Surveillance and Follow-Up of Melanoma Patients
The patient treated for melanoma lives with some risk of recurrence and needs a rational plan for posttreatment follow-up. Appropriate follow-up for melanoma survivors must balance the benefits and harms of repeated surveillance with the needs and goals of the patient and within the capacity and constraints of the healthcare system in which the follow-up occurs.
Routine surveillance by a clinician is an important aspect of follow-up for detection of melanoma recurrence. For decades, attempts have been made to introduce a follow-up schedule that would find international consensus, but to date, there is no consensus on the optimal frequency, intensity, and duration of follow-up in melanoma patients. Dermatologic surveillance is important for detecting new primary and other nonmelanoma skin cancers in this group of patients, a group that frequently has a history of sun damage. A whole-body examination by an experienced dermatologist using technical instruments such as dermoscopy remains the gold standard. During routine follow-up by a healthcare professional, in addition to dermatological examination, a range of strategies including radiologic and laboratory tests are often used. However, there is little evidence to support the value of routine radiologic and laboratory testing particularly in the follow-up of stage I/II melanoma patients.
In addition to visits with a healthcare provider, skin self-examination is recommended to identify primary cutaneous lesions but also for detection of recurrences in the locoregional area. Follow-up clinics and guidelines in melanoma care exist around the world. However, the evidence to date is insufficient to strongly support one specific set of follow-up guidelines. This chapter outlines the principles and components of follow-up care.
Goals of Surveillance
Melanoma is a significant public health problem worldwide. The incidence of melanoma has increased rapidly in the last two decades, while the death rate has stabilized or fallen in many countries resulting in large numbers of patients surviving melanoma. In the United States in 2018, there will be an estimated 91,270 new cases of invasive melanoma and 9320 deaths attributable to melanoma (The National Cancer Institute 2018).
The overall 5-year survival is 90–92% (Australian Institute for Health and Welfare 2018; The National Cancer Institute 2018), thereby dramatically increasing the prevalence of melanoma survivors in need of follow-up. Individuals with regional or distant disease account for approximately 13–15% of patients with newly diagnosed melanoma and are generally thought to warrant close surveillance. Fortunately, today most new cases of invasive melanoma are diagnosed at an early stage, approximately 85% (The National Cancer Institute 2018) of cases are either stage I or stage II, and most of those are expected to have a good prognosis after surgery alone (Jemal et al. 2008; Balch et al. 2009).
Nonetheless, every patient treated for melanoma lives with some risk of recurrence and needs a rational plan for follow-up. Appropriate follow-up for melanoma survivors must balance the benefits and harms of repeated surveillance and the needs and goals of the patient, within the capacity and constraints of the healthcare system in which the follow-up occurs.
After the melanoma treatment is completed, active surveillance can address many goals. The goal most often discussed and pursued is surveillance for the risk of disease recurrence, whether local, regional, or distant. Follow-up is most valuable when it leads to detection of recurrent disease that is potentially curable. Given the success of systemic therapies for treating active stage III and IV melanoma, early detection and treatment of recurrence may further improve survival. Another goal of surveillance is the detection and management of long-term complications of treatment, including lymphedema related to surgical management or side effects from systemic drug therapy. Other appropriate goals for melanoma patients who have completed treatment include assessing quality of life and patient satisfaction with care; providing psychosocial support, providing education regarding melanoma prevention and skin self-examination, and ongoing screening for the risk of new primary skin cancers and screening for the risk of other primary cancers (Morton et al. 2013; Read et al. 2018; Rychetnik et al. 2013). Melanoma clinical quality registries may play a role in long-term data collection for follow-up programs (Jochems et al. 2017).
Patterns of Melanoma Recurrence
Risk of Local and Regional Recurrence
The overall risk of melanoma recurrence is most strongly correlated with stage at presentation (Balch et al. 2009). Between 20% and 25% of patients with (American Joint Committee on Cancer) stage I and II melanoma in the sentinel lymph node biopsy era will have a recurrence (Turner et al. 2011). The pattern of recurrence, that is, whether a first relapse is most likely to be local, regional, or distant, is related to both the stage of the original disease and the type of treatment given.
A number of randomized clinical trials comparing wider versus narrower excision margins have established the current recommendations for excision margins and have also provided documentation of local recurrence rates after such (Balch et al. 2001; Cohn-Cedermark et al. 2000; Khayat et al. 2003; Thomas et al. 2004; Veronesi et al. 1991).
The World Health Organization trial of 1 cm versus 3 cm margins for melanomas less than 2 mm reported local recurrence rates of less than 1% regardless of excision margin (Veronesi et al. 1991). A Swedish trial of 2 cm versus 5 cm margins for melanomas 0.8–2.0 mm reported local recurrence rates of less than 1% with no difference between the two groups; a similar European study of 2 cm versus 5 cm margins for melanomas less than 2.1 mm reported local recurrence rates of 1.5% with no difference between groups (Cohn-Cedermark et al. 2000; Khayat et al. 2003; Veronesi et al. 1991).
In the Intergroup Melanoma Surgical Trial comparing 2 cm versus 4 cm margins for intermediate-thickness (I to 4 mm) melanomas, local recurrence rates were 2.1–2.6% at a median 10-year follow-up but were not correlated with excision margin.
Higher local recurrence rates were seen in patients with ulcerated tumors and primary tumors of the head and neck (Balch et al. 2001). In a study from the United Kingdom of patients with melanomas greater than 2 mm, who were randomized to groups with 1 cm versus 3 cm margins, local recurrence as a first event was seen in 3.1% of patients, and the rates did not differ significantly between the two groups (Thomas et al. 2004). Factors in many of these studies that appear to be associated with higher risk of local recurrence were increased tumor thickness and tumor ulceration. More recently the MelMarT trial (Moncrieff et al. 2018) was designed to ascertain the impact of 1 cm- vs 2 cm-wide excision for melanomas >1 mm Breslow thickness, on local recurrence, and melanoma-specific survival.
Prior to the widespread implementation of sentinel node biopsy, regional lymph nodes were the most common initial site of recurrent disease. In the abovementioned UK study, the nodal relapse rate for stage II patients with melanomas greater than 2 mm was 29.2% at 5-year follow-up (Thomas et al. 2004).
The risk of regional nodal recurrence in patients managed with wide local excision and nodal observation increases with increasing tumor thickness. The risk of nodal relapse in patients randomized to the observation arm of the Multicenter Selective Lymphadenectomy Trial I (with thicknesses ranging from 1.2 to 3.5 mm) was 15.6% at 5 years (Morton 2006). Since the adoption of sentinel node biopsy for patients who are newly diagnosed with melanoma, the regional node basin is no longer the most common initial site of clinical relapse. In-basin recurrence among patients who have had a negative sentinel node biopsy is uncommon, with rates of 1.5–4.1% reported (Chao et al. 2002; Dalal et al. 2007; Gershenwald et al. 1998; Morton et al. 2006; Vuylsteke et al. 2003).
The Multicenter Selective Lymphadenectomy Trial II (Faries et al. 2017) that randomized sentinel node biopsy-positive patients to complete lymph node dissection or nodal observation reported 92% disease control in regional lymph nodes at 3 years versus 77% control for the observed patients. In a series of patients who have undergone sentinel node biopsy as a staging procedure with complete nodal dissection for positive sentinel nodes, the regional node basin was a subsequent site of disease recurrence in 0–10% of patients (Chao et al. 2002; Gershenwald et al. 2000; Vuylsteke et al. 2003).
Recurrence patterns for patients who have had a sentinel node biopsy (with selective node dissection in the event that the sentinel node is positive) now show a predominance of distant and local recurrences, with far fewer regional recurrences (Chao et al. 2002; Gershenwald et al. 2000; Vuylsteke et al. 2003).
In a large Australian study of 3642 patients undergoing sentinel node biopsy (Read et al. 2015), the rate of in-transit metastases was 7.2%. The rate was 4.7% in SN-negative patients and 21.6% in SN-positive patients. Factors that predispose patients to in-transit recurrence include increasing tumor thickness of the primary lesion, tumor ulceration, and sentinel node positivity (read et al. 2015).
Time to Recurrence
In patients who have recurrences, 55–67% of these recurrences will become apparent by 2 years and 65–81% by 3 years after initial treatment of the primary tumor (Balch et al. 2009; Francken et al. 2008a). Tumor ulceration, older patient age, and site of primary melanoma are also associated with earlier recurrence. The time to recurrence varies in inverse order to the thickness of the primary tumor, that is, thicker tumors have a recurrence pattern that favors early recurrence, whereas thinner tumors may recur many years after diagnosis (Lo et al. 2018). In patients treated for melanoma that has metastasized to regional nodes, the time to distant recurrence is usually earlier than in patients without regional nodal metastases. The heterogeneity of prognosis in patients with metastatic regional nodes is striking. The three most important factors contributing to prognosis of node-positive patients are the number of positive nodes, whether the nodes were clinically palpable and whether the primary tumor showed ulceration on histologic examination. Five-year survival rates range from 69% in patients with a single microscopically positive node and a non-ulcerated primary lesion to 13% in patients with four or more clinically positive nodes and an ulcerated primary lesion. The 15-year survival curves for patients with positive nodes are notable for two features. Patients with a greater number of positive nodes have distinctly poorer survival rates than those with fewer positive nodes. In addition, most deaths due to melanoma occur in the first 3 years, with the survival curves all gradually reaching a plateau (Balch et al. 2009). At 15 years, a persistent minority of patients are alive, even with a history of four or more positive nodes (Balch et al. 2009).
In general, patients with late recurrence tended to be younger and have thinner primary lesions than patients with an earlier recurrence, and they almost always initially have clinically negative nodes. In general, the prognosis after late recurrence is similar to that after early recurrence (Faries et al. 2013).
Strategies for Active Follow-Up of Melanoma Patients
There is no general consensus on the optimal frequency, intensity, and duration of follow-up in melanoma patients. Most recurrences are detected within the first 2–3 years after diagnosis, with decreasing likelihood of recurrence over time. The probability that a recurrence will develop more than 5 years after diagnosis is low but is clearly not zero. Surveillance for locoregional and distant recurrence seems most likely to be productive in the first few years after diagnosis, with diminishing yield expected with longer-term follow-up.
It is difficult to define the relationship between intensity of follow-up and outcome in patients with melanoma. The assumption motivating the followup of any cancer patient is that early detection of recurrence will lead to early treatment, which might have an impact on long-term outcomes (Rueth et al. 2015). However, recurrences, when detected, are not always treatable and, if they are treatable, are not always curable. To date, there are no studies of follow-up of melanoma patients that have demonstrated any survival advantage with intensive monitoring for recurrence (Nieweg and Kroon 2006). It is unclear whether surveillance of treated melanoma patients results in earlier curable detection and superior outcomes.
Detection of Recurrences
Patient history and physical examination remain the cornerstone of recurrence detection in patients in all stages of melanoma, since local, in-transit, and regional recurrences are most frequently detected by physical examination. Distribution of recurrences was described as 3–5% local or in transit, 5–13% regional, and 3–10% distant (Francken et al. 2005). Among patients whose melanoma recurred, 20–28% first presented with local or in transit, 26–60% with regional nodal, and 15–50% with distant recurrence. A number of retrospective studies have assessed the detection of first recurrences. Patient-detected recurrences were reported in 44–90% of cases, but a variety of methodologies were used (questionnaires, interviews, and including symptomatic versus asymptomatic patients). Almost all studies described a prescribed follow-up schedule that patients adhered to. The minimum frequency of follow-up was twice a year for the first 3 years in all studies. Patient detection of a first recurrence has consistently been the most commonly reported type of recurrent disease detection (Baughan et al. 1993; Francken et al. 2007; Meyers et al. 2009; Mooney et al. 1997; Romano et al. 2010).
To date, only one prospective study has assessed follow-up of patients with melanoma, with a focus on how recurrences were detected at follow-up visits (Garbe et al. 2003). Only 17% of the 233 recurrences in 112 patients were detected by the patient. Although methodological differences could explain this difference with retrospective studies, a large international cohort study from 8178 patients found skin self-examination to be higher in Australia, the United States, and Southern Europe than in Central Europe (Kasparian et al. 2012). This was confirmed by Livingstone et al. in a German study where 33.3% of recurrences were patient detected, even though 69.4% of recurrences were visible or palpable (Livingstone et al. 2015). We can conclude that there may be large topographical and cultural differences and that there is an urgent need for better patient education in some areas, to guarantee that confirmation of metastasis occurs as early as possible. In this same study, only 12.9% of the patients reported to have received patient education about self-surveillance, 68.1% oral information, and 51.7% written information, respectively.
A few studies analyzed survival according to the person who detected the first recurrence, but most did not find a significant difference in survival regardless of whether the recurrence was detected by the patient or a doctor (Baughan et al. 1993; Francken et al. 2007; Hoffman 2002). Garbe et al. however did find a survival benefit in early detected metastases (Garbe et al. 2003).
Role of Physical Examination
As described above, comprehensive locoregional examination is the most important facet of melanoma follow-up. Most recurrences after treatment of stage I and II melanoma are locoregional and thus detectable by physical examination. Early detection of locoregional recurrence along with surgical intervention may provide better control of disease. A careful examination for local recurrence or visible or palpable in-transit disease, as well as examination of regional nodes, is essential. Up to 30% of patients with locoregional recurrences can be salvaged with surgical treatment.
Basseres et al. reported that of 115 recurrences detected in 528 patients with stage I melanoma, 87% were detected by clinical examination (Basseres et al. 1995). However, even in a study where stage III patients were followed after primary diagnosis and received CT scans every 3 months the first 2 years and every 6 months up to 5-year follow-up, 47% of recurrences were detected by the patients, 21% by the physician, and only 32% by imaging methods (Romano et al. 2010). Physical examination of patients with resected regional disease is useful as well. A study from Gadd et al. reported a series of 1019 patients undergoing lymphadenectomy for melanoma, 403 of whom had a recurrence. Of those 403 patients, 291 (72%) had a recurrence at a single site. Of these 291 single-site recurrences, 190 (65%) were non-visceral and potentially detectable by physical examination (Gadd and Coit 1992). With regard to the role of physical examination in detection of distant metastatic disease, in patients who have a recurrence with remote nodes or soft tissue metastases, physical examination represents an efficient, low-cost method of detection. It is particularly important to detect metastases, because there is a 20–25% survival rate after surgical resection alone in this group of patients (Faries and Morton 2006). Improved disease-free survival in patients with extensive unresectable soft tissue metastases may be achieved with the use of systemic therapies. Visceral metastases are not frequently detected by physical examination. Therefore for high-risk patients, screening with imaging techniques may be required.
As a corollary to the preceding observations, an integral part of the follow-up of patients with melanoma could be the teaching of skin self-examination, not only for detection of new primary cutaneous lesions but also for detection of recurrences in the locoregional area. Successfully implementing skin self-examination requires patient education on whole-body skin examination with particular attention given to melanoma surgical scars and the corresponding lymphatic drainage areas for in-transit and lymph node recurrence. Patients should also be given education regarding persistent symptoms that may warrant further investigation. In addition, the use of brochures or videos and the engagement of relatives in the education process may be helpful (Mills et al. 2017; Murchie et al. 2007, 2015; Francken et al. 2005, 2008b; Dancey et al. 2005; Poo-Hwu et al. 1999).
Randomized controlled trials are underway (ACTRN12616001716459: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=371865). In Australia, patients themselves detect up to 75% of recurrences, while in other countries this can be as low as 20% (Francken et al. 2008a, b; Garbe et al. 2003; Poo-Hwu et al. 1999; Hofmann et al. 2002). These data highlight that even with education, there are great differences in patients’ individual ability to detect recurrences.
A history of melanoma diagnosis by itself does not seem to improve patients’ ability to detect new lesions by themselves (Francken et al. 2008b).
Self-examination is recommended following definitive local treatment for melanoma patients of any stage. The Australian clinical practice guidelines (Cancer Council Australia 2018) further recommend that high-risk patients be educated to recognize and document lesions suggestive of melanoma and to perform the skin self-examination.
This surveillance for at high-risk people aims to detect recurrence or progression at an early stage, identify treatment-related morbidity, identify new melanomas or non-melanoma skin cancers, and provide support.
Patient Well-Being and Follow-Up
Improved methods for melanoma detection and treatment have led to increasing numbers of people surviving melanoma for many years. Thus, cancer survivorship should be a primary focus, and there is a recognized need for more research to increase the well-being of cancer survivors.
For decades, physical outcomes such as recurrence and survival have been used to evaluate treatment effects in people with melanoma. Researchers have neglected to examine how routine follow-up can impact patients’ well-being. Few studies have investigated patient well-being in patients with melanoma and hardly any in relation to follow-up surveillance. Most studies report that follow-up is much appreciated by patients; although it evokes anxiety, consultation with doctors, psychologists and nurses can help patients to cope with uncertainties (Bell et al. 2017; Lim et al. 2018; Morton et al. 2013; Brandberg et al. 1995; Wheeler 2006).
Studies of psychological and educational interventions have been shown to result in lower levels of distress, at least in short-term follow-up (Dieng et al. 2016; Boesen et al. 2005; Trask et al. 2003).
Melanoma follow-up guidelines
Basis of follow-up guideline
History and Physical Examination
H&P, CXR, CT, PET, MRI, S100 annually for life
H&P every 3–12 months for 5 years and then annually as clinically indicated
H&P every 6–12 months for 2 years and then 3–12 months for 3 years and then annually as clinically indicated
Consider CXR, CT+/-PET every 3–12 months and annually MRI of the brain. No imaging in asymptomatic patients after 5 years
Guidelines for Management of Melanoma in Australia and New Zealand
H&P annually for 10 years
History and Physical Examination every 6 months for 2 years, annually for 8 years
H&P every 3 months for 2 years, every 6 months for 2 years, annually for 5 years
Every 3 months for 2 years, every 6 months for 1 year
Considered for 3 years, but no survival advantage
German Cancer Society and German Dermatological Society
H&P every 6 months for 3 years, every 12 months for 7 years
H&P every 3 months for 3 years, every 6 months for 2 years, every 6–12 months for 5 years
Every 6 months ultrasonography. Every 3 months S100B
Stages IIC–IV, not resected
H&P every 3 months for 5 years and then 6 months for 5 years
Every 3 months ultrasonography and S100B for 3 years, every 6 months for 2 years, every 3 months S100B. Cross-sectional imaging every 6 months for 3 years
Comprehensive Cancer Network of the Netherlands
Once at 1 month after surgery
Once at 1 month after surgery
H&P every 3 months 1st year, every 6 months 2nd year, every yearly 3–5 years
No specific recommendations
Although most guidelines recommend frequent follow-up, overall adherence seems to be poor. An Austrian study of patients with melanomas less than 1.5 mm thickness found a mean annual dropout rate of 11.2%, with only 55.3% of patients still in follow-up at 5 years. The dropout rate was not related to sex, age, or tumor thickness (Kittler et al. 2001). Similar dropout was seen in Germany (Livingstone et al. 2015), and Australian figures were even worse: 43.2% stage I and 28.7% stage II had a maximum of 1 post-up visit in their specialized clinic. Only 13.2% stage I and 4.1% stage II had received follow-up according to the guideline over 5 years. Nonetheless patients might have found their consultation for follow-up at their GP or elsewhere (Memari et al. 2015).
Huibertse et al. studied patients’ preferences in the Netherlands for the healthcare professional providing follow-up care (Huibertse et al. 2017). Most patients preferred a medical specialist, but the authors concluded this might be due to unfamiliarity with other healthcare providers such as specialist nurses or nurse practitioners. In the United Kingdom, a randomized controlled trial was performed on GP-led follow-up. The authors found the strategy was safe and feasible and engendered high patient satisfaction (Murchie et al. 2010). Few studies are done on reducing follow-up schedules. The MELFO study in the Netherlands examined the well-being of patients with stages Ib–IIc melanoma in a randomized controlled trial in which patients received reduced, stage-adjusted follow-up. At 1-year follow-up, no difference in well-being was found nor any adverse results (Damude et al. 2016). The same (MELFO) follow-up schedule was studied in Australia by modelling the delay in diagnosis. Turner et al. (2011) did find a potential delay in diagnosis of about 2 months in only 44.9 per 100 patients. Fields and Coit concluded in their review on the follow-up of melanoma that many authors conclude their work with recommendations to reduce follow-up. In the absence of a randomized trial evidence, patient-related factors such as physical and mental health, travel distance, personal preferences, and available resources determine follow-up schedules, and most follow-up guidelines have remained unchanged (Fields and Coit 2011).
Radiologic Studies and Laboratory Tests
There is little evidence to support the value of routine radiologic and laboratory testing in the follow-up of stage I/II melanoma patients. The use of routine chest X-ray exams for the detection of small pulmonary metastases has been investigated; however, false-positive and false-negative findings are frequent. The sensitivity of chest X-ray is poor with reports varying from 7.7% to 48%. A large study of 1969 patients with stages I–III melanoma undergoing routine follow-up found only 10/204 relapses were discovered by chest X-ray: the majority (7/10) of which were observed in patients with stage III disease (Leiter et al. 2009).
A large prospective study of 1235 patients found only 0.9% of chest X-rays identified pulmonary metastases, less than 10% of which were amenable to resection, with a false-positive rate of 3.1% (Brown et al. 2010).
A cost-effectiveness analysis using data from the Roswell Park Cancer Institute and the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program found CXR screening was not cost-effective at $165,000 per quality-adjusted life year gained (Mooney et al. 1997).
A recent systematic review of PET imaging studies (Danielsen et al. 2013) was undertaken to assess the diagnostic value of PET as a tool for surveillance in the regular follow-up program of asymptomatic cutaneous malignant melanoma patients. The majority of the 739 patients in the studies were stage IIB and III. The authors repeated the mean sensitivity of PET was 96% (95% CI: 92–98), and the specificity was 92% (95% CI: 87–95). Overall, PET had a high diagnostic value; however, there were no data available to demonstrate better survival outcomes for patients as a result of routine PET surveillance. In addition, PET produces false-positive findings leading to subsequent unnecessary procedures.
The usefulness of ultrasonography for follow-up of patients without a sentinel node biopsy treated for stage I/II melanoma depends entirely on the technical skill and experience of the personnel involved. There is a consensus of opinion that ultrasound is superior to clinical examination of regional lymph nodes, although its survival advantage is unproven (Bafounta et al. 2004). A prospective cohort study of 373 patients with a primary tumor Breslow thickness of ≥1.5 mm (Machet et al. 2005) reported a sensitivity of 93% for ultrasound compared with only 71% for the clinical examination of regional lymph nodes. The specificity was equally high for both procedures (>98%). Despite the superiority of ultrasound, very few patients actually benefited from the addition of ultrasound to clinical examination, due to deleterious effects such as unnecessary stress caused by repetition of ultrasounds for benign lymph nodes or the useless removal of benign lymph nodes. In summary, ultrasound was advantageous in only 1% of patients. Fine needle aspiration is the current standard method to confirm the presence of suspected nodal metastases for lymphadenopathy identified after definitive local treatment of cutaneous melanoma (Dalle et al. 2006).
Ultrasound may be used to identify the extent of in-transit and nodal disease and also to diagnose liver metastases. The current German guidelines, for example, include ultrasound examinations of regional lymph nodes and in-transit areas at regular, risk-adapted time intervals (Garbe et al. 2007).
Furthermore, reduced intensity and frequency of follow-up recommendations are known to be more cost-effective (Hengge et al. 2007).
Some centers have adopted a risk-stratified approach using CT scans of the chest and abdomen exclusively for stage III patients with a high risk of distant metastases and MRI of the brain as cerebral metastases are more readily detected by MRI than by CT. Routine radiological investigations every 3–12 months may be considered for the first 3 years of follow-up after definitive local treatment of stage IIC and III melanoma where detection of recurrence would allow early commencement of systemic therapy. However, there are currently no high-quality data that early detection and treatment of recurrence improves survival.
Positron emission tomography (PET) with or without concurrent CT scans (PET-CT) has been met with enthusiasm as promising imaging techniques for high-risk melanoma patients. The specificity of CT scans alone may be improved by adding a concurrent PET scan and by clinical correlation. PET-CT scans are at present best employed in the diagnostic evaluation of patients with established regional or distant disease. The routine use of PET-CT is troubled by possible false-positive results, leading to anxiety, additional investigations, and expense. Even when true distant disease is found, it is unclear whether such detection will be associated with improved survival. However, PET-CT imaging is becoming a standard of care in many melanoma treatment centers (Pflugfelder et al. 2013; The National Cancer Institute 2018), particularly in the era of adjuvant immunotherapies for stage III melanoma. Early detection of advanced metastatic disease and early treatment with systemic therapies may lead to an improvement in overall survival (Rueth et al. 2015).
Laboratory evaluations are still performed in melanoma treatment centers and practices specializing in melanoma, although they rarely lead to the detection of metastatic disease. As a tumor marker, S100B displays a sensitivity of 86–91% and specificity of 76–91% (Deichmann et al. 1999; Krahn et al. 2001) and may portend recurrence; however there are no data demonstrating superior survival outcomes for patients undergoing routine S100B testing in follow-up. The use of serum LDH or melanoma inhibitory activity (MIA) protein in follow-up for the detection of asymptomatic melanoma recurrence has been reviewed (Schultz et al. 1990). Abnormal blood tests were rarely the first sign of metastases. Low sensitivity, specificity, and accuracy for general laboratory profiles make them ineffective in the detection of subclinical recurrence, and their roles are yet to be defined.
Other investigations during follow-up include skin self-examination, physician-led medical history, and clinical examination. A review of nine clinical practice guidelines (2014) (Marciano et al. 2014) reveals consensus that patients should be taught skin self-examination, as most recurrences are first detected by patients (Francken et al. 2007). In a large prospective study, approximately 50% of recurrences were identified by history taking/physical examination, 80% of which were local recurrences, in-transit metastases, and regional lymph node metastases (Garbe et al. 2003).
Screening for Risk of New Primary Melanomas
Patients with a history of melanoma have a higher risk for the development of new primary melanomas compared with the general population. The reported incidence of new primaries ranges from 2% to 8% (Ferrone et al. 2005; Francken et al. 2005; Nieweg and Kroon 2006) and the rate remaining relatively constant over 20 years of follow-up at 6.01 per 1000 person-years indicating a high lifetime risk of second primary invasive melanomas (McCaul et al. 2008).
This risk does not diminish over time and does not differ significantly between patients first diagnosed with lentigo maligna, in situ melanoma, or invasive melanoma. The risk is even higher for patients with a parental history of melanoma (Zhang et al. 2008).
A second invasive melanoma is most commonly thinner than the initial primary melanoma and has a more favorable prognosis (Jones et al. 2016).
However, a large population-based study of 32,238 patients reported a hazard ratio of death within 10 years from melanoma two times higher for those with two melanomas and nearly three times higher when three melanomas were diagnosed, compared with people with a single melanoma (Youlden et al. 2016).
In general, subsequent primary invasive melanomas are more likely to occur at the same body site as the initial invasive or in situ melanoma (Youlden et al. 2014).
The subset of melanoma patients at very high risk for developing a second primary skin cancer include people with a hereditary predisposition for melanoma (i.e., germline CDKN2A mutations or the CDK4 gene or xeroderma pigmentosum) and those with multiple atypical nevi or a strong family history of melanoma (Ferrone et al. 2005; Hansson et al. 2007). Whole genome sequencing has identified common variations of single-nucleotide polymorphisms (SNPs) in at least 20 genes that influence melanoma risk in the population, accounting for about 20% of the excess risk to relatives of melanoma cases ( Cancer Council Australia 2018).
Recent clinical practice guidelines suggest clinical genetic testing for CDKN2A mutations, and genetic counselling should be considered in individuals with a strong family history of melanoma (three or more cases related in the first or second degree) where predictive features are present, such as multiple primary melanoma, early age of onset, or pancreatic cancer ( Cancer Council Australia 2018).
While follow-up guidelines for this population are variable (Watts et al. 2015), clinical surveillance in specialized clinics for people at high or very high risk of melanoma has been shown to be effective and cost-effective (Moloney et al. 2014).
Dermatologic surveillance is important in detecting new primary and other nonmelanoma skin cancers in this group of patients, a group that frequently has a history of sun damage.
Screening for these second melanomas is therefore essential, because early detection of primary melanoma is associated with improved survival. A wholebody examination by an experienced dermatologist in a structured follow-up is still the gold standard. Apart from the ABCD rule to differentiate between benign nevi and melanomas, patient concerns and symptoms are important in early detection. Other skin screening approaches include total body photography repeated at regular intervals as an adjunct to skin examination. Total body photography is commonly used to monitor patients at increased risk for melanoma, particularly those with high nevus counts and dysplastic nevi (Cancer Council Australia 2018). Comparison with prior photos may allow identification of subtle changes that may lead to biopsy or, conversely, may provide reassurance that no change has occurred and biopsy can be avoided. Recent studies have reported total body photography reduces the biopsy rate of benign nevi and improves diagnostic accuracy of melanoma in high-risk patients (Truong et al. 2016; Moloney et al. 2014).
Currently the most useful technical instrument in the follow-up of melanoma is the dermatoscope. Dermoscopy is based on the ability of light to penetrate the epidermis and illuminate the superficial dermis. Many features of the appearance of the dermis under dermoscopy have been described that may help distinguish between benign and malignant lesions. Dermoscopy, with or without computer imaging, is widely used in Europe and Australia particularly in highrisk patients. The proper use of dermoscopy requires a certain amount of focused training and experience (Binder et al. 1997; Argenziano 2005).
It can be a useful tool not only in detecting early melanomas but also in preventing the unnecessary removal of benign melanocytic lesions. Clinical guidelines recommend the use of short-term sequential digital dermoscopy imaging (dermoscopy monitoring) to detect melanomas that lack dermoscopic features of melanoma and long-term sequential digital dermoscopy imaging (dermoscopy monitoring) in patients who are at high risk of a new primary melanoma ( Cancer Council Australia 2018).
Teledermoscopy is a form of teledermatology that specifically involves the store and forwarding of digital dermoscopic images. When compared with other imaging techniques, teledermoscopy improves diagnostic accuracy and has recently been shown to be cost-effective (Snoswell et al. 2018) as a referral mechanism for specialist dermatological review of skin cancers versus a standard referral letter without images. Monitoring of suspicious lesions particularly amelanotic tumors (Guitera et al. 2016) and lesions typified by regression (Borsari et al. 2016) may be best performed using reflective confocal microscopy used by a skilled dermatologist.
Screening for Other Primary Cancers
For patients with a history of melanoma, Bradford et al. found significantly elevated risks for specific subsequent primary cancers other than melanoma (Bradford et al. 2010).
The most common cancers with elevated risks after an initial melanoma were prostate cancer, female breast cancer, and non-Hodgkin lymphoma. Risks were also found to be significantly increased for cancers of the salivary gland, small intestine, kidney, ocular melanoma, and thyroid as well as soft tissue sarcomas and chronic lymphocytic leukemia (Bradford et al. 2010). In the absence of other medical indications, routine age-appropriate surveillance guidelines should be followed.
Current Recommendations for Surveillance
Given the lack of evidence of any improvement in outcomes as a result of intensive surveillance examination after definitive treatment for melanoma, one may wonder whether follow-up guidelines should exist at all (Nieweg and Kroon 2006; Fields and Coit 2011).
Regardless, follow-up clinics and guidelines in melanoma care exist around the world. Among other places, follow-up guidelines have been developed in the United Kingdom, Germany, Switzerland, Scotland, the Netherlands, the United States, and Australia. The content of these guidelines varies widely. The duration of follow-up varies from 3 to 10 years total, often depending on the perceived level of risk. Many guidelines do not recommend any routine radiologic or laboratory investigations, except when specific symptoms are present, as seems to be concordant with the evidence. However, some do consider routine or optional chest radiographs, lymph node ultrasound imaging, blood tests, or PET-CT imaging for higher-risk patients.
The optimal duration of follow-up is unknown; late recurrences more than 10 years after treatment of localized melanoma are uncommon but well recognized, and the risk of developing a second primary melanoma is spread out over a lifetime. Current recommendations for follow-up meet the goals of surveillance for recurrence of treated melanomas, screening for new primary skin cancers, and monitoring for complications of treatment. The current guidelines in the United States, Australia, Germany, and the Netherlands in patients with stages 0–IV melanoma are outlined in Table 1 (Saiag et al. 2007; Garbe et al. 2007).
An optimal follow-up program for patients with melanoma should be defined by the results of a large-scale randomized trial. However in the absence of this evidence, and given the increasing incidence of melanoma, the development of rational, productive, and cost-effective follow-up plans is of great importance. The evidence in the existing literature is insufficient to strongly support one specific set of follow-up guidelines. The wide variance in guidelines currently in use demonstrates that historical policy, cultural experience, and personal views still play an important role in both the guidelines and the practice of follow-up care in patients with melanoma.
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