Keratinocyte cancer

7.5 Post-surgical care and interpretation of the pathology report

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Clinical practice guidelines for keratinocyte cancer > 7.5 Post-surgical care and interpretation of the pathology report


Ascertaining if surgical treatment for keratinocyte cancer (KC) has been adequate is crucial, because this will determine the follow-up regimen, and whether to offer further surgery, adjuvant treatment or other additional treatment (see Follow-up after treatment for keratinocyte cancer).

Overview of evidence (non-systematic literature review)


Usually the histopathology will be consistent with expectations based either on clinical diagnosis or biopsy prior to surgery. Certain histologic features, anatomical sites or other factors indicate a high likelihood of recurrence, despite appropriate surgical treatment (Table 5).

Occasionally the histopathology may be different from pre-surgical expectations, usually worse. The finding of features associated with higher risk than expected after excision may alter a clinician’s determination of optimal treatment for the individual, leading to further surgery or adjuvant therapy.

Table 5. Tumour-specific factors associated with recurrence of keratinocyte cancers Table 5 KC guideline Tumour specific factors BBC cSCC.png

Perineural invasion

Perineural invasion (PNI) occurs in both cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC).[1] Note that previously traumatised specimens from either biopsy or previous excision can show ’re-excision PNI’, a benign reparative process.[2][3][4] The finding of PNI should be discussed with the pathologist.

See: Biopsy considerations and the biopsy report.

Perineural invasion of cutaneous squamous cell carcinoma

Perineural invasion complicates the course of up to 5% of all patients with SCC.[5] Perineural invasion appears to be more common in lesions located in the head and neck. Perineural invasion may be incidental or clinical.

Symptoms that suggest clinical PNI include tingling, pain, paraesthesia, formication (a sensation like ants crawling under the skin), reduced sensation or reduced motor function. Preoperative magnetic resonance imaging (MRI) should be undertaken for patients with clinical evidence of PNI.[6] Clinicians should ask specifically for MRI neurography for large-nerve PNI. However, MRI does not always detect nerve involvement. Intraoperative margin control with frozen section can be used to attempt complete excision. Appropriate management usually involves review at a multidisciplinary head and neck clinic, appropriate investigations, and surgical resection of the involved nerve, which is usually followed by adjuvant radiotherapy (RT). Radiotherapy can be palliative or curative in intent, and generally covers the entire course of the nerve back to its origin from the central nervous system. Alternatively, RT alone to the course of the nerve may be appropriate for patients who are unable to undergo, or refuse, further surgery. Treatment invariably causes major morbidity.

Incidental PNI implies early asymptomatic disease and is recognised on pathological examination of the specimen. No further intervention is indicated if complete pathological examination shows that the perineural spread is limited to small dermal nerve fibres < 0.1mm,[7] and the tumour has been completely excised with a wide resection margin.[8]

Features associated with poorer prognosis are involvement of nerves lying deeper than the dermis or outside the tumour (any size), involvement of dermal nerves measuring ≥0.1mm in diameter, multiple nerves, clinical/radiological involvement of nerves or symptomatic nerve involvement.[9]

It may be appropriate to discuss the patient’s pathology with a radiation oncologist.

The presence of PNI is reported to pose a very high risk of both local recurrence (which may be as high as 50%) and distant spread (35% risk).[10] The addition of radiotherapy to the site of the primary lesion and the course of the involved nerve in an uncontrolled series was associated with a very high rate of local control and reduced rate of metastasis.[11] It should be managed by wide surgical excision, where possible, and consultation with the radiation oncologist to arrange or consider postoperative RT. Where appropriate, the patient should be referred to a multidisciplinary head and neck clinic.

Re-excision PNI may not be clinically significant.[12] Perineural invasion is often seen in keratoacanthomas, but may not be clinically significant.[12]

Perineural invasion of basal cell carcinoma

The significance of PNI in BCC is unknown. It may make the tumour more likely to recur, but does not appear to carry the same poor prognosis as true PNI in cSCC. Features that are considered poor prognostic factors in PNI of cSCC might also be indicators of increased risk of recurrence in BCC.

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Low-risk tumours in favourable sites

The findings of case series conducted before 2000 to establish surgical excision margins for BCC[13] and for cSCC[14] report that a 4mm margin is required for most nodular BCCs and well-differentiated cSCCs to ensure complete histologic clearance.

However, excision of a BCC or cSCC with a positive margin does not imply the persistence of tumour or inevitable recurrence. This is a conundrum. The original papers analysed the margins after excision rather than the recurrence rate. While a margin of 4mm may excise most tumours, it may be excessive in some and insufficient in others. Electrodessication and curettage, and some non-surgical treatments, have a high cure rate in favourable histologic subtypes despite most likely resulting in a positive margin.

Incomplete deep margins need a more considered approach. The consequences of recurrence must be considered. If recurrence will impact significantly on quality of life then further management is required.

Tumours with high-risk features or at unfavourable sites

Tumours that are incompletely excised or have close margins probably need wider excision or Mohs micrographic surgery (MMS) when they are at unfavourable anatomical sites (e.g. eyelids, nose, lips, ears, and genitalia) or when high-risk features are present (e.g. more aggressive subtypes of BCC and SCC).

For most patients with high-risk tumours or KCs in unfavourable sites, achieving appropriate tumour clearance (according to the appropriate definition for the tumour subtype) is mandatory. The recurrence rate is not necessarily trivial and can be disastrous.[15] Surgery should be performed by someone who has the expertise to adequately excise and reconstruct the area.

If, on balance, wider excision would benefit the patient’s quality of life, including psychological wellbeing, it may be prudent to re-treat such tumours. Proper clearance should be obtained in high-risk tumours and in unfavourable anatomic sites (see Site below). Other treatment modalities, such as RT, should only be considered after management by surgeons well trained in excision and reconstruction of these difficult tumours.

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Location can also be extremely important in determining how aggressive a treatment needs to be. Certain sites seem to have a high propensity for recurrence, possible because the contours lead to inadequate excision in the first place. However, when considering treatment, one must consider the consequences of recurrence in those locations as unique structures can be at high risk. Such areas are the ears, eyebrows, eyelids, nose, nasolabial areas, lips, genitalia and, on occasion, hands and feet. Hair-bearing areas must also be carefully considered due to the propensity of some of these tumours to recur due to spread down pilosebaceous units.

When excision margins are either close or involve structures that are difficult to reconstruct (e.g. eyelids, facial nerve) the surgeon must consider whether that structure should be sacrificed and reconstructed. Mohs micrographic surgery can be considered or another nonsurgical treatment modality should be added. Well performed surgery by an expert in that particular field achieving good surgical margins and having an expertly performed surgical repair is far preferable to poor surgery, inadequate margins and postoperative RT. In particular, the addition of RT may help prevent the sacrifice of difficult-to-replace structures such as the facial nerve. Radiotherapy of an eyelid is not appropriate after inadequate surgery.


Tumours in fields of previous radiotherapy may also need wider margins, as do those in immunocompromised individuals.

Cutaneous SCCs in younger patients, particularly on the face (especially lips), can have a short and aggressive course, and are more at risk of developing subsequent cancers.[16]


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

In all cases patients, should be educated on the possibility of recurrence, its possible manifestation, and the likelihood of additional tumours elsewhere.

See: Follow-up after treatment for keratinocyte cancer.

Practice Points

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PP 7.5.1. When perineural invasion is reported by the pathologist, the clinician should discuss this finding with the pathologist to ascertain its likely clinical significance.

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PP 7.5.2. Preoperative magnetic resonance imaging should be considered for patients with clinical evidence of perineural involvement.

Key point(s)

When an incomplete margin is reported on an excision specimen, the clinician should discuss the implications of potential recurrence with the patient. If recurrence would significantly compromise the person’s quality of life, further treatment should be offered.

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  1. Adams A, Whiteman D, Panizza B, De'Ambrosis B. Can risk of recurrence of NMSC with perineural invasion be predicted?: A prospective analysis of the PNI registry. 2018 May 19-22; Gold Coast, Queensland, Australia. 2018 Dermcoll, 51st Annual Scientific Meeting: Wiley; 2018. p. Abstract Number: 97. Available from:
  2. Dunn M, Morgan MB, Beer TW, Chen KT, Acker SM. Histologic mimics of perineural invasion. J Cutan Pathol 2009 Sep;36(9):937-42 Available from:
  3. Beer TW. Reexcision perineural invasion: a mimic of malignancy. Am J Dermatopathol 2006 Oct;28(5):423-5 Available from:
  4. Beer TW. Reparative perineural hyperplasia: a series of 10 cases. Am J Dermatopathol 2009 Feb;31(1):50-2 Available from:
  5. Roth JJ, Granick MS. Squamous cell and adnexal carcinomas of the skin. Clin Plast Surg 1997 Oct;24(4):687-703 Available from:
  6. Galloway TJ, Morris CG, Mancuso AA, Amdur RJ, Mendenhall WM. Impact of radiographic findings on prognosis for skin carcinoma with clinical perineural invasion. Cancer 2005 Mar 15;103(6):1254-7 Available from:
  7. Gupta A, Veness M, De'Ambrosis B, Selva D, Huilgol SC. Management of squamous cell and basal cell carcinomas of the head and neck with perineural invasion. Australas J Dermatol 2016 Feb;57(1):3-13 Available from:
  8. Carter JB, Johnson MM, Chua TL, Karia PS, Schmults CD. Outcomes of primary cutaneous squamous cell carcinoma with perineural invasion: an 11-year cohort study. JAMA Dermatol 2013 Jan;149(1):35-41 Available from:
  9. 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].
  10. Goepfert H, Dichtel WJ, Medina JE, Lindberg RD, Luna MD. Perineural invasion in squamous cell skin carcinoma of the head and neck. Am J Surg 1984 Oct;148(4):542-7 Available from:
  11. Cottel WI. Perineural invasion by squamous-cell carcinoma. J Dermatol Surg Oncol 1982 Jul;8(7):589-600 Available from:
  12. 12.0 12.1 Godbolt AM, Sullivan JJ, Weedon D. Keratoacanthoma with perineural invasion: a report of 40 cases. Australas J Dermatol 2001 Aug;42(3):168-71 Available from:
  13. Wolf DJ, Zitelli JA. Surgical margins for basal cell carcinoma. Arch Dermatol 1987 Mar;123(3):340-4 Available from:
  14. Brodland DG, Zitelli JA. Surgical margins for excision of primary cutaneous squamous cell carcinoma. J Am Acad Dermatol 1992 Aug;27(2 Pt 1):241-8 Available from:
  15. Codazzi D, Van Der Velden J, Carminati M, Bruschi S, Bocchiotti MA, Di Serio C, et al. Positive compared with negative margins in a single-centre retrospective study on 3957 consecutive excisions of basal cell carcinomas. Associated risk factors and preferred surgical management. J Plast Surg Hand Surg 2014 Feb;48(1):38-43 Available from:
  16. 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:

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