Keratinocyte cancer

8.4 Radiotherapy for regional (nodal) metastatic disease (non-distant)

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Clinical practice guidelines for keratinocyte cancer > 8.4 Radiotherapy for regional (nodal) metastatic disease (non-distant)


Guideline contents > [[Guidelines:Keratinocyte carcinoma/Radiotherapy for regional metastatic disease|]]

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Prof Gerald Fogarty, Howard Liu, Cancer Council Australia Keratinocyte Cancers Guideline Working Party. Guidelines:Keratinocyte carcinoma/Radiotherapy for regional metastatic disease . In: Clinical practice guidelines for keratinocyte cancer. Sydney: Cancer Council Australia. [Version URL: https://wiki.cancer.org.au/australiawiki/index.php?oldid=208359, cited 2023 Mar 30]. Available from: https://wiki.cancer.org.au/australia/Guidelines:Keratinocyte_carcinoma.


Last modified:
25 November 2019 20:48:35




Unless stated otherwise, tumour stage is according to edition American Joint Committee on Cancer (AJCC) cancer staging manual 8th edition [1] and Union for International Cancer Control (UICC) TNM classification of malignant tumours 8th edition.[2]

Background[edit source]

Radiotherapy (RT) has been used in the treatment of metastasis to lymph nodes, lymph channels (in-transit disease in dermal lymphatics) or via perineural invasion (PNI).

Lymph node metastases[edit source]

Nodal disease is associated with poor prognosis in patients with cutaneous squamous cell carcinoma (cSCC) or basal cell carcinoma (BCC). The prevalence of nodal disease is higher for cSCC than for BCC. Radiotherapy increases regional control rates in both cSCC and BCC.[3][4][5]

Basal cell carcinoma[edit source]

Basal cell carcinomas rarely metastasise to lymph nodes. Most commonly, the patient has a long history of multiple recurrences, extending over many years, or an uncontrolled primary lesion. Other risk factors have been reported, including a history of prior radiotherapy, a large primary tumour, and head and neck site.[6][7]

Cutaneous squamous cell carcinoma[edit source]

The incidence of lymph node metastases from cSCC occurring in UV-exposed skin is very low (less than 5%) but may be considerably higher in certain situations, including when cSCC occurs:[8][9][10]

  • at sites of mucosal–squamous cell junction, including lip, anus and vulva
  • at head and neck sites
  • in a patient with immunosuppression[11]
  • within chronically inflamed/irritated lesions.

Tumour-related factors associated with regional recurrence of cSCC include:[9][12]

  • size – lesions greater than 2cm in diameter are twice as likely as smaller lesions to develop regional recurrence
  • site – lesions located on the ear and lip have a higher rate of local recurrence than cSCC elsewhere
  • grade – poorly differentiated cSCCs have double the metastasis rate of well-differentiated lesions
  • thickness – cSCCs >6mm in thickness recur three times more commonly than thinner lesions
  • recurrence – recurrent cSCC is twice as likely to metastasise than primary cSCC
  • PNI – PNI is the strongest predictor of regional recurrence (up to 50% risk).

The time to development of regional disease is short, usually within 12–24 months after initial treatment of the primary lesion.

Spread of cSCC to regional lymph nodes is uncommon, but is associated with metastasis to distant sites and a poorer outcome.[8][9] Survival after lymph node metastasis is poor, with only one-third of patients surviving 5 years. Half of these patients die of uncontrolled regional disease without distant metastases.[13] For patients with regional spread from cSCC of the lip, survival rates may be twice as high.[8]

Any clinical suspicion of node metastases warrants referral to a multidisciplinary head and neck or skin clinic and further staging investigations. The diagnosis of nodal metastases should be confirmed by fine needle aspiration cytology (FNAC). Occasionally, image-guided FNAC or core biopsy may be necessary. Open incision biopsy of a suspicious lymph node for diagnosis is not advised because it potentially increases the risk of dermal lymphatic involvement, compromises further management, reduces the efficacy of subsequent lymphadenectomy and usually requires an avoidable general anaesthetic.[14]

In Australia the most common malignancy of the parotid gland is metastatic cSCC to intraparotid nodes from a cutaneous malignancy.[15] In many cases these patients have had multiple skin cancers of the head and neck treated and the index lesion may not be known. In this situation, metastatic cSCC arising from a mucosal site needs to be excluded in the first instance.

An Australian retrospective series of patients with metastatic cSCC in the parotid gland observed a low rate (< 15%) of pathological involvement of cervical nodes among patients with clinically negative cervical nodes,[16] comparable to the low rate reported in a US study.[17]

For cervical lymph nodes, most authorities recommend a selective neck dissection.[18] The extent of the lymphadenectomy is determined by the site of the primary lesion, the involved node(s) and the extent of the disease. Generally, the facial nerve, accessory nerve and sternomastoid muscle can be preserved, which reduces the morbidity of the procedure.[18] Occasionally lymph node metastases occur at unusual sites, including the epitrochlear region and popliteal fossa.[19][20]

Perineural invasion[edit source]

Perineural invasion is uncommon. In the past, it was thought to spread as skip lesions but new data suggest this observation was due to specimen processing and that PNI is actually contiguous.[21]

Perineural invasion may be incidental or, more rarely, symptomatic. The vast majority occur in head and neck cutaneous cSCC. Incidental PNI implies early spread, is asymptomatic and is recognised only after complete pathological examination of the specimen.

Perineural invasion is associated with a poor prognosis. Cohort studies reported that perineural invasion involving nerves with a diameter 0.1mm or greater 0.1mm was associated with increased risk of disease-specific mortality. [22][23]

Symptomatic perineural spread shows established spread of cSCC away from the primary cSCC site and carries a poorer prognosis.[24][25]

In patients with PNI of cSCC or BCC, magnetic resonance imaging (MRI) should be considered to map macroscopic extent for further therapy.[26] Intracranial macroscopic disease on MRI carries a poor prognosis and a palliative approach is suitable. Previously PNI was thought to predispose to increased nodal involvement but new data do not support this.[27]

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Overview of evidence (non-systematic literature review)[edit source]

Radiotherapy for lymph node metastasis of basal cell carcinoma[edit source]

Post-lymphadenectomy radiotherapy (BCC)[edit source]

Regional control can usually be achieved with lymphadenectomy. Postoperative RT may be indicated for patients with a high risk of recurrence (i.e. extensive disease, multiple involved nodes, extracapsular extension, or close/involved surgical margins).[28][29]

Radiotherapy as an alternative to surgery[edit source]

Radiotherapy alone is a reasonable alternative to surgery for patients who are poor candidates for surgery or the those requiring palliation.

Radiotherapy for lymph node metastasis of squamous cell carcinoma[edit source]

Post-lymphadenectomy radiotherapy (SCC)[edit source]

The treatment of metastatic disease to lymph nodes is primarily surgical with or without postoperative RT.[8][9][14][30][31]

Postoperative RT is generally recommended for patients with a high risk of recurrence, including those with any of the following:[30][31][32][33][34][35][36][37][38][39][40][41]

  • parotid node metastases
  • ≥ two nodes positive in the neck
  • ≥ three nodes positive in the axilla or groin
  • ≥3cm node
  • significant extra nodal extension
  • close or involved surgical margins
  • skin infiltration
  • major nerve involvement (e.g. facial nerve)
  • recurrent nodal metastases, salvaged surgically
  • node metastases in unusual sites (posterior triangle neck, supraclavicular fossa, occipital nodes from primary cutaneous cSCC of posterior scalp or upper trunk, epitrochlear nodes or popliteal nodes)
  • nodal metastases accompanied by local relapse
  • immunosuppression.

Some centres use one modality to manage parotid node metastases of cSCC:[42] either irradiation[18][43] or surgical lymphadenectomy [37] of the clinically negative ipsilateral neck, but not both. An Australian retrospective consecutive case series study reported that the addition of tissue equivalent bolus to adjuvant RT for intraparotid metastatic head and neck did not reduce local skin failure in the parotid region.[44]

Some,[39][40][41] but not all[19] studies observed worse outcomes for parotid node metastasis in immunosuppressed patients.

The role of postoperative chemoradiotherapy for high-risk cSCC of the head and neck has been resolved by a prospective randomised controlled trial (RCT) phase III conducted by the Trans-Tasman Radiation Oncology Group (TROG).[45] The investigators reported that postoperative RT achieved high rates of locoregional control, and that this was not significantly improved by the addition of postoperative concurrent chemoradiotherapy.[45]

In an observational cohort study in patients with parotid-area lymph node metastases, the combination of surgery and postoperative RT improved locoregional control, compared with RT alone.[46]

Whether postoperative RT increases survival is controversial, based on low-level evidence. A retrospective multicentre study reported adjuvant RT was associated with improved overall survival in patients with cSCC of the head and neck, and improved disease-free survival in a subset of patients with PNI and regional disease.[47] An Australian retrospective study of patients with neck node-positive cSCC of the head and neck reported adjuvant RT was associated with improved disease-free survival and overall survival, compared with surgery alone.[48]

Postoperative RT for cSCC of the groin and axilla increases locoregional control.[49][19] Modern RT techniques, such as volumetric modulated arc therapy, achieves better dosimetry than three-dimensional conformal RT for regionally metastatic cSCC of groin and axilla, and can be used to assist in reducing significant treatment-related adverse events.[50]

Curative radiotherapy as an alternative to lymphadenectomy for nodal metastases of squamous cell carcinoma[edit source]

If lymphadenectomy is not possible in a patient with nodal metastases of cSCC because the patient is unfit for surgery or declines surgery, curative radiotherapy alone for is indicated.[51]

Salvage surgery is sometimes possible if complete or durable control is not achieved with radiotherapy alone.

Palliative radiotherapy[edit source]

Palliative radiotherapy is appropriate for inoperable, advanced regional metastases to treat pain, stave off skin ulceration, and reduce bleeding. It is unlikely to prolong survival.[52]

Radiotherapy for dermal lymphatic spread (in-transit metastases) of keratinocyte cancers[edit source]

Dermal lymphatic spread (in-transit metastasis) of BCC or cSCC is a very uncommon condition and may be seen in association with regional spread and/or locally recurrent disease.

Wide surgical excision is indicated, followed by adjuvant RT. Further recurrence is not uncommon.[53]

Radiotherapy for perineural invasion of basal cell carcinoma or squamous cell carcinoma[edit source]

A 2009 systematic review comparing surgical monotherapy with surgery plus adjuvant RT in patients with high-risk cutaneous squamous cell carcinoma[54] found no controlled trials. In 74 cases of PNI reported in included observational studies, there was no statistically significant difference in outcomes between groups.[54] Clear surgical margins were associated with better outcomes, while involvement of larger nerves was associated with worse outcomes. The benefit of adjuvant RT could not be determined on the data analysed[54] A 2011 narrative review reached the same conclusion.[55]

For symptomatic PNI, the involved nerve must be treated with RT back to the base of skull.[56]

The use of adjuvant RT following Mohs micrographic surgery in cases with incidental PNI is controversial.[57] Positive margins on PNI are associated with worse survival despite RT.[58] Surgical resection of the involved nerve, which is usually followed by adjuvant RT, can be associated with long term remission.[24][3][59][60][61] Alternatively, high-dose RT with palliative or curative intent covering the entire course of the nerve back to its origin from the central nervous system is acceptable. Relief of symptoms occurs in more than 50% of cases, with variable durability.[25]

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Practice Points[edit source]

Practice pointQuestion mark transparent.png

PP 8.4.1. For patients with extensive disease, such as those with very large nodes, multiple nodes, bilateral nodes and involvement of overlying skin or fixation of nodes, perineural invasion, multimodal treatment is indicated. In these instances, or if any doubt exists on the extent or integration of treatment, preoperative assessment and opinion from a multidisciplinary team is recommended. Involvement of a head and neck surgeon, reconstructive surgeon, dental oncologist, surgical oncologist, radiation oncologist and medical oncologist may be necessary for complex cases.


Practice pointQuestion mark transparent.png

PP 8.4.2. Modern radiotherapy techniques should be considered as the modality of choice for treating the regional lymph node basin, to limit rates of significant adverse events.

Key point(s)

Clinically suspected lymph node metastases of keratinocyte cancer should be confirmed by fine needle aspiration cytology (under radiological guidance, if required). Open surgical biopsy should be avoided.

Key point(s)

Symptoms of perineural invasion should be elicited at the time of patient assessment of cutaneous squamous cell carcinoma, especially in cases of persistent, recurrent or locally advanced lesions. A positive response should prompt referral to a specialist clinic for further investigations, which may include magnetic resonance imaging.

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References[edit source]

  1. ↑ 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].
  2. ↑ Brierley JD, Gospodarowicz MK, Wittekind C. TNM Classification of Malignant Tumours, 8th Edition. Wiley-Blackwell; 2017.
  3. ↑ 3.0 3.1 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: http://www.ncbi.nlm.nih.gov/pubmed/25546817.
  4. ↑ Amoils M, Lee CS, Sunwoo J, Aasi SZ, Hara W, Kim J, et al. Node-positive cutaneous squamous cell carcinoma of the head and neck: Survival, high-risk features, and adjuvant chemoradiotherapy outcomes. Head Neck 2017 May;39(5):881-885 Available from: http://www.ncbi.nlm.nih.gov/pubmed/28252823.
  5. ↑ Teli MA, Khan NA, Darzi MA, Gupta M, Tufail A. Recurrence pattern in squamous cell carcinoma of skin of lower extremities and abdominal wall (Kangri cancer) in Kashmir valley of Indian subcontinent: impact of various treatment modalities. Indian J Dermatol 2009;54(4):342-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/20101335.
  6. ↑ von Domarus H, Stevens PJ. Metastatic basal cell carcinoma. Report of five cases and review of 170 cases in the literature. J Am Acad Dermatol 1984 Jun;10(6):1043-60 Available from: http://www.ncbi.nlm.nih.gov/pubmed/6736323.
  7. ↑ Weedon D, Wall D. Metastatic basal cell carcinoma. Med J Aust 1975 Aug 2;2(5):177-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/1160758.
  8. ↑ 8.0 8.1 8.2 8.3 Ames FC, Hickey RC. Metastasis from squamous cell skin cancer of the extremities. South Med J 1982 Aug;75(8):920-3, 932 Available from: http://www.ncbi.nlm.nih.gov/pubmed/7112196.
  9. ↑ 9.0 9.1 9.2 9.3 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 Available from: http://www.ncbi.nlm.nih.gov/pubmed/1607418.
  10. ↑ Burton KA, Ashack KA, Khachemoune A. Cutaneous Squamous Cell Carcinoma: A Review of High-Risk and Metastatic Disease. Am J Clin Dermatol 2016 Oct;17(5):491-508 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27358187.
  11. ↑ Manyam B, Saxton JP, Reddy CA, et al.. Multidisciplinary Head and Neck Cancer Symposium. 2014; Scottsdale, Arizona.;.
  12. ↑ Brantsch KD, Meisner C, Schönfisch B, Trilling B, Wehner-Caroli J, Röcken M, et al. Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study. Lancet Oncol 2008 Aug;9(8):713-20 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18617440.
  13. ↑ Beydoun N, Graham PH, Browne L. Metastatic Cutaneous Squamous Cell Carcinoma to the Axilla: A Review of Patient Outcomes and Implications for Future Practice. World J Oncol 2012 Oct;3(5):217-226 Available from: http://www.ncbi.nlm.nih.gov/pubmed/29147309.
  14. ↑ 14.0 14.1 McGuirt WF, McCabe BF. Significance of node biopsy before definitive treatment of cervical metastatic carcinoma. Laryngoscope 1978 Apr;88(4):594-7 Available from: http://www.ncbi.nlm.nih.gov/pubmed/642657.
  15. ↑ Coombe RF, Lam AK, O'Neill J. Histopathological evaluation of parotid gland neoplasms in Queensland, Australia. J Laryngol Otol 2016 Jan;130 Suppl 1:S26-31 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26511326.
  16. ↑ Kirke DN, Porceddu S, Wallwork BD, Panizza B, Coman WB. Pathologic occult neck disease in patients with metastatic cutaneous squamous cell carcinoma to the parotid. Otolaryngol Head Neck Surg 2011 Apr;144(4):549-51 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21493233.
  17. ↑ Sweeny L, Zimmerman T, Carroll WR, Schmalbach CE, Day KE, Rosenthal EL. Head and neck cutaneous squamous cell carcinoma requiring parotidectomy: prognostic indicators and treatment selection. Otolaryngol Head Neck Surg 2014 Apr;150(4):610-7 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24474713.
  18. ↑ 18.0 18.1 18.2 Wang JT, Palme CE, Wang AY, Morgan GJ, Gebski V, Veness MJ. In patients with metastatic cutaneous head and neck squamous cell carcinoma to cervical lymph nodes, the extent of neck dissection does not influence outcome. J Laryngol Otol 2013 Jan;127 Suppl 1:S2-7 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23046820.
  19. ↑ 19.0 19.1 19.2 Goh A, Howle J, Hughes M, Veness MJ. Managing patients with cutaneous squamous cell carcinoma metastatic to the axilla or groin lymph nodes. Australas J Dermatol 2010 May;51(2):113-7 Available from: http://www.ncbi.nlm.nih.gov/pubmed/20546217.
  20. ↑ Morcos BB, Hashem S, Al-Ahmad F. Popliteal lymph node dissection for metastatic squamous cell carcinoma: a case report of an uncommon procedure for an uncommon presentation. World J Surg Oncol 2011 Oct 15;9:130 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21999203.
  21. ↑ Panizza B, Warren T. Perineural invasion of head and neck skin cancer: diagnostic and therapeutic implications. Curr Oncol Rep 2013 Apr;15(2):128-33 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23269602.
  22. ↑ 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: http://www.ncbi.nlm.nih.gov/pubmed/23324754.
  23. ↑ Ross AS, Whalen FM, Elenitsas R, Xu X, Troxel AB, Schmults CD. Diameter of involved nerves predicts outcomes in cutaneous squamous cell carcinoma with perineural invasion: an investigator-blinded retrospective cohort study. Dermatol Surg 2009 Dec;35(12):1859-66 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19889009.
  24. ↑ 24.0 24.1 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: http://www.ncbi.nlm.nih.gov/pubmed/22185685.
  25. ↑ 25.0 25.1 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: http://www.ncbi.nlm.nih.gov/pubmed/19132719.
  26. ↑ Veness MJ, Goedjen B, Jambusaria A. Perioperative Management of High Risk Primary Cutaneous Squamous Cell Carcinoma: Role of Radiologic Imaging, Elective Lymph Node Dissection, Sentinel Lymph Node Biopsy, and Adjuvant Radiotherapy. Curr Derm Rep 2013 Jun;Volume 2, Issue 2, pp 77–83.
  27. ↑ 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 Available from: http://www.ncbi.nlm.nih.gov/pubmed/28678985.
  28. ↑ Raszewski RL, Guyuron B. Long-term survival following nodal metastases from basal cell carcinoma. Ann Plast Surg 1990 Feb;24(2):170-5 Available from: http://www.ncbi.nlm.nih.gov/pubmed/2180360.
  29. ↑ Farmer ER, Helwig EB. Metastatic basal cell carcinoma: a clinicopathologic study of seventeen cases. Cancer 1980 Aug 15;46(4):748-57 Available from: http://www.ncbi.nlm.nih.gov/pubmed/7397637.
  30. ↑ 30.0 30.1 Giri PG, Gemer LS. Accelerated fractionation radiation therapy for advanced squamous cell carcinoma of the head and neck. South Med J 1991 Sep;84(9):1103-7 Available from: http://www.ncbi.nlm.nih.gov/pubmed/1891731.
  31. ↑ 31.0 31.1 Khurana VG, Mentis DH, O'Brien CJ, Hurst TL, Stevens GN, Packham NA. Parotid and neck metastases from cutaneous squamous cell carcinoma of the head and neck. Am J Surg 1995 Nov;170(5):446-50 Available from: http://www.ncbi.nlm.nih.gov/pubmed/7485729.
  32. ↑ delCharco JO, Mendenhall WM, Parsons JT, Stringer SP, Cassisi NJ, Mendenhall NP. Carcinoma of the skin metastatic to the parotid area lymph nodes. Head Neck 1998 Aug;20(5):369-73 Available from: http://www.ncbi.nlm.nih.gov/pubmed/9663662.
  33. ↑ Bumpous J. Metastatic cutaneous squamous cell carcinoma to the parotid and cervical lymph nodes: treatment and outcomes. Curr Opin Otolaryngol Head Neck Surg 2009 Apr;17(2):122-5 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19346945.
  34. ↑ Goh RY, Bova R, Fogarty GB. Cutaneous squamous cell carcinoma metastatic to parotid - analysis of prognostic factors and treatment outcome. World J Surg Oncol 2012 Jun 25;10:117 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22731750.
  35. ↑ Ch'ng S, Maitra A, Allison RS, Chaplin JM, Gregor RT, Lea R, et al. Parotid and cervical nodal status predict prognosis for patients with head and neck metastatic cutaneous squamous cell carcinoma. J Surg Oncol 2008 Aug 1;98(2):101-5 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18523982.
  36. ↑ Creighton F, Lin A, Leavitt E, Lin D, Deschler D, Emerick K. Factors affecting survival and locoregional control in head and neck cSCCA with nodal metastasis. Laryngoscope 2018 Aug;128(8):1881-1886 Available from: http://www.ncbi.nlm.nih.gov/pubmed/29266236.
  37. ↑ 37.0 37.1 D'Souza J, Clark J. Management of the neck in metastatic cutaneous squamous cell carcinoma of the head and neck. Curr Opin Otolaryngol Head Neck Surg 2011 Apr;19(2):99-105 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21297477.
  38. ↑ Yilmaz M, Eskiizmir G, Friedman O. Cutaneous squamous cell carcinoma of the head and neck: management of the parotid and neck. Facial Plast Surg Clin North Am 2012 Nov;20(4):473-81 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23084299.
  39. ↑ 39.0 39.1 McDowell LJ, Tan TJ, Bressel M, Estall V, Kleid S, Corry J, et al. Outcomes of cutaneous squamous cell carcinoma of the head and neck with parotid metastases. J Med Imaging Radiat Oncol 2016 Oct;60(5):668-676 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27324298.
  40. ↑ 40.0 40.1 McLaughlin EJ, Miller L, Shin TM, Sobanko JF, Cannady SB, Miller CJ, et al. Rate of regional nodal metastases of cutaneous squamous cell carcinoma in the immunosuppressed patient. Am J Otolaryngol 2017 May;38(3):325-328 Available from: http://www.ncbi.nlm.nih.gov/pubmed/28202188.
  41. ↑ 41.0 41.1 Schmidt C, Martin JM, Khoo E, Plank A, Grigg R. Outcomes of nodal metastatic cutaneous squamous cell carcinoma of the head and neck treated in a regional center. Head Neck 2015 Dec;37(12):1808-15 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24995842.
  42. ↑ Wong WK, Morton RP. Elective management of cervical and parotid lymph nodes in stage N0 cutaneous squamous cell carcinoma of the head and neck: a decision analysis. Eur Arch Otorhinolaryngol 2014 Nov;271(11):3011-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24337900.
  43. ↑ Wray J, Amdur RJ, Morris CG, Werning J, Mendenhall WM. Efficacy of elective nodal irradiation in skin squamous cell carcinoma of the face, ears, and scalp. Radiat Oncol 2015 Sep 21;10:199 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26391010.
  44. ↑ Pramana A, Browne L, Graham PH. Metastatic cutaneous squamous cell carcinoma to parotid nodes: the role of bolus with adjuvant radiotherapy. J Med Imaging Radiat Oncol 2012 Feb;56(1):100-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22339753.
  45. ↑ 45.0 45.1 Porceddu SV, Bressel M, Poulsen MG, Stoneley A, Veness MJ, Kenny LM, et al. Postoperative Concurrent Chemoradiotherapy Versus Postoperative Radiotherapy in High-Risk Cutaneous Squamous Cell Carcinoma of the Head and Neck: The Randomized Phase III TROG 05.01 Trial. J Clin Oncol 2018 May 1;36(13):1275-1283 Available from: http://www.ncbi.nlm.nih.gov/pubmed/29537906.
  46. ↑ Hinerman RW, Indelicato DJ, Amdur RJ, Morris CG, Werning JW, Vaysberg M, et al. Cutaneous squamous cell carcinoma metastatic to parotid-area lymph nodes. Laryngoscope 2008 Nov;118(11):1989-96 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18849863.
  47. ↑ Harris BN, Pipkorn P, Nguyen KNB, Jackson RS, Rao S, Moore MG, et al. Association of Adjuvant Radiation Therapy With Survival in Patients With Advanced Cutaneous Squamous Cell Carcinoma of the Head and Neck. JAMA Otolaryngol Head Neck Surg 2018 Dec 20 Available from: http://www.ncbi.nlm.nih.gov/pubmed/30570645.
  48. ↑ Wang JT, Palme CE, Morgan GJ, Gebski V, Wang AY, Veness MJ. Predictors of outcome in patients with metastatic cutaneous head and neck squamous cell carcinoma involving cervical lymph nodes: Improved survival with the addition of adjuvant radiotherapy. Head Neck 2012 Nov;34(11):1524-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22109745.
  49. ↑ Fogarty GB, Christie D, Spelman LJ, Supranowicz MJ, Sinclair RS.. Can Modern Radiotherapy be used for Extensive Skin Field Cancerisation: An Update on Current Treatment Options. Biomed J Sci &Tech Res 2018;4(1).
  50. ↑ Mattes RD, Curran WJ Jr, Powlis W, Whittington R. A descriptive study of learned food aversions in radiotherapy patients. Physiol Behav 1991 Dec;50(6):1103-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/1798763.
  51. ↑ Herman JM, Pierce LJ, Sandler HM, Griffith KA, Jabbari S, Hiniker SM, et al. Radiotherapy using a water bath in the treatment of Bowen's disease of the digit. Radiother Oncol 2008 Sep;88(3):398-402 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18571754.
  52. ↑ Barnes EA, Breen D, Culleton S, Zhang L, Kamra J, Tsao M, et al. Palliative radiotherapy for non-melanoma skin cancer. Clin Oncol (R Coll Radiol) 2010 Dec;22(10):844-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/20716481.
  53. ↑ Shiu MH, Chu F, Fortner JG. Treatment of regionally advanced epidermoid carcinoma of the extremity and trunk. Surg Gynecol Obstet 1980 Apr;150(4):558-62 Available from: http://www.ncbi.nlm.nih.gov/pubmed/7361247.
  54. ↑ 54.0 54.1 54.2 Jambusaria-Pahlajani A, Miller CJ, Quon H, Smith N, Klein RQ, Schmults CD. Surgical monotherapy versus surgery plus adjuvant radiotherapy in high-risk cutaneous squamous cell carcinoma: a systematic review of outcomes. Dermatol Surg 2009 Apr;35(4):574-85 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19415791.
  55. ↑ Waxweiler W, Sigmon JR, Sheehan DJ. Adjunctive radiotherapy in the treatment of cutaneous squamous cell carcinoma with perineural invasion. J Surg Oncol 2011 Jul 1;104(1):104-5 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21360531.
  56. ↑ Gluck I, Ibrahim M, Popovtzer A, Teknos TN, Chepeha DB, Prince ME, et al. Skin cancer of the head and neck with perineural invasion: defining the clinical target volumes based on the pattern of failure. Int J Radiat Oncol Biol Phys 2009 May 1;74(1):38-46 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18938044.
  57. ↑ Geist DE, Garcia-Moliner M, Fitzek MM, Cho H, Rogers GS. Perineural invasion of cutaneous squamous cell carcinoma and basal cell carcinoma: raising awareness and optimizing management. Dermatol Surg 2008 Dec;34(12):1642-51 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19018830.
  58. ↑ Erkan S, Savundra JM, Wood B, Acharya AN, Rajan GP. Clinical perineural invasion of the trigeminal and facial nerves in cutaneous head and neck squamous cell carcinoma: Outcomes and prognostic implications of multimodality and salvage treatment. Head Neck 2017 Jul;39(7):1280-1286 Available from: http://www.ncbi.nlm.nih.gov/pubmed/28474414.
  59. ↑ Garcia-Serra A, Hinerman RW, Mendenhall WM, Amdur RJ, Morris CG, Williams LS, et al. Carcinoma of the skin with perineural invasion. Head Neck 2003 Dec;25(12):1027-33 Available from: http://www.ncbi.nlm.nih.gov/pubmed/14648861.
  60. ↑ 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 Available from: http://www.ncbi.nlm.nih.gov/pubmed/10078643.
  61. ↑ Williams LS, Mancuso AA, Mendenhall WM. Perineural spread of cutaneous squamous and basal cell carcinoma: CT and MR detection and its impact on patient management and prognosis. Int J Radiat Oncol Biol Phys 2001 Mar 15;49(4):1061-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/11240248.

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Medical practitioners who through training, experience and peer opinion specialise in the management of keratinocyte cancers

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