Role of minimally invasive surgery in the treatment of gallbladder metastatic melanoma. A review of the literature and a case report

Abstract Background Primary and secondary gallbladder melanomas are rare, and only 58 cases have been reported in scientific literature to date. This paper aimed to explore the role of minimally invasive surgery in the management of gallbladder metastatic melanomas. Case Herein, we present the case of a 68‐year‐old man with metastatic gallbladder melanoma who was treated with laparoscopic cholecystectomy. Our case management was then compared with that of other cases reported in the literature. Conclusion Currently, metastatic melanomas can be considered as a potentially curable disease. Palliation of symptoms and fast recovery following minimally invasive procedures could be beneficial for these patients. Particularly, laparoscopic procedures appear to prolong the survival of gallbladder melanoma patients.

Cutaneous melanoma metastases can affect all organs of the human body. The most common sites are the lymph nodes, lungs, liver, and brain. Although isolated gallbladder metastases are extremely rare, almost 50% of all secondary gallbladder metastases are attributed to melanoma, as reported by an autopsy series. 3 Gallbladder lesions are usually asymptomatic, but in some cases, no specific symptoms, such as right upper quadrant pain, can be present. 4 Funding Information: Our project is own funding. Ultrasonography (U/S) usually has atypical features, and in most cases, a hyperechoic lesion is observed. Additional information can be gotten from computed tomography (CT) and magnetic resonance imaging (MRI). 5 MMG is associated with a very poor prognosis, and the optimal treatment strategy remains ambiguous. 1 However, the indication of laparoscopic surgery remains unclear.
Laparoscopic cholecystectomy (LC) is a feasible and efficient technique for metastasectomy of melanoma. LC appears to be the safest option because it is associated with less intraoperative blood loss, low analgesic requirement, shorter length of hospital stay, and brief con- Herein, we presented the case of a patient with MMG detected during typical follow-up examinations. In addition, a review with a statistical analysis of all the cases reported in the past, discussing the most common clinical features as well as the role of laparoscopic surgery as a therapeutic option in the management of the disease was performed. There were no restrictions on the age of the articles included in this review.

| MATERIALS AND METHODS
Ninety-two articles were in English, while 53 were in other languages. All these studies were carefully studied. In the final assessment, we included only full texts, case reports, and case series articles.
We finally selected 58 cases and a database with the patients' characteristics was created. The database included sex, age, primary tumor location, symptoms, symptom duration, tumor size, diagnostic methods, treatment, metastasis, and follow-up. The cases that fulfilled at least eight of these 10 criteria were included in the statistical analysis. One additional case was added from the clinical experience of the authors of this article. Thus, a total of 58 cases were included in the statistical analysis. After obtaining ethical approval and participant consent, personal data were removed, and all clinical data were collected.
Descriptive statistics were used to appropriately express the results. Means, medians, and SD were used for continuous variables and frequencies for categorical variables.
The Spearman test was used to calculate the correlation between histological infiltration and age. An independent samples t-test was used to calculate the distribution of age among males and females.
The histological layer infiltration of the tumor of male versus female subjects was compared using the Mann-Whitney U-test. The Kruskal-Wallis test was also used to calculate the distribution of layer infiltration across categories of survival in months. For layer infiltration and the type of procedure, the Kruskal-Wallis test was calculated for this correlation. Statistical significance was set at p < .05. Statistical analysis was performed using SPSS version 25 (SPSS Inc., Chicago, IL, USA).

| CASE REPORT
Our case was a 68-year-old Caucasian man with a history of hypertension. The patient was brought to the emergency department due to epilepsy. A CT scan revealed a brain tumor in the left temporal region. The patient was urgently taken to the operating theater due to hydrocephaly. The final pathological specimen of the brain tumor revealed a metastatic melanoma.
Complete skin examination did not reveal any primary skin lesions. The history of the patient revealed that, 2 years ago, a scabby lesion was discovered on his right ear. The lesion was subsequently widely excised. The lesion was initially thought to be a basal cell carcinoma. After repetitive consultations and pathological specimen examination, it was revealed that the lesion was a melanoma, which was retrospectively staged as T3N0M0, stage IIa. Thus, the patient was put on observation. After the brain surgery, the patient underwent 10 fractions of whole-brain radiotherapy and received As such, following the multidisciplinary team's discussion, according to the European society for medical oncology guidelines and due to the patient's good performance status, LC was decided.
Patient blood testing revealed a white cell count of 5.89 Â 10 9 /L, According to the oncological multidisciplinary team recommendations, further treatment for resected stage IV metastatic melanoma was decided after the patient was discharged from the hospital. He received nivolumab 240 mg Q2W for 6 months (12 cycles). Restaging imaging at 12 months with CT CAP and brain MRI revealed CNS recurrence of the resected left temporal lobe lesion, and stereotactic radiosurgery with γ Knife was decided in the MDT meeting, which was performed successfully. He continued treatment with nivolumab and is currently still on treatment. He has received 20 cycles and no evidence of metastatic disease was noted at his last restaging visit until today.

| RESULTS
The characteristics of MMGs were determined based on sex, age, primary localization of the tumor, other metastases, major symptoms, infiltration histology layer, type of procedure, and survival.
Regarding sex, 67.2% of the patients were male (39 patients), whereas 32.8% were female (19 patients). The ratio between men and women was 3:1, suggesting a male predominance in the reported MMG population.  The age distribution is shown in Figure 3, from which it is concluded that MMG most frequently appeared in the age ranges of 36-41, 54-59, and 72-77 years. The mean age of the 58 patients (100%) was 55 ± 14.82 years, ranging from 30 to 86 years. The distribution of age among male and female patients was compared, and it was found that the age at which the tumor appeared did not differ statistically between males and females (55.95 ± 15.587 and 53.63 ± 14.241 years, respectively, p = 0.587).
As far as the primary location of melanoma is concerned, in our database, the most common locations, were legs (nine patients,  The predominant symptoms of symptomatic tumors are epigastric pain after eating and fever. Physical examination revealed severe tenderness in the right upper quadrant of the abdomen with a nonpalpable gallbladder.

| Diagnosis
The extreme rarity of the disease is responsible for the absence of standard diagnostic and therapeutic guidelines. First, as highlighted above, physical examination was due to some other indications. Laboratory tests were usually normal; in some cases, they showed an elevation of white blood cell count with neutrophilia and an increased total serum bilirubin level. Liver function studies ranged from normal, in some cases, moderately increased to highly increase due to severe liver dysfunction.
The arrows in the diagnosis quiver were U/S and CT. U/S is the examination of choice for abdominal assessment. In this case, a single polypoid mass was present, but generally, U/S did not demonstrate lithiasis but a single or multiple polypoid, hyperechoic mass with minimal to absent acoustic shadowing. In contrast to gallbladder cancer, MMG does not seem to be associated with cholelithiasis. 2

CONFLICT OF INTEREST
The authors whose names are listed immediately below certify that have no affiliations or involvement in any organization or entity with any financial interest in the subject matter or material discussed in this manuscript. Project administration (equal); supervision (equal); visualization (equal); writingreview and editing (equal).