Whether keratoacanthoma is a variant of cutaneous squamous cell carcinoma cSCC or is a separate entity has been the subject of debate for many years.
Keratoacanthoma primarily differs from cSCC in its natural history of rapid growth, which is often followed by regression. Histopathologists differ widely in their approach to the diagnostic classification of keratoacanthoma; one study found that the ratio of SCC diagnoses to keratoacanthoma diagnoses ranged from 2.5:1 to 139:1.
Pathological diagnosis of keratoacanthoma depends on a combination of clinical history and microscopic appearance. There can be significant overlap between the histological features of keratoacanthomas and cSCCs, which at least partly accounts for the variation in pathological diagnosis. It is well documented that there are keratoacanthomas with cSCC components, keratoacanthoma-like cSCCs, and keratoacanthomas with malignant transformation.
From a genetic perspective, recent studies have shown that the MAP3K8 (TPL2) oncogene may be a driver of the development of both keratoacanthoma and cSCC.
Taking all current evidence together, the editors of the 2018 edition of the World Health Organization (WHO) classification of skin tumours consider keratoacanthoma to be a variant of cSCC, rather than a separate entity.
Overview of evidence (non-systematic literature review)
Histological diagnosis of keratoacanthoma
Keratoacanthoma may occur at sites of trauma of various types, such as following burns and previous radiotherapy, at skin-graft donor sites and at the sites of previous skin cancer excision. These lesions also occur in immunocompromised individuals (see Organ transplantation and other conditions associated with prolonged immunosuppression), and with the rare Muir-Torre syndrome, which may be associated with a variety of sebaceous tumours and various visceral neoplasms.
A keratoacanthoma has a symmetrical crateriform architecture with overhanging shoulders, relatively limited nuclear atypia and a predominance of cells with abundant pale glassy cytoplasm within the lesion. Occasionally perineural invasion may be apparent, most often in facial lesions. Such a finding warrants close follow-up to help rule out cSCC.
On partial biopsies it can be difficult to distinguish between keratoacanthoma and invasive cSCC. A history of rapid growth and a characteristic architecture help establish the diagnosis of keratoacanthoma, but occasionally, a clear distinction from a cSCC is not possible.
In a phase of regression, prominent scarring is characteristically noted beneath an irregular shallow epidermal depression and commonly, apoptosis (individual keratinocyte death) may be observed. Frequently, overlap features occur with those of cSCC and a clear histological distinction may not always be possible.
These aspects need to be considered in planning clinical management, particularly as these lesions may be locally destructive, and early diagnosis and treatment can avoid the need for more extensive therapy.
Clinical correlation is required to distinguish between keratoacanthoma and invasive cutaneous squamous cell carcinoma in cases where partial biopsy does not enable a definitive diagnosis.
- Carr RA, Houghton JP. Histopathologists' approach to keratoacanthoma: a multisite survey of regional variation in Great Britain and Ireland. J Clin Pathol 2014 Jul;67(7):637-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24764326.
- Misago N, Inoue T, Koba S, Narisawa Y. Keratoacanthoma and other types of squamous cell carcinoma with crateriform architecture: classification and identification. J Dermatol 2013 Jun;40(6):443-52 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23414327.
- Lee JH, Lee JH, Lee SH, Do SI, Cho SD, Forslund O, et al. TPL2 Is an Oncogenic Driver in Keratocanthoma and Squamous Cell Carcinoma. Cancer Res 2016 Nov 15;76(22):6712-6722 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/27503930.
- Elder DE, Massi D, Scolyer RA, Willemze R. WHO Classification of Skin Tumours. 4th edn. Lyon, France: International Agency for Research on Cancer; 2018.
- LeBoit PE, Burg G, Weedon D, Sarasin A (Eds). Pathology and Genetics of Skin Tumours: WHO Classification of Tumours (3rd edn, Vol 6). Lyon, France: International Agency for Research on Cancer, World Health Organization; 2006 [cited 2018 Oct 12] Available from: http://publications.iarc.fr/Book-And-Report-Series/Who-Iarc-Classification-Of-Tumours/Pathology-And-Genetics-Of-Skin-Tumours-2005.