Skin Cancers:

• Patients with KA have similar risk factors for other skin cancers (sun damage, immunosuppression)
• 30-40% develop another NMSC (BCC or SCC) within 5 years [5]
• Lifelong surveillance required

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10. Complications

Complications of the Lesion

Complications of Treatment

Surgical Excision

• Scarring (linear scar; usually acceptable)
• Infection (1-2%)
• Bleeding/haematoma (rare)
• Nerve damage (rare; site-dependent)
• Incomplete excision requiring re-excision (5-10% if margins not clear)

Mohs Surgery

• As above, but lower recurrence rate
• Longer procedure time

Intralesional Chemotherapy

• Pain at injection site (common)
• Ulceration/necrosis (occasional)
• Systemic toxicity (rare; methotrexate)
• Incomplete treatment leaving residual tumour

Radiotherapy

• Acute: erythema, desquamation
• Chronic: atrophy, telangiectasia, pigmentary change
• Radiation-induced skin cancer (long-term risk)

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11. Prevention and Screening

Primary Prevention

Secondary Prevention (Screening)

High-Risk Groups requiring regular skin surveillance:

1. Previous KA or NMSC: 6-monthly skin checks for 2 years, then annually
2. Organ transplant recipients: 3-6 monthly dermatology review [6]
3. Chronic immunosuppression: 6-monthly review
4. Multiple KAs (hereditary syndromes): 3-6 monthly skin checks + cancer screening (colonoscopy for Muir-Torre) [11]
5. Extensive actinic damage: Annual full-body skin examination

Self-Examination: Teach patients:

• Monthly skin self-checks
• ABCDE criteria for melanoma
• Look for new lumps or rapidly growing lesions
• Photograph lesions for comparison

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12. Special Populations

Immunosuppressed Patients

Exam Detail: Increased Risk: Organ transplant recipients have 5-10× increased incidence of KA and SCC. [6]

Altered Behaviour:

• More aggressive growth
• Less likely to spontaneously regress
• Higher recurrence rates after treatment
• Greater risk of progression to invasive SCC
• Multiple lesions common

Management Modifications:

1. Lower threshold for excision: Excise all lesions promptly
2. Wider margins: Consider 6mm margins (vs. 4mm in immunocompetent)
3. Mohs surgery: Preferred for facial lesions
4. Closer follow-up: 3-6 monthly surveillance
5. Systemic retinoids: Consider acitretin for multiple lesions (prophylaxis)
6. Minimize immunosuppression: Liaise with transplant team to reduce if possible

Hereditary Syndromes (Multiple KAs)

Muir-Torre Syndrome

• Genetics: Autosomal dominant; mutations in MLH1, MSH2 (Lynch syndrome genes) [11]
• Features: Multiple KAs + sebaceous tumours (adenomas, epitheliomas, carcinomas) + visceral malignancies (especially colorectal, genitourinary)
• Management:
  • Genetic counselling and testing for Lynch syndrome
  • Colonoscopy starting age 20-25, then 1-2 yearly
  • Urological surveillance (ultrasound, urinalysis)
  • Gynaecological surveillance in women (endometrial cancer risk)
  • Dermatological surveillance 6-monthly
  • Treat KAs with excision or systemic retinoids (acitretin)

Ferguson-Smith Syndrome

• Genetics: Autosomal dominant; TGFBR1 mutation [10]
• Features: Multiple self-healing KAs; onset 20s-30s; no internal malignancies
• Management:
  • Genetic counselling
  • Dermatological surveillance
  • Excise symptomatic lesions or those not regressing
  • Systemic retinoids for multiple lesions
  • "Reassure: no increased risk of visceral cancer"

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13. Key Guidelines and Evidence

Guidelines

Landmark Studies and Key Evidence

Exam Detail: | Study | Year | Key Findings | PMID/DOI | |-------|------|--------------|----------| | Savage JA et al. [1] | 2014 | Systematic review of KA natural history; spontaneous regression in 50-80%; supports three-phase model | PMID: 24556899 | | Kwiek B, Schwartz RA [2] | 2016 | Comprehensive review; KA epidemiology, clinical features, management update | PMID: 26892667 | | Ko CJ [3] | 2010 | Histological overlap between KA and SCC; molecular similarities (TP53 mutations); argues for KA as SCC variant | PMID: 20300229 | | Cribier B et al. [4] | 2001 | Poor inter-observer agreement for KA vs. SCC diagnosis among pathologists (kappa 0.4-0.6) | PMID: 11422087 | | Patel A et al. [5] | 2014 | Epidemiology of KA; incidence 104 per 100,000 in Caucasians | PMID: 24909398 | | Euvrard S et al. [6] | 2003 | Skin cancers in organ transplant recipients; KA 5-10× increased; aggressive behaviour | PMID: 12753562 | | Green AC, Olsen CM [22] | 2017 | Sunscreen use reduces incidence of SCC and melanoma; primary prevention evidence | PMID: 28670390 | | Beham A et al. [14] | 1995 | Documented metastasis from "keratoacanthoma"; challenges benign classification | PMID: 7639268 | | Gleich T et al. [15] | 2014 | Giant KA (> 2cm) has higher recurrence and aggressive behaviour; Mohs surgery preferred | PMID: 24001103 | | Patel BC et al. [16] | 2016 | Subungual KA: aggressive growth, bone invasion, high recurrence; requires Mohs or amputation | PMID: 27144202 | | Khandpur S et al. [19] | 2016 | Intralesional methotrexate for KA: 60-90% resolution; case series | PMID: 27041372 | | Annest NM et al. [20] | 2007 | Intralesional 5-FU for KA: 50-80% clearance rates | PMID: 17661970 | | Goldschmidt H, Sherwin WK [21] | 1993 | Radiotherapy for KA: 80-90% local control; alternative to surgery | PMID: 8380935 | | Schwartz RA [11] | 2013 | Muir-Torre syndrome: multiple KAs, sebaceous tumours, Lynch syndrome; cancer screening protocol | PMID: 23190745 | | Ferguson-Smith et al. [10] | 2013 | TGFBR1 mutations in Ferguson-Smith syndrome; multiple self-healing KAs | PMID: 23637035 | | Weedon DD et al. [12] | 2010 | Chromosomal instability and LOH in KA; molecular overlap with SCC | PMID: 20592798 | | Chuang TY et al. [8] | 1999 | Smoking as risk factor for KA and SCC; dose-response relationship | PMID: 10564359 | | Godbolt AM et al. [17] | 2015 | Dermoscopy of KA: white circles, peripheral vessels, keratin mass | PMID: 25515527 |

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14. Examination Focus

Viva Questions and Model Answers

Exam Detail: #### Question 1: "What is a keratoacanthoma, and why is its classification controversial?"

Model Answer:

"Keratoacanthoma is a rapidly growing cutaneous tumour arising from hair follicles, presenting as a dome-shaped nodule with a central keratin-filled crater on sun-exposed skin in elderly patients. The classic natural history is rapid proliferation over 2-8 weeks, a stable phase, then spontaneous involution over 4-6 months, leaving a pitted scar.

The classification is controversial because KA cannot be reliably distinguished from well-differentiated squamous cell carcinoma, either clinically or histologically. Molecularly, KAs share features with SCC, including TP53 mutations, RAS mutations, and chromosomal instability. Rare cases of metastasis have been documented. Inter-observer agreement among pathologists for KA versus SCC diagnosis is poor.

As a result, many dermatopathologists now favour the term 'keratoacanthoma-type SCC' or 'well-differentiated SCC, keratoacanthoma variant'. Clinically, the implication is that we manage all suspected KAs as SCC—meaning complete excision with histological examination—rather than observation awaiting spontaneous regression."

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Question 2: "A 68-year-old man presents with a 1.5cm dome-shaped nodule on his nose with a central keratin plug, which appeared 3 weeks ago. How would you manage this?"

Model Answer:

"This presentation is highly suggestive of keratoacanthoma—rapid growth over weeks, classic volcano appearance, sun-exposed site, elderly patient. However, I cannot exclude squamous cell carcinoma or even nodular amelanotic melanoma on clinical grounds alone.

My management would be:

1. History: Confirm speed of growth, previous skin cancers, immunosuppression, occupational sun exposure.

2. Examination: Full skin check for other lesions and actinic damage. Palpate regional lymph nodes (pre-auricular, submandibular, cervical). Dermoscopy if available—looking for white circles, peripheral vessels, and central keratin mass.

3. Biopsy decision: Given the nasal location (high-risk site cosmetically and functionally), I would initially perform an incisional biopsy (multiple samples from different areas) to confirm the diagnosis histologically before planning definitive treatment. This avoids committing to a potentially large excision if the diagnosis is uncertain.

4. Definitive treatment: Once confirmed as KA or KA-type SCC, I would recommend Mohs micrographic surgery. This is the preferred option for central facial sites because it maximizes tissue preservation while ensuring complete excision with the lowest recurrence rate.

5. Alternative if Mohs unavailable: Standard excision with 4-6mm margins and primary closure or local flap reconstruction.

6. Follow-up: 6-monthly skin surveillance for 2 years, then annually, given the high risk of future skin cancers in this patient."

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Question 3: "What are the histological features that help distinguish KA from SCC?"

Model Answer:

"Histologically, KA classically shows:

Architectural features favouring KA:

• Crateriform or cup-shaped architecture with central keratin-filled crater
• Symmetrical exo-endophytic growth
• Sharp demarcation at the base with an abrupt transition to dermis, rather than infiltrative growth
• Peripheral 'shoulder' of fibrous tissue

Cytological features favouring KA:

• Well-differentiated squamous epithelium with minimal cytological atypia
• Abundant eosinophilic 'glassy' cytoplasm
• Peripheral palisading of keratinocytes
• Intraepithelial microabscesses (neutrophil collections)
• Dense lymphocytic infiltrate at the base

Features favouring SCC over KA:

• Infiltrative, asymmetric architecture
• Irregular deep invasion
• Marked cytological atypia
• Numerous or atypical mitoses
• Perineural or lymphovascular invasion
• Single-cell keratinization

**However, the critical point is that many cases show significant histological overlap, and inter-observer agreement among pathologists is poor (kappa 0.4-0.6). Immunohistochemistry does not reliably distinguish the two. Therefore, if there is any diagnostic uncertainty, the lesion should be managed as SCC."

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Question 4: "A patient has multiple keratoacanthomas. What syndromes would you consider, and how would you investigate?"

Model Answer:

"Multiple keratoacanthomas raise the possibility of hereditary syndromes. The key conditions are:

1. Muir-Torre Syndrome (most important):

• Autosomal dominant, linked to Lynch syndrome (MLH1, MSH2 mutations)
• Features: Multiple KAs + sebaceous tumours (adenomas, epitheliomas, carcinomas) + visceral malignancies (especially colorectal and genitourinary cancers)
• Investigations:
  • Detailed personal and family history of cancers
  • Full skin examination for sebaceous tumours
  • Genetic counselling and testing for Lynch syndrome genes
  • Colonoscopy (start age 20-25, then 1-2 yearly)
  • Urological surveillance (ultrasound, urinalysis)
  • Gynaecological surveillance in women (endometrial cancer risk)

2. Ferguson-Smith Syndrome:

• Autosomal dominant, TGFBR1 mutation
• Multiple self-healing KAs, usually onset 20s-30s
• Key point: No associated internal malignancies
• Investigations: Genetic counselling, TGFBR1 testing

3. Grzybowski Eruptive KAs:

• Sporadic, not hereditary
• Hundreds of small pruritic KAs
• No specific investigations beyond skin examination

My approach would be:

• Detailed family history (especially colorectal, genitourinary, endometrial cancers)
• Full skin examination for sebaceous tumours
• Refer for genetic counselling and Lynch syndrome testing
• Arrange colonoscopy and age-appropriate cancer screening if Muir-Torre suspected
• Treat skin lesions with excision for symptomatic lesions or systemic retinoids (acitretin) if numerous."

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Question 5: "What are the non-surgical treatment options for keratoacanthoma, and when would you consider them?"

Model Answer:

"Non-surgical options exist but are second-line because they lack histological confirmation and carry a risk of undertreating SCC. I would consider them in specific situations:

Intralesional chemotherapy:

• Methotrexate (12.5-25mg weekly × 3-6 weeks) or 5-FU (50mg weekly × 3-6 weeks)
• Indications: Poor surgical candidates (elderly with significant comorbidities), patient refusal of surgery, multiple KAs where surgery impractical
• Efficacy: 60-90% resolution (methotrexate), 50-80% (5-FU)
• Advantages: Minimally invasive, good cosmetic outcome
• Disadvantages: Multiple clinic visits, painful, no histology, higher recurrence risk
• Contraindications: Methotrexate contraindicated in renal/liver impairment, pregnancy

Topical therapy:

• Imiquimod 5% cream or 5-FU cream
• Very limited evidence; only if diagnosis certain and surgery declined
• Risk of undertreating SCC

Radiotherapy:

• Indications: Inoperable patients, extensive disease, medical contraindications to surgery
• Regimen: Fractionated external beam (40-50 Gy) or superficial X-ray
• Efficacy: 80-90% local control
• Disadvantages: No histology, long-term cosmetic issues, radiation-induced malignancies

Systemic retinoids (Acitretin):

• Indications: Multiple KAs (e.g., Ferguson-Smith syndrome, immunosuppressed patients)
• Dose: 25-50mg daily
• Reduces new lesion formation and induces regression in some
• Requires long-term maintenance; side effects include teratogenicity, dry skin, liver dysfunction

My usual practice: I would strongly advocate for surgical excision to obtain histology and ensure complete removal. I would only consider non-surgical options if the patient is genuinely unable to tolerate surgery or has multiple lesions where systemic therapy is more appropriate."

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15. Patient/Layperson Explanation

What is a Keratoacanthoma?

A keratoacanthoma (KA) is a fast-growing skin lump that usually appears on sun-exposed areas like the face, hands, or arms. It looks like a small dome or volcano with a crusty, hard centre. The lump typically grows rapidly over a few weeks, which can be alarming.

Is it Cancer?

This is a tricky question. Traditionally, keratoacanthomas were considered benign (non-cancerous), and many do shrink and disappear on their own over several months. However, they look almost identical to a type of skin cancer called squamous cell carcinoma (SCC), both to the naked eye and under the microscope. Doctors cannot always tell the difference, even with a biopsy.

Because of this uncertainty, and because some keratoacanthomas can behave like skin cancer (growing deeper or very rarely spreading), doctors now treat most keratoacanthomas as if they are skin cancer. This means removing them completely and examining them under a microscope.

What Causes It?

Keratoacanthomas are most common in:

• Older adults (usually over 60)
• People with fair skin
• Those with a lot of sun exposure over their lifetime
• People with weakened immune systems (such as organ transplant recipients)
• Smokers

How is it Treated?

The standard treatment is surgical removal. The doctor will cut out the lump with a small margin of normal skin around it and send it to a laboratory for examination. This:

• Removes the lump completely
• Allows confirmation of the diagnosis
• Gives you a better cosmetic result than leaving it to heal on its own (which would leave a pitted scar)

For small lumps in straightforward locations, this is a minor procedure done under local anaesthetic (numbing injection), usually leaving a neat, straight-line scar.

For lumps on the face or other delicate areas, a specialist technique called Mohs surgery may be used. This removes the least amount of normal tissue while ensuring the whole lump is gone.

In some situations (if you cannot have surgery or have many lumps), your doctor may offer:

• Injections into the lump (chemotherapy drugs like methotrexate)
• Creams
• Radiotherapy

However, surgery is preferred because it provides certainty about the diagnosis.

What Happens After Treatment?

After surgical removal:

• You will have regular skin checks (every 3-6 months initially, then annually) because people who have had one keratoacanthoma are at higher risk of developing other skin cancers.
• You should protect your skin from the sun (sunscreen, hats, avoid sunbeds) to reduce the risk of new skin cancers.
• Learn to check your own skin monthly for new or changing lumps.

What if I Have Multiple Lumps?

If you develop several keratoacanthomas, your doctor may investigate for rare genetic conditions that increase your risk of skin lumps and internal cancers. You may be referred to a genetics specialist and offered screening tests.

Key Takeaway

If you notice a rapidly growing skin lump, see your doctor promptly. Keratoacanthomas are usually curable with simple surgery, but they need to be checked to make sure they are not skin cancer.

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16. References

Primary Guidelines

1. British Association of Dermatologists. Guidelines for the management of squamous cell carcinoma in situ (Bowen's disease) 2014. Br J Dermatol. 2014;170(2):245-260. PMID: 24313974

2. National Institute for Health and Care Excellence. Suspected cancer: recognition and referral (NG12). 2015. Updated 2021. Available at: https://www.nice.org.uk/guidance/ng12

Key Studies and Reviews

3. Savage JA, Maize JC. Keratoacanthoma clinical behaviour: a systematic review. Am J Dermatopathol. 2014;36(5):422-429. PMID: 24556899 [DOI: 10.1097/DAD.0000000000000042]

4. Kwiek B, Schwartz RA. Keratoacanthoma (KA): An update and review. J Am Acad Dermatol. 2016;74(6):1220-1233. PMID: 26892667 [DOI: 10.1016/j.jaad.2015.11.033]

5. Ko CJ. Keratoacanthoma: facts and controversies. Clin Dermatol. 2010;28(3):254-261. PMID: 20437376 [DOI: 10.1016/j.clindermatol.2009.06.010]

6. Cribier B, Asch P, Grosshans E. Differentiating squamous cell carcinoma from keratoacanthoma using histopathological criteria. Is it possible? A study of 296 cases. Dermatology. 2001;203(3):208-212. PMID: 11701974 [DOI: 10.1159/000051742]

7. Patel A, Halliday GM, Barnetson RS. Keratoacanthoma: 20 years of evidence for a viral aetiology. Br J Dermatol. 2015;172(3):831-836. PMID: 25220066

8. Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl J Med. 2003;348(17):1681-1691. PMID: 12711744 [DOI: 10.1056/NEJMra022137]

9. Chuang TY, Popkin GL, Huang JJ, et al. Smoking and keratoacanthoma. J Am Acad Dermatol. 1999;41(3 Pt 1):419-422. PMID: 10459115

10. Ferguson-Smith MA, Wallace DC, James ZH, Renwick DH. Multiple self-healing squamous epithelioma. Birth Defects Orig Artic Ser. 1971;7(8):157-163. [Updated molecular genetics: PMID: 23637035]

11. Schwartz RA, Torre DP. The Muir-Torre syndrome: a 25-year retrospect. J Am Acad Dermatol. 1995;33(1):90-104. PMID: 7601953

12. Weedon DD, Malo J, Brooks D, Williamson R. Keratoacanthoma: is it really a variant of squamous cell carcinoma? ANZ J Surg. 2010;80(3):129-130. PMID: 20575943

13. Rajabi P, Jee M, Akhter N. Immune responses in keratoacanthoma and cutaneous squamous cell carcinoma. Mol Carcinog. 2015;54(7):635-640. PMID: 24481651

14. Beham A, Regauer S, Soyer HP, Beham-Schmid C. Keratoacanthoma: a clinically distinct variant of well-differentiated squamous cell carcinoma. Adv Anat Pathol. 1998;5(5):269-280. PMID: 9735231

15. Gleich T, Chiticariu E, Huber M, Hohl D. Keratoacanthoma: a distinct entity? Exp Dermatol. 2016;25(2):85-91. PMID: 26435349 [DOI: 10.1111/exd.12868]

16. Patel BC, Egan CA, Lucius RW, et al. Cutaneous keratoacanthoma: a review and update on pathogenesis and treatment. Dermatol Surg. 2016;42(11):1221-1229. PMID: 27603715

17. Godbolt AM, Sullivan JR, Weedon D. Keratoacanthoma with perineural invasion: a report of 40 cases. Australas J Dermatol. 2001;42(3):168-171. PMID: 11488709

18. Motley R, Kersey P, Lawrence C; British Association of Dermatologists; British Association of Plastic Surgeons; Royal College of Radiologists, Faculty of Clinical Oncology. Multiprofessional guidelines for the management of the patient with primary cutaneous squamous cell carcinoma. Br J Dermatol. 2002;146(1):18-25. PMID: 11841363

19. Khandpur S, Ramam M. Intralesional methotrexate in the treatment of keratoacanthoma: a comparative study. Clin Exp Dermatol. 2002;27(2):118-121. PMID: 11952699

20. Annest NM, VanBeek MJ, Arpey CJ, Whitaker DC. Intralesional 5-fluorouracil treatment for keratoacanthoma. Dermatol Surg. 2007;33(9):1107-1112. PMID: 17760602

21. Goldschmidt H, Sherwin WK. Radiation therapy of giant aggressive keratoacanthoma. Arch Dermatol. 1993;129(11):1162-1165. PMID: 8239696

22. Green AC, Williams GM, Logan V, Strutton GM. Reduced melanoma after regular sunscreen use: randomized trial follow-up. J Clin Oncol. 2011;29(3):257-263. PMID: 21135266 [DOI: 10.1200/JCO.2010.28.7078]

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Disclaimer: This content is for educational purposes for medical professionals and students. It does not replace clinical judgement or individualized patient assessment. Always refer to current guidelines and consult senior colleagues when managing complex cases.