What investigations should be performed when in-transit and/or regional node disease (stage III melanoma) is diagnosed?

From Clinical Guidelines Wiki


Introduction

Stage III melanoma is defined as the presence of nodal metastatic disease and/or the presence of intransit/satellite/microsatellite metastasis. Investigations are required to confirm the diagnosis of stage III disease as well as to assist in determining accurately the extent of disease. Accurate assessment is crucial in determining management and prognosis. Patients with isolated stage III melanoma are usually treated with surgical resection in the first instance. However, if widespread metastatic disease is identified, the treatment plan will be completely different.

Investigations to diagnose stage III disease

Clinically node-negative patients

Should be investigated as per the question What investigations should be performed following a diagnosis of primary cutaneous melanoma for asymptomatic stage I and stage II patients?”

Palpable disease

Lymph node disease

i. Fine needle biopsy (FNB)

There are no prospective studies to define the accuracy of FNB in the diagnosis of metastatic melanoma in a mass (lymph node or subcutaneous or internal nodule). However, a systematic review of 10 retrospective studies has been performed.[1] This has found the overall diagnostic accuracy of FNB for metastatic melanoma is high, with a sensitivity and specificity of 0.97 and 0.99 respectively. The authors also suggest because of its low procedural cost, minimal risk of harm to the patient, and rapid turnaround time, FNB allows treatment decisions to be expedited.

False negative results occur more commonly in axillary specimens, which can be offset by increasing the number of needle passes. Other causes of a false negative result include obesity, difficult areas for aspiration (deep inguinal lymph nodes), superficial subcutaneous lesions associated with fibrosis or a previous scar, enlarged lymph nodes with only small focal deposits of metastatic melanoma or poor circumscription of the suspicious lesion. The most common cause of a false-negative result in FNB was an inadequate specimen, and the most common cause of a false-positive result was the presence of a second malignancy.

FNB can be palpation-guided or ultrasound (US)-guided. Meta-regression analysis found no difference in accuracy between palpation-guided and US-guided FNB (P = .75). Diagnosis of lesions <10mm in diameter appears to have a slightly less sensitivity (~0.94) but an unchanged specificity.

FNB morbidity was negligible (<0.002%). Data obtained from studies of other cancers suggest seeding of tumour cells along the needle tract is a rare event.

FNB retrieved material is suitable for assessment for BRAF mutation status, being successful in >90% of cases.[2][3][4]


Evidence summary Level References
Sensitivity and specificity for FNB of a mass confirming melanoma is 0.97 and 0.99 respectively II [1]
FNB can be performed by clinical palpation or with ultrasound guidance II [1]
FNB retrieved material is suitable for BRAF mutation analysis in >90% cases III-1 [2], [3], [4]
Evidence-based recommendationQuestion mark transparent.png Grade
FNB, with or without ultrasound guidance can be used to confirm the diagnosis of lymph node or intransit metastatic melanoma
B


ii. Core biopsy

There is only one study assessing the role of core biopsy in melanoma lymph node metastases.[5] This showed a sensitivity 97.9% and specificity 100%, which is very similar to FNB. There are no comparative studies between core biopsy and FNB for melanoma, but the studies in other cancers suggest that FNB should be the preferred initial test as it is less expensive, may not require local anaesthesia and is associated with little patient discomfort. Core biopsy should be used if FNB is unable to provide an adequate diagnosis or to avoid a surgical excision which may be more morbid. Core biopsy retrieved material can also be used for assessment of mutation status, and may in fact be more successful than FNB retrieved material due to the increased volume of tissue available for testing.


Evidence summary Level References
Core biopsy can be used to confirm the diagnosis of stage III melanoma with a sensitivity of 97.9% and specificity of 100% III-2 [5]
Evidence-based recommendationQuestion mark transparent.png Grade
Core biopsy can be used to confirm the diagnosis of lymph node or intransit metastatic melanoma
C


Intransit disease

Histological diagnosis of the presence of intransit/satellite disease can be obtained by any type of skin biopsy (shave, punch or excision) or even FNB if it is bulky. This tissue would then also be available for mutational testing if clinically appropriate.

Investigations following the diagnosis of stage III disease

Accurate assessment to identify the presence of occult systemic metastatic disease is particularly important for patients following the diagnosis of stage III melanoma as it directly affects clinical management and prognosis.

The assessment of whether investigations should be performed can be measured in various ways; diagnostic accuracy, cost, morbidity and ease of performing the investigation. Diagnostic accuracy can be measured as being lesion based or patient based. Lesion based diagnostic accuracy assesses the number of metastatic lesions identified on an investigation and determines the specificity and sensitivity of the test. Patient based diagnostic accuracy assesses whether the investigation resulted in a treatment change for the patient.

The literature available to assess the various investigations has been particularly poor and heterogeneous with small numbers, methodological deficiencies, inadequate descriptions of the patient group studied, whether they were of a retrospective or prospective design, the inconsistent availability of a diagnostic gold standard (biopsy or surgical pathology) and in particular for tests assessing diagnostic accuracy, not assessing both lesion based and patient based measures. This has resulted in wide ranges in sensitivity and specificity, and an inability to compare between studies. The following recommendations should be taken in the light of these deficiencies.

PET/CT and CT

The present standard for PET imaging in cutaneous melanoma is combined PET/CT imaging, using [18F]Fluorodeoxyglucose (FDG). Prior to 2005 positron emission tomograph (PET) scans only were used, instead of PET/CT scans. The addition of low dose CT to a PET scan provides clinically important anatomical detail (Von Shulthesss 2006) and attenuation correction of PET data by CT can also reduce scanning duration by 20–30% (Buck 2010). This guideline will therefore only assess studies using PET/CT scans.

The sensitivity of PET/CT is dependent on the size of the lesion, its anatomical location, and its rate of FDG uptake per volume unit of tissue. Tumour deposits less than 3 to 5mm in diameter are unable to be detected by PET/CT scans.[6]

The brain is not well imaged with PET/CT scans and consideration should be given to imaging the brain separately with CT or MRI.[7][8]

i. The role of PET/CT in SNB positive patients

The role of PET/CT in SNB positive patients has been investigated in 5 retrospective studies. The yield of cross-sectional imaging in detecting occult metastases ranged from 0.5 to 3.7% (Holtkamp 2017).[9][10][11][12]


Evidence summary Level References
The yield of PET/CT and CT in detecting occult metastases ranges from 0.5 to 3.7%. III-2 [9], [10], [11], [12]
Evidence-based recommendationQuestion mark transparent.png Grade
Consider NOT performing PET/CT or CT in newly diagnosed sentinel node positive patients
C


ii. The role of PET/CT in clinically palpable nodal disease

Six systematic reviews have been performed to assess the role of PET/CT in clinically palpable nodal metastatic melanoma.[13][14][15][16][17][18] Five of the systematic reviews showed that the diagnostic accuracy of PET/CT is better than conventional CT. However, the only one of the systemic reviews that limited the review to prospective studies[17] did not come to this conclusion. The reviews found the sensitivity of PET/CT ranged from 68% to 87%, and the specificity from 92% to 98% for lesion based analysis. CT scans had a lesser sensitivity (42-28%) but comparable specificity to PET/CT. However, CT scans showed a higher predictive value for liver and lung lesions.[19]

Two prospective trials and a systematic review have shown a change in treatment occurred in 19% to 35% of stage III patients after the use of PET/CT scans.[20][21][18]

The cost effectiveness of imaging for stage III melanoma has been assessed in three studies.[19][22][23] One study[22] showed that staging with radiography (chest x-ray) is the least cost-effective option, resulting in greater costs than CT alone, and fewer accurate diagnoses. PET/CT incurs a greater incremental cost compared to CT alone, but achieves a more accurate diagnosis of metastatic disease, particularly for lung lesions.[19][22][23] Authors suggest that the cost benefit of PET/CT over CT alone depends on a health system’s priorities and willingness-to-pay.


Evidence summary Level References
A PET/CT scan has a higher sensitivity compared to conventional CT in identifying metastatic lesions in Stage III melanoma patients with palpable nodal disease. The specificity of the 2 investigations is similar. II [13], [14], [15], [16], [17], [18]
A CT scan has a higher predictive value than a PET/CT scan in identifying metastases to the liver and lung. II [19]
A treatment change occurs in 19-35% of stage III patients after the use of a PET/CT scan. II [20], [21], [18]
PET/CT is more costly than CT alone, but achieves a more accurate diagnosis of extent of metastatic disease. II [19], [22], [23]
Evidence-based recommendationQuestion mark transparent.png Grade
Perform a PET/CT scan for the initial staging of stage III melanoma patients with palpable nodal disease.
B


Evidence-based recommendationQuestion mark transparent.png Grade
A brain scan (high resolution CT or MRI) should be added to a PET/CT scan to assess for the presence of brain metastases.
B


MRI

The accuracy of whole body MRI appears to be less than that of PET/CT scans. It is also limited by its contraindications (the presence metal implants), long scan times, reduced diagnostic accuracy in the detection of lung nodules, high inter-reader variability and cost.[24][25][26][27]

MRI is superior to CT and PET/CT when examining the neural system, in particular, for cerebral metastases. MRI is undoubtedly superior for lesion detection, anatomic localisation and differentiating between single and multiple lesions[28], but there are no studies specifically related to melanoma metastases, and MRI is more costly than CT.


Evidence summary Level References
Whole body MRI is not as accurate as PET/CT in stage III melanoma patients with palpable nodal disease. II [24], [25], [26], [27]
An MRI scan is superior to a CT or PET/CT scan in identifying cerebral metastases. N/A [28]
Evidence-based recommendationQuestion mark transparent.png Grade
Consider using an MRI scan rather than a CT scan to assess for the presence of brain metastases.
B


Ultrasound

Ultrasound may be used to identify the extent of intransit and nodal disease, and also to diagnose liver metastases.


Practice pointQuestion mark transparent.png

Ultrasound may be used for identification of the extent of intransit and nodal disease, and also used to diagnose liver metastases.

S100B, LDH and MIA in locoregional melanoma

It is difficult to compare the studies investigating the value of any of these blood markers in patients with melanoma, because groups of patients with different stages of disease have been studied and several different assays and cut-off points have also been employed resulting in different recommendations at different institutions.

Even a meta-analysis of S100B levels of stage I to stage IV melanoma patients did not separately assess stage III patients. It still showed that an elevated level of S100B signified poor prognosis at whatever stage.[29] Two studies have analysed the value of S100B in patients with palpable nodal disease and found that an elevated S100B preoperatively was associated with poorer disease-free survival[30][31] and with increased tumor size[31]. Henry et al showed S100B could discriminate stage III patients before and post lymphadenectomy (p .0.007), but did not separately assess the role of S100B in stage III survival (Henry 2013).

LDH and MIA do not appear to have a role in the assessment of stage III disease.

S100B and MIA blood tests are currently not PBS available in Australia.


Evidence summary Level References
Elevated S100B may correlate with poorer disease free survival, increased tumour size and presence of systemic metastatic disease in patients with palpable nodal disease III-1 [31], [30]
LDH and MIA are not useful in stage III disease III-1 [30]


Practice pointQuestion mark transparent.png

Other countries consider performing S100B in stage III patients with palpable nodal disease, but this is not PBS available in Australia.

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?

References

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