Keratinocyte cancer

7.7 Protocol to manage rapidly growing tumours

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Background[edit source]

Rapidly growing tumours are more likely to quickly enlarge to a size of more than 2cm diameter.[1]

Basal cell carcinoma (BCC) is generally regarded as a slow-growing tumour. Features of BCCs reported to be associated with rapid growth include those at the periocular site (particularly when recurrent, large, or in men).[2]

Cutaneous squamous cell carcinomas (cSCCs) in younger patients, particularly cSCCs of the face (especially lips), can have a short and aggressive course, and are more at risk of developing subsequent cancers.[3]

Systematic review evidence[edit source]

What should be the protocol to manage rapidly growing tumours?

A systematic review was undertaken to answer this clinical question.The search strategy, inclusion and exclusion criteria, and quality assessment are described in detail in the Technical report.

A total of nine studies reported relevant outcomes for cSCCs or BCCs with perineural invasion (PNI), or for poorly differentiated cSCCs, after different treatments.

These included one retrospective cohort intervention study[4] and eight retrospective case series.[5][6][7][8][9][10][11][12]

One case series[5] had a moderate risk of bias. All other studies had a high risk of bias.

Treatment modalities included radiotherapy, chemotherapy, excision and Mohs micrographic surgery (MMS).

Reported outcomes included recurrence, local control, local treatment failure, distant metastasis, recurrence-free survival and disease-free survival.

No study specifically investigated the management of rapidly growing tumours. The studies provided only indirect evidence to answer this clinical question.

A small Australian retrospective case series reported higher recurrence-free survival numbers for high-risk tumours treated with MMS plus radiotherapy or MMS, compared with excision alone or excision plus radiotherapy.[9]

Two other Australian case series[5][6] reported high cure rates with surgery and radiotherapy, although lower if PNI was symptomatic.

Another Australian case series[10] and a US retrospective cohort study[11] reported a possible survival benefit with extensive subcranial and cranial resection including nerve for patients with symptomatic PNI.

An Australian retrospective case series[12] found that most failures occurred in patients with gross PNI. Those with microscopic extensive PNI also received a benefit with radiotherapy, but those with microscopic focal PNI did well with or without irradiation.

A US cohort study[4] found a possible benefit with MMS and radiotherapy in head and neck cSCC, compared with surgery and RT.

A US retrospective case series in 131 patients with 155 cSCCs[7] found a benefit with RT in both incidental and symptomatic PNI. A Dutch retrospective case series[8] found that metastasis-free survival at 5 years was significantly higher in well-differentiated cSCCs (70%) compared with moderately differentiated (51%) and poorly differentiated cSCCs (26%; p=0.012).

Evidence summary and recommendations[edit source]

Evidence summary Level References

BCCs and cSCCs with PNI had higher recurrence rates with excision or excision with RT than MMS or MMS plus RT.

Recurrence-free survival

For tumours with PNI, recurrence-free survival rates were 58.6% after surgical excision in one study, and 62- 71% after surgery plus adjuvant RT in two studies.

For tumours with microscopic focal PNI, recurrence-free survival was significantly higher after RT (94%) than observation (25%).

However, there was no significant difference between radiotherapy and observation for tumours with microscopic extensive PNI.

III-3, IV [9], [5], [6], [10], [12]
Cancer-specific mortality

Among various observational studies, reported disease-free survival was highest after postoperative RT plus chemotherapy, followed by surgery plus RT (87%), MMS plus RT (84%) postoperative RT (76%), RT (58–74%), not MMS plus RT (68%), observation (40–62%), skull base/subcranial surgery (50–53.6%) and RT and palliative therapies (0%), and was only found to be significantly higher for MMS plus RT, RT and subcranial and skull base therapies than not MMS and RT, observation and palliative therapies.

Cancer-specific mortality ranged from 10% to 53% after surgical excision.

III-3, IV [5], [7], [8], [10], [6], [4], [12], [11]
Locoregional control

Locoregional control was highest after postoperative RT plus chemotherapy (100%), then treatment other than MMS plus RT (92%), RT alone (84%), postoperative RT (77%), RT plus chemotherapy (62%) and postoperative RT (50%) for poorly differentiated cSCCs and cSCCs with PNI.

III-3, IV [4], [5], [7]
Distal metastasis

Most metastasis for mostly cSCCs with PNI or poor differentiation occurred after surgical excision (26%) or excision plus RT (12.5%), whereas distant metastasis-free survival at 2–5 years of follow-up was 100% for tumours treated with observation or RT.

III-3, IV [8], [9], [12]
Evidence-based recommendationQuestion mark transparent.png Grade
EBR 7.7.1. For patients with cutaneous squamous cell carcinomas with features associated with poor prognosis, wider surgical margin should be planned, adjuvant radiotherapy should be considered, and regular follow-up for locoregional or distant recurrence should be provided.
Evidence-based recommendationQuestion mark transparent.png Grade
EBR 7.7.2. For tumours with perineural invasion, the combination of surgery and radiotherapy is recommended when a nerve with diameter >0.1mm is involved.
Evidence-based recommendationQuestion mark transparent.png Grade
EBR 7.7.3. Cutaneous squamous cell carcinomas with high-risk features should be managed with wider surgical margins, adjuvant radiotherapy, and regular follow-up for locoregional or distant recurrence.

Practice pointQuestion mark transparent.png

PP 7.7.1. For patients with cutaneous squamous cell carcinoma, consider referral to a specialist or multidisciplinary team if there are any risk factors for poor prognosis, such as:

  • size >2 cm in diameter
  • tumour depth > 4 mm
  • recurrent lesion
  • high-risk anatomic location
  • perineural invasion or lymphovascular invasion
  • poorly differentiated subtype
  • immunosuppression.

Practice pointQuestion mark transparent.png

PP 7.7.2. Patients with rapidly growing squamous cell carcinomas should be referred timely for assessment for specialised therapies or combination therapies.

Notes on the recommendations[edit source]

Follow-up of patients after treatment is individually tailored according to patient factors, tumour factors, anatomic site and the perceived adequacy of treatment.

The available evidence supports an individualised approach in the management of incompletely resected cSCCs at low-risk sites with low-risk histopathology. High-risk tumours in high risk sites warrant further surgery, possibly including a wider excision or excision with a margin control technique.

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Appendices[edit source]

Jutta's magnifying glass icon.png PICO question SX4 View Evidence statement form SX4Evidence statement form SX5 View Systematic review report SX4Systematic review report SX5

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References[edit source]

  1. Alam M, Ratner D. Cutaneous squamous-cell carcinoma. N Engl J Med 2001 Mar 29;344(13):975-83 Available from:
  2. Tan E, Lin FP, Sheck LH, Salmon PJ, Ng SG. Growth of periocular basal cell carcinomas. Br J Dermatol 2015 Apr;172(4):1002-7 Available from:
  3. Ong EL, Goldacre R, Hoang U, Sinclair R, Goldacre M. Subsequent primary malignancies in patients with nonmelanoma skin cancer in England: a national record-linkage study. Cancer Epidemiol Biomarkers Prev 2014 Mar;23(3):490-8 Available from:
  4. 4.0 4.1 4.2 4.3 Kropp L, Balamucki CJ, Morris CG, Kirwan J, Cognetta AB, Stoer CB, et al. Mohs resection and postoperative radiotherapy for head and neck cancers with incidental perineural invasion. Am J Otolaryngol 2013 Sep;34(5):373-7 Available from:
  5. 5.0 5.1 5.2 5.3 5.4 5.5 Jackson JE, Dickie GJ, Wiltshire KL, Keller J, Tripcony L, Poulsen MG, et al. Radiotherapy for perineural invasion in cutaneous head and neck carcinomas: toward a risk-adapted treatment approach. Head Neck 2009 May;31(5):604-10 Available from:
  6. 6.0 6.1 6.2 6.3 Warren TA, Panizza B, Porceddu SV, Gandhi M, Patel P, Wood M, et al. Outcomes after surgery and postoperative radiotherapy for perineural spread of head and neck cutaneous squamous cell carcinoma. Head Neck 2016 Jun;38(6):824-31 Available from:
  7. 7.0 7.1 7.2 7.3 Balamucki CJ, Mancuso AA, Amdur RJ, Kirwan JM, Morris CG, Flowers FP, et al. Skin carcinoma of the head and neck with perineural invasion. Am J Otolaryngol 2012 Jul;33(4):447-54 Available from:
  8. 8.0 8.1 8.2 8.3 Brinkman JN, Hajder E, van der Holt B, Den Bakker MA, Hovius SE, Mureau MA. The Effect of Differentiation Grade of Cutaneous Squamous Cell Carcinoma on Excision Margins, Local Recurrence, Metastasis, and Patient Survival: A Retrospective Follow-Up Study. Ann Plast Surg 2015 Sep;75(3):323-6 Available from:
  9. 9.0 9.1 9.2 9.3 DeAmbrosis K, De'Ambrosis B. Nonmelanoma skin cancer with perineural invasion: report of outcomes of a case series. Dermatol Surg 2010;36(1):133-8 Available from:
  10. 10.0 10.1 10.2 10.3 Panizza B, Solares CA, Redmond M, Parmar P, O'Rourke P. Surgical resection for clinical perineural invasion from cutaneous squamous cell carcinoma of the head and neck. Head Neck 2012 Nov;34(11):1622-7 Available from:
  11. 11.0 11.1 11.2 Solares CA, Lee K, Parmar P, O'Rourke P, Panizza B. Epidemiology of clinical perineural invasion in cutaneous squamous cell carcinoma of the head and neck. Otolaryngol Head Neck Surg 2012 May;146(5):746-51 Available from:
  12. 12.0 12.1 12.2 12.3 12.4 Sapir E, Tolpadi A, McHugh J, Samuels SE, Elalfy E, Spector M, et al. Skin cancer of the head and neck with gross or microscopic perineural involvement: Patterns of failure. Radiother Oncol 2016 Jul;120(1):81-6 Available from:

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