Cutaneous squamous cell carcinoma(cSCC) is one of the most common non⁃melanoma skin cancers (NMSC). In recent years, the research on pathogenesis and treatment of cSCC has made great progress . However, currently there is still no authoritative and reliable cSCC diagnosis and treatment guidelines or consensus in China, which is not conducive to the development of epidemiological investigations, clinical research, standardized diagnosis and treatment of the disease. According to the ranking conducted by the Lancet in 2018, China received the lowest ratings over all in medical quality and accessibility of NMSC, and the level of diagnosis and treatment of cSCC in China needed to be improved urgently. For this reason, we formulated the Chinese cSCC diagnosis and treatment nomogram as the basis and guarantee for standardized and precise diagnosis and treatment. At present, the NCCN (The National Comprehensive Cancer Network) guidelines® remain the predominate basis for staging and analyzing cSCC in clinical practice. However, risk factors of recurrence according to the NCCN guidelines® are not appropriate for Chinese as different race, skin color, risk genes, living quality and skincare consciousness comparing with Caucasians. Concerning with skin color and risk genes, Chinese supposed to be less vulnerable to skin cancers. However, with low sun care consciousness and ignorance of skin diseases, the incidence of skin cancer is still worryingly high with poor prognosis especially in the aged. Additionally, the classification attributes and definition in NCCN guidelines® are not quite suitable for Chinese such as tumor location/size, borders, immunosuppression, prior radiotherapy since few Chinese cSCC patients would take positive intervention and treatment measure before the first visit in hospital. Basing on the specialty of low understanding and visiting hospital of Chinese cSCC population, we found it important to collect demographic and clinical characteristics of patients before surgery to figure out a better clinical net and a larger threshold probability range in predicting the recurrence of cSCC.
According to the NCCN guidelines®, high-risk factors in clinical inquiry and physical examination might be classified as: (i) tumor-related high-risk factors including tumor diameter (> 2 cm), localisation on “mask areas” of face, genitalia, hands, and feet, recurrent lesion, poorly defined borders, rapid growing, site of prior RT or chronic inflammatory process, neurologic symptoms, (ii) patient-related high-risk factors including immunosuppression. However, since a considerable number of patients were from rural areas and the economic level was low, there was a lack of health awareness, and delays in treatment were very common; patients often ignored the skin lesions until they developed severe symptoms, such as recurrent large ulcers, or lymph nodes involved. Based on different race and low recognition of skin cancers, we found that NCCN guidelines® was not quite appropriate to evaluate the risk factors of recurrence in our patients, so we summarized several indicators that could measure the risk scores of Chinese cSCC patients better. As we all knew that cSCC could be cured by proper surgical resection (such as MMS) and reduced the chance of relapse if it was diagnosed and preoperative assessment was improved early [21, 22].
In this study, we improved the classification of tumor size into three levels: small(< 2cm), medium(2cm ≤ diameter༜4cm) and large((4cm ≤ diameter༜6cm) with a P = 0.002. Ulcer was one of the typical clinical characteristics of cSCC which was also crucial to measure the depth of tumor invasion and infiltration. We also found that tumor with ulcer lesion was an important affected factor in evaluating the recurrence of Chinese cSCC patients with a P < 0.001 in the multivariate predictive model. Besides, precancerous lesion of cSCC (such as preceding AK, burn, verruca with atypical hyperplasia) was also a common risk factor in patients with cSCC and its large value indicated a high risk of recurrence. As ultraviolet radiation was the most important risk factor for cSCC, it was not difficult to understand that SCC mostly occurred in populations over 60 years old, and we also found that cSCC in sun-exposed location was easier to recur than that in non-exposed location with p = 0.008. From our observation, higher recurrence was consistent with lymph nodes metastasis and perineural invasion.
Nowadays, nomograms have become an important modern predictive tool to analyze and predict the risk of recurrence or survival outcomes [24, 25]. The model integrates a variety of risk factors which is notably associated with disease and quantify and score each variable’s influence and to visualize the ending of each patient [26, 27]. Through univariate and multivariate logistic analysis, we found that sun-exposure, tumor size, ulcer, precancerous lesions and neural invasion were strong prognostic variables of recurrence in postoperative patients with cSCC.
In most studies, nomograms are established for predicting overall survival in cancers, and few nomograms are applied in the prediction of recurrence in patients with skin non-melanoma cancers[28, 29]. This report constituted the first retrospective series of Chinese patients with cSCC and was the first nomogram in existence that was simultaneously based on abundant clinical data and had excellent predictive ability through the evaluation of C-indexes and calibration plots. Compared with NCCN guidelines®, the nomogram showed better accuracy in predicting recurrence according to ROC analyses’ outcomes. Nevertheless, great discrimination performance and strong calibration power did not necessarily mean the established model could be useful in daily clinical application. Thus, DCA was performed to evaluate the nomograms’ clinical usefulness, and also this nomogram was of better clinical utility in the proper range than NCCN guidelines® in Chinese patients in our samples. Additionally, CICs based on DCA in the nomogram further demonstrated the good discriminatory ability. Moreover, prediction points of recurrence’s probability were defined as a new prognostic factor in Chinese patients with cSCC [30, 31]. About 14% ~ 15% of primary and 23% ~ 50% of recurrent cSCC have subclinical infiltration (not clinically visible, only histopathologically can be confirmed), so we should pay attention to the margin inspection of cSCC with high-risk scores and appropriate clinical interventions (such as resection margin extension or sentinel lymph node biopsy and dissection) should be carried out[32, 33].
Patients were divided into three prognostic groups according to the optimal cutoff value: low-risk group, medium-risk group and high-risk group (Figure S1). Patients with fewer than 116 points were considered to have low risk of recurrence. Patients with points between 117 and 167 points belonged to medium-risk group and were recommended to expand incisal edge properly to decrease the possibility of recurrence. If recurrence was confirmed, ultrasonography of the adjacent lymph nodes, chest CT and abdominal ultrasonography as well as PET-CT if necessary were recommended to exclude the possibility of lymph node metastases, neural invasion and distant organ or blood metastases. Patients scoring higher than 168 points were at high risk in cSCC recurrence. Thus, perienchyma CT and MRI, ultrasonography of lymph nodes, chest CT, abdominal ultrasonography and PET-CT were recommended to guide the choice of surgical approach. Close follow-up is essential for patients of high-risk group.
In the present study, we focused on the prognostic value of clinical observation and physical examination at initial diagnosis and didn’t incorporate the pathology indicators into our nomogram. Compared with routine diagnostic examinations combined with clinical observation and pathologic examination, the novel predictive model was more suited to low rate of understanding skin cancers and visiting doctor, and also mitigated the economic burden for patients. Through comparing our model with NCCN guidelines®, our nomogram was more comprehensive with a high degree of concordance index, which could facilitate better prognosis and decrease the recurrence rate. However, as this was a single center and retrospective study, there is inevitable selection bias, as well as referral bias. Thus, external validation of the prognostic models is extremely important to test their prognostic significance and identify potential weaknesses, which could be improved in subsequent studies. A lack of external validation is a limitation of this study.