Association of Tumor Metabolic Activity on PET/CT Scan with Pathological Characteristics in Patients with Malignant Melanoma

authors:

avatar Mohammad Reza Erfaghi 1 , avatar Abtin Doroudinia ORCID 1 , * , avatar Mehrdad Bakhshayesh Karam 1 , avatar Habib Emami ORCID 1

Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran

how to cite: Erfaghi M R, Doroudinia A, Bakhshayesh Karam M, Emami H. Association of Tumor Metabolic Activity on PET/CT Scan with Pathological Characteristics in Patients with Malignant Melanoma. I J Radiol. 2022;19(2):e122258. https://doi.org/10.5812/iranjradiol-122258.

Abstract

Background:

Melanoma is one of the most serious types of skin cancer and one of the leading causes of cancer-related mortality worldwide.

Objectives:

This study aimed to investigate the association between 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) scan findings and the pathological characteristics of primary tumors in patients with malignant melanoma.

Patients and Methods:

In this cross-sectional study, the baseline data of 103 patients with cutaneous or mucosal melanoma (stage III or IV) were recorded, and tumor characteristics and PET/CT scan findings were analyzed. The association between each pathological finding and PET/CT results was also investigated.

Results:

Patients without a free margin had a significantly higher mean standardized uptake value (SUVmax) of lung metastasis compared to patients with a free margin (3.12 vs. 1.69; P = 0.047). Also, patients with ulceration had a significantly higher mean SUVmax of lung metastasis compared to patients without ulceration (3.28 vs. 1.81; P = 0.041). Based on the results, increased primary tumor thickness was associated with a higher SUVmax of lung metastasis. However, there was no significant association between the metastasis type (single vs. multiple) and free margin, ulceration, or Ki-67 protein. The mean SUVmax of lung metastasis was significantly higher in mucosal melanoma compared to cutaneous melanoma. However, the mean SUVmax values of other metastases (bone, liver, and lymph nodes), even the primary lesion itself, were not significantly different between cutaneous melanoma and mucosal melanoma.

Conclusion:

The primary tumor margin status, ulceration, tumor thickness, primary tumor location (cutaneous vs. mucosal), and the presence of lung metastasis were significantly associated with PET/CT scan findings.

1. Background

Malignant melanoma is a well-recognized mucosal or cutaneous malignancy, with a high potential for an extensive and unexpected metastasis to different organs (1). The current staging/restaging methods are based on the lesion thickness, lymph node involvement, and metastatic status. Different imaging modalities, such as computed tomography (CT) scan, magnetic resonance imaging (MRI), and recently positron emission tomography/CT (PET/CT) scan, have been used as significant diagnostic tools, especially for more advanced diseases (stage III/IV) (2).

The survival rate of patients with malignant melanoma depends on the size and depth of the lesion, as well as the presence of regional and/or distant metastasis (3-5). Advanced malignant melanoma refers to stage III/IV of the disease according to the American Joint Committee on Cancer (AJCC) criteria and includes melanoma with nodal and/or distant metastasis (6, 7). Lymph node and distant metastases may be identified by clinical examination, sentinel lymph node biopsy (SLNB), and imaging techniques. Overall, early diagnosis and treatment can significantly improve prognosis and survival (8, 9).

18F-fluorodeoxyglucose (FDG) PET/CT scan is based on the evaluation of cellular metabolism; the higher glucose metabolism of cancer cells compared to normal cells can be very helpful in the detection of tumor lesions (10). FDG PET/CT scan is now considered a standard method for the initial diagnosis, staging, treatment planning, evaluation of treatment response, and tumor restaging after treatment for many cancers (11). Recent evidence suggests that FDG PET/CT parameters, including the maximum standardized uptake value (SUVmax), are associated with the prognosis of different malignancies. Although FDG PET/CT may be considered an ideal method for the detection of melanoma metastasis, there is still controversy regarding its clinical application. Some studies have demonstrated that FDG PET/CT is a sensitive and accurate method for staging of advanced melanoma (10, 12, 13). There are also few studies evaluating the association between pathological features and FDG PET/CT findings in patients with advanced melanoma (14). pathological features and immunohistochemical (IHC) markers have been integrated in melanoma staging, disease prognosis, and selection of new treatments (15, 16). Therefore, it can be interesting to determine the association between pathological features and FDG PET/CT findings.

2. Objectives

This study aimed to investigate the association between FDG PET/CT scan findings and tumor pathological features in patients with malignant melanoma.

3. Patients and Methods

In this cross-sectional study, the baseline information of adult patients (age > 18 years) with a definitive diagnosis of cutaneous or mucosal melanoma (stage III or IV according to the pathological findings and the AJCC criteria), who were admitted to Masih Daneshvari Hospital (Tehran, Iran) for FDG PET/CT scan during 2016 - 2021, was collected by reviewing their medical records. The demographic information of all patients, including age and sex, as well as their medical history, was also retrieved. The inclusion criteria were as follows: (1) age over 18 years; (2) a definitive diagnosis of advanced melanoma stage III or IV according to the AJCC criteria, confirmed by a histological evaluation; (3) availability of pathological and FDG PET/CT scan findings; and (4) a signed informed consent form. On the other hand, patients who met the following criteria were excluded from the study: (1) a concomitant malignancy or a history of malignancy in the last 10 years; (2) a history of systemic treatment for melanoma or metastasectomy; and (3) unwillingness to continue the study at any stage. The variables under study included age, sex, cutaneous versus mucosal lesions, primary tumor thickness, ulceration, tumor margin, metastasis, Ki-67, and SUVmax.

All PET/CT images were acquired using a Discovery 690 VCT system (GE Healthcare, Milwaukee, USA), equipped with a 64-slice CT scanner (LightSpeed VCT, GE Healthcare, Milwaukee, USA). The calculation of SUVmax was automatically performed on a 4.5 advantage PET/CT workstation in the defined region of interest (ROI) for all lesions. Finally, the association between each pathological feature and FDG PET/CT findings was investigated. This study was approved by our institutional review board (IRB) with the ethical code, IR.SBMU.MSP.REC.1399.564.

3.1. Statistical Analysis

Data were analyzed using SPSS version 22 (released in 2013, IBM SPSS Statistics for Windows, IBM Corp., Armonk, NY, USA). Frequency was calculated for qualitative variables, such as cutaneous versus mucosal lesions, ulceration, tumor margin, and metastasis, and for quantitative variables with a normal distribution, such as the primary tumor thickness, Ki-67, and SUVmax, the mean and standard deviation (SD) were calculated; the median value was compared if the distribution was not normal. Besides, the association of SUVmax and the frequency of metastases with the lesion size and diameter was examined using Pearson’s correlation test. The mean values of the two groups were compared using Student’s t-test and Mann-Whitney test. For multiple-group comparisons, one-way analysis of variance (ANOVA) or Kruskal-Wallis test (or median test) was used for parametric or non-parametric data, respectively. A P-value less than 0.05 was considered statistically significant.

4. Results

A total of 103 patients with malignant melanoma were included in this study, with a mean age of 54.7 ± 16.99 years. Sixty-four patients (62.1%) were male, and 39 (37.9%) patients were female. The baseline demographic and clinical characteristics of the patients are presented in Table 1.

Table 1.

The Basic Demographic and Clinical Characteristics of the Patients

FactorsNo. (%)
Sex
Male64 (62.1)
Female39 (37.9)
Reasons for PET scan
Initial staging24 (23.3)
Metastatic evaluation46 (44.7)
Recurrence2 (1.9)
Treatment response11 (10.7)
Restaging20 (19.4)
Primary tumor location
Sinus5 (5.0)
Limb67 (67.0)
Anal4 (4.0)
Eye4 (4.0)
Scalp11 (11.0)
Mouth2 (2.0)
Chest2 (2.0)
Esophagus 1 (1.0)
Abdomen3 (3.0)
Vagina1 (1.0)
Primary location
Cutaneous 83 (83.0)
Mucosal 17 (17.0)
Brain metastasis
Yes2 (2.0)
No100 (98.0)
Bone metastasis
Yes13 (12.7)
No89 (87.3)
Lung metastasis
Yes49 (48.0)
No53 52.0 ()
Liver metastasis
Yes11 (10.8)
No91 (89.2)
Regional lymph node metastasis
Yes66 (65.3)
No35 (34.7)
Other metastases
Yes48 (48.0)
No52 (52.0)
Metastasis type
No metastasis18 (17.6)
Single metastasis24 (23.5)
Multiple metastases60 (58.8)
Type of pathology
Nodular16 (34.0)
Acral lentiginous melanoma25 (53.2)
Superficial1 (2.1)
Spindle2 (4.3)
Epithelioid2 (4.3)

The most common pathological types were acral lentiginous melanoma and nodular melanoma with frequencies of 53.2% and 34%, respectively. The mean thickness of the primary tumor was 5.03 mm, and the mean mitotic rate was 3.32 per mm3. In most cases (44.7%), the reason for FDG PET/CT request was metastasis evaluation. Lymph node metastasis was the most common type of metastasis, as reported in 65.3% of cases. The prevalence of bone, liver, and brain metastases was also estimated at 12.7%, 10.8%, and 2%, respectively. More than half of the patients (58.8%) had multiple metastases. The metastasis data were presented based on the current PET/CT findings, and no previous data were included. The mean SUVmax values for metastases and pathological features are shown in Table 2. There was a significant association between the SUVmax of lung metastasis and the primary tumor thickness (P = 0.029). Associations between the pathological features and the SUVmax of primary tumor and metastasis, based on Spearman’s test, are described in Table 3.

Table 2.

The Mean SUVmax for Each Metastasis and Pathological Feature

ParametersValid NMean ± SDMedian25th percentile75th percentile
Age10254.70 ± 16.9956.5042.0068.00
SUVmax of involvement in the primary lesion 637.89 ± 5.836.103.2010.50
SUVmax of brain metastasis0----
SUVmax of bone metastasis125.50 ± 5.714.350.009.00
SUVmax of lung metastasis872.80 ± 4.270.000.004.20
SUVmax of liver metastasis830.76 ± 2.850.000.000.00
SUVmax of regional lymph node metastasis1003.80 ± 4.942.750.005.85
Primary tumor thickness (mm)555.03 ± 7.614.001.605.00
Mitotic rate253.32 ± 4.331.001.004.00
IHC marker: Ki-672220 ± 2020130
Table 3.

Association Between Pathological Features and SUVmax of Primary Tumor and Metastasis

VariablesSUVmax of involvement in the primary PETSUVmax of bone metastasisSUVmax of lung metastasisSUVmax of liver metastasisSUVmax of regional lymph node metastasis
Spearman’s correlation
N62128581100
Primary tumor thickness (mm)
Correlation coefficient0.2320.2890.3160.1530.117
P-value0.2160.6370.029 a0.3170.397
N305484555
Mitotic rate
Correlation coefficient-0.250-0.014-0.2710.015
P-value0.4100.9560.2760.943
N131191825
IHC marker: Ki-67
Correlation coefficient0.039-1.000 b0.0700.273
P-value0.900NA0.7890.230
N133171521

The analysis of the association between the SUVmax and free margin revealed a significant association between the SUVmax of lung metastasis and free margin (P = 0.047). In other words, patients without a free margin had a significantly higher mean SUVmax of lung metastasis compared to patients with a free margin (3.12 vs. 1.69; P = 0.047). Regarding the association between the SUVmax and ulceration, a significant relationship was found between the SUVmax of lung metastasis and ulceration (P = 0.041). In other words, patients with ulceration had a significantly higher mean SUVmax of lung metastasis compared to patients without ulceration (3.28 vs. 1.81; P = 0.041). However, no significant association was observed between the SUVmax of each metastasis and regional lymph node involvement.

Moreover, the associations between the primary tumor location and pathological features are shown in Table 4. There was a significant association between the primary tumor location and the primary tumor thickness (P = 0.021). In other words, the mean primary tumor thickness in patients with mucosal involvement was significantly higher than that of patients with skin involvement (15.60 vs. 3.97; P = 0.021). In contrast, the mean Ki-67 index was significantly higher in patients with skin involvement compared to patients with mucosal involvement (22.0 vs. 1.0; P = 0.008). Nevertheless, no significant association was observed between the primary tumor location (cutaneous vs. mucosal) and the tumor mitotic rate.

Table 4.

The Association Between the Primary Tumor Location and Pathological Features

VariablesPrimary locationP-Value a
CutaneousMucosal
Valid NMean ± SDMedianValid NMean ± SDMedian
Primary tumor thickness (mm)503.97 ± 4.473.00515.60 ± 19.609.000.021 a
Mitotic rate243.42 ± 4.391.0011.001.000.401
IHC marker: Ki-672022 ± 202021 ± 010.008 a

Considering the association between the metastasis type (no metastasis vs. single or multiple metastases) and pathological features, no significant association was found between the metastasis type and free margin, ulceration, or Ki-67 index. Associations between the metastasis type and pathological features are demonstrated in Table 5.

Table 5.

Association Between Metastasis Type and Pathological Features

VariablesMetastasis typeP-Value
No metastasisSingle metastasisMultiple metastases
Valid NMean ± SDMedianValid NMean ± SDMedianValid NMean ± SDMedian
Primary tumor thickness (mm)93.26 ± 1.974.00112.74 ± 1.513.00356.21 ± 9.304.000.322
Mitotic rate52.80 ± 2.172.0053.20 ± 3.901.00153.53 ± 5.131.000.887
IHC marker: Ki-67614 ± 1410522 ± 21301025 ± 24200.659

Moreover, the relationship between the primary tumor location and the SUV values of primary tumor and metastases is shown in Table 6. The mean SUVmax of lung metastasis was significantly higher in mucosal melanoma compared to cutaneous melanoma. However, the mean SUVmax values of other metastases (bone, liver, and lymph node), and even that of the primary lesion itself, were not significantly different between the two groups (Figures 1 & 2).

Table 6.

Association Between the Primary Tumor Location and SUV of Primary Tumor and Metastasis

VariablesPrimary locationP-value
CutaneousMucosal
Valid NMean ± SDMedianValid NMean ± SDMedian
SUVmax of involvement in the primary PET527.40 ± 5.495.85811.10 ± 7.688.100.123
SUVmax of lung metastasis104.03 ± 4.892.50212.85 ± 3.7512.850.049 a
SUVmax of bone metastasis702.61 ± 4.160.00153.38 ± 4.640.000.476
SUVmax of liver metastasis680.63 ± 2.350.00141.48 ± 4.690.000.401
SUVmax of regional lymph node metastasis823.33 ± 4.262.50156.80 ± 7.466.000.135
A, A lung tissue with interstitial infiltration of atypical cells with a clear cytoplasm; B, Some tumor cells are positive for S-100 protein; C, All cells are positive for human melanoma black-45 (HMB45) as a monoclonal antibody that reacts against an antigen in melanocytic tumors, such as melanomas; D, Some pigment deposition is present.
A, A lung tissue with interstitial infiltration of atypical cells with a clear cytoplasm; B, Some tumor cells are positive for S-100 protein; C, All cells are positive for human melanoma black-45 (HMB45) as a monoclonal antibody that reacts against an antigen in melanocytic tumors, such as melanomas; D, Some pigment deposition is present.
A very aggressive case of melanoma with extensive lung, liver, and lymph node metastases. The maximum intensity projection (MIP) image is on the left, and the selected axial and coronal images on the right are merged together.
A very aggressive case of melanoma with extensive lung, liver, and lymph node metastases. The maximum intensity projection (MIP) image is on the left, and the selected axial and coronal images on the right are merged together.

5. Discussion

This study aimed to investigate the association between FDG PET/CT findings and the pathological features of primary tumors in melanoma patients. The results revealed that patients with a free margin had a significantly lower SUVmax of lung metastasis compared to patients without a free margin. Patients with ulceration also had a significantly higher SUVmax of lung metastasis compared to those without ulceration. There was also a significant relationship between the SUVmax of lung metastasis and the primary tumor thickness. In other words, an increase in the primary tumor thickness was associated with a higher SUVmax of lung metastasis.

Moreover, the present findings demonstrated that patients with single metastasis and multiple metastases had higher SUVmax values than those without metastasis. A significant association was also observed between the location of melanoma lesion (cutaneous versus mucosal), the level of Ki-67 protein (an IHC marker), and the primary tumor thickness. These results indicate that increased tumor thickness, ulceration, and margin involvement on pathology reports are likely to be associated with higher SUVmax values, especially in lung metastases. Therefore, it can be interpreted that higher SUVmax values are potentially associated with more significant high-risk pathological features and a poorer prognosis.

A high SUV in lymph node metastasis is an independent negative prognostic factor for disease-free survival; however, it has no impact on the overall survival (17). In a previous study, Rasmussen et al. examined the association between the expression of IHC markers, including Bcl-2, β-tubulin-1 and 2, EGFR, Ki-67, and glutathione-s-transferase, and PET parameters in head and neck squamous cell carcinoma. They found a significant negative relationship between the SUVmax and the expression of Bcl2 and β-tubulin I and II. They concluded that there was a significant relationship between the expression of IHC parameters in primary tumors and FDG PET/CT results (18).

In another study, Bitencourt et al. evaluated the relationship between the expression of IHC biomarker and PET results in 50 patients with breast cancer. Their findings showed a significant positive relationship between the SUVmax and histology type, histology grade, molecular subtype, tumor diameter, mitotic index, and Ki-67 expression (19). It is generally accepted that some pathological features of melanoma patients are associated with positive FDG PET/CT findings. These pathological features include a mitotic rate > 3/mm2, tumor thickness > 4 mm, regional lymphadenopathy, and bleeding/ulceration (5, 20). PET is more useful in detecting distant metastasis than regional metastasis, given the established role of SLNB (21).

FDG PET/CT may be a highly useful tool for the surveillance of melanoma patients. For the follow-up of patients with advanced stage melanoma (stage III/IV), the National Comprehensive Cancer Network (NCCN) guidelines recommend imaging (including PET/CT) every three to 12 months to screen for recurrence or metastatic disease. However, routine imaging to screen asymptomatic cases is not recommended after three to five years (22). According to our literature review, few researchers have investigated the association between FDG PET/CT scan findings and pathological features of patients with malignant melanoma. This may be considered the novelty of our study, although we could only demonstrate few associations, and further studies are strongly recommended.

In conclusion, based on on the results of the present study, there may be an association between FDG PET/CT findings and some pathological features of melanoma patients. Factors, such as the primary tumor thickness, cutaneous versus mucosal tumor location, metastasis type, free margin, and ulceration, were significantly associated with PET/CT findings. Further multicenter and community-based studies are recommended with a larger sample size to obtain more reliable results.

References

  • 1.

    Leiter U, Eigentler T, Garbe C. Epidemiology of skin cancer. Adv Exp Med Biol. 2014;810:120-40. [PubMed ID: 25207363]. https://doi.org/10.1007/978-1-4939-0437-2_7.

  • 2.

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7-34. [PubMed ID: 30620402]. https://doi.org/10.3322/caac.21551.

  • 3.

    Balch CM, Soong SJ, Gershenwald JE, Thompson JF, Reintgen DS, Cascinelli N, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol. 2001;19(16):3622-34. [PubMed ID: 11504744]. https://doi.org/10.1200/JCO.2001.19.16.3622.

  • 4.

    Xing Y, Bronstein Y, Ross MI, Askew RL, Lee JE, Gershenwald JE, et al. Contemporary diagnostic imaging modalities for the staging and surveillance of melanoma patients: a meta-analysis. J Natl Cancer Inst. 2011;103(2):129-42. [PubMed ID: 21081714]. [PubMed Central ID: PMC3022618]. https://doi.org/10.1093/jnci/djq455.

  • 5.

    Schule SC, Eigentler TK, Garbe C, la Fougere C, Nikolaou K, Pfannenberg C. Influence of (18)F-FDG PET/CT on therapy management in patients with stage III/IV malignant melanoma. Eur J Nucl Med Mol Imaging. 2016;43(3):482-8. [PubMed ID: 26384681]. https://doi.org/10.1007/s00259-015-3187-2.

  • 6.

    Kalady MF, White RR, Johnson JL, Tyler DS, Seigler HF. Thin melanomas: predictive lethal characteristics from a 30-year clinical experience. Ann Surg. 2003;238(4):528-35. discussion 535-7. [PubMed ID: 14530724]. [PubMed Central ID: PMC1360111]. https://doi.org/10.1097/01.sla.0000090446.63327.40.

  • 7.

    Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Atkins MB, Byrd DR, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009;27(36):6199-206. [PubMed ID: 19917835]. [PubMed Central ID: PMC2793035]. https://doi.org/10.1200/JCO.2009.23.4799.

  • 8.

    Bronstein Y, Ng CS, Rohren E, Ross MI, Lee JE, Cormier J, et al. PET/CT in the management of patients with stage IIIC and IV metastatic melanoma considered candidates for surgery: evaluation of the additive value after conventional imaging. AJR Am J Roentgenol. 2012;198(4):902-8. [PubMed ID: 22451559]. [PubMed Central ID: PMC3880209]. https://doi.org/10.2214/AJR.11.7280.

  • 9.

    Perng P, Marcus C, Subramaniam RM. 18F-FDG PET/CT and Melanoma: Staging, Immune Modulation and Mutation-Targeted Therapy Assessment, and Prognosis. AJR Am J Roentgenol. 2015;205(2):259-70. [PubMed ID: 26204273]. https://doi.org/10.2214/AJR.14.13575.

  • 10.

    Petersen H, Holdgaard PC, Madsen PH, Knudsen LM, Gad D, Gravergaard AE, et al. FDG PET/CT in cancer: comparison of actual use with literature-based recommendations. Eur J Nucl Med Mol Imaging. 2016;43(4):695-706. [PubMed ID: 26519292]. [PubMed Central ID: PMC4764641]. https://doi.org/10.1007/s00259-015-3217-0.

  • 11.

    Goldschmidt N, Or O, Klein M, Savitsky B, Paltiel O. The role of routine imaging procedures in the detection of relapse of patients with Hodgkin lymphoma and aggressive non-Hodgkin lymphoma. Ann Hematol. 2011;90(2):165-71. [PubMed ID: 20706721]. https://doi.org/10.1007/s00277-010-1044-8.

  • 12.

    Bourgeois AC, Chang TT, Fish LM, Bradley YC. Positron emission tomography/computed tomography in melanoma. Radiol Clin North Am. 2013;51(5):865-79. [PubMed ID: 24010910]. https://doi.org/10.1016/j.rcl.2013.06.004.

  • 13.

    Veit-Haibach P, Vogt FM, Jablonka R, Kuehl H, Bockisch A, Beyer T, et al. Diagnostic accuracy of contrast-enhanced FDG-PET/CT in primary staging of cutaneous malignant melanoma. Eur J Nucl Med Mol Imaging. 2009;36(6):910-8. [PubMed ID: 19156409]. https://doi.org/10.1007/s00259-008-1049-x.

  • 14.

    Deckers EA, Kruijff S, Brouwers AH, van der Steen K, Hoekstra HJ, Thompson JF, et al. The association between active tumor volume, total lesion glycolysis and levels of S-100B and LDH in stage IV melanoma patients. Eur J Surg Oncol. 2020;46(11):2147-53. [PubMed ID: 32819759]. https://doi.org/10.1016/j.ejso.2020.07.011.

  • 15.

    Weide B, Elsasser M, Buttner P, Pflugfelder A, Leiter U, Eigentler TK, et al. Serum markers lactate dehydrogenase and S100B predict independently disease outcome in melanoma patients with distant metastasis. Br J Cancer. 2012;107(3):422-8. [PubMed ID: 22782342]. [PubMed Central ID: PMC3405231]. https://doi.org/10.1038/bjc.2012.306.

  • 16.

    Wong VK, Lubner MG, Menias CO, Mellnick VM, Kennedy TA, Bhalla S, et al. Clinical and Imaging Features of Noncutaneous Melanoma. AJR Am J Roentgenol. 2017;208(5):942-59. [PubMed ID: 28301211]. https://doi.org/10.2214/AJR.16.16800.

  • 17.

    Bastiaannet E, Hoekstra OS, Oyen WJ, Jager PL, Wobbes T, Hoekstra HJ. Level of fluorodeoxyglucose uptake predicts risk for recurrence in melanoma patients presenting with lymph node metastases. Ann Surg Oncol. 2006;13(7):919-26. [PubMed ID: 16788752]. https://doi.org/10.1245/ASO.2006.02.007.

  • 18.

    Rasmussen GB, Vogelius IR, Rasmussen JH, Schumaker L, Ioffe O, Cullen K, et al. Immunohistochemical biomarkers and FDG uptake on PET/CT in head and neck squamous cell carcinoma. Acta Oncol. 2015;54(9):1408-15. [PubMed ID: 26256482]. https://doi.org/10.3109/0284186X.2015.1062539.

  • 19.

    Bitencourt AG, Lima EN, Chojniak R, Marques EF, de Souza JA, Graziano L, et al. Correlation between PET/CT results and histological and immunohistochemical findings in breast carcinomas. Radiol Bras. 2014;47(2):67-73. [PubMed ID: 25741051]. [PubMed Central ID: PMC4337160]. https://doi.org/10.1590/S0100-39842014000200006.

  • 20.

    Danielsen M, Kjaer A, Wu M, Martineau L, Nosrati M, Leong SP, et al. Prediction of positron emission tomography/computed tomography (PET/CT) positivity in patients with high-risk primary melanoma. Am J Nucl Med Mol Imaging. 2016;6(5):277-85. [PubMed ID: 27766186]. [PubMed Central ID: PMC5069280].

  • 21.

    Wagner JD, Schauwecker D, Davidson D, Coleman III JJ, Saxman S, Hutchins G, et al. Prospective study of fluorodeoxyglucose-positron emission tomography imaging of lymph node basins in melanoma patients undergoing sentinel node biopsy. J Clin Oncol. 1999;17(5):1508-15. [PubMed ID: 10334538]. https://doi.org/10.1200/JCO.1999.17.5.1508.

  • 22.

    Kumar R, Alavi A. Clinical applications of fluorodeoxyglucose--positron emission tomography in the management of malignant melanoma. Curr Opin Oncol. 2005;17(2):154-9. [PubMed ID: 15725921]. https://doi.org/10.1097/01.cco.0000152626.98124.3a.