Melanoma: Staging and Follow-Up

Cancer staging is the process determining to which extent a cancer has spread and where it is located in the body. A thorough staging is of utmost importance, not only because it provides the most accurate prognostic estimation, but also because several crucial decisions, such as the treatment choice and the follow-up strategy, vary according to the tumor’s stage. The current staging system for melanoma is based on the 8th edition of TNM classification issued by the American Joint Committee on Cancer (AJCC) in 2017. It includes a clinical and a pathological staging, both consisting of 5 stages (0–IV). The stage of a melanoma is determined by several factors, among which the Breslow thickness, the pathological presence or absence of ulceration in the primary tumor, the presence and the number of tumor-involved regional lymph nodes, the presence or absence of in-transit, satellite and/or microsatellite metastases, and the presence of distant metastases. Following melanoma diagnosis, an accurate medical workup, in line with the stage and the physical examination, should be performed. A continuous patient monitoring is fundamental to detect a potential relapse or a second primary melanoma and should be lifelong. However, there is still no universally adopted follow-up strategy program and different follow-up schemes have been suggested. Future prospective studies are needed to evaluate different follow-up protocols according to the adopted therapy, as novel recent therapies (targeted and immunotherapies) are being increasingly used. Key Messages Proper staging is of utmost importance because it provides accurate prognostic estimation. Several crucial decisions, such as the treatment choice and the follow up strategy, are based on the tumor stage. Physical examination during staging procedure and follow-up visits are important to avoid unnecessary imaging and laboratory tests that could increase the patients’ anxiety. A personalized approach taking into consideration the patient’s risk factors, is strongly recommended. Melanoma patients should be kept under surveillance lifelong due to an increased risk of developing a second primary melanoma and the risk of recurrence. Higher intensity follow-up strategies during the first 5 years are recommended due to higher rates of regional or distant relapse.


Introduction
Staging is a process determining the extent to which a cancer has spread in a person's body and where it is located.Cancer stage is categorized from 0 to IV, with stage IV cancer corresponding to a cancer that has metastasized at distant locations.The most used system to stage solid tumors, including melanoma, is the universally accepted TNM (Tumor, Node, Metastasis) staging system.Cancer staging can be divided into clinical and pathological staging.Clinical and pathological stages are defined by different criteria and may differ but are generally considered as complementary to each other.In general, clinical staging is based on all the available information obtained before surgical excision of the tumor (eg by physical examination, blood tests, and imaging), while pathological staging is performed by a pathologist and relies on the information provided by microscopic examination of the tumor following surgical resection.
The clinical stage of a melanoma can be determined only following a complete excision of the primary tumor, a clinical examination of the skin and lymph nodes, and a radiologic assessment for regional and distant metastases' detection.
Pathological staging of a melanoma takes into account not only the microstaging of the primary tumor and the wide excision but also considers the information on regional lymph nodes after partial or complete lymphadenectomy, when performed.A proper staging is extremely important, because it provides the most accurate prognostic estimation and allows to take several crucial decisions, such as the treatment choice and the follow-up strategy, that are based on clinical tumor stage.
A continuous patient monitoring is fundamental to detect a potential relapse or a second primary melanoma and should be lifelong.However, there is still no universally adopted follow-up strategy program and different follow-up schemes have been suggested.Future prospective studies are needed to evaluate different follow-up protocols according to the adopted therapy, as novel recent therapies (targeted and immunotherapies) are being increasingly used.

Key Messages
• Proper staging is of utmost importance because it provides accurate prognostic estimation.Several crucial decisions, such as the treatment choice and the follow up strategy, are based on the tumor stage.
• Physical examination during staging procedure and follow-up visits are important to avoid unnecessary imaging and laboratory tests that could increase the patients' anxiety.A personalized approach taking into consideration the patient's risk factors, is strongly recommended.
• Melanoma patients should be kept under surveillance lifelong due to an increased risk of developing a second primary melanoma and the risk of recurrence.Higher intensity follow-up strategies during the first 5 years are recommended due to higher rates of regional or distant relapse.

Melanoma Staging System
The current staging system is based on the 8 th edition of TNM classification for staging of melanoma issued by the AJCC in 2017 and is summarized in Tables 1-5 [1].This relatively new system has been broadly accepted after its publication and is considered the cornerstone for classifying melanomas [2,3].
There is both a clinical and a pathological staging, both consisting of 5 stages as follows: Clinical Staging: • 0: in situ disease and the presence or absence of ulceration after the pathological assessment of the primary tumor (Tables 1 and 2).Of note, mitotic rate and Clark's level of invasion, previously used for sub-classification, no longer influence melanoma staging.• III: regional disease Regional disease is defined by the presence of metastases in regional lymph nodes and/or "in transit metastases", "satellite metastases", and microsatellite metastases.Satellite metastases are defined as cutaneous or subcutaneous metastatic lesions up to 2 cm from the margin of the primary tumor.In-transit metastases are defined as cutaneous or subcutaneous lesions located between 2 cm from the primary tumor and the regional nodal basin.Microsatellite metastases are defined as tumor nests larger than 0.05 mm in diameter in the reticular dermis, subcutis, or vessels beneath the primary invasive tumor, but separated from it by at least 0.3 mm of normal tissue on the section in which the Breslow measurement was taken.
Regional lymph nodes metastases are defined as metastases in the lymph node basin that drains lymph from the region around the tumor.Involvement of regional lymph nodes is confirmed by their pathological examination after sentinel lymph node (SLN) biopsy (for clinically occult lymph node metastases) or therapeutic lymph node dissection when performed (for clinically evident regional lymph node disease).
Involvement of regional lymph nodes may be also detected by clinical, radiologic examination and/or diagnostic biopsies (clinical staging).Therefore, there is only 1 stage group for clinical stage III.In contrast, pathological stage III is divided into A, B, C, and D stage groups depending on Breslow thickness, the pathological presence or absence of ulceration in the primary tumor, the number of tumor-involved regional lymph nodes, and the presence or absence of in-transit, satellite and/ or microsatellite metastases (Table 4).for prognostic reasons (Table 5).

Histopathologic Examination
When a suspicious lesion is detected, a biopsy should be performed.A narrow-margin (1-3 mm) excisional biopsy is strongly preferred.In case of primary melanoma, the histopathological features along with clinical examination are determining factors for staging and further management.
Therefore, the pathology report should include the Breslow thickness, the ulceration status, the dermal mitotic rate, the margin status, the presence, or absence of microsatellitosis, and the presence or not of pure desmoplasia.

Physical Examination
Special attention should be paid to the physical examination of the entire skin surface to look for satellites or in-transit metastases but also for a second primary melanoma.Physical examination of the regional lymph node basin should be included.

Sentinel Lymph Node Biopsy and Imaging
Patients with a melanoma in situ and a clinical stage IA melanoma with normal physical examination and no other symptoms need no further imaging or laboratory tests.They also are not candidates for SLN biopsy at baseline.The staging procedure is completed with the performance of wide excision [1].plasma LDH should also be assessed [1].

Follow-Up
After melanoma diagnosis, the role of ongoing surveillance of disease-free patients is of paramount importance.The main goals of the follow-up are the following: 1. Early identification of relapse (local, distant) and subsequent guidance for adjuvant treatment, where appropriate.
2. Early detection of a second primary melanoma and/or non-melanoma skin cancer.
3. Recognition and management of side-effects, in case of adjuvant systemic treatment.
Early detection of relapse is associated with a higher survival rate, highlighting the importance of an adequate follow-up.The likelihood of recurrence varies according to melanoma stage at first presentation.Patients with melanoma in situ, are very unlikely to recur following wide excision.
There are a few exceptions though, such as lentigo maligna type [18][19][20].In general, patients with earlier stage melanoma at first presentation are less likely to recur compared to Patients with a personal history of melanoma are at high risk of developing a second primary melanoma.Concerning the risk of developing a second primary melanoma, data reported in the literature is very heterogenous.The reported percentage of melanoma patients developing a second primary melanoma ranges between 2% and 20% [23,[27][28][29][30].
In a cohort of prospectively monitored melanoma patients, the cumulative 5-year risk of second primary melanoma was 8% [30].Interestingly, the risk appears to be higher within the first year after the diagnosis of the first melanoma, but it remains considerable for at least 5 years and very possibly even more [23,[27][28][29][30].Therefore, individuals with melanoma history should rather be considered at a life-long increased risk of developing a new primary melanoma.
Although the need for a follow-up in patients with melanoma is not a matter of debate, surveillance recommendations vary widely in terms of methods and frequency of visits, and examinations.As there is currently lack of evidence regarding the efficacy of follow-up strategies, different follow-up schemes have been proposed and are mainly based on expert opinions.The suggested follow-up schemes consider the melanoma stage and the presence or not of additional risk factors.
As mentioned above, the first 5 years following the excision of the primary tumor are the most crucial due to high rates of relapse.This is why current guidelines suggest adopting higher intensity follow up strategies during this period.
Still, because of the lifetime increased risk of a second primary melanoma or a non-melanoma skin cancer, as well as the risk for late recurrence, monitoring programs for melanoma patients should go beyond 5 years, including at least 1 strongly recommended annual skin exam lifelong [31].
The modalities used to monitor melanoma patients include whole body skin examination, physical examination of the regional lymph nodes, blood tests, and imaging exams,  in these visits should emphasize on the regional nodes and skin.
For patients with stage IIB to IV (with no evidence of disease), scheduled visits should be conducted every 3 to 6 months for the first 2 years, every 3 to 12 months for the next 3 years and annually thereafter, as clinically indicated again emphasizing on the regional nodes and skin.Moreover, in these stages, imaging (chest x-ray, CT and/or PET/CT) every 3 to 12 months could be considered to screen for asymptomatic recurrence.Regarding central nervous system (CNS), a periodic brain MRI should be performed for up to 3 years to screen for asymptomatic brain metastases in high-risk patients with stage IIIC or higher melanoma, while more frequent surveillance is recommended for patients with prior brain metastases.However, routine imaging is not recommended after 3 to 5 years.Nonetheless, in any case and at any time of follow-up period, when clinically indicated, an appropriate imaging should be offered to evaluate specific signs or symptoms.
Finally, if relapse occurs, imaging is recommended to assess the extent of the disease.In addition, when complete surgical resection of relapse is not feasible and active non-surgical treatment is initiated, clinical examination and/or imaging may be appropriate throughout treatment to assess treatment response.
In Europe, follow up schemes vary among countries, ranging in frequency from 2 to 4 times per year for 5-10 years, again with higher-intensity strategies in more advanced stages and during the first years.Current European consensus-based interdisciplinary guidelines for melanoma have proposed an example of follow-up schedule examinations based on stage and is shown in Table 6 [2].
Irrespectively of the selected follow-up scheme, an individualized approach taking into consideration patient's risk factors, such as risk for recurrence, prior primary melanoma, family history of melanoma and atypical mole syndrome, is optimal.Moreover, patients' education must be an integral part of the surveillance strategy and should include:

Conclusion
In conclusion, although there is still no universally adopted follow-up strategy program to monitor melanoma patients, current recommendations, as described above, could serve as a guide for clinicians while future prospective studies are necessary to better standardize this follow-up protocols.
a. Communication on what to expect from follow-up examinations and why it is important to be compliant with the regular follow-ups.b.Awareness that family members often have an increased melanoma risk.
c. Guidance on how to perform regular self-examination of the skin and peripheral lymph nodes.d.Information regarding correct sun exposure behavior.

Table 4 . Definition of N according to AJCC 8th edition [1]. Category Number of Tumor-Involved Regional Lymph Node Presence of In-transit, Satellite, and/or Microsatellite Metastases
This stage includes distant metastases to lung, central nervous system (CNS) or other organs as well as to skin, soft tissue and nonregional lymph nodes.Although there is no further division to substages, a sub-classification according to the number of organs involved, which organs are involved, and serum levels of lactate dehydrogenase (LDH) is essential