What investigations should be performed following a diagnosis of primary cutaneous melanoma for asymptomatic stage I and stage II patients?

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Contents

Introduction

Investigations for patients with clinical stage I/II melanoma are undertaken to determine prognosis and identify early metastatic disease in the regional lymph nodes (stage III) or distant organs (stage IV). Investigations such as diagnostic imaging, ultrasonography, skin examination and blood tests are conducted for initial staging and also as a part of a follow-up program after definitive surgical treatment. Sentinel node biopsy, is also undertaken for staging and prognostic purposes, however for discussion of this procedure we refer readers to the specific guideline for use of sentinel node biopsy in staging cutaneous melanoma.

The main purpose of follow-up is to detect recurrences early so that early treatment can be undertaken. This assumes that earlier treatment is likely to result in improvements in regional disease control, quality of life and survival. Therefore, follow-up should be mainly prognosis-oriented but should also include the detection of new invasive melanomas. The reported incidence of new primaries ranges from >0.5% to 5% annually dependent on risk features.[1][2] A second invasive melanoma is most commonly thinner than the initial primary melanoma and has a more favourable prognosis that does not adversely affect survival.[3] The rate of occurrence of a subsequent in-situ melanoma is about four times higher than the risk of a subsequent invasive melanoma[4], but most series do not recommend follow-up for in-situ melanomas.[5]

After systematic review of the literature (2012-2016) including previous melanoma guidelines, we considered the evidence base for the use of diagnostic tests for initial staging and follow-up. NHMRC levels of evidence (I-IV) were assigned to each evidence summary statement and recommendations were formed and graded with regard to consistency, clinical impact, generalisability, and applicability for the Australian context. Investigations reviewed in this chapter include chest x-ray, computed tomography (CT) imaging, positron emission tomography (PET)/CT imaging, ultrasonography, and S 100B, MIA, LDH blood tests. Additional experimental investigations identified through our systematic search, are discussed in the section for further research.

The evidence below is a summary of the key findings of test accuracy and clinical usefulness for each diagnostic investigation. We report sensitivity and specificity, positive and negative predictive values where available as the main test performance characteristics for the index test compared to the referent (gold) standard. For follow-up, the proportion resulting in a change in management and/or a change in morbidity and mortality are presented if known. The evidence and recommendations for optimal follow-up settings, duration and frequency are discussed in a separate chapter (see following section)

Nearly all studies for initial staging and follow-up were retrospective in design, at high risk of bias and of NHMRC level III or IV (lower quality) evidence. Several follow-up studies grouped stage II and III patients making ascertainment of benefits or harms from diagnostic investigations difficult. All included results are for stage I/II patients unless otherwise indicated.

Investigations for stage I and stage II melanoma in patients with a negative sentinel node

Imaging

Chest x-ray (CXR) for initial staging

There was only one new study published since 2012. This retrospective study investigated use of pre-operative imaging for 546 clinically node negative cutaneous melanoma patients undergoing sentinel lymph node biopsy. In total 409/546 (75%) had an imaging study: 383 (70%)had a CXR, 53 had CT scans (10%; included 43 CT chest, 34 CT abdomen/pelvis, 2 CT head, 4 CT neck), 25 PET scans (5%), 20 MRI scans (4%; included 18 head MRI, 1 extremity MRI and 1 spine MRI), and 2 people had extremity X-rays (0.4%).[6] Of the 383 people who had CXR, three had positive findings, all of which were false positives (all had negative chest CT scans; false positive rate 0.8%, true positive rate 0%). The 380 negative results were all true negatives. Pre-operative imaging for detection of metastases was not recommended.

Given the limited number of new studies on CXR, a review of the recommendations from previous guidelines was warranted.[3] Among 17 studies, CXR detected stage IV metastatic disease in a few patients; however the test results did not change clinical management, and did not improve overall survival. CXR had a false positive rate of between 2-71%, and a true positive rate of 0%.[7] The evidence base for guidance on use of CXR consisted of small observational studies, with no RCTs, with medium to high risk of bias (NHMRC level of evidence III-2 to IV).

Chest x-ray (CXR) during follow-up

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 stage I-III melanoma undergoing routine follow up found that only 10/204 relapses were discovered by chest X-ray: the majority (7/10) of which were observed in patients with stage III disease.[8] A large prospective study of 1 235 patients found that 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%.[9] 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 that the cost of CXR screening per quality-adjusted life year was $165,000, respectively, in 1996 US dollars.[10] Based on these findings, the investigators suggested reducing the frequency of screening CXR.

Computed tomography (CT) imaging for initial staging

One retrospective study of 172 patients with clinically stage IIB or IIC melanoma evaluated the use of CT of the head, chest, abdomen and pelvis for initial staging.[11] In total 75 patients had 104 CT scans for initial staging, with 8 positive results, of which 6 were false positives and two true positives in one patient with metastatic disease, and one patient with a secondary non-melanoma cancer.

Computed tomography (CT) imaging during follow-up

No new studies of CT surveillance of asymptomatic patients treated for stage I/II melanoma were identified. Existing guidelines and prior studies report little benefit in terms of early detection of metastatic disease, a change in clinical management, improved survival, or cost-effectiveness.[12][13]

Positron emission tomography (PET) or computed tomography (PET/CT) imaging for initial staging

One retrospective study among 106 patients with head and neck primary melanoma, clinically negative nodal disease and negative CT, evaluated the use of FDG-PET for initial staging.[14] In total 47 patients had FDG-PET, with 10 positive results, of which 8 were false positives and two true positives in patients with secondary non-melanoma cancers. Of the 37 patients with a negative FDG-PET, 33 results were true negatives and four were false negatives in patients with occult nodal disease. FDG-PET was found to have no clinical utility in this patient population.[14]

Five new studies using PET/CT were identified, including one systematic review[15], two primary studies assessing detection of nodal disease[16][17] and four assessing detection of distant metastases.[15][17][18][19] In one retrospective study of 149 patients undergoing pre-operative PET/CT imaging for clinically stage I/II melanoma of at least 1 mm thickness, 41 had positive findings, 35 were false positives and 6 were true positives (metastatic involvement of lymph node confirmed histologically; false positive rate 85%, true positive rate 15%).[18] There was no clinical utility associated with PET/CT above and beyond SNB: false positives led to unnecessary invasive procedures, and true positives yielded no further information to the SNB. The authors concluded pre-operative PET/CT was of limited benefit in staging clinical stage I/II patients.[18] Another study compared sensitivity and specificity of PET/CT versus high resolution ultrasound for the identification of metastatic involvement of sentinel lymph node.[16] The sensitivity, specificity, PPV and NPV of PET/CT were 0%, 100% (95%CI 91.6–100.0), 0% and 71.1% (95% CI 58.6–81.2) respectively. The authors concluded high resolution ultrasound was better value than PET/CT in preoperative identification of positive SLNs. A second retrospective study of 77 clinically stage I/II melanoma patients aimed to identify a threshold thickness for the primary melanoma, above which PET/CT might be useful.[19] All but 1 of the 11 patients with positive PET/CT findings had melanomas ≥5mm (only 5 positive PET/CT results were confirmed true positives histologically: 4 lymph node metastases, 1 distant metastasis). Four of the 11 patients with positive PET/CT (36%), and 5 of 66 patients with negative PET/CT (8%), died from melanoma. It was unclear whether the PET/CT results influenced clinical management.[19]

In general, against a histopathology reference standard PET/CT generally had moderate to low sensitivity and higher specificity. High false positive rates including detection of benign lesions and other cancers led to additional investigations including invasive procedures.[15][18] Some melanoma metastases were missed on PET/CT being detected clinically within 6 months of the index scan,[17] or detected with SNB.[14]

Positron emission tomography (PET) or computed tomography (PET/CT) imaging during follow up

A recent systematic review by Danielson et al[20] of 7 studies 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 concluded that the mean sensitivity of PET was 96% (95% CI: 92-98) and the specificity was 92% (95% CI: 87-95). Overall, PET has a high diagnostic value. However, there were no data available to demonstrate better survival outcomes for patients as a result of routine PET surveillance.[20]

Magnetic resonance imaging (MRI) for initial staging

The retrospective study of 546 patients discussed above under CXR also included MRI scans used for initial staging in 20 patients (4%; included 18 head MRI, 1 extremity MRI and 1 spine MRI).[6] The one positive MRI test result was a false positive in a patient with a benign thyroid nodule. The 19 negative results were all true negatives.

Magnetic resonance imaging (MRI) for during follow-up

Cerebral metastases are more readily detected by magnetic resonance imaging (MRI) than by CT or FDG-PET/CT.[21], however no new studies published since 2012 of MRI follow-up of stage I/II patients were identified.

Blood tests

S100B, MIA, LDH blood tests for initial staging

Two small studies were identified assessing the diagnostic accuracy of either p-proteasome, MIA, S-100B, or LDH for melanoma metastases.[22][23] In the first study of 53 clinical stage I-II melanoma patients, 68 stage III-IV patients and 40 healthy volunteers, plasma samples were obtained before definitive surgical excision or treatment and followed for a median of 17 months. Reference standard positive patients were a mixture of patients with clinical stage III/IV disease at the outset and patients with clinical stage I/II who then developed metastases during follow-up (detected through clinical examinations and imaging tests). Likewise reference standard negative patients were a mixture of healthy volunteers and patients with clinical stage I/II disease who did not develop metastases during follow-up. Within the limitations of the substantial spectrum bias arising from the selection of the study population which was not limited to asymptomatic stage I/II patients, the area under the receiver operating curves (ROC) for p-proteasome and S100B were the highest (0.81,and 0.82 respectively), whereas LDH and MIA showed lower values (0.79, and 0.72 respectively).[22] In the second study, of 87 stage I/II patients, 71 stage III/IV patients and 50 healthy volunteers, serum concentrations were measured before surgery.[23] The reference standard was again a composite of clinical exams and imaging tests to define whether or not the patient had stage III/IV disease at either the outset or during a median of 32.8 months follow-up. The authors reported that a cut-off value for MIA of 9.4 ng/ml, had 77% sensitivity and 94% specificity for the detection of stage IV disease. Among the 87 patients with stage I/II disease after imaging, 66% of those with MIA serum values greater than 9.4 ng/mL developed regional or distant metastases during follow-up , while 5% of those with values below this threshold developed metastases.[23]

Standard blood tests for initial staging and follow-up (e.g. electrolytes, urea, creatinine, liver function tests [LFTs], full blood count [FBC])

Evidence from previous guidelines states the routine use of standard blood tests rarely identifies occult stage IV disease in patients presenting with stage I or II melanoma and is not recommended. See [ANZ Melanoma guidelines]. These tests are not new and were therefore outside the scope of the current systematic review and guideline.

S100B, MIA, LDH blood tests during follow-up

As a tumour marker, S100B displays a sensitivity of 86–91 %, specificity[24][25] 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 by Fields and Coit.[26] 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.

Investigations for stage I-II patients with no sentinel node biopsy (ie. declined or patient unfit)

Ultrasonography for initial staging

For situations where SLNB has been declined or is not possible for technical reasons or patient co-morbidities, ultrasound monitoring may be considered, however 4 studies have shown poorer accuracy (both sensitivity and specificity) compared to SLNB[27][28][29][30], and so the latter is preferred whenever feasible (see chapter on SNLB). No studies were identified in patients who were not eligible for SLNB.

In three of the studies assessing ultrasonography against a reference standard of SNLB, the sensitivity of ultrasound ranged from 13% to 71%; the specificity from 57% to 97%[27][28][29]; and in two studies the positive predictive value ranged from 37% to 97%, while the negative predictive value ranged from 13% to 84%.[27][29] In one study that assessed a particular ultrasound characteristic (the echo free island) the sensitivity was 11%, the specificity 98%, the positive predictive value was 50% and the negative predictive value was 80%.[30]

One small study compared high resolution ultrasound (HRUSS) with PET/CT against a reference standard of SNB in 20 patients with clinically stage I/II disease.[16] HRUSS correctly identified two of 12 patients with positive SLNs whereas PET/CT imaging identified none; both imaging tests correctly identified all 12 patients with negative SLNs.[16]

Ultrasonography during follow-up

The usefulness of ultrasonography for follow-up of patients 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.[31] A prospective cohort study of 373 patients with a primary tumour Breslow thickness of ≥1.5mm[32], reported a sensitivity of 93% for ultrasound compared with only 71% for the clinical examination of regional lymph nodes. Their 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. The reasons cited for this were that although ultrasound was useful in the earlier detection of regional disease or avoidance of unnecessary surgery in 7% of patients, 6% had deleterious effects such as unnecessary stress caused by repetition of ultrasounds for benign lymph nodes or useless removal of benign lymph nodes.[32] Thus in sum, in only 1% of patients was the use of ultrasound advantageous.

Ultrasound +/- Fine needle aspiration (FNA) +/- core biopsy for initial staging

One prospective study assessed whether the combination of ultrasound and fine needle biopsy could be used as a ‘triage’ test for SLNB in 107 asymptomatic patients with clinically stage I/II melanoma.[33] Using this test strategy, only two patients had final positive results, of which one could not be confirmed on histopathology (possible false positive) and the other was confirmed (true positive). Of the 105 patients who were negative on ultrasound +FNA, 36 were false negatives (nodal metastases found on SLNB), and 69 were true negatives.

Ultrasound +/- Fine needle aspiration (FNA) +/- core biopsy during follow-up

FNA is the current standard method to confirm the presence of suspected nodal metastases for lymphadenopathy identified after definitive local treatment of cutaneous melanoma.[34][35] Ultrasound guidance should be used as the diagnostic yield is superior, particularly for small lymph nodes <10mm in size. Core biopsy has higher sensitivity and specificity compared with FNA and should be considered where FNA is negative but clinical suspicion remains high. There is no role for routine lymph node biopsy during follow up of asymptomatic patients.[36]

Other investigations during follow-up

Skin Self-Examination

A review of 9 clinical practice guidelines by Marciano et al (2014)[37] reveals consensus that patients should be taught skin self-examination; this was based on retrospective evidence from several studies that recurrences were commonly first detected by patients. For this recommendation, 4 guidelines varied in evidence content while 5 guidelines provided consensus opinion only. Education on sun-smart behaviour was recommended by 4 guidelines.[37]

Successfully implementing 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 symptoms that may warrant further investigation, such as pain, fatigue, weight loss, nausea and vomiting, dyspneoa, and headache. In addition, the use of brochures or videos, and the engagement of relatives in the education process may be helpful.[38][39][40] Randomized controlled trials do not exist. In Australia, patients themselves detect up to 75% of recurrences, while in other countries this can be as low as 20%.9-13 These data highlight the fact that even with education, there are great differences in patients’ individual ability to detect recurrences.[40]

History and physical examination during follow-up

There is general consensus that the most cost-effective component of a strategy resulting in the detection of the majority of recurrences is careful history taking and physical examination. The detection of distant metastases in patients with early localised disease is unusual.

As with self-examination, history and physical examination include specific history taking, a full skin examination looking for new primaries, palpation of melanoma surgical scars, and lymphatic drainage areas for in-transit and lymph node recurrence. Apart from patient self-detected relapses, most relapses and secondary melanomas are detected during physical examinations.[41][42] In a large prospective study12, roughly 50 % of recurrences were identified by history taking/physical examination, 80 % of which were local recurrences, in-transit metastases, and regional lymph node metastases.[41] Indeed, the vast majority of operable recurrences (96%) are those detected by physical examinations.14 In summary, history and physical examinations for patients with stages I–III melanoma are the most effective procedure for early recurrence detection.[43][8]

Evidence summary and recommendations

Evidence summary Level References
Chest x-ray for initial staging produces high rates of false positive and incidental findings. III-2 [6], [3], [7]
Chest x-ray can detect stage IV disease occasionally; however knowledge of these results was not shown to change management, and did not improve overall survival. III-2 [3]
Evidence-based recommendationQuestion mark transparent.png Grade
Chest x-ray imaging for initial staging should not be performed
C


Evidence summary Level References
No studies of CT imaging for stage I or stage IIA patients were identified. CT imaging for initial staging of patients with stage IIB and IIC melanoma detects more false positives than true positives. Diagnostic accuracy is greater in symptomatic rather than asymptomatic patients. IV [11]
Evidence-based recommendationQuestion mark transparent.png Grade
CT head, chest, abdomen and pelvis imaging are not recommended for initial staging in asymptomatic patients with stage IIB or IIC melanoma. In addition, there is no evidence to support CT imaging in Stage I and IIA melanoma.
C


Evidence summary Level References
PET/CT demonstrates a moderate to low sensitivity and a high specificity. III-2 [14], [17], [18], [15]
High false positive rates including detection of benign lesions and other cancers may lead to unwanted additional investigations including invasive procedures. III-2 [18], [15]
PET/CT accuracy may be improved when used among patients with a higher risk of metastases (i.e. with thick primary melanomas) III-3 [19]
Evidence-based recommendationQuestion mark transparent.png Grade
CT imaging for initial staging is not recommended for patients with stage I-II melanoma
C


Evidence-based recommendationQuestion mark transparent.png Grade
PET/CT imaging for initial staging is not recommended for patients with a thin, or intermediate Breslow thickness primary melanoma (Stage I-IIB).
C



Evidence summary Level References
There are few data regarding MRI for initial staging. MRI may lead to additional investigations for false positive results, without any identification of true positive cases in stage I/II patients. IV [6]
Evidence-based recommendationQuestion mark transparent.png Grade
MRI imaging of the head, spine or extremities is not recommended for initial staging in patients with stage I or stage II melanoma.
D


Evidence summary Level References
Blood tests – S100B, p-proteasome, MIA, LDH.

P-proteasome and S100B showed good predictive ability for identifying metastatic disease, and this was superior to either MIA or LDH, however the studies were subject to several biases. In one study MIA was predictive of melanoma recurrence at 6 months in two thirds of pre-operative stage I/II patients using a cut-off value of 9.4 ng/mL.

III-3 [22], [23]
There is insufficient evidence to recommend routine measurement of S100B in asymptomatic patients at primary diagnosis of melanoma. There is insufficient evidence to determine whether MIA is as sensitive as S100B and therefore cannot be recommended. Serum LDH is not recommended. No evidence was identified supporting the use of standard blood tests (e.g. electrolytes, urea, creatinine, LFTs, FBC) in initial staging or follow-up of Stage I/II melanoma. [3]
Evidence-based recommendationQuestion mark transparent.png Grade
S100B, MIA and LDH or standard blood tests are not recommended at initial staging for diagnosis of metastatic melanoma.
C



Practice pointQuestion mark transparent.png

Low sensitivity, specificity, and accuracy for general laboratory profiles (S100B, MIA, LDH blood tests) make them ineffective in the detection of subclinical recurrence and their roles are yet to be defined.

How should patients at each stage of melanoma be followed after initial definitive treatment

How should patients at each stage of melanoma be followed after initial definitive treatment?

What is the ideal setting, duration and frequency of follow-up for melanoma patients?

What is the ideal setting, duration and frequency of follow-up for melanoma patients?

Issues requiring more clinical research study

Should liquid biopsy be performed following a diagnosis of primary cutaneous melanoma for asymptomatic Stage I and II patients?

References

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Appendices