A Clinical and Biological Review of Keratoacanthoma

A. Tisack; A. Fotouhi; C. Fidai; B.J. Friedman; D. Ozog; J. Veenstra

The British Journal of Dermatology. 2021;185(3):487-498.

Abstract and Introduction

Abstract

Keratoacanthoma (KA) is a common skin tumour that remains controversial regarding classification, epidemiology, diagnosis, prognosis and management. Classically, a KA manifests as a rapidly growing, well-differentiated, squamoid lesion with a predilection for sun-exposed sites in elderly people and a tendency to spontaneously regress. Historically, KAs have been considered a variant of cutaneous squamous cell carcinoma (cSCC) and are often reported as KA-type cSCC. However, the penchant for regression has led many to categorize KAs as biologically benign tumours with distinct pathophysiological mechanisms from malignant cSCC. The clinical and histopathological similarities between KA and cSCC, particularly the well-differentiated variant of cSCC, have made definitive differentiation difficult or impossible in many cases. The ambiguity between entities has led to the general recommendation for surgical excision of KAs to ensure a potentially malignant cSCC is not left untreated. This current standard creates unnecessary surgical morbidity and financial strain for patients, especially the at-risk elderly population. There have been no reports of death from a definitive KA to date, while cSCC has an approximate mortality rate of 1·5%. Reliably distinguishing cSCC from KA would shift management strategies for KAs towards less-invasive treatment modalities, prevent unnecessary surgical morbidity, and likely reduce associated healthcare costs. Herein, we review the pathophysiology and clinical characteristics of KA, and conclude on the balance of current evidence that KA is a benign lesion and distinct from cSCC.

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Abstract and Introduction
History
Clinical Behaviour of Cutaneous Squamous Cell Carcinoma and Keratoacanthoma
Tumour Biology
Tumour Microenvironment
Discussion
References

Table 1. Keratoacanthoma (KA) variants and syndromes
Type of KA	Clinical features	Genetic defect
Solitary KA	Most common, sporadic, 5–15-mm solitary lesions³⁸	Multiple (i.e. Wnt and TP63 upregulation)^49,56,57
KA centrifugum et marginatum	Solitary or multiple annular plaques progressively expanding peripherally with elevated, rolled margins and central resolution rapidly reaching 3 cm in diameter, but may be as large as 30 cm^{45,46,48,50,65}	HPV 6 and 11 have been associated⁴⁷
Giant KA	Greater than 2–3 cm, can be > 20 cm in diameter associated with slower, but prolonged, growth and frequently involving the nose and eyelids^42,43,66,67	HPV 6 and 11 have been associated^44,68
Generalized eruptive KAs of Grzybowski	Thousands of papules resembling milia or xanthomas with frequent mucous membrane involvement and severe pruritus most frequently affecting patients in their 50s to 70s; resolve slowly over months with scarring and ectropion; associated with visceral malignancies^41,53–55	HPV 16 and 39 have been associated^41,51
Multiple self-healing squamous epithelioma (also known as Ferguson–Smith disease)	Multiple spontaneously regressing KAs in sun-exposed sites beginning in the third decade of life; regress over weeks to months; overlapping features of Grzybowski and of Witten and Zak^52,58	Autosomal dominantly inherited loss-of-function mutations in TGFBR1 ⁵²
Multiple familial KA of Witten and Zak	Multiple KAs in childhood, heal spontaneously; overlapping features of Ferguson–Smith and Grzybowski^61,63	Likely autosomal dominant inheritance of an unknown gene⁶³
Muir–Torre syndrome	Characterized by sebaceous neoplasms, KAs and several internal malignancies^60,64	Defective mismatch repair genes (MLH1, MSH2, MSH6) leading to microsatellite instability^59,60

HPV, human papillomavirus.

Table 2. Evidence for treatment modalities of keratoacanthoma
	Treatment	Sample size	Clearance rate	Recurrence rate	Follow-up	Study	Evidence quality^a
Decreasing invasiveness	Excision	84	100%	0%	6–8 weeks	Moss¹⁰¹	B
	Electrodesiccation and curettage	111	100%	3·8%	≥ 2 years	Nedwich¹⁰²	B
	Cryosurgery, electrodesiccation and curettage	90	98%	0%	2 years	Panagiotopoulos¹⁰³	B
	Intralesional methotrexate	73	88%	0%	6–8 weeks	Moss¹⁰¹	B
		69	96%	NR	NR	Smith⁹⁹	B
		60	92%	NR	NR	Seger¹⁰⁴	A
		38	92%	0%	1 month to 7·6 years (average 1·8 years)	Annest¹⁰⁵	B
	Intralesional 5-fluoruracil	53	96%	NR	6–8 weeks	Seger¹⁰⁴	A
	Intralesional bleomycin	6	100%	0%	1–3 months	Sayama¹⁰⁶	C
	MAL photodynamic therapy	4	100%	0%	4 years	Farias⁹⁸	C
	Topical 5-fluoruracil	41	98%	NR	6–8 weeks	Seger¹⁰⁴	A
	Topical imiquimod	24	100%	NR	6–8 weeks	Seger¹⁰⁴	B
	Topical imiquimod	4	100%	0%	6 months to 4 years (average 19 months)	Jeon⁹⁷	C
	Watchful waiting	18	78%	0%	9 months to 8 years	Griffiths⁹³	B

MAL, methyl aminolaevulinate; NR, not reported. ^aEvidence was evaluated using the grading criteria described by Robinson et al.¹⁵⁵

Table 3. Cell-cycle regulators
Cell-cycle regulator	Role	KA vs. SCC	Subjects examined	Clinical relevance
TP53	Critical tumour suppressor gene involved in the activation of apoptosis. Mutated in close to all skin carcinomas due to UV radiation^18,122	cSCCs frequently harbour UV radiation-induced TP53 mutations while KAs have infrequent p53 aberrations and, when present, they correlate with age of the lesion and associated atypia^122–125	30 squamoid lesions	Frequently mutated in cSCC.¹²² Squamoid lesions without TP53 mutations are more likely to exhibit histopathological features similar to those of KA¹²⁶
NOTCH	Direct target of p53; plays key role in epidermal keratinocyte differentiation	Loss-of-function mutations in NOTCH1 and NOTCH2 found in 75% of cSCCs^107,108	20 cSCCs	Study by Mascitti et al. looking at a patient with eruptive KAs of Grzybowski found no genetic alterations in NOTCH1, NOTCH 2 or TP53 ⁵¹
Zmiz1, also known as retinoic acid-induced protein 17¹⁰⁹	Encoded protein regulates activity of various transcription factors, including Smad3/4 and p53	Premature truncation of the protein led to the formation of KAs in the mouse model⁷⁶	33 Zmiz1 mutated mice vs. 42 control mice	Rogers et al. found that skin tumours induced by Zmiz1 expression were consistent with diagnosis of KA rather than cSCC¹¹⁰
TPL2	Upstream regulator of MAPK, NF-κB and p38^111,112	NF-κB activity promotes development of KA in mice; Lee et al. found that TPL2 is required for KA-like cSCC maintenance and that it is overexpressed in cSCC and KA compared with normal skin¹¹¹	105 cSCCs, 64 KAs and 8 samples of normal skin	TPL2 is a driver in cSCC and KA development and could be a possible drug target for treatment of cSCC and KA¹¹¹
TGF-β	Widespread effects on tissue regeneration, homeostasis and immune cell regulation	Loss-of-function mutations in TGFBR1 are causative in cases of Ferguson–Smith disease, also known as multiple self-healing squamous epithelioma¹¹³	Genetic information from 143 members of 22 families with multiple self-healing squamous epitheliomas	Recipients of fresolimumab, a TGF-β inhibitor, may develop unanticipated cutaneous toxicities, primarily KAs, as an adverse effect¹¹⁷
SOX2	Stem cell transcription factor	Drives cSCC formation and is absent in normal human epidermis; SOX2 deletion in cSCC induces tumour regression and decreases the tumour's ability to propagate¹¹⁸	39 cSCCs and 8 samples of normal skin	SOX2 is expressed in postnatal dermal papillae of hair follicles; KA could be of follicular origin¹¹⁹
p27	Inhibits cyclin-dependent kinases	Expressed in regressing KAs but not in expanding KAs¹³	5 expanding and 15 regressing KAs	Could be considered as a target to involute proliferating or stable KAs
p63	Supports proliferation by suppressing expression of cyclin-dependent kinase inhibitor 1 and members of the NOTCH pathway⁵⁶	Diffuse expression in cSCC while in KA expression is confined to basaloid cells^{56, 127}	16 KAs and 17 cSCCs	Expressed in a unique pattern in skin and other types of stratified epithelia making it a possible target for future inhibitor therapies⁴⁹
Ki-67	Functions in the cell cycle, with roles such as maintaining integrity of mitotic chromosomes	Expression in cSCC more than KA¹¹⁴	35 KAs and 36 cSCCs	cSCC with widespread expression of Ki-67 denotes a greater potential for growth compared with KA¹¹⁴
HIPK2	Regulates cell cycle and apoptosis, also directs transcription by inducing p53-mediated apoptosis	KA more than cSCC¹¹⁵	43 KAs and 90 cSCCs	As a tumour suppressor and apoptosis mediator, HIPK2 may be a future target for activating involution of KAs¹¹⁵
p50	Induces proinflammatory cytokines	KA more than cSCC¹¹⁶	20 KAs and 20 cSCCs	Greater expression of p50 likely contributes to the more active immune response surrounding KAs^116,121
Cortactin	Strengthens cadherin-dependent cell–cell junctions	KA more than cSCC¹¹⁶	20 KAs and 20 cSCCs	Greater cortactin expression in KA likely represents lower metastatic potential due to stronger intercellular connections¹²⁰

KA, keratoacanthoma; MAPK, mitogen-activated protein kinase; NF, nuclear factor; cSCC, cutaneous squamous cell carcinoma; TGF, transforming growth factor; TPL2, tumour progression locus 2; UV, ultraviolet.

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A Clinical and Biological Review of Keratoacanthoma

Abstract and Introduction

Abstract

Tables

Tables

Tables

References

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Authors and Disclosures

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