# Radiation Oncology/Skin/Nonmelanoma

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Non-Melanoma Skin Cancers

## Epidemiology

* US incidence is estimated at 3.5 million lesions in 2.2 million patients
* Multi-Institutional; 2010 (1996-2006) PMID 20231499 -- "Incidence estimate of nonmelanoma skin cancer in the United States, 2006." (Rogers HW, Arch Dermatol. 2010 Mar;146(3):283-7.)
** Claims analysis. Multiiple US government data sets
** Outcome: Medicare fee-for-service procedures 2.05 million in 2006 Age-adjusted procedure rate 6,075/100,000. Increase by 16% from 2002 to 2006. Total number of non-melanoma skin cancers estimated 3.5 million lesions in 2.2 million patients
** Conclusion: Much higher overall totals of skin cancer diagnoses than previous estimates

## Staging

AJCC 7th Edition (2009)
Note: Beginning with the 7th edition, Merkel cell carcinoma is no longer included in this staging classification and was given its own staging. SCC of Eyelid receives new staging system (previously excluded).
Primary Tumor:
* Tis - in situ
* T1 - 2 cm or less in greatest dimension with fewer than 2 high risk features
* T2 - >2 cm; or tumor any size with 2 or more high risk features
* T3 - invasion of maxilla, mandible, orbit, or temporal bone
* T4 - invasion of skeleton or perineural invasion of skull base
    High risk features:
   * depth/invasion: > 2 mm thickness, Clark level >= IV, perineural invasion
   * location: primary site ear, primary site hair-bearing lip
   * differentiation: poorly differentiated or undifferentiated
Regional Lymph Nodes:
* N0 - No regional lymph nodes metastasis
* N1 - Single ipsilateral lymph node, <= 3cm in greatest dimension
* N2
** N2a - Single ipsilateral lymph node, 3-6 cm in greatest dimension
** N2b - Multiple ipsilateral lymph nodes, <= 6cm in greatest dimension
** N2c - Bilateral or contralateral lymph nodes, <= 6cm in greatest dimension
* N3 - Lymph node(s) >6 cm in greatest dimension
Distant Metastases:
* M0 - no
* M1 - yes
Stage Grouping:
* I - T1 N0
* II - T2 N0
* III - T3 N0, T1-3 N1
* IV - N2-N3, or T4, or M1
Changes from 6th Edition:
* T-stage incorporates high risk features (e.g. grade, site) for T1 vs T2
* No longer size cutoff of 5 cm
* T3 and T4 reclassified
* N-stage now N1/N2abc/N3 (same as H&N cancer)
* Change in Stage Grouping

### Older staging systems

AJCC 6th Edition (2002)
Note: this staging system included Merkel cell carcinomas (was changed beginning with the 7th edition)
Primary Tumor:
* Tis - in situ
* T1 - 2 cm or less in greatest dimension
* T2 - >2 cm and <= 5 cm
* T3 - more than 5 cm in greatest dimension
* T4 - invades deep extradermal structures (i.e. cartilage, muscle, bone)
Regional Lymph Nodes:
* N0 - no
* N1 - yes
Distant Metastases:
* M0 - no
* M1 - yes
Stage Grouping:
* I - T1 N0
* II - T2-3 N0
* III - T4 N0, N1
* IV - M1

## Surgery vs RT

* Gustave Roussy (1982-1988) -- surgery vs RT
** Randomized. 347 patients, primary BCC of the face, <4 cm, confirmed by bx. Arm 1) Surgical resection, at least 2 mm margin vs Arm 2) RT using 3 available techniquest: interstitial brachytherapy Ir-192 65-70 Gy over 5 days (55%), superficial contact RT 50 kV 36/2-40/2 over 2 weeks (33%), orthovoltage RT 8-250 kV 60 Gy in 2-4 Gy/fx 3x/week (12%).
** 1997 PMID 9218740 -- "Basal cell carcinoma of the face: surgery or radiotherapy? Results of a randomized study." (Avril MF, Br J Cancer. 1997;76(1):100-6.)
*** Outcome: 4-year local failure surgery 0.7% vs RT 7.5% (SS), by modality interstitial BT 9% vs contact RT 7% vs orthovoltage RT 5%.
*** Toxicity: Cosmesis significantly better after surgery than RT, good result according to patients surgery 87% vs RT 69% (SS). Dyspigmentation and telangiectasia in 65%
*** Conclusion: Surgery preferred to RT in smaller BCC of the face

## Cutaneous SCC
### Prognosis

* Tubingen, Germany; 2008 (1990-2001) PMID 18617440 -- "Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study." (Brantsch KD, Lancet Oncol. 2008 Aug;9(8):713-20. Epub 2008 Jul 9.)
** Retrospective. 615 white patients, surgery. Median size 1.5cm, median thickness 3mm, desmoplasia 8%. Median F/U 3.6 years
** Outcome: LR 3% (75% within 1st year), DM 4%.
** Predictors: Local recurrence desmoplastic 24% vs. non-desmoplastic 1% (SS); thickness <6 mm 3% vs. >6 mm 12% (SS). Distant mets <2 mm thick no mets; 2-6 mm thick 4% mets, >6 mm thick 16% mets
** Conclusion: Tumors >6 mm thick associated with high risk of local recurrence and DM; desmoplastic growth independent risk for local recurrence
** Editorial (PMID 18672208): Should change staging from size to thickness

### Lymph Node Staging

* Drexel, Philadelphia; 2006 PMID 17083582 -- "Sentinel lymph node biopsy in cutaneous squamous cell carcinoma: a systematic review of the English literature." (Ross AS, Dermatol Surg. 2006 Nov;32(11):1309-21.)
** Literature review. 607 patients with anogenital SCC and 84 patients with nonanogenital SCC analyzed.
** Outcome: Identification rate 96-97%. False negative rate by CLND 4-5% (most of these from early studies when combination radioisotope and blue dye was not used)
** Toxicity: Rare
** Conclusion: SLNB accurately diagnoses subclinical LN mets, with few false negatives and low morbidity

## RT alone

* U. Florida, 1987
** PMID 3597161 — "T2-T4 carcinoma of the skin of the head and neck treated with radical irradiation." Mendenhall WM et al. Int J Radiat Oncol Biol Phys. 1987 Jul;13(7):975-81.
** PMID 8360054 (T4 tumors)
** Poor results for tumors with bone, cartilage, or nerve invasion. Only 50% LC with XRT alone.
* Washington University, 2001 (1966-97) - PMID 11697321 — "Radiotherapy for epithelial skin cancer." Locke J et al. Int J Radiat Oncol Biol Phys. 2001 Nov 1;51(3):748-55.
** Retrospective. 468 pts treated with RT alone.
** Control rate for basal cell was 95% (86% if recurrent), 89% for squamous cell (68% if recurrent). For basal cell, improved control with larger fraction size (>2 Gy). No apparent dose response for SCCa.
** Guidelines: Treat at 2.5 Gy/fx, 4 days/week. Basal cell - 40 Gy (< 1 cm), 45-50 (1-3), 60 Gy (>3). Squamous cell - 45-50 Gy (<1 cm), 60 Gy (> 1cm).

## Perineural invasion

* Differentiate microscopic perineural invasion from clinical perineural invasion (symptoms of formication, numbness, etc.)1965-
* LN+ in 15% (Garcia-Serra et al., see below)
* U. Florida
** 2003 PMID 14648861 (1965-99) — "Carcinoma of the skin with perineural invasion." Garica-Serra A et al. Head Neck. 2003 Dec;25(12):1027-33.
*** Retrospective. 135 pts treated with RT who had PNI (59 microscopic, 76 clinical). >80% were squamous cell, ~20% basal cell. 15% with clinical LN+.
*** Microscopic PNI - 93% treated with RT postoperatively. 56% were recurrent, 29% with positive margins. Median RT dose 60 Gy in 32 fx. Most (88%) treated with once daily RT. 50% treated with local fields only, 50% with large fields to base of skull. Elective nodal RT in 18%.
**** Results - 5-yr LC 87%, LRC 72%. Initial failure - local 14%, regional 14%, distant 3%. 19% of squamous cell carcinomas recurred in regional LNs.
*** Clinical PNI - 53% treated with post-operative RT, 45% treated with definitive RT. 69% recurrent, 55% (22 of 40 who had resection) with positive margins. Median RT dose 70 Gy in 39 fx (40% treated twice-daily). 12% treated with local fields only, ~2/3 treated with large fields to base of skull, 22% with extended fields. Elective nodal RT in 44%.
**** Results - 5-yr LC 55%, LRC 50%. Initial failure - local 38%, regional 5%, distant 0%. 9% of SCC recurred in regional LNs.
*** Lower local control in those with clinical PNI. **Low rate of successful surgical salvage (12-30%). **Symptomatic improvement in neuropathy in only 7% after treatment.
*** High rate of nodal failure in the microscopic PNI cohort (of whom only 18% received RT to the nodal areas) versus only 10% failure in the clinical PNI group (44% received nodal RT).
*** Conclusion: Nodal RT should be considered in pts with 1) SCC with perineural invasion, 2) clinical PNI with any histology.
** 2012 PMID 22185685 (1965-2007) -- "Skin carcinoma of the head and neck with perineural invasion." (Balamucki CJ, Am J Otolaryngol. 2012 Jul;33(4):447-54.)
*** 216 pts.
*** Clinical PNI: 5-yr LC 54%, LRC 51%, FFDM 94%.
*** Incidental PNI: 5-yr LC 80%, LRC 70%, FFDM 90%.

### Hypofractionation

* France - PMID 2710943 (Abatucci et al, 1989)
** 675 pts. 10.2 Gy x 3 fractions given once a week. Superficial X-ray. 96% local control. Excellent cosmetic outcome.

## RT of the Pinna

* Approximately 5-20% of all skin cancers
* Skin is thin, SQ fat is sparse, and muscle layer is discontinuous, which makes surgery challenging but also increases risk of cartilage necrosis during RT
* Tumor infiltration may be deep due to ear location within embryonic fusion planes
* Anatomical irregularities make dosimetry difficult
* Historically, with superficial and orthovoltage machines in 1950's, RT was considered contraindicated near bone/cartilage
* Recent literature using modern techniques and fractionation shows RT to be safe and effective
* Dose absorption of cartilage is comparable to other soft tissues
* Local control of squamous cell and basal cell appears comparable
* Consider lower Gy/fx (2-2.5) for large tumors, recurrences, and long life expectancy for good cosmesis; shorter schedules for elderly, debilitated patients with small tumors.
* Milan, 2005 (Italy) PMID 15941445 -- "Radiotherapy of skin carcinomas of the pinna: a study of 115 lesions in 108 patients." (Caccialanza M, Int J Dermatol. 2005 Jun;44(6):513-7.)
** Retrospective. 115 cases (99 basal, 16 squamous) tumors of the pinna. Some large (18 T2, 7 T3). RT kilovoltage. Total dose 45-70 Gy, fraction size 2.5-5 Gy, given 2-3 fractions per week. Mean F/U 2.4 years
** 5-year LC: 78%; relapse 8% in-field, 3% marginal. All relapses basal cell
** Cosmesis: Good/acceptable (no signs/mild atrophy or dyschromia) 88%; no long term complications observed
** Conclusion: High remission without damaging cartilage
* Princess Margaret, 2000 (1982-1993) PMID 10802373 -- "Results of radiotherapy for epithelial skin cancer of the pinna: the Princess Margaret Hospital experience, 1982-1993." (Silva JJ, Int J Radiat Oncol Biol Phys. 2000 May 1;47(2):451-9.)
** Retrospective. 334 lesions treated (201 basal, 122 squamous, 11 mixed). RT orthovoltage (278) or magavoltage electrons (39) prescribed to 90%/95%/100% isodose. Most common doses 35/5 (field size 5 cm2), 45/10 (field size 10.5 cm2), 50-65/20-30 (field size 81 cm2). Median F/U 3.3 years
** 5-year LC: 79%; relapse in-field 14%, marginal 2%, LN 1%. Predictors for failure tumor size >2cm, and low BED (<54 Gy using a/b=14). 5-year CSS: 96%
** Toxicity: Grade 4 was 7.3%; Predictors tumor size (T2 worst-why?), field size (>5 cm2), and fraction size (>4 Gy)
** Conclusion: RT effective including megavoltage electrons, large tumor and low BED not good; fraction size <4Gy better to reduce necrosis, esp in large fields.
* Kingston, 1996 (Canada)(1982-1991) PMID 8985024 -- "Necrosis following radiotherapy for carcinoma of the pinna." (Hayter CR, Int J Radiat Oncol Biol Phys. 1996 Dec 1;36(5):1033-7.).
** Retrospective. 138 curative treatments for (70 basal, 62 squamous, or 6 mixed) tumors of the pinna. RT orthovoltage (79) or megavoltage electrons (59). Most common dose 35/5. Total dose range 17.5-64 Gy. Median F/U 4.8 years
** 5-year LC: 93%
** 5-year necrosis (any skin ulceration): 13%; most healed with conservative management, only 2% required surgery
** Predictors for necrosis: daily fraction size >6 Gy (16% vs. 2%), treatment time <5 days (18% vs. 3%)
** Conclusion: RT for pinna effective, but protracted schedule should be used for minimal risk of necrosis
* Birmingham, 1993 (UK) PMID 8305363 -- "Cartilage: the 'F'-factor fallacy." (Atherton P, Clin Oncol (R Coll Radiol). 1993;5(6):391-2.)
** Data based on tissue composition and mass absorption coefficients, supporting use of superficial X-rays compared to historical electrons

## Chemotherapy

Imiquimod cream 5% (Aldara)
* Germany; 2007 PMID 17610993 -- "A phase III, randomized, open label study to evaluate the safety and efficacy of imiquimod 5% cream applied thrice weekly for 8 and 12 weeks in the treatment of low-risk nodular basal cell carcinoma." (Eigentler TK, J Am Acad Dermatol. 2007 Oct;57(4):616-21.)
** Randomized. 90/102 patients with nodular basal cell. Arm 1) imiquimod TIW x8 weeks vs. Arm 2) imiquimod TIW x12 weeks. Both followed by excsion
** Outcome: No difference between arms. Clinical clearance 78%, histological clearance 64%. Residual tumor in 17% of clinical CR
** Toxicity: minor/moderate local inflammation in 92%
** Conclusion: No difference between arms. Modest activity, due to 17% residual tumor after clinical CR, recommend excision for all

## See also

Skin pathology links:
* "Immunohistochemistry of the Skin" - No PMID - Tacha D et al. Lab Med 2003 Apr;34(4):311-6.