National guidelines for diagnosis and treatment of melanoma 2022 in China (English version)

National Health Commission of the People’s Republic of China

Contents

1.Overview

2.Screening and diagnosis

2.1 Surveillance and screening of high-risk population

2.2 Diagnosis of melanoma

2.2.1 Clinical symptoms

2.2.2 Imaging diagnosis

2.2.3 Laboratory tests

2.2.4 Focus biopsy

2.3 Pathological diagnosis of melanoma

2.3.1 Criteria for pathological diagnosis

2.3.2 Standard pathological diagnosis of melanoma

2.3.3 Pathological report of melanoma

2.4 Clinical diagnostic criteria and route map of melanoma

3.Staging

4.Treatment

4.1 Surgery and postoperative adjuvant therapy

4.1.1 Wide excision

4.1.2 Sentinel lymph node biopsy (SLNB)

4.1.3 Lymph node dissection

4.1.4 Treatment of local recurrence or local metastasis

4.1.5 Postoperative adjuvant therapy

4.2 Radiotherapy

4.3 Systemic therapy

4.3.1 Systemic therapy and response evaluation criteria

4.3.2 Advanced melanoma by different primaries

4.3.3 Therapy of special lesions

4.3.4 Symptomatic supportive therapy

1.Overview

Although melanoma is a rare malignant tumor in China,the mortality rate is high and the incidence rate is increasing year by year.There is a big difference between melanoma in China and Caucasians in Europe and America. The differences in pathogenesis,biological behavior,histological morphology,treatment methods and prognosis are quite different.Among Asians and other colored people,the primary melanoma of the extremities accounts for about 50%.The common primary sites are more common in the soles of the feet,toes,ends of fingers,and lower extremities.They originate in the mucosa,for example,the melanoma of the rectum,anus,vulva,eye,or nasopharynx accounts for 20%-30%;for whites,the primary melanoma of the skin accounts for about 90%,and the primary site is common in the back,the skin of the chest,abdomen and lower limbs;melanoma originating from the extremities and mucosa only accounts for 5% and 1%,respectively.

2.Screening and diagnosis

2.1 Surveillance and screening of high-risk population

Surveillance and screening for high-risk population of melanoma is helpful for early detection,diagnosis and treatment,and is also the key to improve the efficacy of melanoma treatment.In China,the high-risk population of skin melanoma mainly includes the history of severe sunburn,skin cancer,pigmented nevus and chronic inflammation of acral skin,as well as inappropriate treatment,such as salting,cutting,needle picking,rope stranding,and so on.The high-risk factors for mucosal melanoma remain unclear.It is suggested that the high-risk population should check themselves regularly and go to a specialized hospital when necessary.They should not deal with it at will.

2.2 Diagnosis of melanoma

Melanoma occurs mostly on the skin,so visual inspection is the easiest way to early diagnosis.Visual examination and palpation of primary lesions,affected sites and regional lymph nodes are common methods for the initial diagnosis of melanoma.

2.2.1 Clinical symptoms

Skin melanoma is mostly developed from nevus.The early malignant symptoms of nevus can be summarized as the following ABCDE rules:

A.Asymmetry: These lesions usually present as an asymmetrical pigmented macule.

B.Border irregularity: Irregular edge,or with incision or serration,and it does not have a smooth circular or elliptical contour like normal pigmented nevus.

C.Color variation: Normal pigmented nevus is usually monochromatic,while melanoma often manifests as dirty black,and can also have many different colors such as brown,brownish black,blue,pink,black,and even white.

D.Diameter: It is necessary to pay attention to pigmented nevus with diameter of ＞5-6 mm or obviously growing pigmented nevus.Melanoma is usually larger than normal nevus.It is better to perform biopsy on pigmented nevus with a diameter of ＞1 cm.

E.Elevation: Some melanomas usually have a slight bulge in an early stage.

The only downside of the ABCDE rule is that it does not take the growing rate of melanoma into account,which can have a significant change in weeks or months.Dermatoscope can make up for visual observation,and can detect and compare changes in suspected melanoma,and its application can significantly improve the accuracy of early diagnosis of melanoma.Melanoma can further develop satellites,ulceration,repeated unhealed wound,regional lymph node metastasis and transitional metastasis.Latestage melanoma has different symptoms according to different metastatic sites,usually lung,liver,bone and brain.Melanoma of the eye and rectum is likely to metastasize to liver.

2.2.2 Imaging diagnosis

Imaging examination should be based on local conditions and the patient’s economic situation.The necessary items include regional lymph nodes ultrasound (neck,armpit,groin,popliteal space,etc.),chest computed tomography(CT),abdominal pelvic ultrasound,CT or magnetic resonance imaging (MRI),whole body bone scan and brain CT or MRI.Patients with good economic conditions can take a full-body positron emission tomography-computed tomography (PET-CT),especially those with unknown primary origins.PET is an examination method that is easier to find subclinical metastases.For early-stage melanoma,PET is not sensitive to metastatic lesions and has a low benefit rate.For patients with stage III,PET-CT scans are more useful and can help identify lesions that cannot be clearly diagnosed by CT,as well as sites that are not visible on conventional CT scans (such as limbs).PETCT has advantages over ordinary CT in finding distant lesions.

(1) Ultrasound examination

Ultrasonography (US) is the most commonly used imaging examination method in clinical practice because it is easy to use,flexible,intuitive,non-invasive and portable.US of melanoma is mainly used to determine the nature of regional lymph nodes and subcutaneous nodules,and provides important information for the choice of clinical treatment methods and the development of surgical plans.Real-time contrast-enhanced ultrasound can reveal hemodynamic changes in metastases,especially in identifying small liver and lymph node metastases.

(2) CT

Conventional plain and enhanced scanning (using iodine contrast agent) are widely used in clinical diagnosis and staging of melanoma.Besides,it is also commonly used in the evaluation efficacy of melanoma,tumor volume measurement,and metastasis evaluation of lung and bone and other organs.

(3) MRI

Conventional plain and enhanced scanning (using contrast agent Gd-DTPA) becomes a common imaging technique for clinical melanoma diagnosis and efficacy evaluation because of its non-radiation,high-tissue resolution,multiazimuth and sequence parameter imaging,as well as morphological binding function (including diffusionweighted imaging,perfusion-weighted imaging and spectral analysis).

(4) PET-CT

The advantages of whole body imaging of18Ffluorodeoxyglucose (18F-FDG) PET-CT are: 1) Tumor staging: it can comprehensively evaluate lymph node metastasis and distant organ metastasis through one examination;2) Re-staging: PET functional imaging is unaffected by the anatomical structure,it can accurately show the recurrence and metastasis of the anatomical structure or the complex part of the anatomical structure;3) Efficacy evaluation: for the targeted drugs that inhibit tumor activity,the efficacy evaluation is more sensitive and accurate;4) Guiding delineation of the target area and biopsy of the active area of the tumor lesion;and 5)Evaluation of the malignancy and prognosis of the tumor.Conventional CT is less sensitive to the diagnosis of skin or subcutaneous metastasis,and PET-CT can make up for it.

2.2.3 Laboratory tests

Indictors like blood routine,liver and kidney function and lactate dehydrogenase (LDH),are mainly used for the preparation of follow-up treatment,while understanding the prognosis.Although LDH is not a sensitive indicator of metastasis,it can guide the prognosis.There is no specific serum tumor marker for melanoma,and it is not recommended to examine the tumor marker at present.

2.2.4 Focus biopsy

Biopsy methods for cutaneous melanoma include excisional biopsy,incisional biopsy and punch biopsy.Shave biopsy is not usually used. Routine excisional biopsy is recommended.The incision margin is 0.3-0.5 cm.The incision should follow the direction of dermatoglyph (such as the incision along the long axis of limbs).Avoid direct enlarged resection,biopsies should also be planed so as not to interfere of sentinel lymph node biopsy.Partial biopsy is not conducive to histological diagnosis and thickness measurement,and increases the risk of misdiagnosis and staging.Generally,incisional biopsy and punch biopsy are only used for diagnostic biopsy of large-scale lesions or special parts,such as lesions in the face,palm,sole,ear,finger,toe or subnail parts,or huge lesions,when complete excisional biopsy is not available,incision biopsy and punch biopsy can be considered.

2.3 Pathological diagnosis of melanoma

2.3.1 Criteria for pathological diagnosis

The most important method for the diagnosis of melanoma is histopathology,and immunohistochemistry staining is a main assistant method for differential diagnosis.Histopathological diagnosis is required for both primary superficial melanoma and a metastatic lesion,either by biopsy or surgical excision of tissue samples.Pathological diagnosis should be combined with clinical evidence,and the patient’s medical history,imaging examination and other information should be fully evaluated.

2.3.2 Standard pathological diagnosis of melanoma

The standard of pathological diagnosis of melanoma consists of specimen handling,specimen sampling,pathological examination and pathological report.

(1) Key points of specimen handling:1) The surgeon should provide some important information of the lesion(ulcer,nodule,or colored patches),and surgical margins and important lesions can be marked with dye or suture;2)Larger specimens must be cut and fixed at intervals of 3 mm or so;and 3) The specimens should be fixed in 10%neutral buffer formalin for 6-48 h.

(2) Key points of specimen sampling:Ink the margins first,and then cut the tissue at 2-3 mm intervals vertically to the skin surface in order to identify the thickness and invasion depth of the tumor.Choose an appropriate sampling method according to clinical requirements,specimen type and size,as well as the distance between the lesion and the cutting edge.Make sure that the thickest or deepest regions and the ulcer,if there are,are sampled.The skin between the main tumor and the satellite must be evaluated to find out the relationship between them.For tumors less than 2 cm in diameter,all tissues should be collected,and for tumors over 3 cm,1 piece per 5 mm is recommended. There are two methods for margin sampling,that is,radial sampling perpendicular to actual margins and lateral cutting parallel to actual margins.Since lateral cutting cannot measure the distance between negative margin and the tumor,the radial sampling method is suggested as far as possible (Figure 1).Never place two pieces or more of skin tissues in an embedding box.And in order to precisely evaluate T staging by histology,make sure that the embedded sections have shown the structural layers of skin or mucous membrane at the site of tumor.

Figure A1 Clinical stage of melanoma and treatment modalities.IHC,immunohistochemistry;H&P,history and physical examination.

Figure 1 Sample of margin in skin melanoma.(a) Radial sampling perpendicular to actual margins;(b) Lateral cutting parallel to actual margins.

(3) Essential components of pathological examination

A.Gross evaluation: Orientate a specimen in anatomical position,and then examine and descript the size,shape and color of the tumor.For a skin melanoma,inspection of superficial ulceration and transferred satellite focuses is essential,accompanied with the number,size and its distance to the main tumor if any satellite exists.

B.Microscopic evaluation: Diagnosis of melanoma refers to the WHO classification of skin tumors 2010 edition,and essential description contents should contain the following indexes: 1) Origin of melanoma,is it from skin or mucosa;2) Histology subtypes of melanoma,of which the major four subtypes are superficial spreading,lentigo maligna,acral lentigine and nodular type.Rare subtypes include desmoplastic melanoma,melanoma arising from blue nevus,melanoma arising in giant congenital naevus,childhood melanoma and nevoid melanoma;3) Invasion depth of melanoma.Breslow thickness is a quantitative index of depth in millimeters,and Clark level is a qualitative indicator indicating which level of the skin is infiltrated by melanoma;and 4) Other prognostic indexes,including ulceration,lymphovascular invasion,satellite or microsatellite nodules,mitotic rate and neurotropism.

Breslow thickness,defined as tumor thickness of melanoma of skin,is a fundamental index for T staging.It is a vertical dimension measured from the top of the granular layer of the epidermis to the deepest invasive cell for non-ulcerated lesions,while for the ulcerated lesions it is measured from the base of the ulcer to the deepest invasive part.Clark levels are defined as five levels according to the invasion depth: Level 1,tumor cells are confined to the epidermis (melanomain situ).Level 2,tumor cells invade into but do not fill the papillary dermis.Level 3,tumor cells fill the papillary dermis and infiltrate into the papillary-reticular dermal interface.Level 4,tumor cells infiltrate into the reticular dermis.Level 5,tumor cells infiltrate into the subcutaneous tissues.

C. Immunohistochemistry: Because of the diversity morphologies of tumor cells,melanomas,especially the amelanotic lesions,need to be distinguished from different kinds of tumors such as carcinoma,sarcoma and lymphoma.Common characteristic markers of melanocytes include S100,Sox-10,Melan-A,HMB45,tyrosinase and MITF.S100 is the most sensitive and is used as a marker to rule out melanoma if it is negatively expressed,but its specificity is relatively low and generally cannot be considered a definite diagnostic marker for melanoma.Melan-A,HMB45 and tyrosinase are more specific,but their sensitivities are various.So we recommend that more than 2-3 former markers as well as S100 should be used if a differential diagnosis is necessary,in order to improve the detection rate of melanoma.

D.Special melanoma subtypes: Mucosal melanomas:usually they are invasive lesions,and a pagetoid dissemination of melanocytes in mucosal epithelium can be seen sometimes.The tumor cells manifest as epithelioid,spindle,plasmacytoid or balloon-like,with melanin or not.Commonly,immunohistochemistry is needed to make a diagnosis of melanoma. Uveal melanomas: Uveal melanomas are classified as spindle cell type,epithelioid cell type and mixed type based on the morphology of melanocytes.Cell type is an independent prognostic factor of uveal melanoma in predicting metastatic risks,with the best prognosis for spindle cell type and the worst outcome for epithelioid cell type.

2.3.3 Pathological report of melanoma

A histopathological report of primary skin melanoma should contain all the essential factors associated with the treatment and prognosis predicting of the tumor,including: tumor site,specimen type,tumor size,histological subtype,Breslow thickness,with or without ulceration,invasion depth (Clark level),mitotic rate,surgical margin status (including the distance between the neoplasm and resection margin by the unit of millimeter under the microscope and the melanoma subtype in the margin if it is positive),satellite or microsatellite,lymphovascular invasion and neurotropism (Appendix 1).For sentinel of the regional lymph nodes,the total number of lymph nodes detected,the number of metastatic lymph nodes,and the presence or absence of extracapsular lymph node involvement should be reported.Driver genes testing related to targeted therapy,includingBRAF,CKIT,andNRAS,is also generally recommended.Frozen section technique is not recommended for intraoperative pathological diagnosis.For the cases which are difficult to make a diagnosis,the multi-center consultation is recommended.

2.4 Clinical diagnostic criteria and route map of melanoma

Melanoma diagnosis mainly depends on clinical symptom and pathological diagnosis,and gets complete information on the stage combined with the examination of systemic imaging (Appendix 1).

3.Staging

The staging of melanoma is crucial for prognostic assessment and treatment decision-making.Melanomas in different sites have different pTNM staging parameters.The pTNM staging of cutaneous melanomas is given inAppendix 2which can be applied to melanomas in lip,eyelid,external ear,other parts of face,skin of scalp and neck,trunk,upper limb,shoulder,lower limb,buttock,skin spanning lesions,labium majus,labium minus,clitoris,transvaginal lesions,vulva,prepuce,glans,corpus penis,transvaginal lesions of penis,penis and scrotum.The pTNM staging of head and neck mucosal melanoma can be seen inAppendix 3.The scope of application includes nasal cavity,sinus,oral cavity,oropharynx,nasopharynx,larynx and hypopharynx. Ocular melanoma includes iris melanoma,ciliary choroidal melanoma and conjunctival melanoma,and they all have different pTNM staging systems respectively.Details can be found in the relevant chapters of the eighth edition (2016) American Joint Committee on Cancer (AJCC) staging system (Appendix 4).However,there is no pTNM staging system for melanoma arising from the digestive tract (esophagus,small intestine and large intestine).According to the guidelines on clinical diagnosis and treatment of melanomas in China,it is suggested to describe the depth of invasion of the digestive tract.Vaginal melanomas do not have pTNM staging either.We can determine the pTNM staging of cervical melanoma by reference to the staging of cervical cancer.The pTNM staging system of meningeal melanoma is same as that of other meningeal tumors.

4.Treatment

Since a variety of methods and disciplines are involved in the treatment of melanoma,we should attach importance to multidisciplinary team-based diagnosis and treatment,avoiding the limitations of single-discipline treatment.Thus,we can provide one-stop medical services for patients,promote disciplinary communications,and facilitate the development of principles and guidelines of treatments based on multi-disciplinary consensus.Proper treatment decisions should be made by support of highlevel evidence.The regional and economic differences should also be taken into account.

4.1 Surgery and postoperative adjuvant therapy

4.1.1 Wide excision

Wide excision is recommended for patients who were preliminary diagnosed as melanoma without distant metastasis.The safe margin/optimal surgical margins of complete resection is determined by the depth of tumor invasion (Breslow thickness) according to the pathological report: 1) Thickness ≤1.0 mm,margin 0.5-1 cm;2)Thickness 1.01-2 mm,margin 1-2 cm;3) Thickness 2.01-4 mm,margin 2 cm;4) Thickness ＞4 mm,margin 2 cm.For patients whose biopsy pathology fails to report a clear depth or whose lesions are huge,direct enlarged resection of 2 cm can be considered.

The surgical margin of melanoma in special sites can be adjusted according to the anatomical structure and function of the patient’s specific primary lesion.Facial melanoma can be completely removed by surgery,and the cutting margin is not required.After complete excision of acromelanoma,the enlarged resection range is generally determined according to the pathological stage.From the perspective of surgery,acral lentiginous melanoma should not only consider complete tumor removal,but also fully consider the functions as much as possible,especially finger function.Amputation is not recommended for the treatment of most acral lentiginous melanomas,except melanomas on fingers or toes.As it does not cause too much loss of function,and can remove the tumor more thoroughly.

4.1.2 Sentinel lymph node biopsy (SLNB)

Sentinel lymph node is defined as the first lymph node for acromelanoma and cutaneous melanoma metastasis.SLNB is a surgical procedure developed to accurately stage patients with cutaneous melanoma. It is generally recommended for patients with tumor thickness greater than 1 mm.SLNB is recommended for patients with ulcer when biopsy and pathological examination techniques cannot obtain reliable invasion depth.SLNB can be performed at the time of wide resection or subsequently.SLNB is helpful to accurately obtain N stage and improve recurrence-free survival rate of patients.The lymphatic drainage pathway can only provide anatomical reference for SLNB,and the final detection of sentinel lymph nodes depends on a radionuclide detector.Frozen sections are not recommended for pathological diagnosis of sentinel lymph nodes and regional lymph nodes.

4.1.3 Lymph node dissection

Indications: patients with positive sentinel lymph nodes (if the patient receive lymph node ultrasound examinations regularly,the complete lymph node dissection can be delayed),and patients with stage III disease diagnosed by physical examination,imaging and pathology.

Principles of surgery: An anatomically complete dissection of involved nodal basin is required.As a measurement of the completeness of a regional lymph node dissection,the number of lymph nodes dissected is required at least 10 on the groin,and 15 for cervical or axillary lymph node dissection.Prophylactic lymph node dissection is not recommended.

Inguinal lymph node dissection: Superficial group and deep group dissection was required for patients with pelvic lymph nodes metastasis diagnosed by imaging;it is also required for patients with 3 or more suspected lymph nodes metastasis in the superficial group or metastasis of Cloquet’s node (lymph node is black or swollen) during operation.

Axillary lymph node dissection: A complete dissection of LEVEL I-III lymph nodes is recommended when subclavicular lymph node metastasis is confirmed before or during operation.While dissection of LEVEL I-II lymph nodes is recommended when there is no evidence of subclavicular lymph node metastasis or the sentinel lymph node is confirmed as micrometastasis.

Cervical lymph node dissection: An extensive or total cervical lymph node dissection should be avoided.For patients in clinical stage III disease,the range of dissection should be determined according to the region of swollen lymph nodes and primary lesions.

4.1.4 Treatment of local recurrence or local metastasis

Local recurrence or limb metastasis may be treated by surgical excision,intratumoral injection of oncolytic virus,isolated limb infusion chemotherapy (ILI),and isolated limb perfusion chemotherapy (ILP).Surgery remains the primary treatment for local recurrence.

4.1.5 Postoperative adjuvant therapy

The main purpose of adjuvant therapy is to reduce the risk of recurrence and metastasis.At present,the recommended strategy of adjuvant therapy includes: high-dose interferon α-2b,BRAF inhibitors and MEK inhibitors (for patients withBRAFmutation) and anti PD1 monoclonal antibody.Principles of adjuvant therapy for different subtypes of melanoma:

(1) Cutaneous melanoma: For patients with high-risk stage II melanoma,high-dose interferon α -2b is still recommended. For stage III melanoma,anti PD1 monoclonal antibody is recommended.For stage IIC melanoma with BRAF V600: vemurafenib for 1 year;stage III melanoma with BRAF V600: dabrafenib and trametinib for 1 year.

(2) Acral melanoma: High-dose interferon α -2b is still recommended.For patients with stage IIIB-IIIC acral melanoma or with ≥3 nodal metastases,one year regimen may be preferred;for high-risk acral melanoma patients in stages IIB-IIIA,4-week high-dose interferon treatment could be an option for patients who could not tolerate 1-year regimen.

(3) Mucosal melanoma: Temozolomide combined with cisplatin for 6 cycles is recommended,this regimen prolonged relapse-free survival (RFS). High-dose αinterferon,anti-PD1 could be optional,while they demonstrated less RFS improvement than adjuvant than chemotherapy.For head and neck mucosal melanoma,local radiotherapy may help to improve local control rate.

(4) Uveal melanoma: Studies have proved that high-dose interferon can improve the RFS of uveal melanoma.Patients are encouraged to take part in clinical trials.

4.2 Radiotherapy

In general,melanoma was considered to be insensitive to radiotherapy,but in some special situations,radiotherapy is still one of important treatment.Radiotherapy included radical radiotherapy for primary lesions of patients who could not tolerate operation or who had positive surgical margins but were not suited for reoperation;adjuvant radiotherapy for patients whose surgery margin of the primary lesion resection was insufficient,and meanwhile,could not receive secondary surgery,and palliative radiotherapy for patients who received lymph node dissection and had brain and bone metastases as well as treatment for small-and medium-sized uveal melanomas.

4.3 Systemic therapy

For advanced melanoma patients without contraindications,systemic therapy can reduce tumor burden,improve tumor-related symptoms,improve quality of life,and prolong survival.

4.3.1 Systemic therapy and response evaluation criteria

(1) Targeted therapies

To date,molecular-targeted drugs approved by the National Medical Products Administration (NMPA) for the treatment of melanoma include: BRAF inhibitors(vemurafenib,dabrafenib),MEK inhibitor (trametinib) and KIT inhibitors (imatinib,nilotinib).

(2) Chemotherapy

Traditional cytotoxic drugs,including dacarbazine,temozolomide,fluoxetine,paclitaxel,albumin paclitaxel,cisplatin and carboplatin,are not effective in advanced melanomas with an overall response rate (ORR) of 10%-15%.

(3) Immunotherapy

To date,checkpoint inhibitors approved by NMPA for the treatment of melanoma include: anti-PD1 antibodies(pembrolizumab,toripalimab).

(4) Response evaluation criteria of systemic therapy

Response Evaluation Criteria in Solid Tumors 1.1(RECIST 1.1) is usually used to evaluate efficacy in chemotherapy and targeted therapy,changes of LDH and tumor necrosis also help evaluate efficacy. Imaging evaluation is usually performed every 6-8 weeks during treatment.At the same time,comprehensive assessment of the patient’s symptoms,signs and treatment-related adverse reactions through dynamic observation showed be considered.Immunotherapy can be evaluated by RECIST 1.1 or immune RECIST (iRECIST) criteria.

4.3.2 Advanced melanoma by different primaries

(1) Cutaneous melanoma: BRAF inhibitor ± MEK inhibitor therapy can be considered if patients carryingBRAFgene mutation.For advanced cutaneous melanoma without targeted mutations,chemotherapy+antiangiogenic drugs or immunotherapy can be selected.Treatment options for brain metastases include whole brain radiation therapy(WBRT),stereotactic radiosurgery (SRS),or surgery.

(2) Acral melanoma: BRAF inhibitor ± MEK inhibitor could be considered if patients carryingBRAFmutation.Chemotherapy or immunotherapy could be used for patients without driver gene mutations. Immune checkpoint inhibitors (ICI) monotherapy seems less effective in patients with acral melanoma,clinical trials combining ICI with other therapies are still ongoing in acral melanomas.

(3) Mucosal melanoma: For advanced mucosal melanoma,chemotherapy+anti-angiogenic drugs could be considered,and BRAF inhibitor ± MEK inhibitor is an important choice;anti-PD1/PD-L1 combined with anti-angiogenic drugs is expected to become the standard regimen in the future.

(4) Uveal melanoma: Outcomes for those with metastatic uveal melanoma remain dismal: low mutation rate,easy liver metastasis,low response rate of immunotherapy.Chemotherapy+antiangiogenic drugs ± hepatic arterial chemoembolization is still an important clinical choice.

4.3.3 Therapy of special lesions

(1) Therapy of liver metastases

Compared with systemic chemotherapy,The platinumor fotemustine based hepatic arterial chemoembolization can improve the efficacy and survival.

(2) Therapy of brain metastases

Surgery is still an important treatment approach for brain metastasis of malignant melanoma (BMM).Indications for surgery: isolated metastasis,increased intracranial pressure and obstructive hydrocephalus caused by mass tumor occupation,uncontrollable epilepsy.SRS is recommended as the first choice for BMM,and WBRT is recommended for patients with symptomatic brain metastases and clinical or pathological meningeal metastases but cannot receive SRS.However,the benefit of WBRT for patients with poor performance score or excessive brain metastases may be uncertain.

(3) Therapy of bone metastases

The therapy of melanoma bone metastases,similar to the other tumor bone metastases,aims to reduce the occurrence of bone-related events and relieve pain.It is mainly treated according to the site of metastasis (whether or not load-bearing bone) and symptoms.For isolated bone metastasis,surgery and local radiotherapy after surgery will be optimal therapy.For patients with multiple bone metastases,systemic treatment combined with local treatment can be considered,and local treatment includes surgery,bone cement filling and local radiotherapy.Patients with bone metastases should use bisphosphonate regularly to reduce the occurrence of bone-related events,while painkillers should be used regularly to relieve pain.Strategic decision for patients with spinal cord compression should be made according to different individual situations.Surgery and postoperative radiotherapy are preferred for patients who were diagnosed with better prognosis and light tumor burden.However,radiotherapy alone may be considered for patients who were diagnosed with poor prognosis.Radiotherapy could be performed after internal fixation to relieve bone pain.

4.3.4 Symptomatic supportive therapy

Moderate rehabilitation exercises can enhance immune function.In addition,symptomatic supportive therapy should be strengthened in patients with advanced melanoma,including active analgesia,correction of anemia,correction of hypoalbuminemia,enhancement of nutritional support,control of blood glucose in patients with diabetes,and treatment of accompanying symptoms such as hydrothorax,ascitic fluid and jaundice.

For patients with poor performance status,understanding the mentality of patients and their families can be considered.We should take measures to adjust their corresponding state into positive psychology,and reduce their depression and anxiety through soothing treatment to make them feel safe and comfortable.

Working group members

Group leader:Jun Guo

Associate group leaders:Xiaohui Niu,Tongyu Lin,Shukui Qin

Group members:Shengji Yu,Jiwei Liu,Ting Liu,Weifeng Liu,Yongheng Li,Di Wu,Hongtu Zhang,Yanhua Zhang,Xiaoshi Zhang,Aiping Lu,Xiaohong Chen,Yu Chen,Lu Si,Jianqiang Cai,Hongming Pan

Secretary:Lili Mao,Bin Lian

Translation group members

Group leaders

Jun GuoKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing),Peking University Cancer Hospital &Institute

Lu SiKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing),Peking University Cancer Hospital &Institute

Group members

Lili MaoKey Laboratory of Carcinogenesis and TranslationalResearch (Ministry of Education/Beijing),Peking University Cancer Hospital &Institute

Xuan WangKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing),Peking University Cancer Hospital &Institute

Bin LianKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing),Peking University Cancer Hospital &Institute

Siming LiKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing),Peking University Cancer Hospital &Institute

Li ZhouKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing),Peking University Cancer Hospital &Institute

Jiayong LiuKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing),Peking University Cancer Hospital &Institute

Yongheng LiKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing),Peking University Cancer Hospital &Institute

Yumei LaiKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing),Peking University Cancer Hospital &Institute

Yu ChenDepartment of Medical Oncology,Fujian Cancer Hospital &Fujian Medical University Cancer Hospital

Appendix 1 Clinical stage of melanoma and treatment modalities

Appendix 2 Staging of cutaneous melanoma (AJCC 8th edition)

Table A1 T stage

Table A2 N stage

Table A3 M stage

Table A4 Pathological staging of cutaneous melanoma (AJCC 8th edition)

Appendix 3 Staging of head and neck mucosal melanoma (AJCC 8th edition)

Table A5 TNM staging of head and neck mucosal melanoma (AJCC 8th edition)

Appendix 4 Staging of ciliary body and choroid melanoma (AJCC 8th edition)

Table A6 TNM staging of ciliary body and choroid melanoma (AJCC 8th edition)

Table A7 Pathological staging of ciliary body and choroid melanoma (AJCC 8th edition)