Japanese Dermatological Association Guidelines: Outlines of Guidelines for Cutaneous Squamous Cell Carcinoma 2020

In consideration of the development of treatment options for squamous cell carcinoma (SCC), the Japanese Skin Cancer Society issued the first guidelines of SCC in 2007 and revised them in 2015. Here, we report the English version of the 2020 edition of the Japanese SCC guidelines. The first half of this article is an overview of SCC including actinic keratosis and Bowen’s disease, and the second half discusses three clinical questions: (i) treatment of actinic keratosis; (ii) determination of the resection margin of the primary lesion; and (iii) treatment of radically incurable cases, as contemporary problems encountered in treating SCC. In these evaluations, all processes were implemented according to the Grading of Recommendations, Assessment, Development, Evaluation system. Also, items of recommendation concerning each clinical question were determined by a multidisciplinary expert panel consisting of dermatologists, plastic/reconstructive surgeons, radiologists, and oncologists through a comprehensive literature search and systematic reviews.


| Concepts and Definitions
Squamous cell carcinoma is a malignant neoplasm differentiating into stratified squamous epithelium (i.e., epidermal keratinocytes).
Squamous cell carcinoma is characterized by differentiation into keratinocytes and shows intercellular bridge formation, 1 keratinization, 1,2 sheet-like proliferation, 1 and keratin expression. 2 Squamous cell carcinoma remaining in the epidermis is called SCC in situ. Typical SCC in situ are Bowen's disease and actinic keratosis (solar keratosis). Actinic keratosis may be excluded from SCC in situ and be regarded as a precancerous lesion 3 or carcinoma precursor. 4

| Epidemiology
In Japan, SCC is the commonest cutaneous malignancy next only to BCC and is increasing with aging of the population. Although there are no clear statistics concerning the incidence of SCC in Japan, 2507 cases were reported during the 5 years from 1987 to 1991.
The incidence is reported to be approximately 2.5/100 000 persons annually, 5 and it is estimated to be approximately 1.5-2-times higher than the incidence of malignant melanoma. 6,7 Also, according to a The incidence of solar keratosis is estimated to be 100-120/year per 100 000 people in Japan, and this means that 100 000 or more people in Japan develop solar keratosis annually. 12 As for the number of SCC patients overseas, more than 69 000 patients with non-melanoma cutaneous cancer were registered in 2007 in the UK (population: 65 million), and the annual number of cases is estimated to exceed 100 000. 13 SCC is also increasing in the USA (population: 327 million), and 9-14% of men and 4-9% of women are considered to develop the disease during their lifetime. 14 There is also a report that one of every four people suffer skin cancer by the age of 70 years, 15 and ultraviolet light is considered responsible in 90% of these cases. 16 According to the Medicare data in the USA, the incidence of non-melanoma cutaneous malignancies per 100 000 people was 6075 in 2006 but increased to 7320 in 2012. 17 However, it must be noted that this figure includes patients with BCC and carcinoma in situ and a considerable number of those with solar keratosis. Also, according to the data in 2012, 3278 of 100 000 people were treated for SCC including carcinoma in situ. 17 Therefore, in the USA, more than 1 million people are diagnosed with SCC including SCC in situ annually with more than 15 000 deaths. 18 Another report estimated that the number of newly diagnosed cases of SCC is 180 000-520 000 annually with 3932-8791 deaths. 19 By race, the incidence of SCC per 100 000 people is estimated to be 7-360/year in whites, 2.6-2.9/year in Asians, and 3/year in blacks. 20 In addition, solar keratosis, which is a precursor lesion of SCC, is the most frequent precancerous A judgment that a majority of wellinformed people would make but a substantial minority would not 2 (weak) against Probably not do it (i.e., suggest not doing) A judgment that a majority of wellinformed people would not make but a substantial minority would make 1 (strong) against Not do it (i.e., recommend not doing) A judgment that most well-informed people would not make TA B L E 2 Strength of recommendation lesion estimated to be affecting more than 40 million people in the USA. 21 Pathogenic factors can be classified into external and host factors. Typical external factors are ultraviolet light, radiation, and chemicals, and ultraviolet light in sunlight, in particular, is considered to be involved in carcinogenesis as it directly damages DNA and causes mutations. When exposed to ultraviolet light, pyrimidine dimers are generated in DNA, and the damage is repaired by the DNA repair mechanisms including nucleotide excision repair. 23 However, if more lesions than can be repaired have been caused in DNA, their repair becomes insufficient, and pyrimidine dimers are considered to persist. This is considered to cause gradual accumulation of many mutations, which leads to carcinogenesis. Chronic inflammation is also considered to be involved in carcinogenesis by increasing oxidative stress as it also directly damages DNA. 24 Host factors include genetic diseases, such as xeroderma pigmentosum, porokeratosis, and epidermodysplasia verruciformis, and immunodeficiency due to treatment for other diseases, such as organ transplantation, is also considered to be a possible factor. For the prevention of SCC, resection of intraepidermal cancer, which serves as the tissue of origin, appropriate treatment, and control of exposure to ultraviolet light, which is an external factor, such as avoiding massive exposure to sunlight are recommended.

| Clinical features
Squamous cell carcinoma occurs frequently in areas exposed to sunlight, such as the face, forehead, scalp, ear, and dorsum of the hand of elderly people, but can also affect other areas and the mucocutaneous junction. 27,28 Generally, SCC occur as slightly elevated reddish or normal skincolored plaques or nodules with hyperkeratotic surface. However, they may show an eroded surface, be ulcerated and crusted or necrosed, or present with a cauliflower-like appearance. 29 Actinic keratosis occurs frequently in light-exposed areas of elderly people, 30  C. Immunohistochemical findings 33,42 Cytokeratin 1 and CK10 are often positive. AE1/AE3 and CK5/6 are also positive in most cases. CK19 is often positive, but CK7 is negative except in only a few cases. Epithelial membrane antigen (EMA) is also positive in many cases. Ber-EP4 is basically negative 43 but is positive in rare cases.  Palpation is performed first for the examination of the presence or absence of lymph node metastasis, but if the judgment by palpation is difficult due to scar or chronic skin ulcer, modalities, such as ultrasonography and CT, are employed. Also, as the presence or absence of perineural infiltration is related to the recurrence, it must be detected before surgery, and the knowledge is useful for the evaluation of the indication for postoperative adjuvant therapies. 50 Exploration for distant metastases is necessary for the evaluation of indications for radical surgery of regional lymph nodes in patients already confirmed to have regional lymph node metastasis, but how much it contributes to the improvement in the outcome is unknown.
Since the occurrence of distant metastasis is very rare in SCC patients without lymph node metastasis, it is unnecessary to perform imaging examinations as a routine for exploration of distant metastases except when it is clinically suspected.

| After treatment
Although there have been no reports that convincingly showed how much imaging examinations after treatment of cutaneous SCC can contribute to the detection of local recurrence, regional lymph node metastasis, or distant metastasis and improvements in the survival rate, careful examination of the primary focus and regional lymph nodes by inspection and palpation to check the presence or absence of recurrence and metastasis is considered important in the high-risk groups as indicated by the report that 95% of local recurrences and metastases occur within 5 years after treatment. Histopathologically, the lesion shows asymmetric exophytic and endophytic proliferation. 51,52 It is differentiated from usual SCC by the following points. First, the tips of the epidermal processes are rounded and bulbous (contrasting with thin and sharp tips of pseudocarcinomatous hyperplasia). 53 Second, the lesion shows expansive/pushing growth rather than infiltrative/destructive growth 51 (progresses by "bulldozing" rather than "stabbing" the surrounding tissues). 54  c. KA The disease concept of KA is controversial, with some considering it to be benign 56,57 and others regarding it as a subtype of SCC. 58 Also, KA has been suggested to be a single entity or to be a term that generally indicates different tumors similar in architecture. [59][60][61][62] Clinically, KA occurs frequently in the head and neck region and face of older people as crater-like nodules containing keratinous plugs in the center, and its periphery seems to be a glossy extension of the normal epidermis.
Histopathologically, the lesion has a crater-like structure with  Since the local recurrence rate was low after Mohs surgery although many high-risk patients were included in the subjects of this study, complete resection is suggested to be most important. As observed above, Mohs surgery has the advantage of a low recurrence rate and is considered to be more useful than usual surgical resection.
However, this technique is complicated, requires special training for acquisition, and requires time and labor for implementation of a series of processes, and it has not gained wide acceptance in Japan because of these disadvantages.

| Resection of distant metastases
In existing reviews (Cochrane Library, Clinical Evidence: Issue 9, Evidence-based Dermatology) and English and Australian  From these results, although there is presently no high-level evidence concerning whether sentinel lymph node biopsy contributes to the survival of SCC patients, it appears reasonable to consider sentinel lymph node biopsy in patients considered to be at a high risk for metastasis despite the absence of abnormality in lymph nodes by physical or imaging examinations, because SCC metastasizes primarily via the lymphatic system, and because exact staging is expected to become more important in the future as novel drugs will also become available for the treatment of SCC.

| Lymph node dissection
Since the therapeutic results of SCC without regional lymph node metastasis are favorable, the presence or absence of lymph node metastasis is suggested to be an important prognostic factor. In  77 Conventionally, in Japan, prophylactic lymph node dissection for SCC has been avoided, in principle, and radical dissection has been performed when evident lymph node metastasis has been confirmed. In some non-randomized controlled studies, comparisons were made between a group that received prophylactic lymph node dissection for SCC of the face (superficial parotidectomy and cervical lymph node dissection) and a group that received tumor resection alone, and the life prognosis was reported to be more favorable in the prophylactic lymph node dissection group, 78 but none of the Western guidelines or reviews mention the benefits of prophylactic lymph node dissection. For these reasons, the clinical significance of prophylactic lymph node dissection for SCC is unclear, and the procedure is basically not recommendable.

| Reconstruction
There are various methods for reconstruction after resection, including epithelialization of the raw surface from the surrounding areas, primary plication, skin grafting, local flap, distant flap, and free flap.
The reconstruction method is determined in consideration of the site, size, and depth of the defect, type of deep tissue, and functional and aesthetic aspects. Generally, an approach called reconstructive ladder devised by Harold Gillies is applied. 79 In the reconstructive ladder, reconstruction is designed by first considering a less invasive simple method, which may be conservative therapy or simple closure, and serially advancing to skin grafting, local flap, regional flap, distant flap, and free flap (Figure 1). 80 Recently, however, a theory called the reconstructive elevator, which is an approach to determine the reconstruction method by attaching more importance to functional and aesthetic aspects than the reconstructive ladder, has become the mainstay. 81 Yet, there has been no randomized control trial (RCT) that compared reconstruction methods, such as simple suture, skin grafting, and skin flaps after surgery, for SCC, and the evidence is mostly case reports.
In Japan, SCC occurs most frequently in the head and neck region (51%), followed by the trunk (9.6%), upper extremity ( 84 Concerning older patients, also, there is a report that skin flap surgery is recommended as a reconstruction method that requires fewer days for postoperative treatments. 85 1.1.9 | Radiation therapy

| Introduction
In many cases, SCC stays in the primary focus, and surgery is standard therapy. However, radical radiation therapy is considered for inoperable cases, cases in which surgery is undesirable from functional and aesthetic viewpoints, cases with perineural infiltration, and locally advanced cases. 86 The results of radiation therapy in early and small SCC are favorable, and local control can be achieved in approximately 90% of the patients, similar to surgery. 87 Close cooperation between dermatologists and radiation oncologists is important for the designing of treatment.

| Postoperative radiation therapy
Postoperative radiation therapy is considered for patients with a positive resection margin or a resection margin near the tumor and those with perineural invasion, bone or nerve infiltration, and recurrence. 88 The radiation dose is generally 50 Gy/25-66 Gy/33 fractions. Since the frequency of lymph node metastasis is low, the usefulness of prophylactic irradiation of the lymph node region has not been established, but lymph nodes are included in the irradiation area in patients positive for lymph node metastasis. The effectiveness of the combination of chemotherapy is still under evaluation.
In a retrospective study, the recurrence-free period was prolonged by concomitant administration of a platinum preparation in patients with two or more positive lymph nodes, a positive resection margin, and extranodal infiltration. 89 Skin graŌing

| Radical radiation therapy using special radiations
Particle-beam radiation therapy is used for the treatment of malignant melanoma but not SCC.

| Palliative radiation therapy
Palliative irradiation for skin lesions is discussed in the CQ.

| Future prospects of radiation therapy
Electron beam therapy is performed as routine irradiation, but, for tumors with lymph node metastasis, intensity-modulated radiation therapy shows better tumor coverage and fewer complications and is considered promising. While brachytherapy has been suggested to be effective overseas, the facilities capable of this therapy are limited in Japan.

| Conclusion
As prior mentioned, close discussion between dermatologists and radiation oncologists is necessary for the determination of the extent of the tumor and volumes used for the planning of radiotherapy for SCC.

| Future prospects of drug therapy
Immune checkpoint inhibitors are the most promising as drug therapy. Their use in postoperative treatment and their combination with surgery and chemotherapy will be evaluated. In the USA, the annual number of patients who develop SCC is estimated to be 180 000-520 000 with some differences among reports, and metastasis is observed in 2-5% of these patients. 19 The cure rate is reportedly 95% if the primary focus is completely resected. 102 According to a systematic review, if high-risk SCC was completely resected, the local recurrence rate was 5%, regional lymph node metastasis rate was 5%, distant metastasis rate was 1%, and mortality rate was 1%. 103

| Actinic keratosis
Actinic keratosis is a precancerous lesion or intraepithelial cancer of keratinocytes that develops primarily in sun-exposed areas such as the face and dorsum of the hand. Capillary proliferation is the primary finding in an early stage, but erythema accompanied by keratinization gradually develops. By dermoscopy, slightly reddish pseudonetwork reflecting this capillary proliferation is noted, and the characteristic strawberry pattern, which shows white hyperkera- The incidence of actinic keratosis in the Japanese population is estimated to be 100-120/100 000 people per year. 12 Actinic keratosis is more common in white populations and was relatively rare in Japanese. However, the number of patients in Japan has increased steadily with rapid aging of the population and nearly doubled from 1987 to 2001. 12 Actinic keratosis is known to be related to chronic exposure to ultraviolet light. Concerning the preventive effect of sunscreen agents against actinic keratosis, there have been two RCT in Australian subjects, in which the incidence could be reduced by 38% and 24%, respectively. 109,110 In Japan, also, there is a cohort study of the relationship between the latitude and the incidence of skin can- of SCC in Japanese occurs in sun-exposed areas, suggesting that ultraviolet light is involved in its etiology, although not so much as in whites. 11 Treatments for actinic keratosis include surgery, cryotherapy, PDT, external application of imiquimod, and external application of 5-FU ointment. See CQ1 for the selection of these treatments.

| Bowen's disease
Bowen's disease is an intraepidermal lesion of SCC, and 3-5% of the lesions are considered to progress to SCC. 112 The disease, consid- In Japan, surgical treatment is performed widely, but evidence concerning the extent of resection is scarce. There have been reports that the local recurrence rate 1 year after resection of actinic keratosis with a margin of 1 mm was 4% 114 and that, in a retrospective study, the recurrence rate during a follow-up period of 1-5 years was 2.8%, although information concerning the margin was scarce. 115 Since the resection margin for low-risk SCC is set at 4 mm or more in CQ2 of the present guidelines, a resection margin of 1-4 mm is recommended for Bowen's disease, but further evaluation is considered necessary. In Western countries, Mohs surgery is performed widely, but recurrence was observed in 6.3% of the 95 patients, approximately half of whom were recurrent cases, after Mohs surgery. 116 Although this procedure is considered excellent in that the resection margin can be minimized, it has not gained wide acceptance in Japan, because special training is necessary to acquire the technique, and the procedure is time-and laborconsuming. As observed above, although the evidence is insufficient, surgery is considered to be the most reliable treatment, because it provides a high local control rate and a chance for histopathological evaluation.
Cryotherapy is adopted widely primarily for mild cases because of its simplicity. Holt reported that the recurrence rate of Bowen's disease after cryotherapy was 0.5% (1/128) and that the recurrence was observed half a year after the treatment. 117 However, when Morton et al. compared cryotherapy and PDT, the complete response rate after one cycle of treatment was 75% in the PDT group and 50% in the cryotherapy group, and the PDT was also superior with regard to adverse events. 118 In a subsequent report, the complete response rate 12 months after treatment was 80% in the PDT group, 67% in the cryotherapy group, and 69% in the 5-FU external therapy group, also being significantly higher after PDT than after cryotherapy. 119 However, Ahmed et al. compared cryotherapy and curettage and reported that the recurrence rate 24 months after treatment was 13/36 in the cryotherapy group and 4/44 in the curettage group. 120 Thus, cryotherapy, which is easy to perform and is less expensive and can also be performed readily for multiple lesions, is considered a useful treatment for Bowen's disease. However, periodic check is necessary for recurrence after treatment.
There is a systematic review of treatment of Bowen's disease by PDT (uncovered by health insurance as of April 2019), and its usefulness is generally established. 121 As mentioned above, the complete response rate is higher in PDT than in cryotherapy, and according to the report by Salim et al., 122 the complete response rate 12 months after treatment was 82% in PDT and 48% in external application of 5-FU with a significant difference. There are also multiple reports concerning the combination of PDT and CO 2 laser, and, according to Cai et al., 123 the complete response rate was 63.63% in PDT alone but improved to 72.73% with a combination of PDT and CO 2 laser.
In Japan, facilities capable of PDT are limited, and since it is not covered by health insurance as of April 2019, caution is necessary in selecting this therapy.
External therapy using 5-FU ointment has also become more prevalent than before. The recurrence rate is reported to be 8-14%, [124][125][126] and the response rate is slightly inferior to that in PDT as observed above. However, it is also useful as a treatment for Bowen's disease, because it is simple and applicable also to multiple lesions similar to cryotherapy.

Imiquimod (uncovered by health insurance as of April 2019) is
a Toll-like receptor 7 agonist known to induce antitumor immunity.
Patel et al. 127 reported that the complete response rate 12 weeks after treatment by external application of imiquimod was 73% without serious adverse effects, and the treatment is considered effective for Bowen's disease, but it is not covered by health insurance in Japan as of April 2019.

[Scientific Evidence]
Surgery is one of the most effective treatments. If the resection stump is negative, the response rate is theoretically 100%. However, because of problems, such as surgical invasion and scars, surgery should be performed by selecting patients. Although there are no reports with a high evidence level comparing surgery with other treatments in terms of the response rate, the recommendation grade was set at 1B based on the above discussion.
Cryotherapy using liquid nitrogen is a simple treatment effective for actinic keratosis. Regarding the effectiveness of cryotherapy, the complete response rate has been reported to be 68-86%. [128][129][130][131][132][133] Also, the incidence of local adverse effects has been reported to be 35-43%, and major adverse effects include pain, scarring, and depigmentation. 128,131,132,133 Since there have been many reports about cryotherapy, and since it has been performed in a large number of patients, the recommendation grade was set at 1B.
Photodynamic therapy is effective for diffusely distributed multiple lesions of actinic keratosis. Concerning its effectiveness, the local response rate has been reported to be 68-93%. The incidence of local adverse effect is reported to be relatively high at 26-100%, and they include mild adverse events such as local erythema. 128,131,132,134 Although PDT is not covered by health insurance in Japan as of March 2019, it is performed as a common treatment overseas, and a large number of cases have been reported. While no statistically significant overall difference is observed, the recommendation grade was set at 1B, because the treatment is more effective than other treatments in individual reports.
Imiquimod is used against diffusely distributed multiple lesions similarly to PDT. The complete response rate is 55-85%. The incidence of local adverse effects is relatively high at 85-92%, but they include mild adverse events, such as local erythema, as in the case of PDT. 134,135 The drug also began to be covered by health insurance in Japan in 2011. Since then, it has been used in many cases, and reports have increased, so the recommendation grade was set at 1B.
5-Fluorouracil ointment is used for diffusely distributed multiple lesions. The complete response rate is 26-96%, and the incidence of local adverse effects is relatively variable at 25-77%. 128,129,130,135,136 However, it is used widely overseas, and there are a number of reports, so the recommendation grade was set at 1B.

[Comment]
As a result of searches of the literature concerning each treatment and selection of the relevant evidence, 11 reports based on RCT were obtained. However, they varied in the subjects, and as a simple comparison of the effects of treatments per se was impossible, the complete response rate and incidence of adverse effects were evaluated as major outcomes.
Treatments not mentioned in the recommendation statements include CO 2 laser, diclofenac, and oral nicotinic acid therapy. The local disappearance rate of lesions is 72-78% in CO 2 laser, 50% in diclofenac, and not reported concerning oral nicotinic acid therapy. 133,136,137,138 Diclofenac and nicotinic acid are not covered by health insurance in Japan, and caution is needed in their use.

[Points of attention in clinical use]
Since there are many treatments for actinic keratosis, physicians should explain multiple treatments to patients before treating them.
If lesions suspected to have intradermal infiltration are treated nonsurgically, a histopathological check by biopsy should be made in advance.
Of the treatments mentioned here, PDT is not covered by health insurance as of April 2019 in Japan, and caution is needed in its use.
Also, imiquimod is used for the treatment of actinic keratosis, but its use in areas other than the face and hairless parts of the head is not covered by health insurance, and caution is also needed.

[Prospects of future research]
In the literature cited here, the outcomes and subjects are not uniform.
Therefore, precise results will not be obtained by comparison of effects and adverse effects of the treatments per se. In the future, studies with standardization of the subjects and outcomes are required.

CQ2 How should the resection margin be determined in surgery
of the primary focus of SCC? [Recommendation] In patients confirmed to be at a low risk, resection with a margin of 4-6 mm (or more) is strongly recommended. In other patients suspected to be at a high risk, resection with a margin of 6-10 mm (or more) is strongly recommended (See Table 2 for the risk classification). [Background/objective] In the treatment of SCC, surgery has long been the first-line option, 139 and it is common to grossly determine the tumor margin and resect the lesion at a certain distance of normal skin ("resection margin"). In Japan, partly because Mohs surgery, which is popular in Western countries, has not gained wide acceptance, resection with a relatively wide margin has been performed for radical treatment. 140  For high-risk groups, recommendations differ among guidelines: besides ≥6 mm in the British guidelines, ≥9 mm, 147 a maximum of 10 mm or more, 144 10 mm, 151,152 and Mohs surgery or CCPDMA (complete circumferential peripheral and deep margin assessment) are recommended, 146,148,150 but some guidelines do not recommend standard margins. 149,150 In the older Japanese guidelines, 146,153 a resection margin of 4 mm was recommended for the low-risk group and 6 mm for the high-risk group. The present guidelines recommend 4-6 mm for the low-risk group and 6-10 mm for the high-risk group in consideration of the differences among systematic reviews and guidelines.
However, since complete resection is impossible in some cases even by following these recommendations, [147][148][149] it is permitted to set a large resection margin for more assured tumor resection. This is why we expressed our recommendations as 4-6 mm (or more) for lowrisk groups and 6-10 mm (or more) for high-risk groups.

[Points of attention in clinical application]
Generally, whether the tumor has been sufficiently resected or not is checked by first histologically confirming the absence of residual tumor cells in surgical specimens and, then, continuing long-term follow-up for recurrence. It is desirable to set standard resection margins that assure a high complete resection rate and low recurrence rate, but studies to the present have been conducted using the complete resection rate (tumor clearance rate) as an index. 142,147,148,149,150 If resection is incomplete, the disease will recur sooner or later, but whether cases of complete resection remain recurrence-free has not been studied. This means that standard resection margins are recommendations based on the complete resection rate and do not guarantee a low recurrence rate. Even if the resection margin is less than the standard, the research-based outcome is considered to be achieved if complete resection has been histologically confirmed, and additional resection to meet the standard resection margin is not necessarily recommended.
Some systematic reviews and guidelines 140 served that only 1% of the stump can be examined by conventional "breadloafing" or "crisscrossing". By the common method of sectioning along the short diameter of the surgical sample and along a plane perpendicular to it, the false negative rate is unavoidably high. Also, making a judgment of "complete resection" because the section at the end of the sample is negative for tumor is not necessarily a standardized method. However, exhaustive examination of the resection stump requires circumferential sectioning of the sample, but as slightly inside the "true resection stump" is examined by this method, the probability of the judgment of a "positive stump" increases. Therefore, it must also be noted that a slightly wider resection margin is necessary to examine the stump using this method.
All guidelines set the resection margin by dividing SCC patients in to high-and low-risk groups, but the risks factors used to classify the two groups are not necessarily the same. 145 In Japan, the risk classification of the NCCN guidelines ( to each factor, and it is more practical to list conditions of high-risk lesions and regard those that fulfill at least one of the conditions as a high-risk group. Reflecting this, the second edition of the Japanese guidelines 146 set a resection margin at "≥6 mm", in principle, but "≥4 mm" only for "cases confirmed to be at a low risk". In the present guidelines, two groups were defined as "cases confirmed to be at a low risk" and "other possibly high-risk cases".

[Prospects of future research]
For prospective studies of the resection margin for SCC, it is necessary to standardize the sample sectioning method and definition of complete resection. Usually, the outcome is evaluated according to the complete resection rate immediately after surgery, but whether recurrence can be avoided if complete resection has been achieved is an important issue, and analysis of survival time by defining the recurrence rate as the outcome is also required. Also, the lack of uniformity of the criteria for low-risk and high-risk groups poses practical problems. It will also be necessary to evaluate the ratio between the low-risk and high-risk group when patients are classified according to the criterion that a patient with at least one risk factor is classified in a high-risk group and whether the ratio is markedly disproportionate. Furthermore, it would be even better to study the guideline compliance rate by clarifying the actual resection margin in each group and compare the histological complete resection rate or the recurrence rate after a given observation period between the guideline compliance/non-compliance groups.
CQ3 Can the following treatments recommended for unresect- [Background/Objective] 1. Since cutaneous SCC of the skin occurs frequently in sun-exposed areas of the skin, it is often diagnosed in a stage in which the lesions are localized, and relatively favorable therapeutic results are likely to be obtained by local treatments including surgery. However, the disease may be diagnosed in an advanced stage depending on the patient background and location and judged to be unresectable.
The significance, objectives, and benefits of radiation therapy in such cases were evaluated by the approach of EBM.
2. Since cutaneous SCC of the skin occurs frequently in sun-exposed areas, it is often diagnosed in a stage in which the lesions are localized, and relatively favorable therapeutic results are likely to be obtained by local treatments including surgery. However, the disease may be diagnosed in an advanced stage depending on the patient background and affected area and judged to be unresectable. The significance, objectives, and benefits of drug therapies for such cases including cytotoxic agents, molecular targeted drugs, and immune checkpoint inhibitors were evaluated by the approach of EBM.
[Scientific evidence] 1. Cutaneous SCC of the skin is fairly radiosensitive tumor, and relatively favorable therapeutic results have been reported by radiation therapy, in the setting where the lesion is localized and feasible to curative radiotherapy. 157,158 However, in all of the few studies in which radiation therapy was performed for unresectable cutaneous SCC of the skin, radiation therapy was combined with drugs such as anticancer and molecular targeted agents, [159][160][161][162][163] and there has been no report that evaluated the effect of radiation therapy alone against unresectable cutaneous SCC.
The evidence is presently limited to domestic general comments dealing irradiation as palliation for other cancers. 164 2. No large-scale study concerning anticancer drugs (cytotoxic agents) has been reported, and there have only been a few relatively small retrospective studies primarily concerning multidrug chemotherapy including platinum-based ones. 93 , [165][166][167] Concerning molecular targeted drugs, two phase II clinical trials have been performed with both gefitinib 168,169 and cetuximab, 94 , 170 and the response rate has been reported to be 45.5% 168 and 15% 169 for gefitinib and 27.8% 94 and 31.3% 170 for cetuximab.
As for immune checkpoint inhibitors, a phase II clinical trial showed 28 (47.5%) of the 59 patients responded to PD-1 antibody cemiplimab, and that the effect persisted for 6 months or longer in 57% of the responders. 95 [Comment] 1. As a result of a review of the literature concerning radiation therapy for unresectable cutaneous SCC and selection of the relevant evidence, four case series reports could be retrieved.
However, in none of these case series, radiation therapy was performed alone, and since it was combined with cetuximab alone 159,161,163 or multiple drugs including cetuximab, 160,162 the effect of radiation therapy alone was not evaluated, and the data could not be used for comparison of the effect of radiation therapy per se. For these reasons, in the present recommendation, radiation therapy was described as an option for palliation as in other cancers, and its recommendation grade was set at B (moderate).
Since the topic of this CQ is unresectable advanced lesions, the recommendation grade as radiation therapy intended to achieve radical cure or a comparable response is not mentioned, and the recommendation grade is restricted to the use for palliative treatment.
However, since, as observed above, relatively favorable therapeutic results have been reported when the lesion is localized and radically treatable, radiation therapy is undoubtedly an important option also for achieving radical cure or complete control even in patients with lesions difficult to resect radically for reasons, such as location near the eye, and a large vessel invasion by nodal disease. It should be added that the present guidelines do not recommend against radiation therapy in such situations.
2. As a result of a review of the literature concerning drug therapy for unresectable cutaneous SCC and selection of the relevant evidence, a few reports of retrospective studies concerning cytotoxic drugs and two phase II clinical trials each of gefitinib 168,169 and cetuximab 94 , 170 could be retrieved. A phase II clinical trial of the PD-1 inhibitor cemiplimab, which is an immune checkpoint inhibitor, has also been performed, and its effects have been reported. 95 Based on these reports, the administration of the above drugs should be considered with comprehensive evaluation of factors including the patient's general condition. None of the above drugs is covered by health insurance for cutaneous SCC. In consideration of these points, the recommendation grade was set at C (weak).
[Points of attention in clinical application] 1. In considering radiation therapy for unresectable cutaneous SCC, it is necessary to comprehensively evaluate factors including benefits to the life prognosis and QOL, risk of complications by radiation therapy, and the patient's general condition, make judgments about the indication by consultation and discussion with radiologists, and determine the treatment goal, dose, fractions, period, radiation type, and irradiation method.
2. Based on the results of phase II clinical trials, the FDA of the United States approved cemiplimab as a treatment for cutaneous SCC. How the situation in Japan will change in the future is uncertain, but immune checkpoint inhibitors may become a standard therapy for cutaneous SCC. At present, however, none of the above drugs including cemiplimab is covered by health insurance for cutaneous SCC in Japan, and these drugs should be administered in clinical trials or similar situations with approval by the IRB of each institution.
[Prospects of future studies] 1. As observed above, there have not been clinical studies concerning the usefulness of radiation therapy for unresectable cutaneous SCC with standardized subjects or outcomes. Since radiation therapy is unlikely to be clinically performed alone, and since randomized studies are difficult to implement, the possibility that a large-scale study will be conducted in the future is considered low. The attitude to search the limited evidence for data that are of clinical use is considered necessary.
2. Cemiplimab, an immune checkpoint inhibitor, has already been approved by the FDA as a drug for cutaneous SCC. In the future, novel drugs including immune checkpoint inhibitors may also be approved in Japan as treatments for cutaneous SCC as in the case of malignant melanoma, so the trends in Japan and abroad must be carefully monitored.

CO N FLI C T O F I NTE R E S T
H. Kato received a scholarship grant from Taiho Pharmaceutical.