**1. Introduction**

Melanoma is a malignant tumor that arises from the uncontrolled and rapid growth of the melanocytes, which are the pigment-producing cells of the body [1]. The most common form is cutaneous melanoma; however, the tumor can occur in mucosal surfaces, the eye or the brain [1]. Malignant melanoma is one of the aggressive cancers in the skin, with an increasing incidence every year. It is known to represent a small proportion of all cutaneous

**Citation:** Hlongwa, K.N.; Mokoala, K.M.G.; Matsena-Zingoni, Z.; Vorster, M.; Sathekge, M.M. The Use of 18F-FDG PET/CT Metabolic Parameters in Predicting Overall Survival in Patients Undergoing Restaging for Malignant Melanoma. *Diagnostics* **2022**, *12*, 595. https://doi.org/10.3390/ diagnostics12030595

Academic Editors: Lioe-Fee de Geus-Oei and F.H.P. van Velden

Received: 6 January 2022 Accepted: 19 February 2022 Published: 25 February 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

malignancies but causes a higher rate of fatalities in comparison to other deaths related to skin cancer [1]. Melanoma has a better prognosis if diagnosed early and survival tends to decrease once the disease has metastasized. The cost of managemen<sup>t</sup> of melanoma contributes significantly to public health and several strategies are being implemented worldwide to improve outcomes via prevention, assessing the at-risk population and improving managemen<sup>t</sup> strategies [1].

In the South African setting, a country with a diverse population, melanoma is commonly seen in fair-skinned people rather than darker individuals. A retrospective observational study done between 2005 and 2013 from the national cancer registry found that the incidence of melanoma was 2.7 per 100,000 [2]. The different population groups are affected by varying histological subtypes of melanoma, with the superficial spreading subtype being more common in fair individuals and the acral lentiginous subtype seen more in pigmented individuals [2].

Positron emission tomography (PET) with 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG) has been used extensively over the past two decades in staging and assessing responses to therapy in patients with melanoma; this has been due to a significant relationship between 18F-FDG uptake and glucose metabolism [3]. Flourodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) has been demonstrated to be more reliable in the assessment of survival prognosis in comparison to morphological staging. This is because 18F-FDG uptake demonstrates malignant potential, which has been associated with reduced survival [4].

18F-FDG uptake has been demonstrated as an excellent substrate in measuring the malignant potential for melanoma; when compared to immunohistochemistry, it demonstrated a positive correlation between glucose transporters (GLUT)-1 and GLUT-3, which is the mechanism that 18F-FDG uses to demonstrate malignant tissues in patients with melanoma [5].

The sensitivity, specificity and accuracy of 18F-FDG PET to detect metastatic and distant melanoma range from 70 to 100% [6]. The findings in 18F-FDG PET studies have been shown to better stage patients, guide further managemen<sup>t</sup> and provide a better prognosis of patients. This was demonstrated in a study by Reinhardt et al. whereby 250 patients imaged with 18F-FDG PET/CT demonstrated more nodal and visceral metastases in comparison to CT alone [6]. A smaller study in South Africa also demonstrated how 18F-FDG PET/CT altered staging in patients with malignant melanoma, which further changed the managemen<sup>t</sup> by treating physicians [7].

Recently, the use of metabolic parameters of 18F-FDG PET/CT has been investigated as a tool to risk-stratify patients and to determine prognostic value in patients prior to management, either by surgery or immune therapy, or to detect recurrence [8–11].

In this study, we investigated the association of metabolic parameters of 18F-FDG PET/CT in patients with melanoma undergoing restaging with overall survival.

## **2. Materials and Methods**

*2.1. Patients*

18F-FDG PET/CT scans of patients presenting for restaging of melanoma were retrospectively reviewed.

Patients were included in the study if they had a suspicion of recurrent or progressive disease as deemed by the referring clinician. The decision to refer a patient for an 18F-FDG PET/CT scan and the frequency of imaging were at the discretion of the managing physician. Patients were excluded if they had no disease demonstrable on 18F-FDG PET/CT, had advanced primary cancers other than melanoma, were below 18 years of age and had incomplete records.

This retrospective study was approved by the Research Ethics Committee, University of Pretoria (Reference no. 875/2020) and was carried out in accordance with the Declaration of Helsinki.

## *2.2. 18F-FDG PET/CT Imaging*

Imaging was acquired on a dedicated PET/CT scanner (Biograph 40, Siemens). Standard patient preparation was observed. All patients had a minimum of 4 h of fasting, blood sugar was ≤11.0 mmol/L and activity of 18F-FDG injected was calculated based on weight using the formula: [(body weight ÷ 10) + 1] × 37 MBq. Vertex-to-mid-thigh imaging was commenced after 60 min of uptake time. A separate lower limb imaging was done if the initial primary lesion was from the lower limb. PET acquisition was in 3D mode at 3 min per bed position. Except where a contraindication existed, CT was done with intravenous contrast using non-ionic contrast material (Omnipaque) injected at a rate of 2 mL/second. Images were reconstructed using OSEM (ordered subsets expectation maximization) to yield axial, sagittal and coronal slices of PET, CT and fused PET/CT images. Both attenuation-corrected and non-corrected images were reviewed for interpretation. CT data was used for the attenuation correction of PET data according to camera manufacturer specifications. A diagnostic CT with intravenous and/or oral contrast agents was done according to our departmental protocols and guidelines and was in line with EANM procedure guidelines, which were followed by our department [12].

#### *2.3. Image Interpretation and PET/CT Data Analysis*

Image interpretation was performed by two experienced nuclear medicine physicians. The reconstructed images were displayed on a dedicated workstation equipped with syngo software (Siemens Medical Solutions, Buffalo Grove, IL, USA).

A positive finding was defined as a focus of increased 18F-FDG uptake as compared with surrounding normal tissue corresponding to the primary tumor site and metastatic disease. Increased 18F-FDG uptake due to normal physiology or benign uptake was excluded from the analysis. Benign disease was characterized as a disease that did not anatomically represent metastatic disease, e.g., inflammatory lung changes.

Metabolic PET parameters (maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG)) of the primary tumor, as well as whole-body MTV and TLG of the metastatic disease, were measured. To obtain SUVmax, we drew a semi-automatic spherical volume of interest (VOI) around the primary tumor on PET images. We used an SUV threshold of 2.5 and a 3D isocontour of 41%. MTV and SUVmean were automatically computed by the software from the VOI. The TLG was calculated as the MTV multiplied by the SUVmean of the lesion (TLG = MTV × SUVmean). Whole-body MTV was calculated by adding the sum of all the VOI of the metastatic lesions (whole-body MTV = Σ (VOI of all metastatic lesions)), which were obtained on PET images. Whole-body TLG was calculated by adding the sum of all whole-body MTVs and SUVmeans of all the metastatic lesions (whole-body TLG = Σ (all whole-body MTVs and SUVmeans of all metastatic lesions)). 18F-FDG PET metabolic parameters were measured as previously described in our facility [13–15]. Findings on the images were verified using a combination of histological confirmation and medical records.

#### *2.4. Clinical Endpoints and Follow-Ups*

Overall survival was the time from PET/CT date to the date of death due to any cause or the last time the patient was known to be alive. Patient files were reviewed from the referral clinics that sent them for PET/CT. Overall survival was measured in months, as the patient follow-up in our institution is every 3 months, depending on the condition of the patient. Should patients need an additional follow-up, they may present earlier, and should their conditions remain stable, follow-up is increased to 6 monthly and yearly intervals.
