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Diagnostic Applications of Nuclear Medicine: Malignant Melanoma

  • Andrew M. ScottEmail author
  • Marika Ciprotti
  • Sze-Ting Lee
Living reference work entry

Abstract

Malignant melanoma was diagnosed in approximately 74,000 patients in 2015 in the USA. Melanoma accounts for about 3% of all skin cancers. Major parameters that impact prognosis include Breslow thickness, ulceration, tumor location, growth pattern, histological subtype, patient’s age, gender, and tumor status of regional lymph nodes. Melanomas are staged using the American Joint Committee on Cancer (AJCC) TNM system, which has incorporated the histological status of SLN into its latest staging system version of cutaneous malignant melanoma.

In early stage melanoma (AJCC I–II), sentinel lymph node biopsy (SLNB) is the standard of care for nodal staging. Lymphoscintigraphy with SPECT/CT improves the detection of SLN. In AJCC stage I–II melanoma, [18F]FDG PET/CT has poor sensitivity for the detection of nodal metastases but it is sensitive for the detection of distant metastases. In patients with AJCC stage III (regional nodal involvement) or stage IV disease (systemic metastases), [18F]FDG PET/CT is useful to identify metastatic disease. PET imaging in melanoma patients should include the arms and legs, especially in patients whose primary lesions arise on extremities. False-negative results can occur with small skin and brain metastases, and lesions adjacent to the heart, kidneys, or urinary bladder.

Although [18F]FDG PET/CT is more specific in the diagnosis of melanoma pulmonary metastases, chest CT is more sensitive. Most PET false negatives in recurrent disease are typically less than 1 cm in diameter and are mainly pulmonary and hepatic in location, or in the brain. [18F]FDG PET/CT is useful in treatment monitoring of metastatic melanoma and in posttherapy surveillance.

Keywords

Melanoma Imaging in melanoma Malignant melanoma Staging of melanoma Sentinel lymph node biopsy in melanoma 

Glossary

[18F]FDG

2-Deoxy-2-[18F]fluoro-d-glucose

18F-FLT

3′-18F-fluoro-3′-deoxythymidine

AJCC

American Joint Committee on Cancer

APC

Antigen-presenting cell

bFGF

Basic fibroblast growth factor

BRAF

RAF serine-/threonine-specific protein kinase

Breslow thickness

A prognostic factor in cutaneous melanoma, based on description of how deeply tumor cells have invaded the skin (also called “Breslow depth”)

c-KIT

A proto-oncogene encoding for tyrosine-protein kinase Kit (or CD117), also known as mast/stem cell growth factor receptor (SCFR)

CDK4

Cyclin-dependent kinase 4

CDKN2A

Cyclin-dependent kinase inhibitor 2A

ceCT

Contrast-enhanced computed tomography

CI

Confidence interval

Clark level

A staging system for cutaneous melanoma based on description of the level of anatomic invasion of the melanoma in the skin (generally used in conjunction with Breslow’s depth)

COT

A mitogen-activated protein serine/threonine kinase involved in T-cell activation

CR

Complete response

CT

X-ray computed tomography

ERK

Extracellular signal-regulated kinase

FDA

United States Food and Drug Administration

GLUT

Glucose transporter family

HR

Hazard ratio, a statistical parameter used in survival analysis

IDO

Indoleamine 2,3-dioxygenase

IFN

Interferon

IGFR1

Insulin-like growth factor 1

LAG-3

Lymphocyte-activation gene 3

LDH

Lactate dehydrogenase

LS

Lymphoscintigraphy

M

Metastasis status according to the AJCC/UICC TNM staging system

MAGE

Melanoma-associated antigen gene

MAPK

Mitogen-activated protein kinase

MHC

Major histocompatibility complex

MRI

Magnetic resonance imaging

N

Lymph node status according to the AJCC/UICC TNM staging system

NCCN

National Comprehensive Cancer Network

NRAS

Oncogene encoding for a membrane protein that shuttles between the Golgi apparatus and the plasma membrane

ORR

Overall response rate

OS

Overall survival

PD-L1

Programmed death ligand

PDGF

Platelet-derived growth factor

PET

Positron emission tomography

PET/CT

Positron emission tomography/computed tomography

PFS

Progression-free survival

PFS

Progression-free survival

PI3K

Phosphatidylinositol 3-kinase

PlGF

Placental growth factor

PTEN

Gene encoding for the phosphatase and tensin homolog protein, a tumor suppressor (PTEN deletions indicate a poor prognosis)

RAF

Rapidly accelerated fibrosarcoma, related to retroviral oncogenes

RECIST

Response evaluation criteria in solid tumors

S-100

A low-molecular-weight calcium-binding protein expressed in melanomas, but also in other benign and malignant conditions

SLN

Sentinel lymph node

SLNB

Sentinel lymph node biopsy

SLNE

Sentinel lymph node excision

SPECT

Single photon emission computed tomography

SPECT/CT

Single photon emission computed tomography/computed tomography

SUV

Standardized uptake value

SUVmax

Standardized uptake value at point of maximum

T

Tumor status according to the AJCC/UICC TNM staging system

TGF

Transforming growth factor

TIM-3

T-cell immunoglobulin and mucin-domain containing-3

UICC

Union Internationale Contre le Cancer (International Union Against Cancer)

UV

Ultraviolet

VEGF

Vascular endothelial growth factor

WHO

World Health Organization

Epidemiology

Malignant melanoma is an increasingly common public health problem in many countries. It most often arises from the melanocytes found in the basal layer of the skin, although it can also derive from noncutaneous melanocytes such as those lining the choroidal layer of the eye, gastrointestinal and genitourinary mucosal surfaces, or the meninges. It accounts for about 3% of all skin cancers, with an annual increase in the order of 3–7% per year for fair-skinned Caucasian populations [1].

According to the World Health Organization (WHO), the number of melanoma cases worldwide is increasing faster than that of any other type of cancer. The highest incidence of melanoma occurs in Australia and New Zealand where the annual incidence rates are more than two to three times higher than those found in Canada, the USA, and the UK [2]. In Australia, it is the fourth most common cancer. Recently reported statistical data suggest that the risk of an individual being diagnosed with melanoma skin cancer by their 85th birthday is 1 in 18 (1 in 14 males and 1 in 23 females) [3]. In Europe, approximately 100,300 people were estimated to be diagnosed with melanoma in 2012. In the same year, 22,200 Europeans were estimated to have died from the disease [4]. In 2015, an estimated 73,870 patients were diagnosed with melanoma in the USA, and approximately 9,940 of them died of the disease [5]. Data from the USA and Europe show that the lifetime risk of developing malignant melanoma has increased from 1 in 800 individuals in 1960 to 1 in 74 individuals in 2000.

Risk Factors

The factors associated with an increased risk of developing melanoma remain incompletely understood, but people with a family history of melanoma, multiple benign or atypical nevi, and a previous melanoma are at the greatest risk for cutaneous melanoma. Inherited mutations in the cyclin-dependent kinase inhibitor 2A (CDKN2A) and cyclin-dependent kinase 4 (CDK4) genes, which have been documented in some families with hereditary melanoma, confer a 60–90% lifetime risk of melanoma. Overall, CDKN2A mutations have been observed in approximately 25–40% of the members of melanoma-prone families. In addition, around one-half of families with three or more cases of melanoma show evidence of linkage to the 9p21 region [6]. According to the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute (SEER), the rate of subsequent cutaneous melanomas among persons with a history of melanoma was more than ten times the rate of a first cutaneous melanoma among the general population [7].

Immunosuppression, sun sensitivity, and exposure to ultraviolet radiation are also associated with an increased risk of cutaneous melanoma. Sensitivity to ultraviolet light is associated with variations in particular genes (polymorphisms) that affect both the defensive response of the skin to ultraviolet light and the risk of melanoma. A defensive measure to ultraviolet lights includes the tanning response, and variations in pigmentation and tanning response are associated with variations in susceptibility to melanoma [8]. Unlike the more common skin cancers, which are associated with total cumulative exposure to ultraviolet radiation, melanomas are associated with intense intermittent exposure, specifically with exposures that induce sunburn during adolescence [9]. Differences in the amount of exposure to ultraviolet (UV) radiation by geographic latitude may also contribute to the wide geographic variation in melanoma incidence rates. Educational efforts to promote recognition of early lesions (including ABCD criteria for asymmetry, border irregularity, unevenness of distribution of color, and a diameter that is greater than 6 mm or increasing in size) and avoidance of sun exposure have not prevented these increases in incidence and mortality.

Pathogenesis

Understanding of the pathogenesis of melanoma is crucial to develop new markers for diagnosis and prognosis and identify new targets for rational therapy.

Ras/Raf/MEK/Erk Pathway

One of the most studied molecular pathways in melanoma is the intracellular Ras-regulated Raf/MEK/ERK and MAPK signal cascade. Melanocytes require this cascade to maintain a balance between proliferation and differentiation. There is a strong link between dysregulation of this pathway and uncontrolled cell proliferation and survival. Dysregulation of the MAPK signaling pathway through constitutive activation is a frequent event in multiple human cancers [10]. Mutations of the PTEN tumor suppressor have also been reported in up to 25% of melanomas, and alterations of the PI3K pathway, in conjunction with dysregulation of the MAPK pathway, play an essential role in melanoma development and progression.

BRAF is a RAF serine-/threonine-specific protein kinase and has been identified as a common oncogene in many cancers, particularly melanoma where it regulates many cellular responses, such as proliferation, survival, and invasion/metastasis. BRAF mutations occur in about 60% of melanomas occurring on skin without signs of chronic sun-induced damage, but infrequent in melanomas that occur on skin showing evidence of chronic sun-induced damage as well as on sun-protected skin such as the palms, soles, or subungual sites, and on mucosal membranes. Recent studies have shown that over 90% of BRAF mutations occur in codon 600, usually resulting in a valine to glutamate substitution (designated V600E) [11].

Immune Regulation

The immune system plays a vital role in regulating the growth of tumors and immune-regulation of T-cells is an essential link in understanding the pathophysiology of melanoma. When naïve T cells are presented tumor antigens complexed with MHC molecules by antigen-presenting cells (APCs), they mature into effector cells. However, a second costimulatory signal is required to induce activation. This signal is provided by the interaction of B7 molecule on the surface of APCs with the T-cell CD28 receptor. However the immune-checkpoint protein cytotoxic T lymphocyte antigen 4 (CTLA-4), which is upregulated on CD-8+ T cells after activation, can bind to B7 molecule and replace the activation signal with an inhibitory signal.

Once activated (priming phase), the CD-8+ T cell matures and travels from peripheral lymphoid organs to peripheral tissues to carry out its cytotoxic effector function against tumor cells (effector phase). During this phase, binding the MHC-antigen complex is sufficient to induce effector functions, without the need of a costimulatory signal. An inhibitory pathway consisting of the expression of the programmed death 1 (PD-1) receptor on the T-cell surface may lead to the inactivation of the T-cell after binding to the programmed death ligand 1 (PD-L1) on tumor tissue. Tumor cells can upregulate PD-L1 on their surface to evade immune-mediated destruction [12]. The traditional approach to immunotherapy has focused on increasing the frequency of tumor-specific T cells (i.e., vaccines, interleukin-2), improving the presentation of tumor antigens to the immune system, or trigger innate immune activation and inflammation in the tumor microenvironment (i.e., interferons) [12]. More recently, a better understanding of immune regulatory mechanisms has led to the development of agents that can modulate immune checkpoints (i.e., CTLA-4, PD-1, PD-L1) and effectively overcome tumor-induced immune-suppressive mechanisms.

Angiogenesis

Angiogenesis is a fundamental physiological process by which new vascular networks are formed from pre-existing capillaries. Many tumors overexpress multiple angiogenic factors such as vascular endothelial growth factor (VEGF), which is strongly associated with new vasculature formation in melanoma, and its overexpression is correlated with a poor prognosis [13, 14]. Although VEGF is only expressed in 32% of primary melanomas, its expression level in metastases [15, 16] is increased. Several other angiogenic factors have been implicated in the pathology of human melanomas, such as IL-8, placental growth factor (PlGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF)-AA, and PDGF-BB [17, 18]. Innovative antiangiogenic strategies in oncology drug development are currently being explored with monoclonal antibodies and small-molecule kinase inhibitors.

Tumor Histology

Melanoma often arises from precursor pigmented lesions, which demonstrate changes in shape, color, and irregular borders, or develop ulceration. The most common form is superficial spreading melanoma (up to 70% of cases), where lesions may be flat or elevated, demonstrate change in color or border, and is most commonly seen in the legs and trunk. Nodular melanoma (10–20% of cases) typically grows rapidly, is elevated, and also occurs mainly on the legs and trunk. Lentigo maligna melanoma usually occurs on sun-exposed areas such as the face, more typically seen in darker-skinned patients, and is seen in 5–15% of cases. Acral melanoma most commonly occurs on the sole of the feet, or palm and nail beds, and is seen in 2–8% of patients. Superficial spreading melanoma, lentigo maligna melanoma, and acral melanoma are also characterized by an early in situ phase of radial growth, prior to deeper extension, which is associated with a worse prognosis. Microscopic examination of melanomas demonstrates sheets of malignant cells which may be associated with pigment cells and various infiltrative cells including lymphocytes. The extent and depth of malignant cell infiltration, ulceration, mitotic rate, and morphologic appearance all influence diagnosis, treatment, and prognosis; hence, full excision and careful pathologic examination are critical in the initial diagnosis and management of melanoma patients.

Staging Systems for Melanoma

Breslow Staging, AJCC Classification

The histologic pattern and depth of infiltration of the primary melanoma, together with the site and extent of metastatic disease, have a significant impact on treatment selection and prognosis [19, 20]. Clinical and histologic variables that have been shown to impact on prognosis include Breslow thickness (the total vertical height of the lesion: <1 mm, 5-year survival >95%; 1–2 mm, 5-year survival 80–95%; 2.1–4 mm, 5-year survival 60–75%; >4 mm, 5-year survival 37–50%), Clark Level (depth of penetration: Level I, confined to the epidermis; Level II, invasion of the upper dermis; Level III, invasion of the papillary dermis but to the junction of the reticular dermis; Level IV, invasion of the reticular dermis; Level V, invasion of deep subcutaneous tissue), ulceration, tumor location, growth pattern, histological subtype, patient age, gender, and tumor status of regional lymph nodes [21]. Clinical studies exploring risk factors and their impact on prognosis have clearly shown that the metastatic involvement of lymph node(s) draining the primary tumor, also called sentinel lymph node(s) (SLN), is the most powerful prognostic factor in early stage melanoma patients [22, 23]. The American Joint Committee on Cancer (AJCC) has recently incorporated the histological status of SLN into its latest staging system version of cutaneous malignant melanoma (Tables 1 and 2).
Table 1

AJCC definitions of TNM for malignant melanoma

Primary tumor (T)

TX

Primary tumor cannot be assessed (e.g., curettaged or severely regressed melanoma)

T0

No evidence of primary tumor

Tis

Melanoma in situ

Tl

Melanomas 1.0 mm or less in thickness

T2

Melanomas 1.01–2.0 mm

T3

Melanomas 2.01–4.0 mm

T4

Melanomas more than 4.0 mm

Note: a and b subcategories of T are assigned based on ulceration and number of mitoses per mm2 as shown below

T classification

Thickness (mm)

Ulceration status/mitoses

Tl

<1.0

(a) w/o ulceration and mitosis <l/mm2

(b) with ulceration or mitoses >l/mm2

T2

1.01–2.0

(a) w/o ulceration

(b) with ulceration

T3

2.01–4.0

(a) w/o ulceration

(b) with ulceration

T4

>4.0

(a) w/o ulceration

(b) with ulceration

Regional lymph nodes (N)

NX

Patients in whom the regional nodes cannot be assessed (e.g., previously removed for another reason)

NO

No regional metastases detected

Nl-3

Regional metastases based upon the number of metastatic nodes and presence or absence of intralymphatic metastases (intransit or satellite metastases)

Note: N1–3 and a–c subcategories assigned as shown below

N classification

No. of metastatic nodes

Nodal metastatic mass

Nl

1 node

(a) Micrometastasisa

(b) Macrometastasisb

N2

2–3 nodes

(a) Micrometastasisa

(b) Macrometastasisb

(c) Intransit met(s)

Satellite(s) without metastatic nodes

N3

4 or more metastatic nodes, or matted nodes, or intransit met(s)/satellite(s) with metastatic node(s)

 

aMicrometastases are diagnosed after sentinel lymph node biopsy and completion lymphadenectomy (if performed)

bMacrometastases are defined as clinically detectable nodal metastases confirmed by therapeutic lymphadenectomy or when nodal metastasis exhibits gross extracapsular extension

Distant metastasis (M)

M0

No detectable evidence of distant metastases

M1a

Metastases to skin, subcutaneous or distant lymph nodes

Mlb

Metastases to lung

Mlc

Metastases to all other visceral sites or distant metastases to any site combined with an elevated serum LDH

Note: Serum LDH is incorporated into the M category as shown below

Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, IL. The original source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science and Business Media LLC www.springer.com

M classification

Site

Serum LDH

M1a

Distant skin, subcutaneous or nodal mets

Normal

Mlb

Lung metastases

Normal

Mlc

All other visceral metastases

Normal

Any distant metastasis

Elevated

Table 2

AJCC anatomic stage and prognostic groups for melanoma

Clinical staginga

Pathologic stagingb

Group

T category

N category

M category

Group

T category

N category

M category

Stage 0

Tis

N0

M0

0

Tis

N0

M0

Stage IA

T1a

N0

M0

IA

T1a

N0

M0

Stage IB

T1b

N0

M0

IB

T1b

N0

M0

 

T2a

N0

M0

 

T2a

N0

M0

Stage IIA

T2b

N0

M0

IIA

T2b

N0

M0

 

T3a

N0

M0

 

T3a

N0

M0

Stage IIB

T3b

N0

M0

IIB

T3b

N0

M0

 

T4a

N0

M0

 

T4a

N0

M0

Stage IIC

T4b

N0

M0

IIC

T4b

N0

M0

Stage III

Any T

≥N1

M0

IIIA

T1–4a

N1a

M0

T1–4a

N2a

M0

IIIB

T1–4b

N1a

M0

T1–4b

N2a

M0

T1–4a

N1b

M0

T1–4a

N2b

M0

T1–4a

N2c

M0

IIIC

T1–4b

N1b

M0

T1–4b

N2b

M0

T1–4b

N2c

M0

Any T

N3

M0

Stage IV

Any T

Any N

M1

IV

Any T

Any N

M1

Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, IL. The original source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science and Business Media LLC www.springer.com

aClinical staging includes microstaging of the primary melanoma and clinical/radiologic evaluation for metastases. By convention, it should be used after complete excision of the primary melanoma with clinical assessment for regional and distant metastases

bPathologic staging includes microstaging of the primary melanoma and pathologic information about the regional lymph nodes after partial or complete lymphadenectomy. Pathologic stage 0 or stage IA patients are the exception; they do not require pathologic evaluation of their lymph nodes

Melanoma may metastasize through local extension, via lymphatics prior to first draining lymph node (in-transit metastases) to regional lymph nodes, or systemic metastases to distant sites. AJCC stage I–II melanomas usually develop regional nodal metastases as the initial first site of metastatic disease; of those patients who develop nodal metastases, the majority will also present with satellite/in-transit disease or distant metastases [24]. Apart from lymph nodes, the most common sites for metastatic disease are skin, lung, liver, and brain, although almost any site in the body may be affected [24, 25, 26]. The patterns of spread of disease are dependent on tumor site and thickness, with approximately one-third of melanomas from the lower extremities metastasize locally to satellite/in-transit metastases, whereas nearly one-third of melanomas from the trunk and upper extremities disseminated directly to distant sites [24]. In contrast, head and neck primary melanomas develop local, regional, and distant metastases in nearly the same proportions (about one-third). Distant metastases were most often observed in men (mainly trunk melanomas), while locoregional metastases were rather detected in women, who have an increased incidence of lower limb melanomas.

Treatment for Localized Melanoma

Surgical excision is the primary treatment for melanoma. Several randomized, controlled trials have determined appropriate resection margins according to the thickness of the primary melanoma. For melanoma in situ, margins of 0.5–1 cm around the visible lesion or biopsy scar are recommended. Resection margins of 1–2 cm are recommended for 1–4 mm thickness primary lesions, and 2–3-cm margins if the primary lesion is >4.0 mm thick.

Regional lymph node spread of melanoma , or intransit disease, may occur at the time of initial presentation, or usually within 3 years of initial diagnosis. Lymph node resection is usually performed for regional nodal disease. Local radiation treatment may also be performed for regional lymph node metastases, depending on the extent of disease and success of initial surgery, and is also commonly used for in-transit disease.

Prognostic Factors

Patients with melanoma can be stratified into various risk groups: those with stage IA disease who carry a very low risk of recurrence and a 5-year survival of approximately 95%; those with stage IB and IIA disease, who have an intermediate risk and a 5-year survival from 65% to 90%; those with IIB, IIC, and IIIA disease who have a higher risk; and those with stage IIIB and IIIC disease who carry a very high risk of recurrence and a 5-year survival from 45% to 70%.

Over the past 10 years, there has been a debate focused on the optimal diagnostic, prognostic, and therapeutic strategies for cutaneous melanoma. It is important to identify and evaluate prognostic factors that can accurately categorize patients into different risk groups for distant metastatic disease. Currently, the most useful prognostic factors in clinical practice for localized melanoma are Breslow thickness, presence of lymph node involvement, and ulceration.

Sentinel lymph node biopsy (SLNB) is important for planning therapy, although it has failed to show any benefit in overall survival (OS). There has been no consensus on which patient categories benefit from SLNB. The National Comprehensive Cancer Network recommends that SLNB should be considered for patients with high-risk stage IA melanoma and discussed and offered to patients with stage IB–IIC melanomas [27]. SLNB can identify patients who may benefit from more extensive staging investigations and, based on pathology results, may be suitable for adjuvant therapy [28].

Thickness and ulceration of melanoma are highly correlated with each other, and studies have shown that the incidence of melanoma ulceration rises with increasing tumor thickness, ranging from 6–12.5% for thin melanomas to 63–72.5% for thick (>4.0 mm) lesions. The presence of ulceration is associated with decreased survival in all tumor thickness categories. Thin (<1.0 mm) ulcerated tumors have approximately a 4% decreased 5-year survival rate compared to nonulcerated tumors. This survival decrement is as high as 22% in thick (>4.0 mm) tumors [21]. Furthermore, the tumor mitotic rate is an additional independent prognostic factor that has emerged as more powerful than ulceration in several studies [29, 30, 31]. A better understanding of prognostic factors together with accurate staging in cutaneous melanoma allows the identification of patients whose risk of recurrence is sufficiently high to justify adjuvant systemic treatment.

Adjuvant Therapy

Attempts to reduce the incidence of recurrent melanomas with adjuvant therapy have been studied in more than 100 randomized controlled trials [32, 33]. However, adjuvant treatment has historically been challenging, with fewer options available. The role of chemotherapy remains unclear with no tangible benefit in terms of prolonged OS.

Until recently, interferon was the only FDA approved adjuvant option in over 20 years. High-dose interferon (IFN) was evaluated in three large United States cooperative group trials. The data from ECOG 1684, which led to FDA approval of IFN for the treatment of patients with resected stage IIB and stage III melanoma, showed a 5-year relapse-free survival improvement and suggested a statistically significant benefit in overall survival at a median follow-up of 6.9 years [34]. However, at 12.6 years of follow-up, the OS was not significantly different between the two groups, even though the relapse-free survival benefit was confirmed. A pooled analysis of three large randomized trials of high-dose IFN confirmed a consistent and significant effect on recurrence-free survival in patients with high-risk resected melanoma, but did not find a statistically significant improvement in OS [35]. High-dose IFN is approved in the USA and Canada, but it is not currently accepted worldwide due to its considerable toxic effects and to the fact that the benefit occurs in only a minority of the patients at risk. A large phase-III trial (EORTC18991) compared the treatment with pegylated interferon-a2b for up to 5 years with observation in Stage III patients. The results indicated a significant impact on relapse free survival without a significant improvement of distant metastasis-free survival or OS [36]. Based on this data, pegylated interferon alfa received approval by the FDA in March 2011 for the adjuvant treatment of stage III disease. Efforts to improve the efficacy and toxicity profiles of interferon have also included the use of lower-dose regimens, and combination with various drugs and vaccines [37, 38, 39].

Due to the only marginally effective adjuvant therapies with interferons and the recent successes of novel immunotherapeutic agents in metastatic melanoma, several clinical trials using these agents were initiated. In October 2015, Ipilimumab was approved by FDA for use in the adjuvant setting for patients with stage III melanoma. The approval was based on the results from the EORTC 18071 study, which randomly assigned 951 patients to ipilimumab or placebo [40]. Adjuvant ipilimumab significantly improved recurrence-free survival for patients with completely resected high-risk stage III melanoma.

Various phase III studies are currently testing the potential role of other immunotherapies (anti-PD1 antibodies MAGE 3 vaccine), as well as BRAF and MEK inhibitors (vemurafenib, dabrafenib, trametinib) in the adjuvant setting. Decisions regarding adjuvant therapy for neoplastic diseases represent a balancing of risk of disease recurrence against the relative value of the agent used in terms of its activity, toxicity, and cost.

Treatment of Metastatic Malignant Melanoma

Approximately 2–5% of new patients with melanoma present with metastatic disease, and 30% of patients initially diagnosed as localized or regional disease develop distant metastasis [41]. The prognosis for patients with advanced visceral metastatic melanoma in the pretargeted and preimmunotherapy era was particularly poor with 3-year survival rate of only 6–12% [42]. At that time, the only standard first line treatment was dacarbazine despite its limited clinical benefit. The response rate observed with single-agent dacarbazine chemotherapy did not exceed 12% [43] and no other chemotherapeutic agents either alone or in combination have proved superior to single-agent dacarbazine chemotherapy [43]. With the recent development of targeted therapies and immunotherapies which have demonstrated better efficacy than conventional chemotherapy, the therapeutic landscape for metastatic melanoma is rapidly changing.

Targeted Therapies Against BRAF Mutations

About half of patients with metastatic melanoma harbor an activating mutation in BRAF, the most common being BRAF V600E [44].

Vemurafenib is a selective BRAF inhibitor that targets the V600 mutant forms of the BRAF and was the first BRAF inhibitor to gain FDA approval in August 2011. A phase 2 trial (BRIM2) involving patients with previously treated BRAF V600E mutant stage IV melanoma showed a response rate of 53%, with a median duration of response of 6.7 months [44]. A subsequent phase 3 randomized trial (BRIM3) of previously untreated patients compared vemurafenib with dacarbazine. This study demonstrated an improvement in progression free survival (PFS) (6.9 months vs. 1.6 months), OS (13.6 months vs. 9.7 months), and overall response rate (57% vs. 8.6%) [45].

Following vemurafenib, two additional agents targeting BRAF-mutated disease have been approved by the FDA.

Dabrafenib has shown similar results to those with vemurafenib in phase I/II studies [46, 47]. A Phase III randomized trial compared dabrafenib with dacarbazine in previously untreated patients with BRAFV600E-mutated metastatic melanoma. Dabrafenib significantly improved PFS (5.1 months vs. 2.7 months, HR = 0.30, P < 0.001) and response rates (53% vs. 19%) compared with dacarbazine [48]. These results have led to FDA approval in May 2013.

Trametinib is an oral small-molecule inhibitor of MEK 1 and MEK 2, which are downstream of BRAF in the MAP kinase signal transduction pathway. In the open-label phase III trial (METRIC) that led to FDA approval in May 2013, 322 patients with BRAF V600E/K-mutant metastatic melanoma were randomized to receive either trametinib or chemotherapy with either dacarbazine or paclitaxel [49]. The median PFS was improved to 4.8 months in the trametinib group, as compared to 1.4 months in the chemotherapy group (HR = 0.45, 95% CI: 0.33–0.63; P < 0.001). The OS rate at 6 months was 81% in the trametinib group and 67% in the chemotherapy group (HR = 0.54, 95% CI: 0.32–0.92; P = 0.01), despite 65% of patients in the chemotherapy arm crossing over to the trametinib arm.

Numerous studies are being conducted so as to find methods of overcoming or delaying the resistance. In January 2014, FDA approved the first combination of a BRAF inhibitor dabrafenib and a MEK inhibitor trametinib to treat patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutation. A phase 3 study tested the combination of dabrafenib with trametinib versus dabrafenib and placebo [50]. The median PFS was longer in the combination therapy group compared to the dabrafenib only group (9.3 vs. 8.8 months with HR of 0.75, P = 0.03). In the patient population with elevated LDH levels, the median PFS was longer in the combination therapy group compared to monotherapy (7.1 vs. 3.8 months). Interestingly, the BRAF and MEK inhibitor combination demonstrated not only a potential reduction in drug resistance but also a lower incidence of skin toxicity and secondary cancers.

Another combination of Cobimetinib and vemurafenib was associated with a significant improvement in PFS among patients with BRAF V600 mutated metastatic melanoma and was approved by the FDA in November 2015 [51].

Immunotherapy

Although melanoma has historically been considered as one of the most immunogenic types of cancer, clinically translated immunotherapies including treatment with interleukin-2, interferon alpha therapy, vaccination with peptide-pulsed dendritic cells, or adoptive T-cell therapies had not led to a statistically significant improvement in OS until recent years. Three immune-therapeutic agents (ipilimumab, pembrolizumab, and nivolumab) have been approved since 2011 and they have each produced survival advantage in patients with metastatic melanoma.

Ipilimumab, a monoclonal antibody binding to the CTLA-4 receptor expressed in activated T cells, was the first agent to demonstrate an OS benefit in the treatment of advanced melanoma. It received FDA approval in March 2011. Approval was based on a phase III study of 676 previously treated metastatic melanoma patients [52] who were randomized to receive ipilimumab plus a gp100 vaccine versus ipilimumab alone versus the vaccine alone in a 3:1:1 ratio. OS was significantly longer for patients treated with the combination (10 months; HR = 0.68; P < 0.001) or ipilimumab alone (10.1 months; HR = 0.66; P < 0.003) versus gp100 alone (6.4 months). A second phase III study compared dacarbazine with or without ipilimumab in previously untreated melanoma patients [53]. The addition of ipilimumab to dacarbazine significantly improved the OS compared with dacarbazine alone (11.2 vs. 9.1 months; P < 0.05). However, the trial employed a dose of Ipilimumab more than three times higher than currently licensed.

Pembrolizumab, an anti-PD-1 monoloclonal antibody, was approved by FDA in September 2014 for the treatment of patients with unresectable or metastatic melanoma with disease progression after treatment with ipilimumab or BRAF-inhibitor in case of BRAF-positive disease. KEYNOTE-001 was an open label phase Ib study randomizing 655 patients (342 ipilimumab treated (IPI-T) and 313 ipilimumab naive (IPI-N)) with unresectable or metastatic melanoma to receive pembrolizumab 2 mg/kg or 10 mg/kg IV once every 3 weeks or 10 mg/kg every 2 weeks [54]. At the time of analysis, ORR was 34% (29% IPI-T, 38% IPI-N), with a 6% complete remission (CR) rate; median PFS was 5.2 months (IPI-T, 4.9 months (3.0–5.5); IPI-N, 5.4 months (3.1–6.9)) and the 1-year OS rate was 67%. KEYNOTE-002 was a phase 2 randomized study which demonstrated an improvement in PFS in the pembrolizumab 2 mg/kg arm (HR of 0.57 [95% CI: 0.45, 0.73]; P < 0.001) and in the pembrolizumab 10 mg/kg arm (HR of 0.50 [95% CI: 0.39, 0.64]; P < 0.001) when compared to investigator-choice chemotherapy in 540 patients with advanced melanoma who were previously treated with ipilimumab and, if BRAF V600 mutation positive, a BRAF or MEK inhibitor [55]. The phase 3 KEYNOTE-006 study randomized 834 patients with advanced melanoma to receive pembrolizumab (10 mg/kg every 2 or 3 weeks) or ipilimumab [56]. In the planned interim analysis of the coprimary endpoints, pembrolizumab demonstrated superior PFS and OS compared to ipilimumab. Following the results from this study, FDA approved (December 2015) an expanded indication for pembrolizumab to include the first-line treatment of patients with unresectable or metastatic melanoma regardless of BRAF status.

Nivolumab is a monoclonal antibody that targets the PD-1 protein and was initially approved by FDA in December 2014 for patients who progressed after treatment with ipilimumab and in patients whose tumors express BRAF V600 mutation. The indication for nivolumab was then expanded to include the first-line treatment of unresectable or metastatic melanoma. The approvals were based on the results from two phase 3 trials: Checkpoint 037 and Checkmate 066. Checkpoint 037 enrolled 272 patients with metastatic melanoma who had received prior anti-CTLA-4 therapy and a BRAF inhibitor if a V600 mutation was present [57]. Patients were randomly assigned to nivolumab or chemotherapy (either dacarbazine or carboplatin plus paclitaxel). Nivolumab led to a greater proportion of patients achieving an objective response (31.7% vs. 10.6%) and fewer toxic effects than with alternative available chemotherapy regimens. In the previously untreated setting, 418 patients without BRAF mutation were randomly assigned to nivolumab or dacarbazine [58]. OS was significantly increased in those treated with nivolumab (1-year survival rate 73% vs. 42%). PFS was also increased with nivolumab (median 5.1 vs. 2.2 months), as was the ORR (40% vs. 14%).

Finally, the combination of nivolumab and ipilimumab has been recently (September 2015) approved in the USA for the treatment of patients with BRAF V600 wild-type and BRAF V600 mutation-positive unresectable or metastatic melanoma based on findings from the phase 2 CheckMate-069 study and from the phase 3 CheckMate-067 trial. This marks the first approval for an immunotherapy combination for patients with cancer. The phase 3 CheckMate-067 study, where 945 previously untreated patients with advanced melanoma were assigned to nivolumab alone, nivolumab plus ipilimumab, or ipilimumab alone, showed a median PFS of 11.5 months for the nivolumab plus ipilimumab regimen and 6.9 months for nivolumab monotherapy, versus 2.9 months for ipilimumab monotherapy [59]. The combined regimen demonstrated a 58% reduction in the risk of disease progression vs. ipilimumab (HR: 0.42; P < 0.0001), while nivolumab monotherapy demonstrated a 43% risk reduction versus ipilimumab monotherapy (HR: 0.57; p < 0.0001).

Novel Targets and Combination Therapies

The advent of new treatment options has resulted in various novel combination approaches involving targeted therapies, immunotherapies, as well as other treatment modalities (i.e., chemotherapy, radiotherapy). Resistance to BRAF inhibitors develops in the majority of patients within 6–8 months and can be mediated by a number of different mechanisms occurring along the MAPK pathway (e.g., mutations in MEK, NRAS, overexpression of COT) or via bypass signalling pathways (e.g., activation of PI3K/AKT signalling, loss of PTEN, RTK overexpression, IGFR1). In addition to the combinations that have already been approved, other targeted combinations to overcome resistance are currently being evaluated.

Another possible way of overcoming the resistance to BRAF inhibitors is the combination of immunotherapeutic agents and BRAF inhibitors. A phase I/II trial combining vemurafenib and ipilimumab was conducted by Ribas et al. [60]. While the combination was shown not to be feasible due to hepatotoxicity leading to discontinuation of the study, sequential administration was shown to be safe, with some potential for efficacy. Clinical trials evaluating combinations of PD1 pathway inhibitors with BRAF inhibitors such as vemurafenib (NCT01656642), or dabrafenib and with MEK inhibitor trametinib (NCT02224781) are underway. Furthermore, preliminary safety data from the combination trial of MEDI4736 (a PDL1-specific mAb), dabrafenib and trametinib appear promising [61].

Combining immunological agents may also improve response rates and the duration of response by stimulating an antitumor immunological memory regardless of BRAF-mutational status. Dual blockade of PD-1 and CTLA-4 with nivolumab and ipilimumab has proven benefit in advanced melanoma, although it is associated with higher toxicity than either monotherapy. The combination of ipilimumab with the oncolytic virus, T-VEC, another immunotherapy, also obtained a very promising ORR of 55%, with a good safety profile. Novel immunomodulatory candidates for rational combination with immune checkpoint inhibitors are at various stages of clinical development. Early phase studies involve the combination of nivolumab with other immunomodulating antibodies targeting inhibiting receptors, such as LAG-3 or TIM-3, and with antibodies targeting activating receptors, such as CD 137 or OX-40. Other strategies are also being explored, such as agents that may block the inhibition of natural killer cell activity (i.e., KIRs, C-type lectins, CD244 and CD48, ILT family) or target the tumor microenvironment (i.e., IDO, TGFβ).

c-KIT Inhibitors

Mutations in c-KIT are seen in up to 6% of cutaneous melanomas, although the frequency may be higher in mucosal and acral lesions. In an open-label, single-arm, phase II clinical trial 51 patients with mutations were identified out of the 295 screened and 28 patients were treated with imatinib [62]. The authors did find an association between clinical response and mutation pattern. Further clinical studies using other CKIT inhibitors such as dasatinib and nilotinib are in progress and results are pending.

Antiangiogenic Therapy

Blockade of the VEGF pathway has been achieved by many different approaches, including blocking antibodies targeted against VEGF or its receptors, soluble decoy receptors that prevent VEGF from binding to its normal receptors (VEGF trap), as well as small-molecule inhibitors of the tyrosine kinase activity of the VEGFRs. Bevacizumab is a potent antibody against the VEGF and has been shown to be effective for the treatment of various advanced cancers. Bevacizumab has also been studied in phase II trials in metastatic melanoma [63, 64]. Prolonged disease stabilization and response rates have been demonstrated in one-quarter of metastatic melanoma patients after the addition of bevacizumab to low-dose IFN, and dacarbazine [65]. In addition, the combination of temsirolimus and bevacizumab demonstrated an objective clinical response in patients with BRAF/RAS–wild-type melanomas suggesting that the combination of an angiogenesis inhibitor with an mTOR inhibitor may be promising in a subset of melanoma patients who lack activating mutations in both BRAF and RAS and for whom no targeted therapies are currently available [66]. Further trials of bevacizumab combined with chemotherapy, immunotherapy, and other targeted therapies are ongoing in melanoma patients, and numerous other antiangiogenic agents are currently in clinical trials or in development.

Apoptotic Therapy

The Bcl-2 protein is one of the most important inhibitors of apoptosis, and it is overexpressed in approximately 90% of melanomas. Drug resistance in melanoma has been partially attributed to overexpression of Bcl-2. Oblimersen sodium is a Bcl-2 antisense oligonucleotide that selectively targets Bcl-2 RNA for degradation. Although promising results were seen in an initial phase III trial which demonstrated significant increases in PFS and response rate when oblimersen was combined with dacarbazine [67], these findings were not confirmed in a second trial.

Role of Nuclear Medicine in Melanoma Patients

Initial Staging of Primary Melanoma

Staging Nodal Metastases

Lymphoscintigraphy. In early stage melanoma (AJCC I–II), SLNB has become the standard of care for staging the regional draining lymph nodes, which are typically the first site of possible metastatic spread of disease [28, 68]. Compelling evidence from the literature indicates that SNLB is the procedure of choice for detection of occult regional lymph node metastases, particularly in patients presenting with an intermediate Breslow thickness lesion (1–4 mm) [22, 23]. Preoperative lymphoscintigraphy is normally performed, followed by intraoperative detection with blue dye and/or a gamma probe [69]. Precise identification of sentinel lymph node (SLN) site(s) is essential, as there may be true nodal sites, intransit nodes, and alternate drainage basins in some situations (Fig. 1). Lymphoscintigraphy has been shown to be highly sensitive and specific (>90%) for the detection of SLN, thus assisting surgical biopsy and decisions regarding subsequent therapeutic options.
Fig. 1

Lymphoscintigraphy of primary melanoma of the right thumb. Right axillary lymph node (arrow) identified on sentinel lymph node scintigraphy with transmission scan (a) and negative whole-body staging [18F]FDG PET scan (b)

Lymphoscintigraphy for SLN detection must be performed with transmission scans, and/or with hybrid SPECT/CT systems, to precisely define the location of sentinel nodes and eliminate false-positive results. All nodes demonstrating uptake must be evaluated by detailed histology, as a SLN may not be the lymph node which demonstrates the highest tracer uptake, and different drainage basins may occur from a single primary melanoma site (Fig. 2). Intransit and aberrant metastatic lymph nodes occur in 14–22% of cases [69]. Status of the sentinel lymph node is an important prognostic factor for disease-free and overall survival. In the Multicenter Selective Lymphadenectomy Trial (MSLT-1), patients who had immediate lymph node dissection following positive SLNB had a higher survival rate than those who underwent delayed lymphadenectomy [28].
Fig. 2

Lymphoscintigraphy of primary melanoma of the left chest. Planar transmission scan images in the anterior (a) and lateral (b) projections. SPECT/CT confirms two separate SLN, one lateral to left pectoral muscle (c) and one in left midthoracic intercostal space (d) (Courtesy of Dr Martin Cherk, Alfred Hospital, Melbourne, Australia)

Anatomic correlation of the lymphoscintigram with SPECT/CT improves the accuracy of lymphoscintigraphy by defining anatomical site and excluding false-positive results, compared to planar gamma camera imaging. In one study of patients with primary melanoma located in the head and neck or trunk region, SPECT/CT identified “hot” nodes missed on planar images including nodes invaded by metastases in 43% of cases [69]. These SLNs identified by SPECT/CT were nodes hidden by the injection-site-scattered radiation, deeply located or intransit nodes. Multiple draining basins were clearly identified in 50% patients with trunk melanoma and in 33% patients with head and neck malignancy. Further validation of lymphoscintigraphy with SPECT/CT in clinical studies is ongoing and may help to provide additional information on improvement in outcomes of patients evaluated preoperatively with this investigation.

[ 18 F]FDG PET. In patients with AJCC stage I–II melanoma, multiple studies with [18F]FDG PET alone, and PET/CT, have shown a poor sensitivity for the detection of metastatic disease in draining lymph nodes. Cumulative data from over 800 patients with early stage melanoma show that PET has a low sensitivity for detecting SLN metastases (Table 3) [68, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87]. The small size of involved lymph nodes, which are often <5 mm in size, is a major factor in detection of disease, as most metastatic melanoma sites are [18F]FDG-avid. In an early study by Crippa et al., the sensitivity of PET significantly varied with the size of lymph node metastases [88]. The sensitivity of PET was only 23% for lymph nodes <5 mm and increased to 83% and 100% for lymph nodes with a size of 6–10 and >10 mm, respectively. In another study exploring the impact of spatial resolution of PET scanners with typical size of metastatic lymph nodes, a spatial resolution of 4–6 mm resulted in less than 50% of lymph nodes being potentially detectable [89]. Other studies have confirmed the small size of metastatic disease in SLN and corresponding low sensitivity for PET and PET/CT for AJCC stage I–II disease [68, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87] (Table 3).
Table 3

Studies using [18F]FDG PET in regional lymph node staging in early-stage cutaneous melanoma

Study

Study type

Patients

AJCC stage

Clinical use of PET

Reference test

Sensitivity

Wagner et al. [68]

Prospective

70

I–III

Detection of sentinel node metastases

SLNB

PET: Sensitivity 7.7% (stage I–II), 40% (stage III)

Klein et al. [70]

Prospective

17

I–II

Detection of sentinel node metastases

LS/SLNB or clinical follow-up (20 months)

PET: Sensitivity 67%

Acland et al. [71]

Prospective

50

T2–T4 or lymphatic invasion

Detection of regional lymph node metastases

LS/SLNB and clinical follow

PET: Sensitivity 0% SLNB: Sensitivity 100%

Kokoska et al. [72]

Prospective

18

T1–T4 N0 M0

Detection of sentinel node metastases

LS/SLNE

PET: Sensitivity 40%

Belhocine et al. [73]

Prospective

21

T2–T4 N0 M0

Detection of sentinel node metastases

LS/SLNE

PET: Sensitivity 14% SLNB: Sensitivity 86%

Havenga et al. [74]

Prospective

53

T2–T4 N0

Prediction of sentinel node metastases

LS/SLNB

PET: Sensitivity 15% SLNB: Sensitivity 100%

Longo et al. [75]

Prospective

25

T2–T4 N0 M0

Prediction of regional lymph involvement

LS/SLNB

PET: Sensitivity 22% LM/LS: Sensitivity 100%

Schafer et al. [76]

Prospective

40

T2–T4 N0 M0

Detection of regional lymph node metastases

SLNB

PET: Sensitivity 0%

Fink et al. [77]

Prospective

48

T2–T4 N0 M0

Prediction of regional lymph involvement

LS/SLNB

PET: Sensitivity 13% SLNB: Sensitivity 100%

Hafner et al. [78]

Prospective

100

T2–T4

Detection of regional lymph node metastases

LS/SLNB

PET: Sensitivity 8% SLNB: Sensitivity 100%

Libberecht et al. [79]

Retrospective

5

T2–T3 or local recurrence

Detection of regional lymph node metastases

LS/SLNB

PET: Sensitivity 0%

Wagner et al. [80]

Prospective

144

T2–T4 N0 M0 or TxN2cM0

Detection of regional lymph node metastases

LS/SLNB

PET: Sensitivity 8% SLNB: Sensitivity 97.5%

Vereecken et al. [81]

Prospective

43

T2–T4 or T1 with regression and/or ulceration

Preoperative staging

LS/SLNB

PET: Sensitivity 40%

Clark et al. [82]

Retrospective

64

T2–T4

Detection of regional lymph node metastases

LS/SLNB

PET: Sensitivity 10.5%

Kell et al. [83]

Retrospective

37

Breslow > 0.75 mm N0 M0

Detection of regional lymph node metastases

LS/SLNB

PET/CT: Sensitivity 22%

Maubec et al. [84]

Prospective

19

T4 N0 M0

Detection of regional lymph node metastases

LS/SLNB

PET: Sensitivity 0% SLNB: Sensitivity 87.5%

Constantinidou et al. [85]

Retrospective

30

Breslow > 1 mm

Preoperative staging

LS/SLNB

PET or PET/CT: Sensitivity 0%

Singh et al. [86]

Prospective

52

T2–T4 N0 M0

Detection of regional lymph node metastases

LS/SLNB

PET/CT: Sensitivity 14.3% SLNB: Sensitivity 100%

Klode et al. [87]

Retrospective

61

T2–T4 N0 M0

Detection of regional lymph node metastases

LS/SLNE

PET/CT: Sensitivity 5.9%

LS lymphoscintigraphy, SLNB sentinel lymph node biopsy, SLNE sentinel lymph node excision, LM lymph node mapping

There is a potential role for [18F]FDG PET in patients with apparent AJCC stage I–II disease but higher risk of metastatic disease, including those with intermediate/high-risk lesions (Breslow ≥1 mm, regression, ulceration) or high-risk lesions (Breslow >4 mm). These patients have a prevalence of regional lymph node or distant metastases at the time of initial presentation of >10%. For example, in one study of 43 patients with intermediate/high-risk melanomas, extensive staging identified disease resulting in early treatment in 12 patients (28%) [81]. The analysis of melanomas for gene signatures that are associated with a worse prognosis is the subject of ongoing research, and this may also in the future identify patients who would benefit from more extensive staging procedures such as PET [69].

These results have led to [18F]FDG PET not being recommended for the routine detection of regional nodal involvement in AJCC I–II melanoma patients. However, PET in initial staging may have a role in situations where AJCC stage I–II patients are considered at higher risk of distant metastatic disease, such as in intermediate-high-risk or high-risk primary lesions, multiple melanomas, or unusual gene signatures in melanoma lesions [90].

Staging of Metastatic Disease

Initial Staging
Melanoma patients presenting with AJCC stage III disease (regional nodal involvement) are at higher risk of presenting with systemic metastases, and as this can impact on therapy, accurate staging is essential (Fig. 3). [18F]FDG PET has been shown to be more accurate than conventional imaging techniques in identifying metastatic disease in stage III patients in a number of reported studies [91, 92, 93, 94, 95, 96, 97] (Figs. 4, 5, and 6). In a recent large prospective study evaluating 251 patients with PET/CT prior to surgery for known metastatic melanoma and nodal involvement, lymph node metastases were visualized in 91% of patients by PET, and 92% by CT, although in this series most lymph nodes were large [97]. Systemic metastases were suspected in 32% of patients by PET and in 24% by CT. Upstaging by PET was correct in 27% and in 24% by CT, and more bone and soft tissue sites were detected by PET compared to CT. [18F]FDG PET and CT performed at initial diagnosis for patients with confirmed stage III melanoma conferred survival benefits for both the patients who were negative for disseminated disease and those whose disease was upstaged because of distant metastases, which they attributed to the early detection of occult subclinical metastases and subsequent modifications in treatment decisions [98]. The use of PET in assessing systemic metastatic disease in this patient group is also included in established clinical guidelines [90].
Fig. 3

Fifteen-year survival curves for patients with localized melanoma (stages I and II), regional metastases (stage III), and distant metastases (stage IV). The numbers in parentheses are the numbers of patients from the AJCC Melanoma Staging Database used to calculate the survival rates. The differences between the curves are highly significant (p < 0.0001). (Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, IL. The original source for this material is the AJCC Cancer Staging Manual Seventh Edition (2010) published by Springer Science and Business Media LLC www.springer.com)

Fig. 4

[18F]FDG PET/CT staging of biopsy-proven left axillary melanoma metastasis. Whole-body PET image (a) shows a solitary metastatic lymph node in the left axilla (arrow), with no distant metastatic disease. Also seen on axial CT (b), PET (c), and fused PET/CT (d) images

Fig. 5

[18F]FDG PET/CT staging postresection of primary melanoma from right calf. Whole-body PET image (a) shows local and distant lymph node involvement in right popliteal (b), femoral (c), and iliac (d) lymph nodes

Fig. 6

Staging [18F]FDG PET/CT scan of left heel primary melanoma. (a) Transaxial PET, (b) CT, and (c) PET/CT images show metastatic lymph nodes in the left inguinofemoral region (arrow), also seen on (d) whole-body PET image, without other metastatic disease identified

In patients with known or suspected AJCC stage IV disease (systemic metastases), [18F]FDG PET also has an important role in identifying metastatic disease sites and extent (Tables 4 and 5), which can impact on initial treatment, including surgical options and decisions regarding chemotherapy/biologic therapy [69, 90] (Fig. 7). The majority of melanoma metastases are [18F]FDG-avid, provided lesions are >5–6 mm in size. The exceptions are brain metastases, which may be difficult to identify due to gray matter [18F]FDG uptake, and hepatic metastases of uveal melanoma, which have been shown to be negative on [18F]FDG PET in up to 59% of cases and which do not appear to be related to GLUT-1 expression [111].
Table 4

Selected studies of [18F]FDG PET in staging distant metastatic melanoma

Study

Patients

Study type

Clinical use of [18F]FDG PET

Results

Crippa et al. [88]

38

Prospective

Detection of lymph node metastases

Sensitivity 100% of metastases ≥10 mm, 83% of metastases 6–10 mm, and 23% of metastases ≤5 mm

Swetter et al. [99]

104

Retrospective

Initial staging; known or suspected recurrent disease; routine surveillance

Sensitivity 84%

Specificity 97%

Harris et al. [96]

92

Retrospective

Detection of metastases

Sensitivity 92%

Specificity 88%

Wagner et al. [80]

144

Prospective

Preoperative detection of metastases in patients with Breslow > 1.0 mm, local disease recurrence, or solitary intransit metastases

Sensitivity for detection regional lymph node 21% and specificity 97%. Sensitivity for detection of distant metastatic disease 4% and specificity 86%

Brady et al. [100]

103

Prospective

Detection of metastases in patients with stage IIC, III, IV melanoma

Sensitivity PET versus CT 68% versus 48%. Specificity 92% versus 95%

Bastiaannet et al. [97]

251

Prospective

Detection of metastases in patients with palpable and proven lymph nodes metastases

27% patients correctly upstaged by PET and 24% by CT. PET had an additional value over CT in 14%, and CT over PET in 9%. PET detected more metastatic sites, particularly bone and subcutaneous

Veit-Haibach et al. [101]

56

Prospective

Initial staging after resection of the primary melanoma

Sensitivity N-stage: PET/ceCTa and PET-only 38.5%; CT-only 23.1% Sensitivity M-stage: PET/ceCT 41.7%, PET-only 33.3%, CT-only 25.0%

Aukema et al. [102]

70

Prospective

Detection of metastases in patients with palpable lymph nodes

PET/CT: Sensitivity 87%

PET/CT: Specificity 98%

aPET/ceCT: [18F]FDG PET and combined contrast enhanced CT

Table 5

Studies of management impact of [18F]FDG PET in melanoma patients

Study

Type

Patients

AJCC stage

Clinical use of [18F]FDG PET

Reference test

Change in management after PET

Steinert et al. [91]

Prospective

33

II (n = 10)

IV (n = 23)

Initial staging and restaging in stage IV

Histopathology or conventional imaging

PET: treatment changes in 4 of 29 assessable patients (14%)

Damian et al. [92]

Retrospective

100

I–II (n = 6)

III–IV (n = 94)

Preoperative staging, evaluation of disease status and response to treatment

Clinical examination, histopathology, and conventional imaging

PET: treatment changes in 22 patients (22%)

Rinne et al. [93]

Prospective

100

II (n = 52)

III–IV (n = 48)

Initial staging and restaging for recurrent disease

Conventional imaging

PET: treatment changes in 8 patients (8%)

Tyler et al. [94]

Prospective

95

III

Preoperative staging, restaging and response to treatment

Clinical examination and conventional imaging

PET: treatment changes in 15 patients (16%)

Mijnhout et al. [103]

Prospective

58

II (n = 4)

III–IV (n = 54)

Preoperative staging

Conventional imaging

PET: treatment changes in 23 patients (40%)

Stas et al. [95]

Retrospective

84

IV

Restaging for suspected recurrence or progression

Clinical examination and conventional imaging

PET: treatment changes in 26 patients (31%)

Gulec et al. [104]

Retrospective

49

II (n = 3)

III–IV (n = 46)

Evaluation of extent of disease

Clinical examination and conventional imaging

PET: treatment changes in 24 patients (49%)

Fuster et al. [105]

Retrospective

156

I–II (n = 98)

III–IV (n = 58)

Restaging for suspected recurrent disease

Conventional imaging

PET: treatment changes in 36% of patients

Harris et al. [96]

Retrospective

92

I–II (n = 8)

III–IV (n = 84)

Staging and assessment of response

Clinical follow-up and conventional imaging

PET: treatment changes in 40 patients (32%)

Bastiaannet et al. [106]

Prospective

251

III

Staging

CT

PET: treatment changes in 43 patients (17%)

Brady et al. [100]

Prospective

103

II (n = 12)

III–IV (n = 91)

Preoperative staging

CT

PET: treatment changes in 14 patients (14%)

Reinhardt et al. [107]

Retrospective

250

I–II (n = 110)

III–IV (n = 140)

Initial staging, therapy control, restaging, and follow-up

CT

PET/CT: treatment changes in 121 patients (48%)

Falk et al. [108]

Retrospective

60

I–II (n = 35)

III–IV (n = 25)

Initial staging, therapy control, recurrence staging, follow-up

Histopathology, conventional images and clinical follow-up

PET/CT: treatment changes in 35 patients (28%)

Lagaru et al. [109]

Retrospective

106

I–II (n = 76)

III–IV (n = 30)

Disease restaging

Clinical examination and histopathology

PET/CT: treatment changes in 4 of the 30 patients with stage III–IV (13%)

Fulham et al. [110]

Prospective, multicenter

134

IV

Restaging prior to possible surgery

Clinical examination, pathology, and follow-up

PET changed management in 83 patients (62%)

Veit-Haibach et al. [101]

Prospective

56

I–II (n = 38)

III–IV (n = 18)

Initial staging

Clinical examination and histopathology

PET/CT: treatment changes in 6 patients (11%)

Aukema et al. [102]

Prospective

70

III

Staging before lymph node dissection

Histopathology and/or additional images and/or clinical follow-up

PET/CT: treatment changes in 26 patients (37%)

Fig. 7

[18F]FDG PET/CT for staging of melanoma. Whole-body PET image (a) shows multiple metastases in left axillary lymph nodes (b), abdominal mass (c), parasplenic mass, para-aortic lymph node, and mesenteric mass (d)

Melanoma patients should have whole-body PET imaging, including arms/legs in patients whose primary lesions arise on extremities (Figs. 5 and 6). Reported studies have shown the value of whole-body imaging in melanoma patients, where primary lesions were in the limbs. In one retrospective study of 153 patients, abnormal PET findings in the legs were observed in 53 (35%) of patients; in these 53 patients, 72% also had distant metastases detected. Only patients with primary melanoma of the legs had PET findings justifying inclusion of the legs in the whole-body PET scan [112]. Published guidelines support the use of whole-body PET with extremities in patients with primary melanoma of the arms or legs and full images of the head in patients with primary scalp melanoma [113]. False-negative results can occur with small skin and brain metastases, and lesions adjacent to the heart, kidneys, or urinary bladder. Furthermore, while PET is more specific in the diagnosis of melanoma pulmonary metastases, chest CT is more sensitive. [18F]FDG PET/CT provides an improved technique for assessing pulmonary disease (see later section), although it should be performed in conjunction with brain MR imaging to optimally identify brain metastases.

Recurrent Metastatic Disease

Identifying metastatic disease is critically important in melanoma patients, as the median survival after the appearance of distant metastases is approximately 6 months. An additional consideration is that treatment decisions are based on site and extent of disease [21]. While a comprehensive clinical history and physical examination may assist in identifying possible recurrent disease, particularly in stage III and IV patients, accurate staging is vitally important to guide decisions regarding surgery (which may extend survival) or radiotherapy in patients with recurrent disease [114, 115]. It has been shown that conventional staging investigations (CT chest, abdomen, brain MRI with or without bone scan) have limited sensitivity and specificity for the detection of melanoma metastases and have been estimated in patients with stage II–IV melanoma to have a sensitivity of 57–81% and a specificity of 45–87%, respectively, on the basis of single melanoma lesions [92, 93, 95]. In a further study of 347 patients with clinical stage III melanoma, CT scans identified twice as many false positives as true-positive melanoma lesions [116].

In published studies (Table 4) and meta-analyses of the literature, the reported sensitivity, specificity, and accuracy of [18F]FDG PET in detecting recurrent melanoma ranges from 70% to 100% [94, 96, 117]. PET is particularly sensitive and specific for detecting soft tissue and lymph node metastases that are not assessable by clinical examination and have not been demonstrated by CT [92, 93, 96, 99] (Fig. 8). [18F]FDG PET has also been shown to detect disease up to 6 months earlier than conventional techniques. In studies directly comparing PET to conventional imaging in patients with recurrent melanoma, PET has had superior accuracy for the detection of both locoregional and distant metastases [96, 100] (Figs. 9, 10, 11, and 12). In patients with pulmonary metastases, PET-staged patients have also been shown to have improved survival compared to patients staged with conventional imaging techniques [118]. In a prospective, multicenter study of [18F]FDG PET in 134 patients with known or suspected recurrent metastatic melanoma, PET identified an additional 189 lesions in 55.2% of patients, principally in soft tissue, bone, and nodal sites [110]. Most PET false negatives in recurrent disease are typically less than 1 cm in diameter and are mainly pulmonary and hepatic in location, or in the brain (Fig. 13). The majority of these false negatives can be detected by CT scanning or MRI for brain metastases. Therefore, PET should complement rather than replace CT/MRI scanning in patients with suspected recurrent disease. Most CT false negatives are located in the abdomen, suggesting that PET can especially assist in the staging of this region.
Fig. 8

[18F]FDG PET/CT for postoperative restaging in a patient presenting with a seroma postresection of metastatic melanoma in the right axilla. Multiple locoregional and distant metastatic lesions identified on the whole-body PET scan (a), which on axial PET/CT include a cutaneous lesion over right deltoid (b), local metastasis in right axilla (c), and left acetabulum metastasis (d)

Fig. 9

[18F]FDG PET/CT for restaging following resection of left chest and axillary metastatic melanoma lymph nodes, and new liver lesion on CT scan. Two metastatic lesions are identified, in the liver (arrow), and the lower sternum (double arrows)

Fig. 10

[18F]FDG PET/CT for restaging of possible left neck nodal recurrence. Axial CT/PET fused images (ac) and coronal (df) and whole-body PET image (g) show a single metastasis in a left submandibular lymph node (arrow)

Fig. 11

Locoregional recurrent disease in melanoma patient. [18F]FDG PET/CT shows recurrent metastatic involvement of right axillary lymph nodes (arrow), with no evidence of distant metastatic disease

Fig. 12

[18F]FDG PET/CT for restaging posttreatment. (a) Whole-body PET shows left inguinal nodal metastasis in a patient with a left lower leg primary melanoma. A whole-body PET scan performed 6 months postresection of left inguinal nodes shows new intransit and left upper leg and inguinal node metastases and new lung metastases (b)

Fig. 13

Restaging [18F]FDG PET/CT prior to cerebral metastasectomy in a patient with known metastatic melanoma. (a) Whole-body PET shows a lesion in the right abdomen, localized to the right kidney (arrow) on axial PET/CT (c). The left frontal lobe metastasis seen on MRI was not [18F]FDG avid (b)

Unsuspected additional primary tumors may be detected with [18F]FDG PET. In one series of 92 patients with stage IV melanoma staged with [18F]FDG PET, seven new primary tumors were detected, emphasizing the importance of considering differential diagnoses and obtaining a tissue diagnosis particularly at the time of the first relapse [96].

[18F]FDG PET

[18F]FDG PET/CT is superior to PET alone in the assessment of metastatic melanoma, with improved detection of nodal spread and distant metastases, although some false positives are seen [101, 107, 108, 109, 119, 120, 121] (Fig. 14). PET/CT has a significant impact on the interpretation of suspicious metastatic lesions, and the false-negative and false-positive rates of PET can be reduced through the use of PET/CT, particularly by providing clarity for normal [18F]FDG uptake variants. Precise anatomic localization of sites of [18F]FDG uptake can define a patient’s suitability for surgery as well as pinpoint metastases. [18F]FDG PET/CT is also helpful for the staging of unusual sites of primary melanoma such as ocular melanoma and vaginal melanoma (Fig. 15). In addition, [18F]FDG PET/CT can assist in identifying incidental metastatic melanoma in patients with other malignancies, although this is an unusual finding.
Fig. 14

False-positive [18F]FDG PET/CT scan for liver metastasis. Fifty-year-old lady with melanoma in the left ankle resected 15 years ago presents with intransit recurrence in the left knee for restaging. Whole-body PET (a) and PET/CT show increased [18F]FDG uptake in left medial knee intransit metastasis (b) and increased [18F]FDG uptake in a 4-cm liver lesion (c arrow). The liver lesion was biopsied and diagnosed as a hepatic adenoma, with no features of melanoma on immunohistotyping

Fig. 15

Ocular melanoma staged with [18F]FDG PET/CT. Primary melanoma of the right eye (arrow) seen on axial PET/CT images (a) with an involved solitary subcarinal lymph node seen on whole-body PET images (b). The patient represented 9 months later with biopsy-proven cervical nodal metastasis for restaging. Recurrent disease is evident on PET/CT around the right eye prosthesis (c), and widespread distant metastatic disease is seen in pulmonary, liver, mediastinal, skeletal, and subcutaneous sites (d)

The use of contrast-enhanced CT as part of the [18F]FDG PET/CT study has also been evaluated in melanoma patients. In a study of 56 patients evaluated with contrast-enhanced [18F]FDG PET/CT, lymph node detection was poor (38% vs. 23% for CT), and the detection of systemic metastases was slightly improved, although no statistically significant difference was seen [101]. The precise role of contrast-enhanced CT with [18F]FDG PET/CT in melanoma is still to be determined. In a study comparing [18F]FDG PET/CT with whole-body MRI in stage III/IV patients, PET/CT was found to be more accurate (86.7% compared to 78.8%), particularly for nodal and skin/subcutaneous metastases, whereas MRI was more accurate for liver, bone, and brain metastases. Changes in treatment were implemented in 64% of patients due to imaging findings, indicating the potential clinical value of combined [18F]FDG PET/CT and organ-specific MRI in melanoma patients [122].

Monitoring Treatment Response

Whole-body [18F]FDG PET can also play a useful role in the treatment monitoring of metastatic melanoma. This is particularly relevant in patients with unresectable regional or distant metastatic disease who are enrolled in immunotherapy, chemotherapy, or biologic therapy protocols. PET has been shown to accurately detect early metabolic response to conventional and experimental therapies in patients with metastatic melanoma (Fig. 16). Therefore, the timely incorporation of whole-body PET into clinical trial protocols may help improve the efficacy of treatment regimens including dosage and scheduling optimization.
Fig. 16

[18F]FDG PET/CT assessment of treatment response. Initial staging whole-body PET scan (a) shows intransit disease in the right leg (a). Posttreatment whole-body PET scan performed after resection of the primary lesion and radiotherapy (b) shows a partial metabolic response, with persistent intransit disease

In a study of 25 patients with stage IV melanoma, [18F]FDG PET/CT and S-100B (tumor marker) was evaluated after 2–3 cycles of chemotherapy. [18F]FDG PET/CT and CT showed a good correlation with overall response, with a trend for OS to be better in PET initial responders versus nonresponders, and PFS was significantly longer in PET responders versus nonresponders [123]. Brain metastases were better detected with MRI/CT and were often the sites of subsequent relapse. Other studies have also confirmed the utility of [18F]FDG PET in assessing treatment response to chemotherapy and biologic agents [121, 124, 125] (Fig. 17).
Fig. 17

[18F]FDG PET/CT assessment of treatment response to chemotherapy. The patient had a history of metastatic melanoma and right axillary dissection and underwent chemotherapy for systemic disease. Whole-body PET image before treatment (a), and 6 months later (b) shows progressive metastatic disease despite treatment

Early data suggest that [18F]FDG PET may be suitable for monitoring treatment response to mutation-driven therapies such as vemurafenib and dabrafenib. Mutated BRAF kinase has been shown to activate signaling pathways that upregulate glucose metabolism, facilitating tumor growth [126]. The inhibition of this pathway by BRAF inhibitors could theoretically be visualized using [18F]FDG PET (Figs. 18, 19, and 20). In one study the intrapatient heterogeneity of response in metastatic melanoma treated with dabrafenib was evaluated with [18F]FDG PET, and compared with clinical outcomes. They reported that [18F]FDG PET/CT showed responses in all patients, with 26% showing a homogeneous PET response and 74% exhibiting a heterogeneous PET response. Heterogeneity was associated with a shorter time to progression (3.0 months vs. 7.4 months for PET homogeneous responders) [127]. In a phase I study, [18F]FDG PET/CT was found to be a useful marker of an early biologic response to vemurafenib [128]. There was a trend for patients with greater reductions in uptake of [18F]FDG to have longer PFS and the study showed a positive correlation between percentage of injected dose in all identified disease and target-lesion SUVmax, although no relationship was found between the reduction in target lesion SUVmax and best response according to RECIST.
Fig. 18

[18F]FDG PET/CT assessment of treatment response to combination BRAF/MEK1 inhibitor treatment (dabrafenib/trametinib). The patient had [18F]FDG-avid disease in the abdomen and mediastinum seen on baseline (a, b); with posttreatment scans showing a partial metabolic response to treatment (d, f) and the appearance of a [18F]FDG-avid node in the right axilla (c, e) due to reactive node rather than progressive disease

Fig. 19

[18F]FDG PET/CT assessment of treatment response to combination BRAF/MEK1 inhibitor treatment (dabrafenib/trametinib). Baseline study (a, b), with progressive metabolic disease noted in the liver on follow-up study (c, d)

Fig. 20

[18F]FDG PET/CT assessment of treatment response to nivolumab. Baseline study (ac) showing treatment related enteritis which resolved with steroid treatment (df)

[18F]FDG PET/CT is commonly used in evaluating melanoma treatment response to immunotherapy, although there are no published studies that have rigorously assessed its role. Several case reports have described the radiologic features of the immune-related adverse reactions and highlighted the challenges of monitoring immunotherapy response, such as the presence of inflammatory cells which are known to be [18F]FDG-avid and can mimic tumor FDG uptake in lymph nodes. [18F]FDG PET/CT may have a role to in the early detection of immune-related adverse events and in directing earlier treatment [129, 130].

Management Impact of [18F]FDG PET/CT

Information on the direct impact of [18F]FDG PET on the clinical management of patients with melanoma strongly supports its role in the surveillance of patients for recurrent disease. In the majority of cases, this involves alteration of decision-making regarding the surgical treatment of recurrent disease (Table 5). Surgery can be curative for stage III disease and is the only therapy that influences survival in patients with stage IV disease [131] (see Figs. 4 and 5). Up to one-quarter of patients with metastatic disease are candidates for potentially curative surgical resection, and 20% of patients who achieve a curative resection become long-term survivors [132].

Retrospective studies of patients with predominantly stage III and IV disease have suggested that the PET result influences the management of 13–49% of patients [92, 95, 96, 104, 107, 109, 121]. In two prospective studies, the PET result changed patient management 16% of the time in one series of 95 patients with stage III disease and contributed to a change in therapy in 40% of a second series of 58 patients with suspected recurrent melanoma [94, 103]. In a study of 92 patients with primarily stage IV disease, management impact was seen following [18F]FDG PET scans in 40 patient studies (32%), particularly assisting in the selection of patients for surgery [96]. In a recent prospective multicenter study of 134 patients with known or suspected metastatic melanoma evaluated with PET prior to surgery, clinical management was changed in 62% of patients, and the pre-PET surgical plan was reduced by 33%. In addition, patients with additional [18F]FDG-avid lesions were more likely to have progressive disease within 12 months of the initial PET scan [110]. It should be noted that PET can miss small-volume disease and/or micrometastatic disease, as evidenced by some false-negative PET studies and by the number of patients who relapse soon after surgery. It is clear that [18F]FDG PET can assist in appropriate selection of patients for surgery, which in turn can lead to improved progression-free survival, although further studies are required to establish if this may also lead to improved overall survival.

Surveillance

Surveillance follow-up of patients with melanoma is guided by risk factors, patient history, and institutional guidelines. The natural history of melanoma and the likelihood of recurrent disease provide guidance about the frequency and duration of follow-up required. In patients with stage I–II melanoma, most recurrences occur within 2 years after initial diagnosis. In a study of 340 patients with stage III melanoma, the sites of relapse were principally systemic in IIIB and IIIC patients, and most relapses occurred within 2–3 years [133]. In stage IV patients, metastatic recurrence usually occurs within 2 years. Melanoma patients with asymptomatic and locoregional recurrences that are subsequently treated have been shown to have improved survival compared to those with symptomatic and distant recurrences [134]. In addition, the type of metastases (i.e., visceral vs. nonvisceral), the number of metastatic sites, and the evolution of metastatic burden over time are significant prognostic factors in treated melanoma patients [135]. Thus, regular follow-up is required for at least 2 years for most melanoma patients, extending to 5 years or more for long-term survivors.

The selection of follow-up investigations in melanoma patients includes blood tests, CT and MRI, and [18F]FDG PET. Blood tests including serum lactate dehydrogenase (LDH) and S-100B have been explored as markers of possible recurrence, but as yet have not achieved routine use. In asymptomatic melanoma patients CT and MRI are of limited value for detecting nodal and visceral metastases [114]. The role of [18F]FDG PET in routine surveillance is also unclear. In one study of 38 patients (AJCC II–III), the ability of PET to uncover silent metastases from melanoma was estimated at 34%, thereby avoiding futile and cost-prohibitive interventions [136]. In a cost-effectiveness study exploring the use of [18F]FDG PET/CT versus whole-body CT for surveillance of melanoma patients with suspected pulmonary metastases, [18F]FDG PET/CT was found to be less costly and resulted in 20% less futile surgeries and a potential survival benefit at 10 years [137]. The likelihood of PET detecting recurrent disease is higher in patients with symptoms and recent treatment of metastatic disease, and in these clinical scenarios, PET is more likely to detect sites of recurrence compared to other investigations. The use of [18F]FDG PET for surveillance is yet to be formally established in practice guidelines, and its use should be guided by individual patient history and clinical suspicion of recurrence.

Non-[18F]FDG PET Tracers in Melanoma

[18F]FDG PET has gained wide acceptance in patients with malignant melanoma, in particular, for staging, restaging, and therapy monitoring. However, the detection of metastatic lesions in the brain may be difficult due to the high background; elsewhere in the body there may be false-positive sites due to nonmalignant lesions such as inflammation or infection. In view of this, a number of other PET tracers have been evaluated in melanoma patients.

In a study of 18F-fluorothymidine (18F-FLT) PET in 10 patients with clinical stage III melanoma, 18F-FLT PET had a sensitivity of 88% and a specificity of 60% for metastatic disease when compared with histopathological evaluation. The detection limit for lymph node metastases was approximately 6 mm, which is similar to the [18F]FDG and a consequence of the spatial resolution of the PET camera. It is still unlikely that 18F-FLT PET could be a suitable alternative to [18F]FDG PET in melanoma patients with stage III disease [138].

Another PET compound receiving particular interest in melanoma is [18F]fluoro-l-dopa (18F-DOPA). Experimental studies have shown that 18F-DOPA is incorporated into melanin and therefore represents an indicator of melanogenesis [139]. In a study of 11 pretreated patients with metastatic melanoma studied with 18F-DOPA [15O]water and [18F]FDG PET, 18F-DOPA PET was found to provide different information from [18F]FDG PET because its uptake was not perfusion dependent, and the detectability of metastases was enhanced when both tracers were used (combined sensitivity of 95%). 18F-DOPA PET could therefore be helpful to increase the accuracy of PET for therapy management in those patients with treated metastases and negative [18F]FDG findings [140].

18F-Galacto RGD (specific for a beta-integrin found in tumor vasculature and on melanoma cells) is another PET tracer that has been investigated in a clinical setting. In a study of 19 patients, 7 of whom had malignant melanoma, most known lesions were identified; however, intensity of uptake varied, most likely related to differing levels of a b-integrin found in tumors [141]. Additional PET tracers including 18F-N-(2-(diethylamino)ethyl)-6-fluoronicotinamide have been shown to have promise in preclinical studies [142]. Further studies are required to define the utility of non-[18F]FDG PET tracers in melanoma.

Conclusions

Nuclear medicine has a pivotal role to play in the management of patients with melanoma, including initial staging, restaging, assisting in therapy selection, treatment response assessment, and surveillance. Lymphoscintigraphy has a major role in sentinel node identification, and SPECT/CT provides improved lesion detection and anatomical localization in this clinical setting. In initial staging, [18F]FDG PET has an important role in detecting extent of metastatic spread beyond microscopic locoregional nodal involvement and has a potential role in evaluating AJCC stage II patients with thick primary tumors or high risk factors and in patients with stage III disease. Published guidelines clearly indicate the importance of PET in staging patients with stage IV disease and assisting in treatment decisions. Studies comparing PET with [18F]FDG PET/CT have convincingly shown the improved accuracy of [18F]FDG PET/CT over PET alone. In restaging, PET may be indicated where there are suspicious clinical symptoms, intransit disease or palpable lymphadenopathy, or other suggestions of possible locoregional or metastatic disease. PET clearly impacts on patient management and can guide treatment decisions. Although there is controversy over the role of PET in surveillance, the sensitivity of [18F]FDG PET/CT makes it valuable in patients with high-risk disease. The use of new PET tracers may assist in more accurate staging of disease in the future and assist in developing biologic therapies targeted to specific oncogenic pathways in melanomas.

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Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Andrew M. Scott
    • 1
    • 2
    Email author
  • Marika Ciprotti
    • 3
  • Sze-Ting Lee
    • 1
    • 2
  1. 1.Olivia Newton-John Cancer Research Institute and La Trobe UniversityMelbourneAustralia
  2. 2.Department of Molecular Imaging and TherapyAustin HealthMelbourneAustralia
  3. 3.Global Clinical Research OncologyBristol-Myers SquibbLondonUK

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