A retrospective study of acral melanoma that happened on foot

Methods: The aim was to investigate the epidemiological, clinical, and prognostic features of acral melanoma (AM) that occurred on foot, and to provide associated data for further study. A retrospective study was performed on patients with malignant melanoma (MM) who were treated in our hospital from January 2015 to January 2019. The tumor site was screened by foot. Basic data (e.g., gender, age, occupation, tumor location and etiology) of eligible patients, tumor-related data (such as tumor thickness, lymph node metastasis, and systemic metastasis), surgical related data (e.g., surgical site, operation time, bleeding volume, postoperative drainage time and volume), and prognostic data (including local recurrence or metastasis) were extracted. Survival analysis was used to study event-free survival (EFS) and overall survival (OS) and factors influencing survival of patients. Results: A total of 109 patients with AM happened on foot, including 52 males and 57 females, male/female = 0.91, were involved. The patients’ age was 58.31±12.13 years old. The occupations included 69 (63.3%) of farmers, 20 (18.3%) of freelance work, 4, 10 and 6 (18.4% in total) of others, including workers, students, and retirees. Tumor locations were 19 (17.4%) of the thumbs, 9 (8.3%) of other toes, 54 (49.5%) of the inner and outer soles, 20 (18.3%) of the heels, and 7 (6.4%) of the back foot. The causes were 57 cases (52.3%) of malignant nevus, 7 cases (6.4%) of trauma stimulation, and 45 cases (41.3%) without inducement. Additionally, 29 cases (26.6%) were newly diagnosed and treated in our hospital, and 80 cases (73.4%) were previously treated in external hospitals. Symptoms of nudes or ulceration lasted for 1 to 15 months, with an average of 5.92 months. The main surgical methods are tumor (enlarged) resection, lymph nodes resection, and combined resection viscera, and 12 patients died. The EFS was 16 months, and OS was 31 months on average. Univariate analysis suggested that there was a correlation between occupations and EFS, locations and OS. Conclusions: Middle-aged and elderly manual workers were found as the main population of AM that happened on foot. The tumor appeared at the weight-bearing area of the soles and heels. The proportion of metastasis was high, while the prognosis was poor. Preventive resection of precancerous lesions and early diagnosis and treatment of tumors are the primary tasks to improve the efficacy and survival of patients


Introduction
Malignant melanoma (MM) is a highly destructive, insidious tumor originating from melanoma cells in the skin and other tissues. MM has one of the fastest-growing incidence rates in the United States. According to the statistics, the annual rate is about 0.9 per 100,000, and the mortality is about 0.23 per 100,000. In China, up to 8,000 new melanoma patients are diagnosed each year, with approximately 3,400 deaths [1,2].
According to different primary sites and solar exposure levels, MM is currently classified into four basic types: acral type, mucosal type, chronic solar damage type, and nonchronic solar damage type (including unknown primary foci) [3]. The most common pathogenic factor in foreign countries is the malignant transformation of pigment cells induced by ultraviolet irradiation. Clinically, the skin lesions at the site of sun blasting are mainly affected, and the prognosis is relatively satisfactory. In China, the majority of patients are acral type, accounting for about 60% of all MM patients. The leading pathogenic site is limb, which is characterized by a long period of time, thick lesion infiltration, high incidence of ulcer and lymphatic metastasis, with no specific treatment drugs, and poor prognosis [4,5].
Several studies were conducted on MM, while the clinical investigation on a single site is rare. The present study extracted and analyzed the clinical data of foot, the high incident 4 site of MM, in order to clarify the oncologic features and prognosis of this site, and to provide primary data for further study.

General information
In the current study, medical records of MM patients who were admitted to our hospital from January 2015 to January 2019 were extracted, and the stage of the disease was further classified. A retrospective study of acral melanoma (AM) that happened on foot was conducted by medical records. This study included patients' general information, such as age, gender, occupation, location of onset, and risk factors.
The study was approved by the Ethics Committee of He Nan Cancer Hospital.

Surgical methods
Primary tumor resection: Tumor resection followed the principle of 2 cm outside the original surgical margin or tumor boundary (see black cycle line in Fig. 1b, 1c, 1d, 1f, 1 g, 1 h), which reached under the fascia (see Fig. 2a, 2c). The wound was closed in one stage: the tumors of the toes were chosen by toe amputation (28 cases). The medial plantar retrograde flap (4 cases) or the second toe eviscerated flap (11 cases) was used for the medial plantar. The 4th or 5th toe eviscerated flap (13 cases) was used for the anterior outer plantar. The medial leg retrograde flap (5 cases) (see Fig. 2c, 2d), lateral plantar flap (3 cases), medial plantar flap (2 cases) or skin grafting (7 cases) was employed for the lateral plantar. Skin grafting (10 cases) was used for the repair of the medial plantar wound. Medial plantar flap (12 cases) (see Fig. 2e, 2f), sural nerve flap (6 cases) (see Fig. 2a, 2b), and medial leg retrograde flap (2 cases) were adopted to repair the wound in the heel area. All the wounds of the dorsum of the foot were repaired by skin grafting as well.
Inguinal lymph node dissection: Oblique incision was made along femoral vessels, bounded by the inguinal ligament, with 1/3 above the ligament and 2/3 below the ligament. Subcutaneous tissue was separated by the boundary of the femoral triangle (lateral sartorius and medial adductor longus). After dislocating femoral artery and vein, subcutaneous fascia, fat, great saphenous vein, and myofascial tissue were removed entirely. The origin of the sartorius muscle was severed and dissociated downward to transfer to cover the femoral vessels. Close the wound after cutting 1 cm of skin edges.
Two drainage tubes were placed in the wound cavity.

Postoperative treatment
After the operation, the patients laid in bed and received anticoagulants, thrombotic prevention, and other medications. All the wound drainage tubes were placed for more than one week, and the drainage volume was less than 30 ml/day before extubation. Care should be taken to reduce wound contamination and infection.
According to the 8th edition of the American Joint Committee on Cancer (AJCC) [6], patients' clinical staging was determined on their imaging data and pathology. Patients mainly received high-dose interferon (18,000,000 U/day) in stage Ⅱ-Ⅲ and underwent chemotherapy of dacarbazine (DTIC) as the primary treatment in stage IV.

Follow-up
Tumor-related data, including tumor thickness, lymph node metastasis, and systemic metastasis were collected according to results of pathology and imaging postoperatively.
Surgical relevant information, such as surgical site, surgical method, surgical time, blood loss, postoperative drainage time, and drainage volume was surveyed. Follow-up data, involving superficial lymph nodes of the whole body, computed tomography (CT) of chest and abdomen, magnetic resonance imaging (MRI) of brain, pelvic and inguinal site, 6 emission computed tomography (ECT) of whole body etc. were captured through outpatient and inpatient data collection.

Event-free survival (EFS) and overall survival (OS) analysis
In the present research, we defined the period from the first operation to local recurrence, or from discovery of primary lesion to lymph node or organ metastasis and death as EFS.
The period from diagnosis of a tumor to death of a patient was OS.
1.6 Data processing and statistical analysis SPSS 20.0 software (IBM, Armonk, NY, USA) was used to calculate patients' EFS and OS.
The Kaplan-Meier method was used to plot survival curves. The single factor of survival rate was tested by the log-rank method. Independent risk factors influencing OS were analyzed by Cox regression. P < 0.05 was considered statistically significant.

Extraction of clinical data
From January 2015 to January 2019 in our hospital, 357 patients were retrieved by the title "malignant melanoma or melanoma" on the first page of medical records, of which 145 cases (40.62%) had acicular melanoma. Excluding 36 cases of melanoma appeared on hands, there were 109 cases with MM that happened on feet, accounting for 30.53% of all melanoma patients and 75.17% of aromatic melanoma (see Fig. 3). The patients' clinical data were extracted in detail and followed-up by telephone to confirm the following survival status.

Patients' general data
There were 109 patients of acral melanoma occurred on foot, including 52 males and 57 females (male/female = 0.91), with the median age of 58.31 ± 12.13 years old. There were 63 patients at the range of 51 to 70 years old, accounting for 57.8% of all patients. Occupations distributed 69 cases (63.3%) of farmers, 20 cases (18.3%) of freelancers, and 4, 10, and 6 cases (18.4% in total) of workers, students, and retired persons. Locations of disease were great toes in 19 cases (17.4%), remaining toes in 9 cases (8.3%), inside and outside sole in 54 cases (49.5%), heels in 20 cases (18.3%), and dorsal foot in 7 cases (6.4%). Etiology factors included 57 cases (52.3%) with malignant mole, 7 cases (6.4%) with traumatic stimulation, and 45 cases (41.3%) with no inducement. Clinical symptoms showed 81 cases (74.3%) with increased irregular black or nodules nevus and 28 cases (25.7%) complicated by an ulcer with effusion and even stench, with lesions ranging from 1 to 10 cm in diameter. The duration of symptoms was 1-15 months, with an average of 5.92 months, and the majority of patients (54.1%) had symptoms that lasted for 3-6 months.
There were 29 patients (26.6%) who received initial treatment in our hospital, and 80 patients (73.4%) who underwent surgery in other hospitals (see Fig. 1g).

Surgical data
There were mainly three types of operations: primary tumor resection, lymph node dissection, and primary tumor combined with lymph node dissection. Herein, 29 cases were treated at the initial diagnosis in our hospital, and the postoperative pathology confirmed all cases with MM and 5 cases with lymph node metastasis simultaneously.
There were 80 patients who were previously treated in other hospitals, 18 of whom had residual tumor after enlarged resection and pathological examination, 30 of whom had no residual tumor, 21 8 of who had lymph node metastasis, and 11 of whom had no lymph node metastasis. Therefore, a total of 26 patients (23.9%) with lymph node metastasis were diagnosed at the first visit. Lymph node biopsy or dissection was performed and indicated no lymph node metastasis in 16 cases Wound complications: Cutaneous necrosis of the foot occurred in 5 cases, and superficial infection occurred in 9 cases. The incisions were healed after debridement or second-stage skin grafts. In patients who underwent selective lymph node dissection (SLND), there were 10 cases of marginal necrosis, 13 cases of superficial infection, and 2 cases of deep infection. The wound was repaired by debridement, femoris lateralis or rectus femoris myocutaneous flap. The subcutaneous exudate was observed in 7 cases, and tube drainage was required. There were 32 cases with lower extremity edema after SLND, with 3 cases with severe edema. 9

Analysis of EFS and OS and related factors
At the last follow-up (January 9th, 2020), there were 8 cases of local tumor recurrence, 43 cases of inguinal lymph node metastasis, 29 cases of visceral metastasis, and 12 cases of death. A total of 44 tumor-related events occurred (8 recurred, 34 metastasized, and 2 died). EFS was 16.00 months on average. The rates of EFS in 1 year and 2 years were 58% and 37%, respectively. In 50% of patients, the events occurred 17 months postoperatively. OS was 31.00 months on average (see Fig. 4).
Univariate Cox regression analysis revealed a significant difference between the occupations of the patients and EFS (P = 0.002) (see Table 1), in addition to an absolute correlation between OS and the onset site (P = 0.002). The multivariate regression analysis found no factors related to EFS or OS.

Discussion
Acral melanoma was first named by Reed in 1976 [7] and became the fourth melanoma to be listed as a single subtype. The disease has unique clinical and pathological characteristics, such as anatomic structure defined as "acral", including the hands and feet, a pathological type defined as "acral type." Subungual is a particular type of acral melanoma. Acral melanomas account for only 1-7% of cutaneous melanomas in white populations, while 50-58% in Asia populations and up to 60-70% in blacks [8,9]. Acral melanoma is the most distinctive type of melanoma in China. The incidence sites are mostly in the palm, plantar, heel, toe, interdigital and other places where there were rarely exposed to ultraviolet irradiation, indicating that the incidence has nothing to do with sun exposure [5,10]. It is characterized by insidious onset, rapid development, easy occurrence of lymph and systemic metastasis with poor prognosis [11].
In the past five years, a total of 357 patients with MM were admitted and treated in our hospital, including 109 cases of acral melanoma on feet, accounting for 30.53% of all melanoma and 75.17% of acral melanoma patients. Clinical data were extracted and summarized from several foreign centers. The results showed that among the patients with AM, the incidence of the foot was about 77.6%, while that of hand was 22.4%, and the prevalence of hand/foot was about 1/3 (see Table 2).
These outcomes are consistent with those observed in our hospital. The possible reason justifying that the incidence of the foot is noticeably higher than that of the hand is related to the hidden location of the disease and the high probability of trauma. Female patients were slightly more, accounting for about 52.29%. The patients were mainly middle-aged and elderly, and the onset age was 50-60 years old, with an average age of 58.31 years old. Among them, farmers and other manual laborers accounted for 63.3%. The incidence sites were mainly concentrated on the medial and lateral longitudinal arch of the foot, including the big toe, the medial or lateral sole of the forefoot, the lateral sole and the heel, accounting for about 80% of the incidence sites on foot.
Among the causes of the disease, a total of 57 cases, about 52.3% of the patients had malignant nevus. Therefore, moles in the plantar weight-bearing area should be removed to avoid cancerous changes. Secondly, traumatic stimuli [12], such as excision misdiagnosed as "corns" or local ulceration caused by repeated friction, are the main factors to induce malignant tumors. About 40% of patients had "negligence" of the disease.  cases (52.63%) were confirmed to be positive. Therefore, a total of 43 cases (including 2 patients 13 with recurrence or metastasis of iliac fossa and popliteal fossa) accounted for 39.45% of all AM appeared on foot. After lymph node dissection, the drainage lasted for about 8.75 days on average, and the total drainage volume was 802.86 ml. In the current research, the positive rate of lymph nodes was less than 60%. Low rate of metastasis lymph node may be due to the following reasons: Firstly, swollen lymph nodes were found through preoperative imaging data, including ultrasound and MRI; Secondly, the majority of the patients were admitted to our hospital after surgery from another place. Pathological consultation was unable to detail information, including tumor Breslow thickness, cutting edge, etc. Therefore, clinical staging is intricate, and SLND should be adopted in a number of patients.
There were several complications after inguinal lymph node dissection, which were reported to be 20-40% (mean, 39.3%) [16,17]. After the occurrence, the wound should be timely treated with dressing change and debridement. For the patients with a large area of necrosis and difficulty in suture, the thigh lateral muscle flap or 14 rectus femoris myocutaneous flap was adopted in our hospital to repair the wound surface. (3) Postoperative limb edema (about 20.9%). Some of the symptoms can be alleviated by lifting the affected limb, using stretch socks, and taking anti-swelling drugs orally. However, there is no effective treatment for severe edema.
The adjuvant therapy for the melanoma of the foot in our hospital was mainly high-dose interferon and chemotherapy. Dacarbazine (DTIC) has been recognized as the only chemotherapy drug approved by the Food and Drug Administration (FDA) for progressive MM since 1972 [18]. In recent years, with the development of genetic testing technology, exploration of immune-and targetedtherapy, immune therapy has been gradually used for these patients [20,21]. Clinical studies showed that the skin melanoma with more mutated BRAF gene mutation and AM accounted for only 17% of BRAF gene mutations, and KIT gene mutation was 15% ~ 40% (3,22). Additionally, the efficacy of nivolumab in melanoma has been recognized [21]. However, there is still lack of objective data to evaluate AM patients in China, thus, the efficacy of targeted therapy and immunotherapy needs to be studied for a long period of time.
It has been reported [13,23,24] that the main factors affecting the prognosis and survival of patients are the clinical stage of the tumor, lymph node metastasis, and metastasis of vital organs.
Others include lactate dehydrogenase, BRAF gene mutation, etc. A Chinese study confirmed that factors, such as ulcer, tumor resection margin, and lymph node metastasis are the main factors influencing the prognosis of MM patients, and immunotherapy may improve the median survival of patients [25]. In the majority of AM patients, independent factors affecting the prognosis were as follows: duration of damage before diagnosis (2.5 years) or less, Breslow thickness > 4.0 mm (grade 4 primary focal T stage), high mitotic index (> 15 mm), vascular invasion and regional lymph node metastasis, and pathological staging (Ⅱ/Ⅲ/Ⅳ) [5]. The present study unveiled that the occupation of patients was one of the significant factors in the occurrence of tumor-related events. It was noted that our patients were mainly manual laborers, with lack of medical knowledge, delayed detection, irregular treatment, which led to postoperative tumor recurrence, lymph node metastasis, and other Shortly, foot melanoma is a kind of aromatic melanoma. Its features include high incidence in farmers and other manual workers, the leading site of the plantar weight-bearing area, easily misdiagnosing and mistreating tumor, high lymph node and organ metastasis rate. At present, the primary treatment is surgery, postoperative adjuvant chemotherapy, and biological therapy, while the prognosis is relatively poor. Preventive resection of precancerous lesions and early diagnosis and treatment of tumors are the primary tasks to improve the efficacy and survival of patients.

Declarations
Ethics approval and consent to participate: Ethical approval was obtained from the Medical Ethics Committee of the Henan Cancer Hospital.
Consent for publication: All authors have given their consent for publication.

Availability of data and materials:
The datasets used during the current study are available from the corresponding author on reasonable request.

Competing interests:
The authors declare that they have no competing interests Funding: No funding was supported in this study.
Authors' contributions: All authors read and approved the final manuscript Patients' EFS and OS survival curve.