Navigating the Rare: ¹⁸F FDG PET/CT Reveals Uterine Metastasis from Cutaneous Melanoma

Introduction

Melanomas are among the most aggressive cancers, and a majority are resistant to treatment.[1] Their incidence is alarmingly increasing, currently with 0.9/100,000 population.[2] Although cutaneous melanomas are the most common (~95%), they can occur in any site harboring melanocytes. Metastatic melanoma with widespread disease signifies a poor prognosis and is the leading cause of death in these patients.[13] Patients typically present at stage I or II, without metastasis in approximately 90% of cases.[4] However, 4% of patients present with metastatic disease, with lymph node involvement being the most common initial site. Other sites of metastasis may include the lung, liver, brain, bone, heart, and gastrointestinal tract.[12] Metastasis of primary cutaneous melanoma to the uterine endometrium is a rare occurrence.[5] This report describes the case of a 55-year-old postmenopausal woman with primary cutaneous melanoma, in whom rare uterine metastasis was diagnosed using ¹⁸F- fluorodeoxyglucose (FDG) Positron Emission Tomography/ Computed Tomography (PET/CT).

Case Report

A 55-year-old woman presented with a skin ulcer on her right foot, subsequently diagnosed as primary cutaneous melanoma. The lesion was >4 mm thick with ulceration (T4b), for which a staging ¹⁸F FDG PET/CT was advised. The FDG PET/CT revealed a metabolically active primary lesion on the right calcaneum, a metastatic subcutaneous lesion on the middle third of the right leg, and involvement of retroperitoneal, pelvic, and popliteal lymph node groups. The patient was started on treatment with temozolomide for 6 months but was subsequently lost to follow-up. Two years later, she presented with vaginal bleeding, prompting a restaging ¹⁸F FDG PET/CT. The FDG PET/CT identified metabolically active disease in the right foot, chest wall, and lower anterior abdominal wall; thickening of the ileal loops; with metastatic abdominal, retroperitoneal, and perirectal lymph nodes. Notably, there was diffuse uterine involvement with intense FDG uptake [Figure 1]. These findings were highly suggestive of uterine metastasis, which was confirmed by endometrial biopsy. The patient was started on systemic chemotherapy but ultimately died from disease-related complications.

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Figure 1 Maximum intensity projection (MIP) image of the restaging ¹⁸F fluorodeoxyglucose-positron emission tomography/computed tomography (PET/CT) (a) Reveals a metabolically active lesion in the right foot (red arrow) with increased uptake in the abdomen and pelvis and a diffuse increased uptake in the pelvis (blue arrow). PET image, fused PET/CT image (b and c) and CT image (d) Revealed diffuse involvement of the entire bulky uterus with increased myometrial wall thickness, fused PET/CT images revealed metabolically active chest wall deposit (e), Thickening involving the ileal loops (f), Abdominal-retroperitoneal lymph nodes (g and h) and perirectal (i) and lower anterior abdominal wall deposits (j). The patient was started on chemotherapy, but she died due to complications

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Discussion

Melanoma, the most life-threatening skin cancer, is currently the 17^th most common cancer globally.[6] Its incidence has increased drastically over the last 50 years, attributed to multiple environmental and genetic risk factors.[7] It primarily affects young and middle-aged individuals, with a slight male predominance.[1] Melanomas arise from melanocytes, which are neural crest derivatives found not only in the skin but also in various noncutaneous sites.[3] Mucosal and uveal melanomas are considered more aggressive than primary cutaneous melanomas, as they present with metastasis in a significant proportion of cases (~30%).[1] Metastasis can occur within 2–5 years of primary tumor resection or present late after years of disease-free survival.[8]

Initially, approximately 90% of patients present at stage I or II without metastasis. However, recurrence occurs in approximately one-third of patients with stage II disease within 5 years.[4] The 10-year survival rate is >95% for stage I disease but falls to 10%–15% for stage IV.[9]

Normal melanocyte differentiation relies on signaling pathways such as the Wnt pathway and the c-kit receptor tyrosine kinase.[3] Numerous mutations are linked to melanoma pathogenesis, with germline mutations in BRAF, CDKN2A, and MITF being well-established.[10] Key determinants for metastasis risk include tumor thickness, sentinel lymph node status, patient age, and primary tumour location. Metastasis occurs not only to regional sites but also to distant viscera and nodes. The most common regional sites are the skin (satellite or in-transit lesions), subcutaneous tissues, and lymph nodes (~73%). Among distant sites, the lung is most commonly affected (~71%), followed by the liver and brain. Involvement of the adrenal glands, heart, pleura, bone, and gastrointestinal tract is less common.[13]

Metastatic involvement of the female genital tract from primary cutaneous melanoma is rarely reported. When it occurs, the cervix is the most common site, followed by the myometrium, with the endometrium being an exceptionally rare location.[7] The reason for this distribution remains unclear. Clinical presentation often includes postmenopausal or other abnormal uterine bleeding.[3]

Appropriate diagnostic modalities are crucial for effective management. Histopathology remains the gold standard for evaluating tumor thickness and differentiation. For clinically node-negative cases, sentinel lymph node biopsy is the standard for pathological staging. Ultrasound can be a superior imaging modality for detecting regional metastasis.[1112] ¹⁸F FDG PET/CT has become a standard tool for assessing distant metastasis, staging, restaging, and evaluating treatment response. A recent meta-analysis estimated a pooled sensitivity of ~88% and specificity of ~94%.[11] PET/CT offers superior diagnostic performance compared to CT and MRI, except for brain metastases.[12] NCCN guidelines recommend using this functional imaging modality to evaluate for disease recurrence in the follow-up of patients with stage IIB-IV disease. However, false–positive findings are possible, and predictive values can be improved by considering relevant clinical characteristics.[13]

The treatment of melanoma includes surgical excision of the primary neoplasm and involved lymph nodes. Metastasectomy, radiotherapy, and systemic therapies — including tyrosine kinase inhibitors, antivascular endothelial growth factor inhibitors, combined chemotherapy, and immune checkpoint inhibitors (anti-PD-1 and anti-CTLA-4) – are now in clinical use.[14] Targeted therapies, such as those involving toll-like receptors and cytokines, are under evaluation. Organ-specific metastases are treated accordingly; in cases of uterine metastasis with uncontrolled bleeding, a hysterectomy may be necessary.[7] While treatment outcomes have greatly improved with the advent of immunotherapy and targeted therapy, challenges remain, particularly regarding treatment resistance in advanced melanoma.[15]

Conclusion

Uterine metastasis from cutaneous malignant melanoma is an exceptionally rare event, highlighting the aggressive and unpredictable nature of this cancer. ¹⁸F FDG PET/CT is an essential diagnostic modality for identifying such uncommon metastatic sites, providing high sensitivity and specificity for staging, restaging, and assessing treatment response. This case underscores the vital role of advanced imaging in guiding clinical decisions and tailoring treatment approaches for individuals with advanced melanoma. Increased clinical awareness of unusual metastatic locations, such as the uterus, is crucial for timely diagnosis and management. Future research should focus on optimizing imaging protocols and exploring novel therapeutic strategies to improve outcomes for patients with rare metastatic presentations of melanoma.