Unexpectedly Low FDG and FAPI Uptake in Mucosal Melanoma: Case Report with Literature Review

Introduction

Mucosal melanomas (MMs) originate from melanocytes in extracutaneous sites such as mucosal membranes of the respiratory, gastrointestinal, and urogenital tracts. In the head and neck, MM can arise from the mucosal lining of the nasal cavity, sinuses, and oral cavity, as well as from ocular melanocytes and leptomeninges.[1] These primary MMs are rare constituting 0.4%–2% of all malignant melanomas and 4%–10% of head-and-neck melanomas.[234] Their occult nature and late detection contribute to their poor prognosis.

Noncutaneous melanomas (NCMs) are categorized by origin: ocular, mucosal, or unknown primary. Ocular melanomas arise from the uvea or conjunctiva, while MMs can develop in various mucosal surfaces including the head-and-neck (oral cavity, nasal, and paranasal sinuses) and gastrointestinal and genitourinary tracts. NCMs, including ocular and MMs, collectively represent a small fraction of melanoma cases.[56] Unlike cutaneous melanomas, which are linked to sun exposure, the etiology of MM remains poorly understood due to their origin on sun-shielded mucosal linings.[7]

Melanomas typically exhibit high uptake of fluorine-18 fludeoxyglucose (18F-FDG), facilitating their detection via positron emission tomography/computed tomography (PET/CT) and aiding in the assessment of lymph node metastases.[8] 18F-FDG PET/CT has demonstrated superior sensitivity and specificity in detecting both visceral and nonvisceral metastases compared to conventional imaging methods, thereby influencing treatment decisions in a significant percentage of cases.[8]

18F-FDG PET/CT had 100% sensitivity and specificity for the detection of the primary.[9] Here, we report a case of MM notable for its lack of FDG avidity, which appears to be a rare phenomenon in the literature.

Case Report

A 22-year-old male patient came with complaints of blackish discoloration of the tongue for 5 years. No other specific complaints were present. On examination, a nodular lesion black in color was observed on the dorsal surface of the right half of the tongue, measuring approximately 6 cm × 4 cm [Figure 1]. 18F-FDG PET/CT scan was performed in suspicion of MM, which showed no obvious lesion in the tongue. A Gallium-68 fibroblast activation protein inhibitor 46 (Ga-68 FAPI-46) PET/CT scan was also performed that demonstrated mild FAPI avidity of the lesion [Figure 2]. Biopsy was performed, and histopathological examination along with immunohistochemistry confirmed the diagnosis of MM [Figure 3].

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Figure 1 Image showing black-colored nodular lesion with irregular margins on the dorsal surface of the tongue measuring approximately 6 cm × 4 cm

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Figure 2 Fluorine-18 fludeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) maximum intensity projection (MIP) (a) and axial PET (b) and fused PET/CT (c) images, along with sagittal PET (f) and fused PET/CT (g) images, showing no abnormal FDG avid on the dorsal surface of the tongue. Gallium-68 fibroblast activation protein inhibitor (FAPI) PET/CT MIP (e), axial (d), and sagittal (h) fused PET/CT images showing mild FAPI avidity of the lesion (white arrow)

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Figure 3 Images (H and E, ×100 (a) and ×400 (b)) showing tumor composed of submucosal sheets of large pleomorphic and typically a discohesive population of large malignant melanocytes with prominent nucleoli and cytoplasmic melanin pigments. IHC images (c) demonstrating cytoplasmic positivity for Melan A in malignant melanocytes

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Discussion

Unlike cutaneous melanomas, which predominantly arise from the sun-exposed skin, the pathogenesis of MM remains less understood due to their occurrence in sun-protected mucosal linings. This distinct anatomical location contributes to their late detection and poor prognosis compared to cutaneous melanomas.[7]

18F-FDG PET/CT plays a pivotal role in the management of melanomas by detecting primary lesions, evaluating lymph node involvement, and assessing distant metastases. The high FDG avidity typically observed in melanoma cells, driven by increased glucose metabolism, supports the sensitivity of 18F-FDG PET/CT in detecting melanoma lesions and influencing treatment decisions.[10] Cutaneous melanoma exhibits elevated levels of cancer-associated fibroblasts (CAFs), which are influenced by external factors such as prolonged exposure to ultraviolet rays. This leads to high FAPI expression in cutaneous melanomas. However, this mechanism might not be consistent in cases of MM, leading to varying levels of FAPI uptake.[11]

In our presented case, we describe a patient diagnosed with MM where FDG avidity was notably absent in the lesion. This atypical finding challenges the conventional expectation of high FDG uptake in melanomas and raises important considerations regarding the interpretation of 18F-FDG PET/CT in MMs. The absence of FDG avidity and mild FAPI avidity in our case suggests potential biological differences in glucose metabolism and CAFs expression within MMs compared to cutaneous counterparts.

Studies have implicated the role of glucose transporter (GLUT) proteins, particularly GLUT receptors, in facilitating FDG uptake in various cancers, including melanomas.[12] These receptors play a crucial role in transporting glucose into tumor cells, where it undergoes phosphorylation and traps FDG, thus enabling its detection via PET imaging. Furthermore, factors such as cell viability and rate of cell proliferation, as well as hexokinase expression, were directly responsible for glucose uptake.[13]

Genetic studies have highlighted differences between cutaneous and MMs, with mucosal variants showing a lower frequency of B-rapidly accelerated fibrosarcoma and N-rat sarcoma mutations but higher rates of SF3B1 and tyrosine kinase receptor (KIT) mutations.[1415] These genetic variations could influence GLUT expression and metabolic activity, potentially contributing to the observed variability in FDG uptake patterns seen in clinical practice.[16]

Clinically, the absence of radiotracer avidity complicates the accurate staging and management of MMs, as PET/CT imaging forms a cornerstone in treatment planning and monitoring response to therapy. This underscores the importance of integrating clinical, radiological, and molecular data to tailor individualized treatment strategies for patients with MMs.

Further research is warranted to elucidate the biological mechanisms underlying CAF expression and FDG uptake variability in MMs, including the specific roles of GLUT receptors and their molecular pathways. Investigating factors such as tumor microenvironment, molecular subtype, and glucose metabolism pathways may provide insights into optimizing imaging protocols and improving diagnostic accuracy in this challenging malignancy.

In conclusion, while PET/CT imaging remains indispensable in the management of melanomas, including mucosal variants, our case highlights the nuanced interpretation required when FDG avidity is unexpectedly absent. This emphasizes the evolving landscape of personalized medicine and the ongoing need for comprehensive multidisciplinary approaches in the care of patients with MMs.

Conclusion

This case underscores the variability in FDG and FAPI avidity observed in MMs, despite their typically high uptake of the radiotracer. Further research is warranted to understand the underlying factors contributing to such variability and its implications for diagnostic imaging and treatment planning in these rare and challenging malignancies.