5.2 Pathology of cutaneous squamous cell carcinoma and related tumours

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Clinical practice guidelines for keratinocyte cancer > 5.2 Pathology of cutaneous squamous cell carcinoma and related tumours


In recent years there has been a growing appreciation that actinic keratosis (AK), bowenoid AK and cutaneous squamous cell carcinoma (cSCC) in situ (Bowen’s diseasecSCC in situ (also known as intra-epidermal SCC)), and invasive cSCC appear to represent a neoplastic continuum. These conditions are all characterised by keratinocyte nuclear atypia, commonly with large, irregular, crowded and hyperchromatic nuclei with cellular disorganisation.

In many cases, AK regresses spontaneously, while uncommonly, it evolves into invasive cSCC.[1][2] Bowen’s diseasecSCC in situ (also known as intra-epidermal SCC), even after many years, may also evolve into invasive cSCC.[3]Back to top

Overview of evidence (non-systematic literature review)

Actinic keratosis

Actinic keratoses are lesions that have epidermal basal layer nuclear atypia with variable hyperkeratosis and parakeratosis, and background dermal solar elastosis.

Actinic keratoses may have several intraepidermal layers of atypical keratinocytes, even approaching full-thickness atypia. The term ‘bowenoid’ has been applied to such keratoses.

Cutaneous squamous cell carcinoma in situ (Bowen’s diseasecSCC in situ (also known as intra-epidermal SCC))

Cutaneous squamous cell carcinoma in situ (Bowen’s diseasecSCC in situ (also known as intra-epidermal SCC)) refers to a erythematous patch or plaque (in sun-exposed or non-sun-exposed skin) with full thickness epidermal nuclear atypia that often extends down and replaces the follicular infundibular epithelium.

Bowen’s diseasecSCC in situ (also known as intra-epidermal SCC), particularly in non-sun-exposed sites, has increasingly been linked with human papillomavirus.

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Stages of the neoplastic continuum

The variations of patterns of in situ keratinocyte atypia may uncommonly evolve into invasive cSCC and can be viewed as cSCC in situ. In practice, the term 'in-situ keratinocyte atypia' is most commonly used with Bowen’s diseasecSCC in situ (also known as intra-epidermal SCC).

Actinic keratosis uncommonly progresses to cSCC in-situ or invasive cSCC.[1][2] In many cases, AKs appear to regress spontaneously.[1]

Squamous cell carcinoma in situ (whether or not arising de novo), which commonly involves follicular structures, may develop into an invasive cSCC, often after many years. The frequency with which this occurs is unknown. When it becomes invasive, the cSCC is usually not well differentiated. Most invasive cSCCs arise in association with AK.[4]

In clinical practice, it is not always easy to distinguish between a thick (acanthotic) AK and a thin invasive cSCC.[5] Tenderness to palpation may be a clue.

A tumour is designated as an invasive cSCC when the cell masses, showing varying degrees of differentiation, are seen lying clearly in the dermis. Adjacent changes of AK of varying severity may be seen, especially when poorly differentiated; the squamous cell dermal masses show apparent loss of the epidermal basement membrane, loss of normal cell polarity and cytological atypia including nuclear pleomorphism. There are often many mitoses, which may frequently be abnormal. The tumour may extend deeply into the dermis as cell masses of varying sizes and shapes and sometimes as single atypical cells. Occasionally, perineural spread may be noted. Better-differentiated tumours, often showing abundant keratin formation, may at times resemble keratoacanthomas. Poorly differentiated tumoursshowing poor expression of products of differentiation (e.g. keratin or desmosomal attachments) or adnexal differentiation may sometimes resemble invasive melanomas, but a distinction can be seen using immunostaining. Cutaneous squamous cell carcinomas stain positive for pan cytokeratin and CK5/6, and negative for S100 and Sox-10.

Factors associated with a greater risk of metastasis of invasive cSCC include (Table 2):

  • greater tumour size and greater depth of the tumour (>6mm)
  • a poor degree of differentiation
  • an infiltrative growth pattern
  • plentiful mitoses, a spindle cell pattern and single cell infiltrative patterns
  • arising in site of burns and scars
  • scalp, ear, vermilion of the lip or genital sites[6][7][8][9]
  • perineural or endolymphatic spread.

These considerations need to be kept in mind when assessing clinical risks and in planning treatment.

Table 2.Tumour-specific factors associated with recurrence of squamous cell carcinoma Table 2 KC guideline Tumour specific factors cSCC.png

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  1. Marks R, Foley P, Goodman G, Hage BH, Selwood TS. Spontaneous remission of solar keratoses: the case for conservative management. Br J Dermatol 1986 Dec;115(6):649-55 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/3801305.
  2. 2.02.1 Dodson JM, DeSpain J, Hewett JE, Clark DP. Malignant potential of actinic keratoses and the controversy over treatment. A patient-oriented perspective. Arch Dermatol 1991 Jul;127(7):1029-31 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/2064402.
  3. Kessler GM, Ackerman AB. Nomenclature for very superficial squamous cell carcinoma of the skin and of the cervix: a critique in historical perspective. Am J Dermatopathol 2006 Dec;28(6):537-45 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17122500.
  4. Cockerell CJ. Histopathology of incipient intraepidermal squamous cell carcinoma ("actinic keratosis"). J Am Acad Dermatol 2000 Jan;42(1 Pt 2):11-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10607351.
  5. Jones RE. Questions to the Editorial Board and other authorities. What is the boundary that separates a thick solar keratosis and a thin squamous cell carcinoma? Am J Dermatopathol 1984 [cited 2018 Oct 12];6(3):301-306.
  6. Rowe DE, Carroll RJ, Day CL Jr. Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection. J Am Acad Dermatol 1992 Jun;26(6):976-90 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/1607418.
  7. Epstein E, Epstein NN, Bragg K, Linden G. Metastases from squamous cell carcinomas of the skin. Arch Dermatol 1968 Mar;97(3):245-51 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/5641327.
  8. Dinehart SM, Pollack SV. Metastases from squamous cell carcinoma of the skin and lip. An analysis of twenty-seven cases. J Am Acad Dermatol 1989 Aug;21(2 Pt 1):241-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/2768574.
  9. Joseph MG, Zulueta WP, Kennedy PJ. Squamous cell carcinoma of the skin of the trunk and limbs: the incidence of metastases and their outcome. Aust N Z J Surg 1992 Sep;62(9):697-701 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/1520151.

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