LIST OF REVIEWS

Number of studies

Diagnosis of melanoma

1

Visual inspection

49

2

Dermoscopy ± visual inspection

104

3

Teledermatology

22

4

Smartphone applications

2

5a

Computer‐aided diagnosis – dermoscopy‐based techniques

42

5b

Computer‐aided diagnosis – spectroscopy‐based techniques

Review amalgamated into 5a

6

Reflectance confocal microscopy

18

7

High frequency ultrasound

5

Diagnosis of keratinocyte skin cancer (BCC and cSCC)

8

Visual inspection ± Dermoscopy

24

5c

Computer‐aided diagnosis – dermoscopy‐based techniques

Review amalgamated into 5a

5d

Computer‐aided diagnosis – spectroscopy‐based techniques

Review amalgamated into 5a

9

Optical coherence tomography

5

10

Reflectance confocal microscopy

10

11

Exfoliative cytology

9

Staging of melanoma

12

Imaging tests (ultrasound, CT, MRI, PET‐CT)

39

13

Sentinel lymph node biopsy

155

Staging of cSCC

14

Imaging tests review

Review dropped; only 1 study identified

15

Sentinel lymph node biopsy

Review amalgamated into 13 above (n = 15 studies)

Term

Definition

Adjuvant therapy or treatment

A treatment given after the main treatment for cancer to reduce the risk of recurrence.

Adverse event

Detrimental change in health occurring in a person receiving the treatment whether or not it has been caused by the treatment.

Axillary

In the armpit.

Biopsy

Removal of a sample of tissue from the body to assist in diagnosis or inform the choice of treatment of a disease.

BRAF V600 mutation

BRAF is a human gene that makes a protein called B‐Raf, which is involved in the control of cell growth. BRAF mutations (damaged DNA) occur in around 40% of melanomas, which can then be treated with particular drugs.

BRAF inhibitors

Therapeutic agents that inhibit the serine‐threonine protein kinase BRAF mutated metastatic melanoma.

Breslow thickness

A scale for measuring the thickness of melanomas by the pathologist using a microscope, measured in mm from the top layer of skin to the bottom of the tumour.

Cervical (lymph nodes)

Lymph nodes found in the neck area of the body.

Computed tomography (CT)

Imaging technique in which the person lies on a table within an X‐ray gantry. The images are acquired using a spiral (helical) path and banks of detectors, allowing presentation of the internal organs and blood vessels in different projections including 3D views.

Coronal

Frontal plane dividing the body into front and back.

False negative

An individual who is truly positive for a disease, but whom a diagnostic test classifies as disease‐free.

False positive

An individual who is truly disease‐free, but whom a diagnostic test classifies as having the disease.

Histopathology

The study of tissue, usually obtained by biopsy or excision, for example under a microscope.

Incidence

The number of new cases of a disease in a given time period.

Inguinal

Lymph nodes in or just above or just below the groin.

Isolated limb perfusion

A medical procedure that directly delivers a drug through the bloodstream in a limb to the site affected by melanoma.

Local recurrence

Re‐growth of a tumour in the area from which it was originally removed.

Locoregional recurrence

Re‐growth of a tumour in the area from which it was originally removed or in the regional lymph nodes (usually nearest to the original tumour site).

Lymph node

Lymph nodes filter the lymphatic fluid (clear fluid containing white blood cells) that travels around the body to help fight disease; they are located throughout the body often in clusters (nodal basins).

Lymph node dissection

Surgical removal or 1 or more lymph nodes in the absence of proven involvement with melanoma.

Lymphadenectomy

Lymphadenectomy or lymph node dissection is a surgical operation to remove 1 or more groups of lymph nodes.

Lymphoscintigraphy

An imaging technique used to identify the lymph drainage basin, determine the number of sentinel nodes, differentiate sentinel nodes from subsequent nodes, locate the sentinel node in an unexpected location, and mark the sentinel node over the skin for biopsy. It requires the injection of a radioisotope into the skin around the biopsy scar and a scan some hours later to determine to which lymph nodes the tracer has travelled.

Lymphovascular invasion

Tumour cells that have spread to involve the blood vessels and lymphatic vessels within the skin.

Magnetic resonance imaging (MRI)

A type of scan that uses a magnetic field and radio waves to produce images of sections of the body.

Mediastinal and hilar adenopathy

Enlargement of the pulmonary lymph nodes.

MEK inhibitors

Drugs that inhibit the mitogen‐activated protein kinase enzymes, which are often upregulated in melanoma.

Meta‐analysis

A form of statistical analysis used to synthesise results from a collection of individual studies.

Metastases/metastatic disease

Spread of cancer away from the primary site to somewhere else through the bloodstream or the lymphatic system.

Micro‐metastases

Micro‐metastases are metastases so small that they can be seen only under a microscope.

Mitotic rate

Microscopic evaluation of the number of cells actively dividing in a tumour.

Morbidity

Detrimental effects on health.

Mortality

Either (1) the condition of being subject to death; or (2) the death rate, which reflects the number of deaths per unit of population in relation to any specific region, age group, disease, treatment, or other classification, usually expressed as deaths per 100, 1000, 10,000, or 100,000 people.

Multi‐disciplinary team

A team with members from different healthcare professions and specialties (e.g. urology, oncology, pathology, radiology, nursing). Cancer care in the National Health Service (NHS) uses this system to ensure that all relevant health professionals are engaged to discuss the best possible care for a patient.

Nodal basin

Cluster of lymph nodes that filter lymphatic fluid as it travels around the body; clusters are located under the arm (axilla) and in the groin, neck, chest, and abdomen.

Oncology

The study of cancers. This term also refers to the medical specialty of cancer care, with particular reference to the use of radiotherapy or drugs to treat cancer. The medical specialty is often split into clinical oncology (doctors who use radiotherapy and drug treatment) and medical oncology (doctors who use drug treatment).

Palpation

Feeling with the fingers or hands as part of a clinical examination of the body.

Positron emission tomography (PET)

A nuclear medicine imaging technique whereby a radioactive glucose (usually ¹⁸FDG) is administered intravenously before a scan is conducted to create an image using colours to show where the FDG (or other radioactive tracer) has been taken up in the body.

Prevalence

The proportion of a population found to have a condition.

Prognostic factors/indicators

Specific characteristics of a cancer or the person who has it that might affect the patient’s prognosis.

Radiotherapy

The use of radiation, usually high‐energy X‐rays, to control the growth of cancer cells.

RAS‐RAF‐MEK‐ERK signalling pathway

A chain of proteins that allow signals from a receptor on the surface of a cell to be sent to the DNA in the cell nucleus; a mutation in one of the proteins in the pathway is associated with the development of many cancers.

Recurrence

Recurrence occurs when new cancer cells are detected following treatment. This can occur either at the site of the original tumour or at other sites in the body.

Relapse

Where cancer starts to grow again after treatment.

Sagittal

Median plane dividing the body into left and right.

Sensitivity

In this context, the term is used to mean the proportion of individuals with a disease who have that disease correctly identified by the study test.

Sentinel lymph node biopsy (SLNB)

A radioactive tracer and blue dye are injected into the skin surrounding the primary lesion and the 'sentinel' lymph nodes to which the tracer drains are located by imaging (usually lymphoscintigraphy) and then are removed and examined for nodal metastatic spread that cannot be detected clinically or on imaging.

Signal transduction

Occurs when extracellular signalling molecules activate a specific receptor, which then triggers cellular pathways.

Staging

Clinical description of the size and spread of a patient’s tumour, fitting into internationally agreed categories.

Stereotactic radiotherapy

A technique for delivering high‐dose radiotherapy very accurately to small areas inside the body, which reduces damage done by radiotherapy to adjacent healthy tissues.

Subclinical (disease)

Disease that usually is asymptomatic and is not easily observable (e.g. by clinical or physical examination).

Systemic treatment

Treatment, usually given by mouth or by injection, that reaches and affects cancer cells throughout the body rather than targeting one specific area.

Ultrasound

A type of scan in which high‐frequency sound waves are used to outline a part of the body.

Acronym

Definition

μm

micrometre

AK

actinic keratosis

ANN

artificial neural network

BCC

basal cell carcinoma

BD

Bowen’s disease

BPC

between‐person comparison (of tests)

CAD

computer‐assisted diagnosis

CCS

case‐control study

CS

case series

cSCC

cutaneous squamous cell carcinoma

D‐

disease negative

D+

disease positive

Derm–CAD

digital dermoscopy‐based computer‐assisted diagnosis

DF

dermatofibroma

DRS

diffuse reflectance spectroscopy

DRSi

diffuse reflectance spectroscopy imaging

Dx

diagnosis

EIS

electrical impedance spectroscopy

FN

false negative

FP

false positive

FU

follow‐ up

GP

general practitioner

H&E

haematoxylin and eosin stain

HFUS

high‐frequency ultrasound

Hz

hertz

KHz

kilohertz

K–NN

k nearest neighbour

MHz

megahertz

MiS

melanoma in situ (or lentigo maligna)

MM

malignant melanoma

mm

millimetre

MSI

multi‐spectral imaging

N/A

not applicable

NC

non‐comparative

nm

nanometre

NPV

negative predictive value

NR

not reported

P

prospective

PPV

positive predictive value

PSL

pigmented skin lesion

R

retrospective

RCM

reflectance confocal microscopy

RCT

randomised controlled trial

SCC

squamous cell carcinoma

SD

standard deviation

se

sensitivity

sp

specificity

spectro–CAD

spectroscopy‐based computer–assisted diagnosis

SK

seborrhoeic keratosis

SSM

superficial spreading melanoma

SVM

support vector machine

TN

true negative

TS

telespectrophotometry system

VI

visual inspection

UNREF

unreferred population

WPC

within‐person comparison (of tests)

WPC‐algs

within‐person comparison (of algorithms)

Criterion

Inclusion

Exclusion

Study design

For diagnostic and staging reviews

• Any study for which a 2×2 contingency table can be extracted, e.g.

  • diagnostic case‐control studies

  • 'cross‐sectional' test accuracy studies with retrospective or prospective data collection

  • studies where estimation of test accuracy was not the primary objective but test results for both index and reference standard were available

  • RCTs of tests or testing strategies where participants were randomised between index tests and all undergo a reference standard (i.e. accuracy RCTs)

• < 5 melanoma cases (diagnosis reviews)

• < 10 participants (staging reviews)

• Studies developing new criteria for diagnosis unless a separate 'test set' of images were used to evaluate the criteria (mainly digital dermoscopy)

• Studies using 'normal' skin as controls

• Letters, editorials, comment papers, narrative reviews

• Insufficient data to construct a 2×2 table

Target condition

• Melanoma

• Keratinocyte skin cancer (or non‐melanoma skin cancer)

  • BCC or epithelioma

  • cSCC

• Studies exclusively conducted in children

• Studies of non‐cutaneous melanoma or SCC

Population

For diagnostic reviews

• Adults with a skin lesion suspicious for melanoma, BCC, or cSCC (other terms include pigmented skin lesion/nevi, melanocytic, keratinocyte, etc.)

• Adults at high risk of developing melanoma skin cancer, BCC, or cSCC

For staging reviews

• Adults with a diagnosis of melanoma or cSCC undergoing tests for staging of lymph nodes or distant metastases or both

• People suspected of other forms of skin cancer

• Studies conducted exclusively in children

Index tests

For diagnosis

• Visual inspection/clinical examination

• Dermoscopy/dermatoscopy

• Teledermoscpoy

• Smartphone/mobile phone applications

• Digital dermoscopy/artificial intelligence

• Confocal microscopy

• Ocular coherence tomography

• Exfoliative cytology

• High‐frequency ultrasound

• Canine odour detection

• DNA expression analysis/gene chip analysis

• Other

For staging

• CT

• PET

• PET‐CT

• MRI

• Ultrasound +/fine needle aspiration cytology (FNAC)

• SLNB +/high‐frequency ultrasound

• Other

Any test combination and in any order

Any test positivity threshold

Any variation in testing procedure (e.g. radioisotope used)

• Sentinel lymph biopsy for therapeutic rather than staging purposes

• Tests to determine melanoma thickness

• Tests to determine surgical margins/lesion borders

• Tests to improve histopathology diagnose

• LND

Reference standard

For diagnostic studies

• Histopathology of the excised lesion

• Clinical follow‐up of non‐excised/benign appearing lesions with later histopathology if suspicious

• Expert diagnosis (studies should not be included if expert diagnosis is the sole reference standard)

For studies of imaging tests for staging:

Histopathology (via LND or SLMB)

Clinical/radiological follow‐up

A combination of the above

For studies of SLNB accuracy for staging :

LND of both SLN+ and SLn participants to identify all diseased nodes

LND of SLN+ participants and follow‐up of SLN participants to identify a subsequent nodal recurrence in a previously investigated nodal basin

For diagnostic studies

• Exclude if any disease positive participants have diagnosis unconfirmed by histology

• Exclude if > 50% of disease negative participants have diagnosis confirmed by expert opinion with no histology or follow‐up

• Exclude studies of referral accuracy, i.e. comparing referral decision with expert diagnosis, unless evaluations of teledermatology or mobile phone applications

BCC: basal cell carcinoma; cSCC: cutaneous squamous cell carcinoma; CT: computed tomography; FNAC: fine needle aspiration cytology; LND: lymph node dissection; MRI: magnetic resonance imaging; PET: positron emission tomography; PET‐CT: positron emission tomography‐computed tomography; RCT: randomised controlled trial; SCC: squamous cell carcinoma; SLN+: positive sentinel lymph node; SLn: negative sentinel lymph node; SLNB: sentinel lymph node biopsy.

Item

Response (delete as required)

PARTICIPANT SELECTION (1) ‐ RISK OF BIAS

1) Was a consecutive or random sample of participants or images enrolled?

Yes ‐ if paper states consecutive or random

No – if paper describes other method of sampling

Unclear – if participant sampling not described

2) Was a case‐control design avoided?

Yes ‐ if consecutive or random or case‐control design clearly not used

No – if study described as case‐control or describes sampling specific numbers of participants with particular diagnoses

Unclear – if not described

3) Did the study avoid inappropriate exclusions both for melanoma and for cutaneous squamous cell carcinoma (cSCC) staging?

Yes ‐ if inappropriate exclusions were avoided

No – if lesions were excluded that might affect test accuracy, e.g. indeterminate results or where disagreement between evaluators was observed

Unclear – if not clearly reported

4) For between‐person comparative (BPC) studies only (i.e. allocating different tests to different study participants such as randomised controlled trials (RCTs)):

• a) were the same participant selection criteria used for those allocated to each test?

Yes ‐ if same selection criteria were used for each index test

No – if different selection criteria were used for each index test

Unclear – if selection criteria per test were not described

N/A – if only 1 index test was evaluated or all participants received all tests

• b) was the potential for biased allocation between tests avoided through adequate generation of a randomised sequence?

Yes ‐ if adequate randomisation procedures are described

No – if inadequate randomisation procedures are described

Unclear – if the method of allocation to groups is not described (a description of ‘random’ or ‘randomised’ is insufficient)

N/A – if only 1 index test was evaluated or all participants received all tests

• c) was the potential for biased allocation between tests avoided through concealment of allocation before assignment?

Yes ‐ if appropriate methods of allocation concealment are described

No – if appropriate methods of allocation concealment are not described

Unclear – if the method of allocation concealment is not described (sufficient detail to allow a definite judgement is required)

N/A – if only 1 index test was evaluated

Could the selection of participants have introduced bias?

v FOR NON‐COMPARATIVE (NC) STUDIES

If answers to all of questions 1) and 2) and 3) was ‘Yes’:

Risk is Low

If answers to any one of questions 1) or 2) or 3) was ‘No’:

Risk is High

If answers to any one of questions 1) or 2) or 3) was ‘Unclear’:

Risk Unclear

v FOR BETWEEN‐PERSON COMPARATIVE STUDIES

If answers to all of questions 1) and 2) and 3) and 4) was ‘Yes’:

Risk is Low

If answers to any one of questions 1) or 2) or 3) or 4) was ‘No’:

Risk is High

If answers to any one of questions 1) or 2) or 3) or 4) was ‘Unclear’:

Risk Unclear

PARTICIPANT SELECTION (1) ‐ CONCERNS REGARDING APPLICABILITY

For sentinel lymph node biopsy and imaging tests:

1) Does the study report results for participants unselected by stage of disease or site of primary lesion, i.e. the study does not focus solely on those with a particular stage of disease such as American Joint Committee on Cancer (AJCC) stage I or melanoma ≤ 1 mm in thickness?

Yes ‐ if an unrestricted group of participants have been included

No ‐ if a selected group of study participants have been included, e.g. those with clinical stage I disease or only those with thin melanoma

Unclear – if insufficient details are provided to determine the spectrum of included participants

2) Did the study report data on a per patient rather than per lesion basis?

Yes – if a per patient analysis was reported

No – if a per lesion analysis only was reported

Unclear – if it is not possible to assess whether data are presented on a per patient or per lesion basis

For imaging tests only:

3) Does the study focus primarily on participants undergoing primary staging or those undergoing staging for disease recurrence?

Yes ‐ if at least 80% of study participants are undergoing primary staging following diagnosis of a primary cutaneous melanoma or staging of recurrence

No ‐ if less than 80% of study participants are undergoing primary staging following diagnosis of a cutaneous melanoma or staging of recurrence

Unclear – if insufficient details are provided to determine the proportion of patients undergoing primary staging vs those undergoing staging of recurrence

Is there concern that the included participants do not match the review question?

If the answer to question 1) or 2) (and 3)) was ‘Yes’:

Concern is Low

If the answer to question 1) or 2) (and 3)) was ‘No’:

Concern is High

If the answer to question 1) or 2) (and 3)) was ‘Unclear’:

Concern is Unclear

INDEX TEST (2) ‐ RISK OF BIAS (to be completed per test evaluated)

1) Was the index test or testing strategy result interpreted without knowledge of the results of the reference standard?

Yes ‐ if index test described as interpreted without knowledge of reference standard result, or for prospective studies, if index test is always conducted and interpreted before the reference standard

No – if index test described as interpreted in knowledge of reference standard result

Unclear – if index test blinding is not described

2) Was the diagnostic threshold at which the test was considered positive prespecified?

Yes ‐ if threshold was prespecified (i.e. before analysing study results)

No ‐ if threshold was not prespecified

Unclear ‐ if not possible to tell whether or not diagnostic threshold was prespecified

For imaging tests only:

3) For studies reporting the accuracy of multiple diagnostic thresholds (tumour characteristic or parameter) for the same index test, was each threshold interpreted without knowledge of the results of the others?

Yes ‐ if thresholds were selected prospectively and each was interpreted by a different reader, or if study implements a retrospective (or no) cutoff

No ‐ if study uses prospective threshold and report states reported by same reader

Unclear ‐ if no mention of number of readers for each threshold or if prespecification of threshold not reported

N/A ‐ multiple diagnostic thresholds not reported for the same index test

4) For within‐person comparison (WPC) of index tests or testing strategies (i.e. > 1 index test applied per participant), was each index test result interpreted without knowledge of the results of other index tests or testing strategies?

Yes ‐ if all index tests were described as interpreted without knowledge of the results of the others

No ‐ if the index tests were described as interpreted in the knowledge of the results of the others

Unclear – if it is not possible to tell whether knowledge of other index tests could have influenced test interpretation

N/A – if only 1 index test was evaluated

Could the conduct or interpretation of the index test have introduced bias?

v FOR NC and BPC STUDIES item 3) / 4) to be added

If answers to questions 1) and 2) was ‘Yes’:

Risk is Low

If answers to either questions 1) or 2) was ‘No’:

Risk is High

If answers to either questions 1) or 2) was ‘Unclear’:

Risk is Unclear

v FOR WPC STUDIES

If answers to all questions 1), 2) for any index test and 3) was ‘Yes’:

Risk is Low

If answers to any one of questions 1) or 2) for any index test or 3) was ‘No’:

Risk is High

If answers to any one of questions 1) or 2) for any index test or 3) was ‘Unclear’:

Risk is Unclear

INDEX TEST (2) ‐ CONCERN ABOUT APPLICABILITY

1) Were thresholds or criteria for diagnosis reported in sufficient detail to allow replication?

This item applies equally to studies using objective and more subjective approaches to test interpretation. For sentinel lymph node biopsy (SLNB) studies, this requires description of the tracer threshold for identification of the SLN and the histological assessment.

Yes – if the criteria for diagnosis of the target disorder were reported in sufficient detail to allow replication

No – if the criteria for diagnosis of the target disorder were not reported in sufficient detail to allow replication

Unclear – if some but not sufficient information on criteria for diagnosis to allow replication were provided

2) Was the test interpretation carried out by an experienced examiner?

Yes – if the test was interpreted by an experienced examiner as defined in the review protocol

No – if the test was not interpreted by an experienced examiner (see above)

Unclear – if the experience of the examiner(s) was not reported in sufficient detail to judge or if examiners described as 'Expert' with no further detail given

Is there concern that the index test, its conduct, or interpretation differ from the review question?

If answers to questions 1) and 2) was ‘Yes’:

Concern is Low

If answers to questions 1) or 2) was ‘No’:

Concern is High

If answers to questions 1) or 2) was ‘Unclear’:

Concern is Unclear

REFERENCE STANDARD (3) ‐ RISK OF BIAS

1) Is the reference standard likely to correctly classify the target condition?

a) DISEASE POSITIVE ‐ 1 or more of:

‐ Histological confirmation of metastases following lymph node dissection (or SLNB or core biopsy for imaging studies)

‐ Clinical/radiological follow‐up to identify clinically detectable disease in a mapped nodal basin (SLNB studies)

‐ Clinical/radiological follow‐up to identify any metastases (imaging studies) subsequently confirmed on histology

Yes – if all disease positive participants underwent 1 of the listed reference standards

No – if a final diagnosis for any disease positive participant was reached without histopathology

Unclear – if the method of final diagnosis was not reported for any disease positive participant

b) DISEASE NEGATIVE ‐ 1 or more of:

‐ Histological confirmation of absence of disease in a mapped nodal basin following lymph node dissection (or following SLNB for imaging studies)

‐ Clinical/radiological follow‐up of test negative participants

Yes – if at least 90% of disease negative participants underwent 1 of the listed reference standards

No – if more than 10% of benign diagnoses were reached by concurrent imaging test

Unclear – if the method of final diagnosis was not reported for any participant with benign or disease negative diagnosis

2) Were the histology‐based reference standard results interpreted without knowledge of the results of the index test?

Yes – if the histopathologist was described as blinded to the index test result

No – if the histopathologist was described as having knowledge of the index test result

Unclear – if blinded histology interpretation was not clearly reported

3) Were the reference standard results based on patient follow‐up interpreted without knowledge of the results of the index test?

Yes – if the clinician or radiologist was described as blinded to the index test result

No – if the clinician or radiologist was described as having knowledge of the index test result

Unclear – if blinded interpretation was not clearly reported

Could the reference standard, its conduct, or its interpretation have introduced bias?

If answers to questions 1) and 2) and 3) was ‘Yes’:

Risk is Low

If answers to questions 1) or 2) or 3) was ‘No’:

Risk is High

If answers to questions 1) or 2) or 3) was ‘Unclear’:

Risk is Unclear

REFERENCE STANDARD (3) ‐ CONCERN ABOUT APPLICABILITY

1) Does the study use the same definition of disease positive as the primary review question, or is it possible to fully disaggregate data such that data matching the review question can be extracted?

Yes – same definition of disease positive used, or patients can be disaggregated and re‐grouped according to review definition

No – some patients cannot be disaggregated

For SLNB review – disease positive includes participants with any nodal recurrence (not restricted to clinical recurrence in same nodal basin)

For imaging reviews – participants with nodal vs distant recurrences cannot be disaggregated

Unclear – definition of disease positive not clearly reported

For studies of imaging tests:

2) The result of another imaging test (without patient follow‐up to determine later emergence of disease) was not used as a reference standard

Yes – if imaging‐based diagnosis was not used as a reference standard for any participant

No – if imaging‐based diagnosis was used as a reference standard for any participant

Unclear – if not clearly reported

3) Item on observer experience could be included?

Is there concern that the target condition as defined by the reference standard does not match the review question?

If answers to all questions 1), 2) and 3) was ‘Yes’:

Concern is Low

If answers to any one of questions 1) or 2) or 3) was ‘No’:

Concern is High

If answers to any one of questions 1) or 2) or 3) was ‘Unclear’:

Concern is Unclear

***For teledermatology studies only:

If answers to questions 1) and 3) was ‘Yes’:

Concern is Low

If answers to questions 1) or 3) was ‘No’:

Concern is High

If answers to questions 1) or 3) was ‘Unclear’:

Concern is Unclear

FLOW AND TIMING (4): RISK OF BIAS

1) Was there an appropriate interval between index test and reference standard?

• a) For index test positive participants, was the interval between index test and histological reference standard ≤ 1 month?

Yes – if study reports ≤ 1 month between index and histological reference standard

No – if study reports > 1 month between index and histological reference standard

Unclear – if study does not report interval between index and histological reference standard

• b) If reference standard is clinical or imaging‐based follow up of index test negative participants, was there less than 6 months between application of index test(s) and first follow‐up visit?

Yes – if study reports a follow‐up visit within 6 months of application of the index test

No – if study reports the first follow‐up visit beyond 6 months of the index test

Unclear – if study does not report timing of follow‐up visits

2) Did all participants receive the same reference standard?

Yes – if all participants underwent the same reference standard

No – if more than 1 reference standard was used

Unclear – if not clearly reported

3) Were all participants included in the analysis?

Yes – if all participants were included in the analysis

No – if some participants were excluded from the analysis

Unclear – if not clearly reported

4) For WITHIN‐PERSON COMPARISON (WPC) of index tests:

Was the interval between application of index tests ≤ 1 month?

Could the participant flow have introduced bias?

Yes – if study reports ≤ 1 month between index tests

No – if study reports > 1 month between index tests

Unclear – if study does not report interval between index tests

v FOR NON‐COMPARATIVE and BPC STUDIES

If answers to questions 1) and 2) and 3) was ‘Yes’:

Risk is Low

If answers to any one of questions 1) or 2) or 3) was ‘No’:

Risk is High

If answers to any one of questions 1) or 2) or 3) was ‘Unclear’:

Risk is Unclear

v FOR WITHIN‐PERSON COMPARATIVE STUDIES (WPCs)

If answers to all questions 1), 2), 3), and 4) was ‘Yes’:

Risk is Low

If answers to any one of questions 1), 2), 3), or 4) was ‘No’:

Risk is High

If answers to any one of questions 1), 2), 3), or 4) was ‘Unclear’:

Risk is Unclear

Study
Country
Pt/lesion number

Study design
Outcome: prevalence

Presentation
Inclusion criteria
Imaging eligibility

Age, gender, site, BT, Clark

Index test

Threshold

Observers

Reference

Exclusions

Arrangoiz 2012

USA

Patients: 56
Primary lesions: 56
LNBs/Metastases: NR

NC
Retrospective (medical record review not described)
Data: per pt
Nodal mets: 29/56 = 52%

Primary (pre‐SLNB)
Stage of disease: all T4 and clinically node negative and negative for distant metastases
Inclusion: node negative; BT > 4 mm

Mean age: 67; Median age: NR; Range: 26 to 89 years
Male: 32 (57%)

Site: trunk 16, 29%; extremities 28, 50%; HN 12, 21%
BT median 6 mm; mean 9 mm; range 4.1 to 40 mm

PET‐CT. 2D or 3D; CT (U, helical, low dose)
Scan coverage: WB; vertex of the head down to feet for all patients
Contrast: U
CT parameters: Discovery LS ‐ 140 kVp, 90mA; Siemens Biograph ‐ 130 kVp, 100 mA; 5 mm
¹⁸ FDG: 15 mCi (IV)
Breath hold: normal breathing
CT used for: attenuation correction; co‐registered images
Reconstruction: Discovery LS ‐ OSEM algorithm; Siemens Biograph ‐ TrueX (iterative reconstruction) algorithm

SUV of 2.5
Info provided: NR
No. observers: NR; 'in‐house medical physicist' mentioned
Diagnosis: unclear

Histology (54, 96% (48 SLNB and 6 LND))
FNAC (n NR)
FU (n NR): no details
Histology interval: NR; states that 6 "proceeded directly to therapeutic lymph node dissection" after PET
FU interval: NR

Exclusions: n = 0; N/A

Chai 2012

USA

Patients: 325
Primary lesions: 325
LNBs/Metastases: 347

NC
Retrospective (prospective database reported)
Data: per pt
Nodal mets: 64/317 = 20%

Primary (pre‐SLNB)
Stage of disease: NR
Inclusion: node negative, BT > 0.76 mm or < 0.76 mm with high‐risk features such as ulceration, high mitotic rate, or a positive deep margin

Mean age: NR; Median age: 58; Range: 18 to 86
Male: 189 (58%)

Site: HN 34 (10.5%)
Trunk 129 (39.7%)
Upper extremity 101 (31.1%)
Lower extremity 61 (18.8%)
BT median (range) 1.78 (0.42 to 14.4)
Clark’s level III 24 (7.4%), IV 275 (84.6%), V 20 (6.2%), unknown 6 (1.8%)

US. B‐mode; linear array (9 or 12 MHz); US before LS
Scan coverage: according to primary MM site and discretion of attending surgeon

Contrast: N/A

US ‐ classed as ‘‘abnormal,’’ ‘‘suspicious,’’ or ‘‘indeterminate
recommending a short‐term follow‐up’’ were considered positive (criteria described in detail)
Info provided: NR
No. observers: NR (NR)
Diagnosis: NR

Histology (325, 100%)
FNAC (6, 1.8%)
FU (NR; presume 100%): NR; FU for SLNB negatives is reported but no description is given
Histology interval: US performed either immediately or several days before LS
FU interval: NR

Exclusions: n = 8; 1 draining basin identified by LS was not examined with US; plus 7 SLN positive who did not get US

Hafner 2004
Switzerland
Patients: 101
Primary lesions: 101
LNBs/Metastases: 105 LNBs; 136 SLNs

WPC
Prospective
Data: per pt
Nodal mets: 23/97 = 24%

Primary (pre‐SLNB)
Stage of disease: NR; stage IV (evidence of distant mets) excluded
Inclusion: any cutaneous MM with BT ≥ 1 mm without evidence of detectable distant metastasis (includes clinically palpable)
Excluded if < 1 mm

Median age: 55; Range: 18 to 79
Male: 55 (55%)

Site: limbs 49, 49%, trunk 35, 35%, HN 16, 16%
BT: 1.01 to 2 mm 38; 2.01 to 4 mm 43; > 4.0 mm 19

US. B‐mode (5 Mhz); US before LS
Scan coverage: regional lymph nodes of the groins, axillae, and neck (abdominal US also performed)
Contrast: N/A

NR; 'radiologically suspect'
Info provided: unclear; clinical exam by dermatologist and US by radiologist
No. observers: 1; radiologist (NR)
Diagnosis: single

Histology (100; 100%)
FNAC (NR (abstract reports 3 LN mets identified on physical exam, 2 of which were detected by US)):
FU (n NR): 20 months (8 to 39)
Histology interval: 2 weeks
FU interval: 6 months

Exclusions: n = 4; 1 sentinel node was not found intraoperatively; 3 clinically node positive excluded by Bham team

Hinz 2013
Germany

Patients: 20
Primary lesions: 20
LNBs/Metastases: 59 SLN removed

WPC
Retrospective (retrospective computer‐aided search of preoperatively performed staging procedures)

Data: per pt
Nodal mets: 12/20 = 60%

Primary (pre‐SLNB)
Stage of disease: NR
Inclusion: high risk cutaneous MM; implies BT ≥ 2.0 mm or RF such as ulceration or regression
Excluded if 'further risk factors' or classic sonographic signs of lymphatic metastasis

Mean age: full sample: 55.2; Median age: NR; Range: Full sample: SD 13.3 years
Male: 9 (45%). Site: trunk n = 10 (50%); upper extremity n = 3(15%); lower extremity n = 4 (20%); acral n = 3(15%)
BT: 1.01 to 2 mm n = 3 (15%), 2.10 to 4 mm n = 9 (45%), > 4 mm n = 8 (40%);
Clark’s level III n = 1(5%); IV n = 16(80%); V n = 3 (15%)

PET‐CT. 2D/3D NR; CE‐CT, helical. Reinhardt 2006 states helical, dual detector (N/A)
Scan coverage: WB; Reinhardt 2006: "base of the skull to the apex of the lungs, ... from the shoulders to upper thighs, ... from the proximal femur to the tip of the toes"
Contrast: Reinhardt 2006: iodinated oral contrast agent (Peritrast‐oral‐GI; Köhler Chemie GmbH, Alsbach, Germany)
CT parameters: 130 kV, 40 mAs (Reinhardt 2006); 5 mm (Reinhardt 2006)
¹⁸ FDG: 371 ± 41 MBq (Reinhardt 2006)
Breath hold: limited breath hold technique for CT and shallow breathing for PET
CT used for: Reinhardt 2006: attenuation correction based on re‐scaling of the CT image
Reconstruction: iterative as described elsewhere (Kinahan 2003)

US. B‐mode (6.0‐ to 11.0‐MHz linear transducer); US pre‐ and post‐LS
Scan coverage: all relevant regional LN basins depending on localisation of the primary melanoma
Contrast: N/A

PET‐CT: NR
Info provided: NR
No. observers: unclear; no details
Diagnosis: unclear

US: morphology criteria (Solbiati 1988; Vassalo 1992; Voit 2010d); suspicious LNs were re‐examined with US after LS
Info provided: clinical exam/US performed by same clinician
No. observers: unclear; physicians with broad experience in dermato‐oncology (NR)
Diagnosis: unclear; appears as though single observer

Histology (20 (100%))
FNAC (0): histology interval: NR
FU interval: N/A

Exclusions: n = 0

Hinz 2011
Germany
Patients: 81
Primary lesions: 81
LNBs/Metastases: NR; 170 SLNs

NC
Prospective
Data: per pt
Nodal mets: 8/81 = 10%

Primary (pre‐SLNB) (? 1 secondary nodular SSM)
Stage of disease: NR
Inclusion: clinically node negative, BT ≥ 1 mm or < 1 mm with risk factors such as ulceration or regression

Mean age: 52.8; Median age: NR; Range: SD 15.4; node positive given (36 to 62)
Male: 48 (0.5925%). Site: HN 2,2.5%; Trunk 36, 44.4%; Upper extremity 14, 17.2%; Lower extremity 23, 28.4%; Acral 6, 7.4%
Median BT 1.68 mm (0.76 to 6.00 mm)
Clark’s level: 1 1, 1.4%; 2 26, 35.6%; 3 39, 53.4%; 4 7, 9.6%

US. B‐mode (linear array); Doppler (6.0 to 11.0 MHz linear transducer); US pre‐ and post‐LS
Scan coverage: LN areas predicted by sites of melanoma
Contrast: N/A

Positive radiological findings according to published criteria
Info provided: NR; likely full info available
No. observers: 1 of 4 clinicians trained in USS imaging; NR; broad experience in dermato‐oncology and special ultrasound skills (NR)
Diagnosis: unclear; appears as though single observer

Histology (1)
FNAC (n NR)
FU (N/A): not stated
Histology interval: NR
FU interval: NR

Exclusions: n = 0

Hocevar 2004
Slovenia

Patients: 57
Primary lesions: 57
LNBs/Metastases: 61

WPC
Design unclear

Data: per pt
Nodal mets: 14/57 = 25%

Primary (pre‐SLNB)
Stage of disease: NR
Inclusion: MM candidates for SLNB

Mean age: NR; Median age: NR; Range: 1 to 93
Male: 21 (0.37%). Site: 14, 25% head, 19, 38% trunk, 24, 42% extremity
BT < 1 mm 2, 4%, BT 1 to 2 mm 23, 40%, BT 2.01 to 4 mm 20, 35%, BT > 4 mm 12, 21%
Clark’s level unknown ‐ 2, 4%, 3 23; 42%, 4 26; 44%, 5 6, 10%

US. B‐mode; linear array transducer with small parts probe (12 and 15 MHz); US before LS
Scan coverage: NR
Contrast: N/A
Breath hold: regional lymph nodes

US + FNAC for those positive on US

Rounded appearance of the LN, Ioss of the hilar echogenic reflex, and deformed radial nodal vascularity
Info provided: NR
No. observers: 1; oncological radiologist (NR)
Diagnosis: single

Histology (CLND; SLNB)
FNAC (14/17 US positive underwent FNAC)
FU (n NR): no details
Histology interval: NR
FU interval: NR

Exclusions: n = 0

Kell 2007
USA

Patients: 37
Primary lesions: NR
LNBs/Metastases: NR

NC
Retrospective (prospective database reported)
Data: per pt
Nodal mets: 9/37 = 24%

Primary (pre‐SLNB)
Stage of disease: NR
Inclusion: MM, BT > 0.75 mm, candidates for SLNB

Mean age: 61.4 years; Median age: NR; Range: NR
Male: NR (0%). Site: NR
Mean BT: 2.4 mm

PET‐CT. 2D/3D NR; CT (U)
Scan coverage: base of skull to feet
Contrast: U
CT parameters: NR
¹⁸ FDG: NR
Breath hold: NR
CT used for: NR
Reconstruction: NR

Quantitative for areas of abnormally increased ¹⁸FDG uptake
Info provided: NR
No. observers: NR; no details.
Diagnosis: NR

Histology (37, 100%)
FNAC (0):
FU (n NR): no details
Histology interval: NR
FU interval: NR

Exclusions: n = 0; 46 with SLNB but no PET‐CT could not be included

Klode 2010
Germany
Patients: 61
Primary lesions: NR
LNBs/Metastases: NR

NC
Retrospective
Data: per pt
Nodal mets: 14/61 = 23%

Primary (pre‐SLNB)
Stage of disease: NR (I or II)
Inclusion: primary MM AJCC stage I or II (BT > 1 mm)

Mean age: 58.8; Median age: 61; Range: 31 to 82
Male: 36 (0.5901%). Site: trunk and lower limbs 26, 42.6%; upper extremities 9, 14.8%; NR for remaining 27 lesions
BT: mean 2.62 mm, median 2.0 mm, range 1 to 8 mm

PET‐CT. 2D/3D NR; CE‐CT
Scan coverage: cranial base to mid femur; additional views according to melanoma localisation
Contrast: iodine‐containing contrast agent
CT parameters: NR
¹⁸ FDG: 349 mBq
Breath hold: breath hold instructions NR
CT used for: NR
Reconstruction: NR

NR; hypermetabolic tumour focus
Info provided: NR
No. observers: NR; no details
Diagnosis: NR

Histology (61, 100%)
FNAC (N/A)
FU (61, 100%): median 38 months, 13 to 55 months
Histology interval: median 14 days PET to SLNB
FU interval: NR

Exclusions: n = 0; 60 patients with SLNB did not agree to pre‐op PET

Kunte 2009
Germany
Patients: 25
Primary lesions: 25
LNBs/Metastases: 68 LNBs; 35 SLNs

NC
Prospective (Prosp database: N/A)
Data: per pt
Nodal mets: 6/35 = 17%

Data: per SLN
Nodal mets: 6/35 = 17%

Primary (pre‐SLNB) (NR).
Stage of disease: NR
Inclusion: cutaneous MM SLNB candidates; 'mainly' ≥ 1.0 mm BT or RF (ulceration or regression or Clark level IV and V)

Mean age: 54; Median age: NR; Range: NR
Male: 15 (60%). Site: Limbs 14, 56%; HN 2, 8%; trunk 9 36%
BT: ≤ 1 mm 8, 32%; 1.01 to 2 mm 11, 44%; 2.01 to 4 mm 5 20%; > 4.0 mm 1, 4%

US. B‐mode; linear transducer (7.5 to 10MHz); US pre‐ and post‐LS
Scan coverage: regional lymphatic basins
Contrast: N/A
Breath hold: regional LN basins

Qualitative presence of morphological features (described)
Info provided: unclear; may be same dermatologists as for clinical exam
No. observers: 2; dermatologists (experienced).
Diagnosis: unclear

Histology (51% n = 35)
FNAC (0):
FU (0): –
Histology interval: < 24 hours
FU interval: N/A

Exclusions: n = NR

Maubec 2007
France
Patients: 25

Primary lesions: 26
LNBs/Metastases: 20 from 19 pts

NC
Prospective (Prosp database: N/A)

Data: per pt
Nodal mets: 7/20 = 35%; 1 FN identified on FU

Primary (pre‐SLNB)
Stage of disease: all T4; post surgery AJCC stage IIB 10, 40%; IIC 4, 16%; IIIA 4, 16%; IIIB 6, 24%; IIIC in 1, 4%
Inclusion: any MM BT > 4 mm; SLNB planned if clinically node negative

Mean age: 60; Range: 14 to 87
Male: 15 (0.6%). Site: trunk 8, 32%; limbs 8; 32%; head and neck 9, 36%
Mean BT 6.6 mm, range 4.8 to 12.5 mm

PET‐CT. 3D; CT (U)
Scan coverage: WB; "top of the head to the mid‐thigh and included if necessary, the lower limbs"
Contrast: U
CT parameters: 110 kV; 80 mA; 5 mm
¹⁸ FDG: 5 MBq/kg
Breath hold: normal breathing; "no breath hold instructions"
CT used for: NR; integrated system
Reconstruction: iterative algorithm (FORE and AWOSEM)

Uptake site suspicious for malignancy or not clearly explained by a benign etiology (SUV estimated but does not appear to formally contribute to diagnosis)
Info provided: NR
No. observers: NR; no details.
Diagnosis: NR

Histology (22, 88%; 3 node positive underwent CLND; 19 had SLNB; 3 no surgery)
FNAC (N/A)
FU (25, 100%): mean 11 months (2 to 19 months)
Histology interval: NR
FU interval: NR

Exclusions: n = 6; 3 clinically N+ underwent CLND (all PET+ and N+); 3 did not undergo any surgery

Radzhabova 2009
Russia

Patients: 152
Primary lesions: NR
LNBs/Metastases: NR

NC
Design unclear
Data: per pt
Nodal mets: 11/52 = 21%; 2 FNS identified on FU

Primary (pre‐SLNB)
Stage of disease: NR
Inclusion: clinically node negative MM and SLNB (based on US result)

Mean age: NR; Median age: NR; Range: NR
Male: NR (0%). Site: NR
NR

US. B‐mode; sectoral and linear (7 to 10 MHz); pre‐LS
Scan coverage: NR
Contrast: N/A
Breath hold: N/A

High PSV, EDV, Stuart index, and PI < 1000. Mets could not be excluded if PSV and PI were high but EDV = 0, Stuart index was undetectable (PI = pulse index, PSV = peak systolic volume, EDV = end‐diastolic volume, Stuart index)
Info provided: NR
No. observers: NR; no details.
Diagnosis: NR

Histology (52, 100%)
FNAC (0):
FU (NR):
Histology interval: NR
FU interval: NR

Exclusions: n = 100; benign on US did not get SLNB

Revel 2010
France

Patients: 22
Primary lesions: 22
LNBs/Metastases: 21

WPC
Retrospective
Data: per pt
Nodal mets: 10/20 = 50%; 2 FN identified on FU

Primary (pre‐SLNB)
Stage of disease: stage I or II
Inclusion: clinically node negative HN MM with pre‐SLNB PET‐CT
Excluded if > 1 month between PET‐CT and SLNB

Mean age: 60. Range: 18 to 88
Male: 16 (73%). Site: scalp 5, 23%; cheek 3, 14%; cervical or neck 3, 14%; atrial region (ear, mastoid, temples) 6, 27%; palpebral or periorbital 4, 18%; frontal 1, 5%
BT: 4.5 mm (0.26 to 10 mm)

PET‐CT. 2D/3D NR
Scan coverage: WB; vertex to the toes
Contrast: NR
CT parameters: Biograph 2: 130 kV, 80 mAs
Biograph 6: 130 kV, 4D Care Dose; Biograph 2: 5 mm
Biograph 6: 4 mm
¹⁸ FDG: 5.5 MBq/kg for Biograph 2; 4 MBq/kg for Biograph 6 True V; Flucis1, Schering, Cisbio International
Breath hold: no breath hold instructions reported
CT used for: appears to be used for attenuation correction; also describes anatomical localisation on fused images
Reconstruction: OSEM 3D

Any hypermetabolic focus more intense than the surrounding background, including equivocal foci, compared with the corresponding anatomical structure on coupled CT

Info provided: localisation of the initial tumour and the standard clinical and radiological assessment were known
No. observers: 2; no details.
Diagnosis: consensus of 2

Histology (22, 100%)

FNAC (N/A)

FU (22/22, 100%): mean 17 months (range 1 to 44)^

Histology interval: 12 days

FU interval: NR

Exclusions: n = 2; 2 test fails (no SN detected)

Sanki 2009
Australia
Patients: 716
Primary lesions: NR
LNBs/Metastases: 871

NC
Design unclear

Data: per pt
Nodal mets: 125/716 = 17%

Primary (pre‐SLNB)
Stage of disease: NR
Inclusion: SLNB; BT > 1 mm or < 1 mm with adverse histological features, such as Clark’s level IV to V invasion, ulceration, or high mitotic rate

Mean age: NR; Median age: NR; Range: NR
Male: NR (0%). Site: NR
NR

US. B‐mode US; linear array transducer with high‐resolution small‐parts probe 5 to 10 MHz (linear transducer); 10 to 14 MHz (small parts probe); LS before US
Scan coverage: sites marked by nuclear medicine physician during LS
Contrast: N/A
Breath hold: N/A

Re‐classification of original report as suspicious, or highly probable, e.g. increased vascular signature, rounding of the normal ovoid shape of the nodes, loss of normal hilar echoes, presence of focal low‐level subcapsular space echoes
Info provided: NR
No. observers: NR; nuclear medicine physician (NR)
Diagnosis: single

Histology (716, 100%)
FNAC (0)
FU (100% (SLNB; not ref standard for US)): 13.5 months (mean, 18.4 months)
Histology interval: SLN performed within 24 hours of LS and US
FU interval: NR

Exclusions: n = 0

Sibon 2007
France
Patients: 131
Primary lesions: 132
LNBs/Metastases: NR; 189 SLNs

NC

Retrospective (prospective database reported; plus prospective re‐interpretation of US images)
Data: per pt
Nodal mets: 35/133 = 26%

Primary (pre‐SLNB)
Stage of disease: NR
Inclusion: SLNB; BT > 1 mm or < 1 mm with adverse histological features, such as Clark’s level IV to V invasion, ulceration, or high mitotic rate

Mean age: 56; Range: 17 to 92 years
Male: 70 (53.4%). Site: arms 18, 13.6%, legs 43, 33%; trunk 48, 32%; hands/feet 10, 8%; HN 18, 14%
Mean BT 2.60 ± 2.91 mm

Clark’s level II 8, 6%; III 30, 23%; IV 88, 66%, V 7, 5%; unknown 1, 1%

US. B‐mode; linear transducer (6 to 12 MHz); US before LS
Scan coverage: site of the excised primary melanoma scar and followed the paths of the lymphatic vessels to the lymph node area(s)
Contrast: N/A
Breath hold: N/A

Stringent criteria: circular/oval hypoechoic lymph node with a Solbiati index < 1.5 and no hyperechoic hilum; Non‐stringent criteria included the presence of 1 or 2 stringent criteria
Info provided: NR for original interpretation or for re‐interpretation
No. observers: NR; 1 radiologist reviewed all images; radiologist (high)
Diagnosis: single

Histology (131, 100%)
FNAC (‐):
FU (n NR): no details
Histology interval: NR
FU interval: NR

Exclusions: n = 0;
using stringent criteria, US detected 1/24 micro‐metastases < 2 mm (as measured by US) and 2/11 macro‐metastases ≥ 2 mm (both > 5 mm)

Singh 2008
Germany
Patients: 52
Primary lesions: NR
LNBs/Metastases: 67 LNBs; 111 SLNs

NC
Unclear
Data: per pt
Nodal mets: 14/52 = 27%

> 4 mm BT: 7/12 = 58%

≤ 4 mm BT: 7/40 = 18%

Primary (pre‐SLNB)
Stage of disease: all I or II
Inclusion: primary MM undergoing SLNB (all > 1 mm)

Mean age: 55; Median age: 61; Range: 17 to 76
Male: 36 (69 %). Site: extremities 23, 44%; trunk 16, 31%; HN 13, 25%
Mean BT 3.46 mm, range 1.0 mm to 12.0 mm

PET‐CT. Helical, CT (CE, dual detector)
Scan coverage: WB; base of skull to tip of toes in 3 parts
Contrast: Peritrast‐oral‐GI; Kohler Chemie GmbH, Alsbach, Germany
CT parameters: 130 kV, 40 mAs; 5 mm
¹⁸ FDG: 370 ± 40 MBq ¹⁸FDG through an anterior cubital vein
Breath hold: limited breath hold for CT and shallow breathing for PET
CT used for: attenuation correction based on re‐scaling of CT image; image fusion
Reconstruction: iterative (not further detailed)

Any focal uptake more than background unless it was found to be a false positive focus (physiological accumulation or brown fat tissue) in fusion imaging
Info provided: NR
No. observers: 2; two experienced observers assessed ¹⁸FDG PET‐CT fusion imaging independently; also refers to team of radiologists and nuclear physicians (experienced)
Diagnosis: consensus

Histology (52, 100%)
FNAC (N/A)
FU (n NR): no details
Histology interval: PET before LS before SLNB
FU interval: NR

Exclusions: n = 0;
2 TP both BT ≥ 4 mm and FPs < 4 mm

van Rijk 2006
Netherlands
Patients: 107
Primary lesions: 107
LNBs/Metastases: NR; 37 D+ in 42 LNBs

WPC
Retrospective
Data: per pt
Nodal mets: 37/107 = 35%

Primary (pre‐SLNB)
Stage of disease: NR
Inclusion: SLNB candidates; cutaneous MM BT > 1 mm or Clark ≥ level IV

Mean age: 50; Range: 15 to 52
Male: 57 (53%). Site: HN 6, 6%; trunk 43, 40%; arm 24, 22%; leg 34, 32%
median BT 2.0 mm (0.6 to 12.5 mm)
Clark’s level II 1, 1%; III 37, 35%; IV 55, 51%; V 9, 8%; undeterminable 5, 5%

US. B‐mode linear array (7.5 MHz; 6 to 12 MHz); US before LS
Scan coverage: NR
Contrast: N/A
Breath hold: N/A

US + FNAC for US positive

Suspicious ‐ length–depth ratio < 2, conversion of a fatty hilum to a hypoechoic hilum, substantial cortical asymmetry or a focal area of low‐level echoes in the subcapsular sinus of the node and diameter > 5 mm for LN of the neck
Info provided: NR
No. observers: NR; no details
Diagnosis: NR

Histology (107, 100%)
FNAC (22; not part of ref standard)
FU (2/107; 2% (reported only for 2 positive on FNAC)): NR
Histology interval: NR
FU interval: NR

Exclusions: n = 0;
FU of 2 FNAC positive participants is reported but no further reference is made to any recurrences

Voit 2014
Germany
Patients: 1000
Primary lesions: 1000
LNBs/Metastases: NR

WPC
Design unclear
Data: per pt
Nodal mets: 208/1000 = 21%

Primary (pre‐SLNB)
Stage of disease: NR
Inclusion: SLNB candidates; BT > 1 mm thickness, or Clark IV/V, ulcerated and/or regressed

Mean age: 59; Median age: 62; Range: 15 to 94
Male: 567 (57%) Site: NR
Mean BT 2.58 mm; median BT 1.57 mm BT < 1 mm 288 29%; 1 to 2 mm 308 31%; 2 to 4 mm 231 23%; > 4 mm 173 17%
Clarks II 32 3%; III 341 34%; IV 554 56%; V 54 6%, unknown 13 1%

US. B‐mode & Doppler (1 to 18 MHz); LS before US
Scan coverage: LNBs; patients first underwent a lymphoscintigraphy, which assists the ultrasonographist to better focus the examination
Contrast: NA

US + FNAC for US positive

Malignant if total loss of central echoes (LCE) or LN enlarged and balloon shaped (BS); suspicious if peripheral perfusion present or central echo wandering towards the rim
Info provided: NR
No. observers: 3; ultrasonographist (mixed; 1 expert and 2 trained but less expert)
Diagnosis: unclear; likely single?

Histology (1000, 100%)
FNAC (332, 33%; authors report as 342, including 10 US malignant as FNAC positive even though no FNAC was undertaken):
FU (1000; 100%): mean 56 m; median 53 m; range 1 to 132 m
Histology interval: NR
FU interval: NR

Exclusions: n = 0

Wagner 2012
France
Patients: 48
Primary lesions: 48
LNBs/Metastases: NR

NC
Retrospective
Data: per pt
Nodal mets: 14/43 = 33%

Primary (pre‐SLNB)
Stage of disease: stage IIA 8, 16.7%; stage IIB 19, 39.6%; stage IIC 19, 39.6%; 2, 4.2% NR
Inclusion: SLNB candidates; BT ≥ 4 mm or BT > 1 mm with ulceration

Mean age: NR; Median age: NR; Range: NR
Male: 25 (52%). Site: NR
Mean BT 7.6 mm (±4.5) (range 1.1 to 18 mm)

PET‐CT. 2D; CT (NR)
Scan coverage: WB; not further described
Contrast: NR
CT parameters: 140 kV, 200 mA (attenuation correction and anatomical correlation); 7.5 mm
¹⁸ FDG: 370MBq (Glucotep Cyclopharma, St Beauzire, France)
Breath hold: normal breathing; "remain rested, to refrain from speaking, and to minimize swallowing"
CT used for: attenuation correction and anatomical correlation
Reconstruction: iterative OSEM (Ordered Subset Expectation Maximization) algorithm (3 iterations; 10 subsets)

Abnormally increased ¹⁸FDG uptake in a lymph node in the drainage territory of the melanoma
Info provided: aware of all clinical findings
No. observers: NR; nuclear medicine specialist (high)
Diagnosis: unclear; 'at least one'

Histology (43, 89.6%; 2 CLND only, 1 SLNB + CLND, 40 SLNB only)
FNAC (N/A)
FU (1): min 12 months
Histology interval: NR
FU interval: NR

Exclusions: n = 5; SLNB not performed for technical reasons

+: positive; AJCC: American Joint Cancer Committee; AWOSEM: attenuation weighted ordered subsets expectation maximisation; BT: Breslow thickness; CE: contrast enhanced; CLND: complete lymph node dissection; CT: computed tomography; 2D: two‐dimensional; 3D: three‐dimensional; EDV: end‐diastolic volume; 18FDG: 2‐deoxy‐2‐[18F]fluoro‐D‐glucose; FNAC: fine needle aspiration cytology; FORE: Fourier rebinning; FU: follow‐up; HN: head and neck; LN: lymph node; LNB: lymph node basin; LND: lymph node dissection; LS: lymphoscintigraphy; mA: measure of tube current; mets: metastases; MM: malignant melanoma; NC: non‐comparative; OSEM: ordered subsets expectation maximisation algorithm; PET: positron emission tomography; PI: pulse index; PSV: peak systolic volume; prosp: prospective; RF: risk factor; SD: standard deviation; SLN: sentinel lymph node; SLNB: sentinel lymph node biopsy; SSM: superficial spreading melanoma; SUV: standardised uptake value; U: unenhanced; US: ultrasound; WB: whole body.

Study
Country
Pt/lesion numbers

Study design
Outcome Prevalence

Presentation
Inclusion criteria
Imaging eligibility

Age, gender, site, BT, Clark

Index test

Threshold

Observers

Reference

Exclusions

Other result

PRIMARY STAGING OF DISEASE

Arrangoiz 2012
USA
Patients: 56
Primary lesions: 56
LNBs/Metastases: NR

NC
Retrospective (Prosp database: NR)

Data: per pt
Any mets (NR; scan incl head): 32/56 = 57%

Nodal: 29/56 = 52%

Distant mets : 5/56 = 9%

Primary (N/A)
Stage of disease: all T4 and clinically node negative and negative for distant metastases
Inclusion: node negative; BT > 4 mm

Mean age: 67; Median age: NR; Range: 26 to 89
Male: 32 (57.1428571428571%)

Site: trunk 16, 29%; extremities 28, 50%; head and neck 12, 21%
BT median 6 mm; mean 9 mm; range 4.1 to 40 mm

PET‐CT. 2D or 3D; CT (U, helical, low dose)
Scan coverage: WB; vertex of the head down to feet for all patients
Contrast: U
CT parameters: Discovery LS ‐ 140 kVp, 90 mA; Siemens Biograph ‐ 130 kVp, 100 mA; 5 mm
FDG: 15 mCi (IV)
Breath hold: normal breathing
CT used for: attenuation correction; co‐registered images
Reconstruction: Discovery LS ‐ OSEM algorithm with 28 subsets and 2 iterations
Siemens Biograph ‐ TrueX algorithm with 21 subsets and 2 iterations

SUV of 2.5
Info provided: NR
No. observers: NR; 'in‐house medical physicist' mentioned; NR; 'in‐house medical physicist' mentioned (NR)
Diagnosis: unclear

Histology (54, 96% (48 SNB and 6 LND))
FNAC (NR):
FU (NR): NR
Histology interval: NR; states that 6 "proceeded directly to therapeutic lymph node dissection" after PET
FU interval: NR

Exclusions: n = 0; N/A

Hafner 2004

Switzerland
Patients: 101
Primary lesions: 101
LNBs/Metastases: 105 LNBs; 136 SLNs

WPC
Prospective

Data: per pt
Nodal mets: 26/100 = 26%

Primary (N/A).
Stage of disease: NR; stage IV (evidence of distant mets) excluded
Inclusion: any cutaneous MM with BT ≥ 1 mm without evidence of detectable distant metastasis (includes clinically palpable)

Mean age: NR; Median age: 55; Range: 18 to 79
Male: 55 (55%)

Site: limbs 49, 49%, trunk 35, 35%, HN 16, 16%
BT: 1.01 to 2 mm 38; 2.01 to 4 mm 43; > 4.0 mm 19

US. B‐mode (5 Mhz); US before LS
Scan coverage: regional lymph nodes of the groins, axillae, and neck (abdominal US also performed)

NR; 'radiologically suspect'
Info provided: unclear
No. observers: 1; radiology resident (NR)
Diagnosis: single (supervision by senior staff radiologist)

Histology (100; 100%)
FNAC (NR (abstract reports 3 LN mets identified on physical exam, 2 of which were detected by US)):
FU (NR): 20 months (8 to 39)
Histology interval: 2 weeks
FU interval: 6 months

Exclusions: n = 1; sentinel node was not found intraoperatively

No confirmed distant mets detected at time of imaging; 9 patients with suspicious findings on imaging were negative for progression/recurrence at 12 months

Kang 2011

S Korea
Patients: 37
Primary lesions: 37
LNBs/Metastases: NR

NC
Retrospective (Prosp database: no; medical record review)

Data: per pt
Any mets (incl brain): 9/37 = 24%

Primary (N/A)
Stage of disease: stage 0: 7 (18.9%); stage I: 6 (16.2%); stage II: 17 (45.9%); stage III: 6 (16.2%); stage IV: 1 (2.7%)
Inclusion: newly diagnosed cutaneous MM undergoing staging work‐up with PET‐CT (any stage, including clinically node positive)

Mean age: 61.7 years; Median age: NR; Range: 48.1 to 75.3; ± 13.6 years
Male: 17 (45.9%)

Site: hand/foot 23 (62.1%), trunk 6 (16.2), head/neck 4 (10.8%), extremity 4 (10.8%)
BT < 1.0 mm 8, 22%; ≥ 1 mm 15, 41%; NR 14, 38%

PET‐CT. CT (U, 6 slice or 16 slice) (N/A)
Scan coverage: vertex of skull to knees; plus lower limbs if with lower leg MM
Contrast: U
CT parameters: Reveal RT‐HiRez: 130 kV, 95 mA
Discovery ST: 140 kV, 160 mA; Reveal RT‐HiRez: 2.5 mm
Discovery ST: 3.75 mm
FDG: 350 to 400 MBq
Breath hold: NR; 'standard protocol'
CT used for: unclear; combined PET‐CT unit, mentions identification of anatomical location on fused PET‐CT image
Reconstruction: ordered subset expectation‐maximisation

SUVmax ≥ 2.2

Info provided: NR
No. observers: 2; nuclear physicians (experienced)
Diagnosis: consensus of 2

Histology (6 (16.2%))
FNAC (0)
FU (37 (100%)): median follow­up 24.3 ± l l.7 months (range 8 to 55 months)
Histology interval: NR
FU interval: 3 months

Exclusions: n = 0

Maubec 2007

France
Patients: 25
Primary lesions: 26
LNBs/Metastases: NR

WPC
Prospective

Data: per pt
Any (incl brain): 7/25 = 28%

Primary (N/A).
Stage of disease: all T4; 3 clinically node positive
Post surgery: AJCC stage IIB 10, 40%; IIC 4, 16%; IIIA 4, 16%; IIIB 6, 24%; IIIC in 1, 4%
Inclusion: any MM BT > 4 mm; SLNB planned if clinically node negative

Mean age: 60; Range: 14 to 87
Male: 15 (0.6%). Site: trunk 8, 32%; limbs 8; 32%; head and neck 9, 36%
Mean BT 6.6 mm, range 4.8 to 12.5 mm

PET‐CT. 3D; CT (U)
Scan coverage: WB; "top of the head to the mid‐thigh and included if necessary, the lower limbs"
Contrast: U
CT parameters: 80 mA; 110 kV; 5 mm
FDG: 5 MBq/kg
Breath hold: normal breathing; "no breath hold instructions"
CT used for: NR; integrated system
Reconstruction: iterative algorithm (FORE and AWOSEM) with 2 iterations, 8 subsets, and a 5 mm full‐width half maximum (FWHM) Gaussian postfilter

Uptake site suspicious for malignancy or not clearly explained by a benign etiology (SUV estimated but does not appear to formally contribute to diagnosis)

Info provided: NR
No. observers: NR; NR (NR)
Diagnosis: NR

Histology (22, 88%; 3 node positive underwent CLND; 19 had SLNB; 3 no surgery)
FNAC (N/A)
FU (25, 100%): mean 11 months (2 to 19 months)
Histology interval: NR
FU interval: NR

Exclusions: n = 0; all recruited pts can be included in analysis for any mets. 3 PET +ve for distant mets (1 orbital, 1 thyroid, 1 liver)

Prayer 1990

Austria
Patients: 217
Primary lesions: NR
LNBs/Metastases: NR

WPC
Unclear (Prosp database: NR)

Data: per pt
Nodal mets: 29/217 = 13%

Primary
Stage of disease: NR
Inclusion: primary MM investigated either before or after removal of the primary melanoma in postoperative follow‐up

Mean age: 56; Median age: NR; Range: 25 to 82
Male: 104 (47.926267281106%)

Site: HN 42, 19%; arm 61, 28%; shoulder 23, 11%; leg 91, 42%
BT < 0.75 mm 25, 12%; 0.75 to 1.5 mm 96, 44%; 1.5 to 3.00 mm 79, 36%; > 3 mm 17, 8%
Clark level II 936, III 89, IV 33

US. B‐mode (7.5 MHz); N/A
Scan coverage: primary LNs depending on tumour localisation. Cervical (42); axillary (84); inguinal (91)
Contrast: N/A

Suspicious ‐ circular and oval masses with poor echo; longitudinally configurated LNs with echogenic eccentric hilum regarded as “enlarged reactively”
Info provided: unclear; different clinicians for palpation (dermatologist) and for US (radiologist)
No. observers: 1; radiologist (NR)
Diagnosis: single

Histology (29, 13%)
FNAC (0)
FU (188, 87%): 6 months
Histology interval: NR
FU interval: 2 months

Exclusions: n = 0
There were no false‐negative sonographic results i.e. melanoma metastases did not occur within the following 6 months in any of the patients classified as having no suspect regional lymph nodes. The smallest metastasis detected by ultrasound was 11 mm in diameter

Veit‐Haibach 2009
Germany
Patients: 56
Primary lesions: 56
LNBs/Metastases: NR

WPC
Prospective

Data: per pt
Nodal: 13/56 = 23%

Distant (brain NR): 12/56 = 21%

Primary (N/A)
Stage of disease: on presentation: stage I or II 44, 79%; stage III or IV 12, 21%
Inclusion: any primary MM referred for PET‐CT
Excluded if insufficient FU

Mean age: 62 years; Median age: Range: 23 to 86 years
Male: 27 (48.2142857142857%)

Site: trunk 26, 46%; upper extremities 10, 18%; lower extremity 18, 32%; HN 2, 4%
NR

CT. CE; two slice (N/A); NR
Scan coverage: WB; no further detail, just states caudocranial direction
Contrast: dual phase injection of 140 mL of 300 mmol/mL iodinated contrast agent (90 mL at a rate of 3 mL/s, and 50 mL at a rate of 1.5 mL/s; dual phase used to ensure fully diagnostic (portal venous phase) CT data in the abdomen)
CT parameters: NR; NR
Breath hold: NR

PET‐CT. full ring‐CT (CE; 2 slice) (N/A); NR
Scan coverage: WB; no further detail, just states caudocranial direction
Contrast: 140 mL of 300 mmol/mL iodinated contrast agent
CT parameters: NR; NR
FDG: 330 to 350 MBq
Breath hold: NR
CT used for: attenuation correction
Reconstruction: reconstructed iteratively (FORE‐OSEM, 2 iterations, 8 subsets, 128×128 matrix with 5 mm gaussian smoothing)

CT: Lesion size and central necrosis for malignancy; fatty hilum and calcifications for benign. For size: short‐axis diameter threshold of 1.5 cm for jugulodigastric and precarinal LNs and threshold of 1 cm for all other LNs of the neck, thorax, and abdomen [16]

PET‐CT: increased glucose metabolism and independent of their size

Info provided: provided patient‐specific clinical background (first diagnosis of melanoma, postsurgical resection status, location of the resection site) but blinded to clinical exam and histopathology of primary tumour

No. observers: 2; radiologists (NR).
Diagnosis: consensus of 2

Histology (unclear; 14 with SLNB, 25%)
FNAC (0)
FU (56, 100%): mean 780 days (range 102 to 1390 days); roughly equivalent to 25.6 months (3.3 to 45.7 months)
Histology interval: 4 weeks for SLNB
FU interval: NR

Exclusions: n = 0

RE‐STAGING OF DISEASE

Iagaru 2007

USA
Patients: 106
Primary lesions: NR
LNBs/Metastases: 139

WPC
Retrospective (Prosp database: NR)

Data: per pt
Any mets (incl skin and brain):

56/106 = 53% (all tests)

Data: per lesion
Any mets (incl skin and brain):

87/139 = 63%

Re‐staging (all patients had the study requested for disease re‐staging)
Stage of disease: NR; 76 stage I to IIIc and 30 stage IIIb to IV)
Inclusion: PET‐CT for MM re‐staging
Excluded if NR ORNR
PET‐CT for MM re‐staging

Mean age: 56.8 ± 15.9 Median age: nr; Range: 20 to 87
Male: 68 (64.1%)

Site: NR
BT at initial diagnosis (n = 76): mean 3.56 mm, 0.4 to 25 mm; < 1 mm in 6 (8%), 1 to 4.0 mm 58 (76%), > 4 mm 12 (16%)
Clark's level (n = 70): 3 (4%), level II; 13 (19%), level III; 43 (61%), level IV; 11 (16%), level V

CT. U, multislice helical (N/A)
Scan coverage: WB; top of the head to the ankles
Contrast: N/A
CT parameters: 140 kV, 40 mA; 5 mm
Breath hold: no breath hold instructions reported

PET‐CT. 2D; CT (U, multi‐slice helical) (N/A)
Scan coverage: WB ; top of the head to the ankles
Contrast: U
CT parameters: 140 kV, 40 mA, 5 mm
FDG: 15 mCi
Breath hold: no breath hold instructions reported
CT used for: attenuation correction and anatomical localisation
Reconstruction: OSEM, 2 iterative steps, 28 subsets

CT: NR

PET‐CT: SUVmax ≥ 2.5

Info provided: NR for original interpretation or for re‐interpretation
No. observers: NR; board‐certified nuclear medicine physicians and radiologists (board certified)
Diagnosis: consensus

Histology (97, 91.5%)
FNAC (N/A)
FU (9, 8.5%): NR
Histology interval: NR
FU interval: NR

Exclusions: n = 0; N/A

Rubaltelli 2011
Italy
Patients: 436
Primary lesions: NR
LNBs/Metastases: NR

WPC
Unclear

Data: per pt
Nodal mets: 13/436 = 3%

Re‐staging (all undergoing postoperative follow‐up designed to ensure the early identification of lymph node metastases)
Stage of disease: NR
Inclusion: cutaneous MM with US of regional LNs as part of a follow‐up; those with 'common signs of malignancy' on B‐mode US were excluded

Mean age: 54; Median age: 58; Range: 27 to 81 years
Male: Full sample: 240 (52%)

Site: NR

US. B‐mode; linear array transducers (7.5 to 13 MHz)
Scan coverage: variable: axillary lymph nodes for MM of the upper limbs, inguinal lymph nodes for MM of the lower limbs, both axillary and inguinal lymph nodes for MM of the trunk, and cervical and supraclavicular lymph nodes for MM of the head and neck (72 neck, 248 axillary, and 354 inguinal LNBs were examined)
Contrast: N/A

US. contrast‐enhanced US (7.5 to 13 MHz)
Scan coverage: LNBs identified on B‐mode US
Contrast: sulfur hexafluoride microbubbles (SonoVue, Bracco)

US: focal hypoechoic cortical thickening ‐ a focal area of cortex at least twice as thick as the cortex in the remainder of the same lymph node

CE‐US: perfusion defects corresponding to the cortical focal thickening; homogeneous intense enhancement of the cortex considered benign

Info provided: NR
No. observers: 1 of 3; sonologist (high)
Diagnosis: single

Histology (13, 3%)
FNAC (436, 100%)
FU (31/44 FNAC negative, 70%): 6 to 16 months (median, 10 months)
Histology interval: NR
FU interval: NR

Exclusions: n = 24; definite signs of malignancy on B‐mode US

Strobel 2007a

Switzerland
Patients: 47
Primary lesions: 47
LNBs/Metastases: NR

NC
Retrospective (Prosp database: NR)

Data: per pt
Any (incl brain): 39/47 = 83%

Re‐staging (all pts followed up according to updated Swiss melanoma guidelines)
Stage of disease: NR
Inclusion: high risk melanoma (BT > 4 mm, or Clark level III or IV, or known resected metastases) and raised S100 (> 0.2 μg/L) undergoing follow‐up after primary treatment
Excluded if PET‐CT and S100B measurement > 2 weeks apart; treatment initiated between PET‐CT and tumour marker measurement; or systemic therapy before the PET‐CT investigation

Mean age: 58.4 years; Median age: Range: 20 to 83 years
Male: 20 (42.5531914893617%) Site: NR
BT 1.02 mm to 15 mm; unknown in 9

PET‐CT. 2D PET, CT (CE, multi‐slice, helical)
Scan coverage: head to the knees with scanning of the lower legs for patients with primary tumours of the lower extremities
Contrast: oral CT contrast agent given 15 minutes before injection of 18F‐FDG
CT parameters: 140 kV, 40 mAs, 4.25 mm

FDG: 370 to 400 MBq
Breath hold: CT: breath holding in the normal expiratory position
CT used for: attenuation correction, fused
Reconstruction: standard iterative algorithm (OSEM)

FDG uptake clearly greater than background and established morphological CT criteria; if a focal FDG‐active lesion was detected, the exact anatomical localisation was determined on the fused PET‐CT images. Lesions with 18F‐FDG uptake in physiological sites or benign variants, e.g. muscles, brown fatty tissue or pulmonary infiltrations, were determined as benign
Info provided: blinded to serum S100B
No. observers: 2; nuclear radiology physicians (experienced)
Diagnosis: consensus of 2

Histology (29, 62%; 20 distant mets and 9 LN mets)
FNAC (4, 8.5%)
FU (47, 100%): minimum of 6 months (range 6 to 18 months in all patients
Histology interval:
FU interval: 3 months

Exclusions: n = 0; N/A
Reports characteristics of those with elevated S100 but not mets detected on imaging

STAGING IN MIXED OR UNCLEAR POPULATIONS

Abbott 2011
UK
Patients: 34 (microscopic group 20; macroscopic group 14)
Primary lesions: 34
LNBs/Metastases: NR

NC
Retrospective (Prosp. database used)

Data: per pt
Any (excl brain): 7/34 = 21%

Mixed (primary/FU)
Stage of disease: IIIA 18, 53%; IIIB 10, 29%; IIIC 6, 18%
Inclusion: stage III: micro‐metastases on SLNB or clinically detectable nodal metastases on diagnosis or FU

Mean age: NR; Median age: microscopic group: 50; macroscopic group: 63 Range: microscopic group: 19 to 74 years
Macroscopic group: 48 to 79 years
Male: microscopic group: 14
Macroscopic group: 6 (Microscopic group: 70%
Macroscopic group: 43%%) Site: HN 1 (3%), upper extremity 3 (9%), trunk 20 (59%), lower extremity 10 (29%)
BT (mean): microscopic group 2.27 mm (1.2 to 9.7 mm); macroscopic group 2.01 mm (1.0 to 13 mm)

PET‐CT. 2D; CT (NR)
Scan coverage: skull base to upper thigh
Contrast: NR
CT parameters: NR; NR
FDG: 400 MBq
Breath hold: NR
CT used for: attenuation correction and lesion localisation
Reconstruction: iterative technique using an OSEM algorithm

Clearly indicative/highly suspicious for malignancy considered positive
Info provided: clinical ‐ NR; other tests ‐ NR
No. observers: NR; nuclear medicine consultants (experienced)
Diagnosis: NR

Histology (5, 15%)
FNAC (0)
FU (34, 100%): microscopic mean 38 months (21 to 54 months); macroscopic mean 34 months (15 to 52 months)
Histology interval: NR
FU interval: 3 months

Exclusions: n = 0

Aukema 2010a

Netherlands
Patients: 46
Primary lesions: NR
LNBs/Metastases: NR

NC
Retrospective (Prosp database: NR)

Data: per pt
Any (brain NR): 23/46 = 50%

Mixed (imaged on recurrence or after primary melanoma treatment)
Stage of disease: NR; unfavorable primary tumour (n = 6); primary melanoma with simultaneous nodal metastases (n = 18); unknown primary melanoma with nodal metastasis (n = 2); locoregional recurrence (n = 15); distant recurrence (n = 5)
Inclusion: raised S100 during FU after resection of nodal or distant metastases or with high risk primary tumour

Mean age: 59; Median age: ; Range: 25 to 93 years
Male: NR (0%)

Site: NR
NR

PET‐CT. NR; CT (U) (N/A)
Scan coverage: whole body; not described
Contrast: U
CT parameters: kV NR; 40 mAs, 5 mm
FDG: 180 to 240 MBq (4.9 to 6.5 mCi)
Breath hold: No breath hold instructions reported
CT used for: attenuation correction; PET fused to low‐dose CT
Reconstruction: NR

NR; "hypermetabolic lesions"
Info provided: NR
No. observers: 3; nuclear medicine physicians (experienced)
Diagnosis: consensus of 3

Histology (13, 28.3%)
FNAC (0)
FU (33, 71.7%): for D negative only (n = 19): median 12 months (4 to 32 months); NR for full sample
Histology interval: NR
FU interval

Exclusions: n = NR

Other result: "MRI revealed 2 brain metastases of 2 and 4 mm in 1 patient (2%). This patient also had other distant metastases that were detected by PET‐CT"

Aukema 2010b

Netherlands
Patients: 70
Primary lesions: 70
LNBs/Metastases: 73

NC
Prospective

Data: per pt
Any mets: 30/70 = 43%

Unclear (N).
Stage of disease:
≥ stage IIIb (all with clinically palpable nodes)
Inclusion: clinically node positive with no sign of distant metastases; primary/re‐staging NR

Mean age: 58; Median age: NR; Range: NR
Male: 37 (0.54%)

Site: upper extremity 4, 6%; lower extremity 37, 53%; trunk 19, 27%; head/neck 9, 13%; unknown primary 1, 1%
BT: median 3 mm

PET‐CT. 2D ; CT (U) (N/A)
Scan coverage: WB according to primary lesion site (i.e. IRT inclusion of cranium or lower extremities)
Contrast: U
CT parameters: kV NR; 40 mAs, 5 mm
FDG: 180 to 240 MBq
Breath hold: no breath hold instructions reported
CT used for: attenuation correction; PET fused to low‐dose CT
Reconstruction: PET was
fused with the low‐dose CT after correction for attenuation

NR; "metabolically active"
Info provided: NR
No. observers: 3; nuclear medicine physicians (NR)
Diagnosis: consensus of 3

Histology (NR; 11 with histology or cytology)
FNAC (NR; 11 with histology or cytology):
FU (59; 84%): NR; ≥ 6 months
Histology interval: N/A
FU interval: NR

Exclusions: n = 0

Other result: MRI detected brain mets in 5 pts, no reference standard reported

Bastiaannet 2009
Netherlands
Patients: 251
Primary lesions: 251
LNBs/Metastases: NR

WPC
Prospective

Data: per pt
Distant mets: 78/251 = 31%

Mixed (primary (LN mets diagnosed at time of primary diagnosis) 39, 15.5%; recurrence (LN mets identified ≤ 3 years since primary dx) 145, 57.8%; recurrence > 3 years since primary dx 67, 26.7%)
Stage of disease: III (100%)
Inclusion: node positive (clinical or histology/cytology proven) candidates for CLND; imaging to id further disease

Mean age: 56.9 years (n = 253); Median age: NR; Range: 19 to 93 years (reported in Bastiannet 2012)
76 (30.3%) < 50 years; 99 (39.4%) 50 to 65 years; 76 (30.3%) > 65
Male: 152 (0.606%)

Site: HN 29, 11.6%; upper extremities 26, 10.4%; trunk 93, 37.0%; lower extremities 88, 35.0%; unknown primary 15, 6.0%
BT: ≤ 1 mm 32, 12.8%; 1.0 to 2.0 73, 29.1%; ≥ 2.0 129, 51.4%; unknown primary 15, 5.9%; missing 2, 0.8%
Clark level: I/II/III (n = 84; 33.5%), IV/V (n = 144; 57.4%), unknown primary (n = 15; 5.9%), missing (n = 8; 3.2%)

CT. CE, spiral, multi‐slice
Scan coverage: chest, abdomen plus neck for those with LN in the neck
Contrast: oral and IV
CT parameters: NR; NR; 'multi‐slice'
Breath hold: no breath hold instructions reported

NR (presence/absence of mets)
Info provided: NR
No. observers: NR; attending staff nuclear medicine physicians (NR)
Diagnosis: NR

Histology (NR)
FNAC (NR)
FU (251, 100%): median 13.7 months; minimum 6 months stated for index test positive, NR for index test negative
Histology interval: NR
FU interval: NR

Exclusions: n = 8; excluded due to follicular structure (n = 1), > 13 years between primary and lymph nodes (n = 3), incidence abroad (n = 1), mucosal melanoma (n = 2), and primary melanoma treated as benign lesion (n = 1)
(1) accuracy of PET alone, (2) change in treatment resulting from PET and/or CT

Cachin 2014

France
Patients: 87
Primary lesions: 176
LNBs/Metastases: check entry

NC
Prospective

Data: per pt
Any (incl brain, subcut mets): 39/67 = 58%

Data: per lesion
Any (incl brain): 85/176 = 48%

Nodal: 20/39 = 51%

Distant (incl brain): 65/137 = 47%

Bone: 14/34 = 41%

Lung: 10/27 = 37%

Soft tissue: 16/25 = 64%

Skin: 7/9 = 78%

Brain: 7/9 = 78%

Mixed (states imaging was for staging or for re‐staging ).
Stage of disease: NR; 45 (51% were diagnosed with melanoma mets on study Inclusion)
Inclusion: prior history of cutaneous or ocular MM undergoing staging or restaging including: (a) newly diagnosed at any TNM stage, (b) known visceral or cutaneous MM metastases with unknown primary tumour, or (c) MM without metastases (included to assess test specificity)

Mean age: NR; Median age: NR; Range: NR
Male: 42 (48.3%)

Site: NR
Breslow thickness (mm): < 1.0: 12, 13.8%; 1.0 to 2.0: 34, 39.1%; ≥ 2.0, 41, 47.1%
Clark level: I 3, 3.4%; II 2, 2.3%; III 20, 23.0%; IV 46, 52.9%; V 3, 3.4%; not known 13, 14.9%

PET‐CT. NR; SPECT used in 4 of 8 centres
Scan coverage: WB (not further described)
Contrast: NR
CT parameters: SPECT; N/A
FDG: 3 to 5 MBq/kg
Breath hold: NR
CT used for: PET 'correlated' with CT abnormalities
Reconstruction: iterative in 6 of 8 centres; filtered backprojection in 2 of 8 centres

PET. Positive if there was focal uptake greater than mediastinal or liver uptake that could not clearly be related to physiological processes. Negative when a normal distribution of tracer was observed, even if the CT scan showed abnormalities. Bone accumulations were considered positive when the uptake was higher than in normal bone marrow. Any instance of equivocal PET uptake was considered positive
Info provided: NR
No. observers: NR; nuclear physician (experienced)
Diagnosis: single

Histology (25; 28.7%)
FNAC (N/A)
FU (87, 100%): at least 6 months
Histology interval: NR
FU interval: NR

Exclusions: n = 20; 12 did not undergo FDG PET due to imaging cancellation; 8 are unaccounted for (text describes 75 having PET but reports results for only 67)

Dellestable 2011
France
Patients: 40
Primary lesions: 40
LNBs/Metastases: NR; 72 lesions

WPC
Prospective
Data: per lesion
Any (incl brain):

72/119 = 61% (CT)

70/117 = 60% (MRI)

72/119 = 61% (PET‐CT)

Nodal:

31/39 = 79% (CT)

31/40 = 78% (MRI)

31/38 = 82% (PET‐CT)

Bone:

14/17 = 82% (CT)

14/16 = 88% (MRI)

14/17 = 82% (PET‐CT)

Liver:

4/21 = 19% (CT)

4/26 = 15% (MRI)

4/25 = 16% (PET‐CT)

Lung:

13/16 = 81% (CT)

13/14 = 93% (MRI)

13/15 = 87% (PET‐CT)

Mixed (both primary staging and FU; breakdown reported but not legible on pdf)
Stage of disease: AJCC I to II 11, 27.5%; AJCC III to IV 29, 72.5%

Inclusion: PET‐CT for primary staging or follow‐up of MM, regardless of AJCC stage or indication for examination

Mean age: 57 years; Median age: Range: 27 to 85 years
Male: 20 (0.5%). Site: NR
BT mean: 3.2 mm, median 2.7 mm, range 0.6 to 11 mm

CT. CT (N/A); NR
Scan coverage: skull, neck, thorax, abdomen, and pelvis
Contrast: iodised injection was administered by the same venous route as for the previous examinations
CT parameters: NR; NR
Breath hold: no breath hold instructions reported

MRI. WB, DW, T2STIR, CE 3D gradient echo (N/A); NR
Scan coverage: WB; head to lower limbs
Contrast: gadolinium injection
MRI parameters: T2STIR, T1, diffusion and 3D gradient echo T1 after gadolinium injection; 1.5 T
Breath hold: no breath hold instructions reported

PET‐CT. NR; CT (CE) (N/A); NR
Scan coverage: WB; top of the skull to the feet
Contrast: unclear; contrast is reported for CT; however CT component of PET‐CT is not clear
CT parameters: NR; NR
FDG: 5.5 MBq/kg
Breath hold: no breath hold instructions reported
CT used for: attenuation correction and anatomical registration
Reconstruction: NR

CT: NR

MRI: NR

PET‐CT: focal uptake; unusual location or visual or quantitative intensity (SUV measurement)

Info provided: NR
No. observers: 3; NR (NR)
Diagnosis: single with consensus if the results of any modality disagreed

Histology (36 lesions, 28% of 128)
FNAC (0)
FU (72, 56%): > 4 months
Histology interval: NR
FU interval: NR

Exclusions: n = 20 lesions; 4 lesions with indeterminate reference and 16 not picked up by CT

Hausmann 2011

Germany
Patients: 50 eligible; 33 included
Primary lesions: 50
LNBs/Metastases: NR

WPC
Prospective

Data: per lesion
Any mets (excl brain): 455/824 = 55% (all tests)

Nodal: 192/379 = 51%

Distant: 263/445 = 59%

Liver: 33/67 = 49%

Lung: 145/197 = 74%

Subcutaneous: 33/46 = 72%

Other (authors' 'Other' category plus Adrenal, Kidney, Muscle and spleen sites): 51/118 = 43%

Adrenal: 2/5 = 40%

Bone: 1/17 = 6%

Kidney: 2/32 = 6%

Muscle: 22/26 = 85%

Spleen: 4/24 = 17%

Unclear (Pts described as having undergone a previous assessment of tumour spread based on ADO (German) guidelines but staging/re‐staging not described
Stage of disease: full sample only: stage III (19); stage IV (31)
Inclusion: AJCC stage III or IV MM; clinical indication for imaging was positive sentinel‐node biopsy or suspicious lesions on ultrasound or X‐ray studies

Mean age: full sample only: 59.6; Median age: Range: full sample only: 26 to 86
Male: full sample only: 32 (64%)

Site: NR
NR

CT. U + CE, multi‐detector (N/A)
Scan coverage: skull base to pelvis; CT and MR compared for "neck to the pelvis" only; sites imaged included lungs, liver, spleen, kidneys, adrenal glands, subcutaneous tissue, lymph nodes, muscle, bone marrow, and “other”
Contrast: U + CE
CT parameters: NR; NR
Breath hold: no breath hold instructions reported

MRI. U + CE; 'standard sequences' (N/A)
Scan coverage: WB; as above
Contrast: U + CE
MRI parameters: standard sequences with parallel imaging techniques; 1.5 T
Breath hold: no breath hold instructions reported

CT: NR (presence/absence of mets)

MRI: NR (presence/absence of mets)
Info provided: diagnosis/age/sex
No. observers: 4 (2 included); radiologist (high)
Diagnosis: single

Histology (NR)
FNAC (0)
FU (33, 100%): ≥ 3 months
Histology interval: N/A
FU interval: minimum 3 months

Exclusions: n = 17; no WB‐CT follow‐up undertaken.
Results presented by region and for less experienced observers 3 and 4; also presented no. Mets detected by cranial MR but no 2×2 extractable

Jouvet 2014
France
Patients: 37
Primary lesions:
LNBs/Metastases: 209 lesions (n varies per test)

WPC
Prospective
Data: per lesion
Any mets (incl brain):

115/209 = 55% (CT)

125/218 = 57% (MRI)

Any mets (excl brain): 95/186 = 51% (CT)

105/195 = 54% (MRI)

104/191 = 54% (PET‐CT)

Nodal: 23/53 = 43% (all tests)

Bone:

15/33 = 45% (CT/MRI)

16/35 = 46% (PET‐CT)

Liver:

12/27 = 44% (all tests)

Lung:

31/45 = 69% (all tests)

Subcutaneous:

2/15 = 13% (CT)

10/22 = 45% (MRI)

7/15 = 47% (PET‐CT)

Unclear (NR)
Stage of disease: stage IV: 37 (100%)

Inclusion:
AJCC stage IV cutaneous MM referred for simultaneous staging by PET‐CT, CT, superficial lymph node US, and MRI

Mean age: NR; Median age: NR; Range: NR
Male: NR (0%)

Site: NR
NR

CT. CE; Helical; 16 row (N/A)
Scan coverage: neck/chest/ abdomen/pelvis; "cervico‐thoraco‐abdomino‐pelvic helicoidal acquisition"; then skull
Contrast: iodinated IV injection
CT parameters: 120 kV, 250 mAs (neck to pelvis); 140 kV, 120 mAs (skull), 1.25 mm (neck to pelvis), 2.5 mm (skull)
Breath hold: no breath hold instructions reported

MRI. (1) DW alone (N/A);

(2) DW, VIBE ‐ 3D echo gradient CE, T1 ‐ skull (N/A)
Scan coverage: WB; top of skull to feet
Contrast: U
MRI parameters: echo‐planar DW alone; 1.5 T
Breath hold: no breath hold instructions reported

CT and MRI: NR (presence/absence of mets)
Info provided: NR
No. observers: 1; radiologist (experienced).
Diagnosis: consensus of 2 (all images interp independently by 2 examiners, discordant results resolved by consensus)

Histology (0)
FNAC (5, 13.5%)
FU (32; 86.5%): > 9 months
Histology interval: NR
FU interval: NR

Exclusions: n = 0; N/A
Results are also presented by metastatic site. Provides K values for inter‐ and intra‐observer agreements, but not the 2×2 tables for each observer

Klebl 2003

Germany
Patients: 83
Primary lesions: 83
LNBs/Metastases: NR; 653 LNs examined

WPC
Prospective

Data: per pt
Nodal mets: 17/79 = 22%

Mixed (primary (n = 8), follow‐up (n = 75))
Stage of disease: NR
Inclusion: MM Clark level IV or V undergoing FU after primary surgery

Mean age: NR; Median age: NR; Range: NR
Male: 46 (55.421686746988%)

Site: NR
Clark level IV 68, 82%; level V 15, 18%

US. B‐mode US; high resolution linear array (5 to 10 MHz); N/A
Scan coverage: cervical, axillary, and inguinal LNBs
Contrast: N/A

Suspicious/indeterminate/benign based on diameter, shape, echogenicity, and vascularisation pattern

Info provided: unclear; could be same examiner as for LN palpation
No. observers: NR; NR (NR)
Diagnosis: NR

Histology (17, 20%)
FNAC (0)
FU (62, 75%): minimum 1 year; mean time since primary surgery 2.6 ± 2.3 years
Histology interval: NR
FU interval: 6 to 8 weeks for control visit, 6 to 12 months for FU visit

Exclusions: n = 4; 4 were indeterminate on follow‐up so that a final diagnosis could not be made
No

Pfannenberg 2007 2007
Germany
Patients: 64
Primary lesions: 420
LNBs/Metastases: NR

WPC
Prospective

Data: per lesion

Any metastases (excl brain): 297/420 = 71% (all tests)

Nodal: 102/158 = 65% (CT)

Distant (excl brain): 195/262 = 74% (all tests)

Bone: 35/50 = 70% (all tests)

Liver: 35/37 = 95% (all tests)

Lung: 59/80 = 74% (all tests)

Local: 53/70 = 76% (all tests)

Other viscera: 13/25 = 52% (all tests)

Mixed (pre‐surgery; investigation of abnormal findings; surveillance)
Stage of disease: Stage III (25, 39%); Stage IV (39, 61%)
Inclusion: stage III or IV cutaneous MM undergoing imaging for exclusion of widespread disease and confirmation of local disease before surgical resection (n = 9); characterisation of abnormal radiological,
clinical and laboratory findings (n = 48); routine melanoma surveillance in high risk patients (n = 7)

Mean age: 57.8 years; Median age: Range: 23.3 to 79.1 years
Male: 41 (64.0625%)

Site: NR
Mean BT: 2.69 mm (0.6 to 12 mm)

CT. CT (CE, 16 row multi‐slice) (NA); N/A
Scan coverage: base of the skull to the lower legs
Contrast: Ultravist 370, Schering GmbH, Berlin, Germany, plus 1000 mL Mannitol 2% as a negative oral contrast agent before CT
CT parameters: 120 kV, 120 to 160 mAs; 5 mm (axial, with an increment of 5 mm) and 3 mm (coronal with an increment of 2 mm)
Breath hold: CT: patients were asked to stop breathing in normal expiration during the contrast‐enhanced CT scans for optimal co‐registration

MRI. CE; multiple phased‐array; axial and coronal (NA); N/A
Scan coverage: head to toe
Contrast: yes

PET‐CT. 3D; CT (CE, 16 row multi‐slice) (NA); N/A
Scan coverage: base of the skull to the lower legs
Contrast: Ultravist 370, Schering GmbH, Berlin, Germany, plus 1000 mL mannitol 2% as a negative oral contrast agent before CT
CT parameters: 120 kV, 120 to 160 mAs, 5 mm (axial, with an increment of 5 mm) and 3 mm (coronal with an increment of 2 mm)

FDG: 370 MBq F‐FDG IV 55 to 65 minutes before scanning
Breath hold: CT: patients were asked to stop breathing in normal expiration during the contrast‐enhanced CT scans for optimal co‐registration
CT used for: attenuation corrected and co‐registered
Reconstruction: iteratively reconstructed using commercial software (eSoft; Siemens., Erlangen, Germany)

CT: based on morphological characteristics and enhancement pattern; region‐specific nodal size criteria based on measurement of the small axis diameter

MRI: based on morphological characteristics and enhancement pattern; detected lymph nodes smaller than 10 mm but with brighter signal on T1 sequences, due to the paramagnetic effect of melanin, also were rated as suspicious

PET: any focal tracer uptake exceeding normal regional tracer accumulation was assessed as a malignant lesion. Lesions rated malignant or probably malignant were considered to be malignant
Info provided: aware of the clinical status
No. observers: 6; 2 dermato‐oncologists; 2 radiologists (2 specialists in nuclear medicine, 2 CT radiologists, and 2 MRI radiologists)
Diagnosis: consensus of 2 or 4

Histology (65 (15%))
FNAC (N/A)
FU (267 (64%) lesions by imaging follow‐up, 88 (21%) lesions by clinical follow‐up): mean 252.5 days (range, 99 to 474 days)
Histology interval: NR
FU interval: every 3 months

Exclusions: n = 36; no wbMRI (n = 25; due to metallic implants or claustrophobia (5 patients), refuse of a second whole body examination on the same day (17 patients) or abortion of the examination (3 patients); no evidence of tumour spread (3 patients) or lack of follow‐up data for lesion characterisation (8 patients)

Pfluger 2011
Germany
Patients: 50
Primary lesions: NR
LNBs/Metastases: NR; 232 lesions

WPC
Retrospective (Prosp database: NR)

Data: per lesion
Any (incl brain): 151/232 = 65% (CT)

Mixed (PET‐CT was done for primary staging and for follow‐up)
Stage of disease: NR
Inclusion: MM with regional LN metastases (NR if clinically detectable or micro‐metastases) undergoing PET‐CT either for primary staging or during follow‐up. Only included lesions considered malignant by at least 1 of the 3 modalities (NECT, CECT, 18F‐FDG PET)

Mean age: 57; Median age: Range: 29 to 85 years
Male: 36 (72%)

Site: NR
NR

CT. (1) CE, dual slice, helical (N/A); NR (2) U, dual slice, helical (N/A); NR
Scan coverage: WB; from the skull including the legs
Contrast: 120 mL (2.5 mL/s) of iodine‐containing contrast medium
CT parameters: 120 kV, 145 mAs, 2.5 mm
Breath hold: CT expiration protocols for shallow free breathing during the emission scan

PET‐CT

(1) 3D; CT (CE, dual slice, helical) (N/A); NR

(2) 3D‐ CT (U, dual slice, helical) (N/A); NR
Scan coverage: WB; from the skull including the legs
Contrast: 120 mL (2.5 mL/s) of iodine‐containing contrast medium
CT parameters: 120 kV, 145 mAs, 2.5 mm
FDG: 200 MBq
Breath hold: CT expiration protocols for shallow free breathing during the emission scan
CT used for: unclear; reports side by side PET‐CT display with spatially synchronised images
Reconstruction: NR; PET and CT interpreted side by side with spatially synchronised images to ensure that the identical lesion was assessed in both modalities

CT ‐ abnormal soft tissue masses and/or enlarged LNs (diameter > 1.0 cm) plus degree of contrast enhancement for CE CT only

PET alone ‐ non‐physiologically increased uptake of FDG with SUVmax > 2.5. For lesions with discrepant findings on both modalities, the finding of the modality with the higher diagnostic confidence score was accepted. If results from both modalities were discrepant and had the same diagnostic confidence score value, the lesion was judged positive

Info provided: knowledge of clinical data
No. observers: 2; NR (experienced)
Diagnosis: consensus

Histology (41, 17.7%)
FNAC (0)
FU (191, 82.3%): ≥ 6 months; no further detail
Histology interval: NR
FU interval: NR

n = NR; ** In cases of new tumour lesions during the follow‐up period, these lesions were not included in the study. The reason given for not including these lesions was the fact that non‐detectable lesions in CT or 18F‐FDG PET cannot be distinguished from non‐existent lesions in the case of a newly detected tumour lesion during follow‐up

Reinhardt 2006

Germany
Patients: 250
Primary lesions: 250
LNBs/Metastases: NR; 670 lesions identified

WPC
Retrospective (Prosp database: NR)

Data: per pt
Any (excl brain): 116/250 = 46%

Nodal mets: 78/250 = 31%

Distant mets (excl brain): 84/250 = 34%

Mixed (primary staging after sentinel node biopsy (n = 75); therapy control after chemotherapy of metastatic disease (n = 42), staging of clinically suspected recurrent disease (n = 65), during follow‐up within 5 years of primary treatment (n = 68)
Stage of disease: initial pathology: stage I 22, 9%; stage II 88, 35%; stage III 108, 43%; stage IV 32, 13%
Inclusion: cutaneous MM referred for PET‐CT

Excluded if inadequate reference standard (no histology or FU < 1 year)

Mean age: 58; Median age: Range: ±16
Male: 145 (58%)

Site: NR
Tumor depth: ≤ 1.0 mm 29, 12%; 1.01 to 2.0 mm 68, 27%; 2.01 to 4.0 mm 66, 26%; > 4.0 mm 64, 26%

CT. CE, helical, dual detector (N/A); N/A
Scan coverage: WB; base of skull to tip of toes in 3 parts
Contrast: Peritrast‐oral‐GI; Kohler Chemie GmbH, Alsbach, Germany
CT parameters: 130 kV, 40 mAs, 5 mm
Breath hold: limited breath hold for CT and shallow breathing for PET

PET‐CT. CT (CE), helical, dual detector (N/A); N/A
Scan coverage: WB; base of skull to tip of toes in 3 parts
Contrast: Peritrast‐oral‐GI; Kohler Chemie GmbH, Alsbach, Germany
CT parameters: 130 kV, 40 mAs, 5 mm
FDG: 371 ± 40 MBq FDG through an anterior cubital vein
Breath hold: limited breath hold for CT and shallow breathing for PET
CT used for: attenuation correction based on re‐scaling of the CT image
Reconstruction: iteratively reconstructed with attenuation correction on the basis of a re‐scaling of the CT image as described elsewhere (Kinahan 2003)

NR for any test; states only that accuracy was assessed according to according to the current AJCC staging classification

Info provided: routine clinical fashion; same clinical information about each patient
No. observers: NR; NR; consensus by each of 2 experienced investigators (experienced)
Diagnosis: consensus (of 2?)

Histology (100, 40% for N‐staging (including 15 with SLNB)
20, 8% for M‐staging)
FNAC (N/A)
FU (250, 100%): NR; ≥ 1 year
Histology interval: NR
FU interval: NR

Exclusions: n = 0
Reports data for differentiation by metastatic sites (M1A to M1C) and for detection of visceral and non‐visceral mets. Gives Se/Sp by population group but prevalence per group not given to allow 2×2 to be included

Strobel 2007b

Switzerland
Patients: 124
Primary lesions: NR
LNBs/Metastases: NR

NC
Prospective

Data: per pt
Any (incl brain): 53/124 = 43%

Unclear (NR; PET‐CT for depiction or exclusion of metastases)
Stage of disease: NR
Inclusion: high risk melanoma (BT > 4 mm, or Clark level III or IV, or known resected metastases) and raised S100 (> 0.2 μg/L) undergoing follow‐up after primary treatment
Excluded if systemic therapy before the PET‐CT investigation

Mean age: 54.4 years; Median age: Range: 15 to 82 years
Male: 59 (47.5806451612903%)
Site: NR
NR

PET‐CT. CT (CE, multi‐slice, helical) (N/A); NR
Scan coverage: head to the knees with scanning of the lower legs for patients with primary tumours of the lower extremities
Contrast: oral CT contrast agent given 15 minutes before injection of 18F‐FDG
CT parameters: 140 kV, 40 mAs, 4.25 mm

FDG: 350 to 400 MBq
Breath hold: CT: breath holding in the normal expiratory position
CT used for: attenuation correction, fused
Reconstruction: standard iterative algorithm (OSEM)

Mets present if detected by 1 or both readers. FDG uptake clearly greater than background; if a focal FDG‐active lesion was detected, the exact anatomical localisation was determined on the fused PET‐CT images. Lesions with 18F‐FDG uptake in physiological sites or benign variants, e.g. muscles, brown fatty tissue or pulmonary infiltrations, were determined as benign. Semi‐quatitative analysis of FDG uptake in terms of SUVmax also conducted

Info provided: blinded to serum S100B
No. observers: 2; nuclear radiology physicians (experienced (13 years and 7 years))
Diagnosis: consensus of 2

Histology (20, 16.1%)
FNAC (21, 16.9%)
FU (124, 100%, 18 D+ and 61 D‐ had status confirmed by PET‐CT or clinical FU, 4 D‐ had MRI to confirm absence of mets and 10/53 D+): minimum of 6 months (range 6 to 18 months in all patients
Histology interval: NR
FU interval: NR

Exclusions: n = 3; chemotherapy before PET‐CT

van den Brekel 1998

Netherlands
Patients: 26
Primary lesions: 26
LNBs/Metastases: NR

NC
Retrospective (Prosp database: NR)

Data: per pt
Nodal (neck): 21/26 = 81%

Mixed (NR; but interval between treatment of the primary and neck dissection ranged from 0 to 8.8 years (mean 21 months))
Stage of disease: stage III (palpable LN) 18, 69%; stage I and II 8, 31%
Inclusion: HN MM with CT before neck dissection, including therapeutic and elective (negative on palpation). Also included primary and recurrence

Mean age: 54.5 years; Median age: Range: 55 to 83 years
Male: 18 (0.692307692307692%) Site: scalp 6, 23%; temporal 3, 12%; ear 4, 15%; anterior face 4, 15%; neck 1, 4%; shoulder 1, 4%; upper limb 1, 4%; nasal mucosa 1, 4%; unknown primary 5, 19%
BT 0.8 mm to 22 mm

CT. CE (N/A); NR
Scan coverage: neck
Contrast: IV bolus plus drip infusion of iodine contrast
CT parameters: NR; 5 mm for 24 pts; 2 mm for 2 pts (both FN)
Breath hold: NR

Presence of necrosis or axial diameter > 10 or > 11 mm
Info provided: NR
No. observers: 2; NR; co‐authors (NR)
Diagnosis: unclear

Histology (26, 100%)
FNAC (0)
FU (0): N/A
Histology interval: 4 weeks
FU interval: N/A

Exclusions: n = 0
Both FN on CT used 8 mm CT thickness

van Wissen 2016
Netherlands
Patients: 70
Primary lesions: 70
LNBs/Metastases: NR

NC
Retrospective (Prosp database: no)

Data: per pt
Nodal (superficial groin mets only): 59/69 = 86%

Nodal (deep groin mets only): 24/67 = 36%

Mixed (NR. Discussion states "large proportion of our patients were initially treated for their primary tumour at other hospitals, and sometimes years prior to the current groin dissection")
Stage of disease: only stage III B & C
Inclusion: stage IIIB or IIIC MM with palpable groin metastases; selected for therapeutic CGD

Mean age: NR; Median age: 58; Range: 24 to 83
Male: 35 (0.5%)

Site: leg 58, 83%; trunk 6, 9%; arm 0, 0%; unknown 6, 9%
BT mm: ≤ 1.00 6 (9%); ≤ 2.00 15 (21%); 2.01 to 4.00 15 (21%); > 4.00 12 (17%); missing/unknown 22 (31%)

PET‐CT. CT (U) (NA)
Scan coverage: WB; not further described
Contrast: none
CT parameters: Kv NR; 40 mAs, 2 to 5 mm
FDG: 180 to 240 MBq
Breath hold: standard acquisition protocols
CT used for: attenuation correction; fused images
Reconstruction: NR

FDG uptake (qualitative assessment)
Info provided: NR
No. observers: 1; nuclear medicine (nr)
Diagnosis: single

Histology (70, 100%)
FNAC (NA)
FU (not for ref purposes): median 16 months (0 to 71 months)
Histology interval: NR
FU interval: NR

Exclusions: n = 1; missing pathology

7/10 disease negative had a diagnostic resection of a lymph node before lymph node dissection potentially leading to FPs

+ ‐ positive; AJCC: American Joint Cancer Committee; AWOSEM: attenuation weighted ordered subsets expectation maximisation; BT: Breslow thickness; CE: contrast enhanced; CLND: complete lymph node dissection; CT: computed tomography; 2D: two‐dimensional; 3D: three‐dimensional; DW: diffusion weighted; EDV: end‐diastolic volume; 18FDG: 2‐deoxy‐2‐[18F]fluoro‐D‐glucose; FNAC: fine needle aspiration cytology; FORE: Fourier rebinning; FU: follow‐up; GE: gradient echo; HN: head and neck; LN: lymph node; LNB: lymph node basin; LND: lymph node dissection; LS: lymphoscintigraphy; mA: measure of tube current; mets: metastases; MM: malignant melanoma; MRI: magnetic resonance imaging; NC: non‐comparative; OSEM: ordered subsets expectation maximisation algorithm; PET: positron emission tomography; PI: pulse index; PSV: peak systolic volume; prosp: RF: risk factor; SD: standard deviation; SLN: sentinel lymph node; SLNB: sentinel lymph node biopsy; SSM: superficial spreading melanoma; SUV: standardised uptake value; SUVmax: maximum standardised uptake value; U: unenhanced; US: ultrasound; WB: whole body.

Test

Study

Population group

No. patients/cases ^a [Lesions/cases]

Imaging detail

Sensitivity [95% CI] % TP/Diseased

Specificity [95% CI] % TN/Non‐Diseased

Including brain

Excluding brain

Including brain

Excluding brain

Including brain

Excluding brain

Including brain

Excluding brain

CT

Veit‐Haibach 2009

Primary

Per patient data

56

CT (CE)

Not assessed

Not assessed

23

[5 to 54]

3/13

Not assessed

Brain NR

25

[5 to 57]

3/12

Not assessed

Not assessed

100

[92 to 100]

43/43

Not assessed

Brain NR

93

[81 to 99]

41/46

Reinhardt 2006

Mixed

Per patient data

250/116

CT (CE)

81

[73 to 88]

94/116

Not assessed

85

[75 to 92]

66/78

74

[63 to 83]

62/84

Not assessed

77
[69 to 84]

103/134

Not assessed

87
[81 to 92]

150/172

88
[82 to 92]

146/166

Not assessed

Dellestable 2011

Mixed

Per lesion data

40 [118 / 72]

CT (CE)

80

[69 to 89]

53/66

Not assessed

94

[79 to 99]

29/31

59

[42 to 74]

24/41

Not assessed

95
[84 to 99]

40/42

Not assessed

100
[63 to 100]

8/8

87
[73 to 96]

34/39

Not assessed

Hausmann 2011

Unclear

Per lesion data

33 [824 /455]

CT (CE)

Not assessed

78

[74 to 82]

356/455

86

[81 to 91]

166 /192

Not assessed

71

[65 to 76]

186/263

Not assessed

50
[44 to 55]

183/369

29
[22 to 36]

54/187

Not assessed

71
[64 to 77]

129/182

Jouvet 2014

Unclear

Per lesion data

37 [218 / 125]

CT (CE)

90

[82 to 94]

103/115

88

[80 to 94]

84/95

96

[78 to 100]

22/23

88

[80 to 94]

81/92

86

[76 to 93]

62/72

70
[60 to 79]

66/94

69
[59 to 78]

63/91

63
[44 to 80]

19/30

73
[61 to 84]

47/63

72
[59 to 83]

44/61

Pfannenberg 2007

Mixed

Per lesion data

64 [420/297]

CT (CE)

Not assessed

77

[72 to 82]

229/297

76

[67 to 84]

78/102

Not assessed

77

[71 to 83]

151/195

Not assessed

70
[61 to 78]

86/123

77
[64 to 87]

43/56

Not assessed

64
[52 to 76]

43/67

MRI

Dellestable 2011

Mixed

Per lesion data

40 [118 / 72]

MRI (DW)

83
[72 to 91]

58/70

Not assessed

90
[74 to 98]

28/31

77
[61 to 89]

30/39

Not assessed

96
[85 to 99]

45/47

Not assessed

89
[52 to 100]

8/9

97
[86 to 100]

37/38

Not assessed

Hausmann 2011

Unclear

Per lesion data

33 [824 / 455 ]

MRI (NR)

Not assessed

73
[69 to 77]

334/455

82
[76 to 87]

157/192

Not assessed

67
[61 to 73]

177/263

Not assessed

84
[80 to 87]

309/369

77
[70 to 83]

144/187

Not assessed

91
[85 to 94]

165/182

Jouvet 2014

Unclear

Per lesion data

37 [218 / 125 ]

MRI (DW)

68
[59 to 76]

85/125

69
[59 to 77]

72/105

96
[78 to 100]

22/23

62
[52 to 71]

63/102

61
[50 to 72]

50/82

73
[63 to 82]

68/93

72
[62 to 81]

65/90

80
[61 to 92]

24/30

70
[57 to 81]

44/63

68
[55 to 80]

41/60

MRI (DW+ VIBE)

84
[76 to 90]

105/125

81
[72 to 88]

85/105

87
[66 to 97]

20/23

83
[75 to 90]

85/102

79
[69 to 87]

65/82

87
[79 to 93]

81/93

87
[78 to 93]

78/90

100
[88 to 100]

30/30

81
[69 to 90]

51/63

80
[68 to 89]

48/60

Pfannenberg 2007

Mixed

Per lesion data

64 [420/297 ]

MRI (DW+ VIBE)

Not assessed

80
[75 to 84]

237/297

66
[56 to 75]

67/102

Not assessed

87
[82 to 92]

170/195

Not assessed

76
[68 to 84]

94/123

77
[64 to 87]

43/56

Not assessed

76
[64 to 86]

51/67

PET‐CT

Arrangoiz 2012

Primary

56/32

CT (NR)

47

[29 to 65]

15/32

Not assessed

Not assessed

100

[48 to 100]

5/0

Not assessed

88

[68 to 97]

21/24

Not assessed

Not assessed

94

[84 to 99]

48/51

Not assessed

Reinhardt 2006

Mixed

Per patient data

250/116

CT (CE)

97

[91 to 99]

112/116

Not assessed

95

[87 to 99]

74/78

99

[94 to 100]

83/84

Not assessed

98
[94 to 100]

131/134

Not assessed

100
[98 to 100]

172/172

98
[94 to 99]

162/166

Not assessed

Veit‐Haibach 2009

Primary

Per patient data

56/13 Nodal; 12 Distant

CT (CE)

38

[14 to 68]

5/13

Brain NR

42

[15 to 72]

5/12

100

[92 to 100]

43/43

Brain NR

93

[81 to 99]

41/44

Cachin 2014

Mixed

Per lesion data

87 [176 / 85]

CT (NR)

80
[70 to 88]

68/85

Not assessed

85
[62 to 97]

17/20

78
[67 to 88]

51/65

Not assessed

54
[43 to 64]

49/91

Not assessed

37
[16 to 62]

7/19

58
[46 to 70]

42/72

Not assessed

Dellestable 2011

Mixed

Per lesion data

40 [118 / 72]

CT (CE)

74
[62 to 83]

53/72

Not assessed

84
[66 to 95]

26/31

66
[49 to 80]

27/45

Not assessed

89
[77 to 96]

42/47

Not assessed

100
[59 to 100]

7/7

88
[73 to 96]

35/40

Not assessed

Jouvet 2014

Unclear

Per lesion data

37 [218 / 125]

CT (CE)

Not assessed

80
[71 to 87]

83/104

96
[78 to 100]

22/23

PET‐CT did not cover skull

75
[64 to 84]

61/81

Not assessed

93
[86 to 97]

81/87

97
[83 to 100]

29/30

PET‐CT did not cover skull

91
[81 to 97]

52/57

Pfannenberg 2007

Mixed

Per lesion data

64 [420/297]

CT (CE)

Not assessed

91
[87 to 94]

269/297

85
[77 to 92]

87/102

PET‐CT did not cover skull

93
[89 to 96]

182/195

Not assessed

77
[69 to 84]

95/123

89
[78 to 96]

50/56

PET‐CT did not cover skull

67
[55 to 78]

45/67

a studies with per patient data denoted in bold type

CE: contrast enhanced; CT: computed tomography; DW: diffusion weighted; GE: gradient echo; MRI: magnetic resonance imaging; NR: not reported; PET: positron emission tomography; SLNB: sentinel lymph node biopsy; TN: true negative; TP: true positive; U: unenhanced; US: ultrasound; WB: whole body.