- 1 Background
- 2 Overview of evidence (non-systematic literature review)
- 2.1 Stage
- 2.2 Perineural invasion
- 2.3 Histology and growth rate
- 2.4 Anatomical site of primary
- 2.5 Cutaneous squamous cell carcinomas unrelated to UV irradiation
- 2.6 General and skin-specific comorbidities
- 2.7 Host factors
- 3 Practice Points
- 4 References
Unless stated otherwise, tumour stage is according to the American Joint Committee on Cancer (AJCC)cancer staging manual 8th edition and Union for International Cancer Control (UICC) TNM classification of malignant tumours 8th edition.
The biological potential of early cutaneous squamous cell carcinoma (cSCC) and the risk of metastasis can be predicted based on tumour-specific factors, site and tumour disposition.
Current evidence has identified nine broad categories of prognostic indicators (Table 4.3). Accurate weighting of individual prognostic factors has been complicated by the fact that individual participants in reported case series typically had multiple factors.
Table 4.3. Factors associated with recurrence poorer prognosis of cutaneous squamous cell carcinoma
|Stage (see: Appendix A. TNM staging)
Regional spread (lymph nodes)*
Higher risk for poorly differentiated subtype
Higher risk with findings suggesting rapid growth or greater spread (e.g. palpable thickness, diffuse infiltration and induration with poor demarcation of tumour edges, tenderness and inflammation)
Higher risk for ear, lip
Number of skin cancers (higher risk for multiple lesions)
Higher risk for recurrent/persistent lesions
Higher risk for inadequately treated lesions
Higher risk for non-UV-induced lesions e.g. infection with oncogenic HPV subtypes, exposure to arsenic
Higher risk in presence of immunosuppression, skin-related comorbidities (e.g scleroderma, xeroderma pigmentosa)
*The current TMN system does not take into account risk associated with local metastatic spread (lymphatic or perineural).
#Cutaneous SCCs arising from aetiological factors other than ordinary sun exposure in otherwise healthy people (e.g. infection with oncogenic HPV subtypes, arsenic ingestion).
Overview of evidence (non-systematic literature review)
Staging is a fundamental tool in cancer clinical research conducted with the aim of improving outcomes for patients. The application of the generic TNM staging system is a poor fit for cSCC, as a large proportion are classified as T1N0M0. However, until a more sophisticated universal staging system for cSCC is developed, it remains an interim instrument.
T stage (size and depth of invasion of the primary tumour)
The size of a primary cSCC is three-dimensional. The maximum clinical diameter is the most reproducible measurement, but also a reasonable surrogate for depth of invasion and/or tumour burden. The rare exception is cSCC in situ (Bowen’s diseasecSCC in situ (also known as intra-epidermal SCC)), which can grow to a large area and even become exophytic, yet remain in situ. A size greater than 2cm in greatest dimension remains a significant cut-off point for poorer prognosis.
The T4 staging category identifies advanced (beyond subcutis) clinical invasion and has the poorest prognosis (Table 4.4). However, lesser intermediate depths of invasion are still not directly accounted for in the T1–3 staging system.
For T1 and T2 tumours, limited evidence suggests that increasing depth of invasion of the dermis or tumour thickness measured histologically is associated with increasing incidence of nodal metastases.
Other clinical parameters useful for assessing depth of invasion include:
- palpable thickness
- diffuse infiltration and induration with poor demarcation of tumour edges
- tenderness and inflammation.
All these clinical parameters are validated (though crude) signs of a more aggressive tumour.
Table 4.4. 5-year disease-free survival for primary cutaneous squamous cell carcinoma according to T stage
|T-stage||5-year disease-free survival|
- local recurrence 3%
- nodal metastasis 4%
- mortality 1.5–3%.
N stage (nodal status)
Recurrence in a nodal basin after standard lymphadenectomy (radical node dissection) almost invariably leads to the development of distant disease. Treatment is difficult and the patient should be referred to a specialistMedical practitioners who through training, experience and peer opinion specialise in the management of keratinocyte cancers unit for management and offered participation in a clinical trial, if possible.
- the number of nodes containing metastases on histopathology
- the presence of extranodal spread, manifested clinically by gross fixation of node(s).
In modern oncology practice, the criteria for determining risk of regional relapse and indication for adjuvant therapies are based on the surgical pathology findings and on preoperative attempts at predicting this on clinical assessment and imaging using computed tomography (CT).Table 4.5. 5-year survival for cutaneous squamous cell carcinoma according to presence of nodal metastasis
|Nodal involvement||5-year survival|
|Number of involved nodes|
M stage (metastasis)Once haematogenous metastases have occurred, the cSCC is no longer curable. The most common site of metastases is the lung. Recent and ongoing clinical trials evaluating therapies directed against the programmed cell death 1 receptor (PDCD1) in patients with metastatic cSSC have reported very promising findings (see: Cutaneous squamous cell carcinoma: metastatic disease and systemic therapies).
Perineural invasion is identified in two ways, each with different clinical significance and prognosis:
- on histopathological examination of a primary cSCC (usually involving a minor dermal nerve)
- symptomatic presentation with either neuralgic-type pain, progressive paraesthesia or anaesthesia.
Perineural invasion identified on histopathological examination
The incidental finding of PNI (usually a minor dermal nerve) reported on histopathological examination of a primary cSCC is the earliest indication in an asymptomatic patient.
While this occurrence is relatively uncommon (2–14%), its frequency is unknown in the absence of controlled pathology studies.The incidental finding of PNI appears to confer a poorer prognosis. Based on current data, it may require a more aggressive management approach such as wider excision, Mohs micrographic surgery, post-operative radiotherapy or, at the least, an opinion from an appropriate specialist.
Perineural invasion identified following symptomatic presentation
The second, later, indication of PNI is symptomatic presentation as either of the following:
- neuralgic-type pain, or progressive paraesthesia/anaesthesia. These symptoms may arise due to involvement of various divisions of the sensory trigeminal nerve.
- a palpable lump along the course of a nerve (e.g. near the supraorbital or infraorbital notch or mental foramen)
- paresis of facial muscles due to involvement of the facial nerve.
These symptoms and signs most often occur after initial, seemingly successful, treatment of the primary cSCC.
Not uncommonly, the primary cSCC is no longer traceable by any means.Magnetic resonance imaging (MRI) is the imaging modality of choice in diagnosing or assessing PNI in a symptomatic patient. However, a normal MRI does not preclude PNI. Clinically diagnosed PNI carries a poor prognosis.
Locally recurrent, persistent or inadequately treated primary cutaneous squamous cell carcinoma
Locally recurrent cSCC and persistent cSCC are considered to be clinical expressions of the same category of ‘uncontrolled cSCC at its primary site’, as their pathogenesis, prognosis and treatment are similar.
Locally recurrent cSCC is clinically manifest by regrowth of a lump or ulcer at the primary site after clinical treatment that initially seemed adequate (e.g. complete excision) or clearance of the primary tumour (e.g. after radiotherapy).
The term ‘persistent cSCC’ signifies either of the following:
- high histopathological risk of residual cSCC reported by a pathologist following incomplete excision
- clinical observation of macroscopic tumour that has not completely resolved after treatment.
Histology and growth rate
Cutaneous SCCs are graded histologically as well-differentiated, moderately differentiated or poorly differentiated. Growth patterns that are poorly differentiated and more infiltrative are associated with an increasing risk of recurrence and metastases.Spindle cell variants are particularly aggressive. Identification of perineural and/or lymphatic infiltration carries a poorer prognosis.
Anatomical site of primaryCutaneous SCCs of the scalp, ear or vermilion border of the lower lip, genitalia, perineum and more recently, temple have been shown to be associated with poorer prognosis and to have a higher recurrence and subsequent nodal metastasis rate than cSCCs elsewhere.
Cutaneous SCCs arising in a chronic scar include:
- chronic osteomyelitis sinus
- burns scars (‘Marjolins ulcer)
- skin damaged by medical radiotherapy or other radioactive sources
The observed latent period of scar presence and cSCC development is in the order of 10–30 years. This group of tumours carries a particularly poor prognosis.
General and skin-specific comorbidities
Skin comorbidity can be site-specific and related to areas of poor healing, most typically below the knee and pretibial region. In older patients this is heightened by a higher incidence of peripheral vascular disease, varicosities and oedema. The optimal treatment is surgical excision and skin grafting or other flap repair, which can demand several days of strict bed rest in hospital. Patients with asymptomatic lesions can be reluctant to undertake the required bed rest, and bed rest may compound comorbidities such as arthritis, thrombosis and diabetes in the elderly.
Younger adults (especially women) with facial skin cancers may seek unrealistic guarantees of good cosmetic results from treatment, potentially compromising appropriate and timely cancer treatment. In all these instances it is essential to provide careful patient counselling and education on the prognosis and results of treatment.
Immunosuppression both increases the risk of developing cSCCs and results in a poorer prognosis (see: Organ transplantation and other conditions associated with immunosuppression).
PP 6.2.1. Incompletely excised cutaneous squamous cell carcinomas should be prophylactically re-excised or treated with radiotherapy.
PP 6.2.2. If a cutaneous squamous cell carcinoma recurs in a nodal basin after standard lymphadenectomy, the patient should be offered referral to a specialistMedical practitioners who through training, experience and peer opinion specialise in the management of keratinocyte cancers advanced skin cancer clinic that can provide access to a multidisciplinary team (including surgeons, radiation oncologists, medical oncologists and allied health professionals) and the opportunity to participate in clinical trials.
- Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, Washington MK, Gershenwald JE, Compton CC, Hess KR, et al. (Eds.). AJCC Cancer Staging Manual (8th edition). Springer International Publishing: American Joint Commission on Cancer; 2017 [cited 2016 Dec 28].
- Brierley JD, Gospodarowicz MK, Wittekind C. TNM Classification of Malignant Tumours, 8th Edition. Wiley-Blackwell; 2017.
- Breuninger H, Black B, Rassner G. Microstaging of squamous cell carcinomas. Am J Clin Pathol 1990 Nov;94(5):624-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/2239827.
- Goudie D. Non-melanoma skin cancer In: WD Foulkes, SV Hodgson. Inherited Susceptibility to Cancer: Clinical, Predictive and Ethical Perspectives Cambridge, UK: Cambridge University Press; 1998.
- Ashby MA, Smith J, Ainslie J, McEwan L. Treatment of nonmelanoma skin cancer at a large Australian center. Cancer 1989 May 1;63(9):1863-71 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/2702595.
- 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.
- Friedman HI, Cooper PH, Wanebo HJ. Prognostic and therapeutic use of microstaging of cutaneous squamous cell carcinoma of the trunk and extremities. Cancer 1985 Sep 1;56(5):1099-105 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/4016700.
- 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.
- 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.
- 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.
- Karia PS, Morgan FC, Ruiz ES, Schmults CD. Clinical and Incidental Perineural Invasion of Cutaneous Squamous Cell Carcinoma: A Systematic Review and Pooled Analysis of Outcomes Data. JAMA Dermatol 2017 Aug 1;153(8):781-788 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/28678985.
- Migden MR, Rischin D, Schmults CD, Guminski A, Hauschild A, Lewis KD, et al. PD-1 Blockade with Cemiplimab in Advanced Cutaneous Squamous-Cell Carcinoma. N Engl J Med 2018 Jul 26;379(4):341-351 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/29863979.
- McCord MW, Mendenhall WM, Parsons JT, Amdur RJ, Stringer SP, Cassisi NJ, et al. Skin cancer of the head and neck with clinical perineural invasion. Int J Radiat Oncol Biol Phys 2000 Apr 1;47(1):89-93 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10758309.
- McCord MW, Mendenhall WM, Parsons JT, Flowers FP. Skin cancer of the head and neck with incidental microscopic perineural invasion. Int J Radiat Oncol Biol Phys 1999 Feb 1;43(3):591-5 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10078643.
- Morris JG, Joffe R. Perineural spread of cutaneous basal and squamous cell carcinomas. The clinical appearance of spread into the trigeminal and facial nerves. Arch Neurol 1983 Jul;40(7):424-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/6860179.
- Rintala A. Surgical therapy of basal cell carcinoma. Correlation of the macroscopic and microscopic control of excision with recurrence. Scand J Plast Reconstr Surg 1971;5(2):87-90 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/5136061.