Targeted diagnostics and therapy in salivary gland adenoid cystic carcinoma

INTRODUCTION 

Adenoid cystic carcinoma (AdCC) is a rare and aggressive salivary gland malignancy characterised by slow growth, perineural invasion, and an unpredictable clinical course. Diagnosis on biopsies is challenging due to overlapping features with other tumours, necessitating novel biomarkers and advanced molecular techniques. Locoregional control at ten years has improved significantly over recent decades to nearly 60%, while disease-free survival remains around 50%, largely due to the frequent occurrence of distant metastases. Local recurrences are difficult to treat due to the effects of prior surgeries and radiotherapy. This thesis focuses on integrating diagnostic biomarkers, targeted imaging, and therapies to gain new insights into the pathogenesis, diagnosis, and treatment of AdCC.

PART A: Biomarkers

Chapters 2, 3, and 4 explore the biomarkers myeloblastosis gene (MYB), chemokine receptor type 4 (CXCR4), and prostate-specific membrane antigen (PSMA). The fusion of MYB with nuclear factor I B-type (NFIB), an oncogenic translocation that influences cell proliferation and apoptosis, is pathognomonic for AdCC and observed in 56% of tumours. MYB immunohistochemistry offers a fast and cost-effective alternative to FISH for detecting this translocation, with a 60% MYB-expression cutoff providing 100% specificity and positive predictive value. CXCR4, involved in cell migration and metastasis, is expressed in 81% of tumours, where >25% expression predicts a 7.2-fold increased risk of recurrence. PSMA, a type II transmembrane glycoprotein and key theranostic biomarker in prostate cancer where it correlates with tumour grade and stage. It is expressed in 94% of primary AdCCs, 80% of recurrences, and 90% of metastases, with median staining of 31%, 60%, and 23%, respectively. Its intracellular localisation makes PSMA suitable for targeted imaging and radionuclide therapy.

PART B: Targeted Imaging

Chapter 5 presents an anatomical atlas mapping physiological PSMA PET/CT uptake in salivary glands to provide reference values that differentiate physiological from pathological uptake. Chapter 6 contains the first study to evaluate PSMA PET/CT in AdCC patients. PSMA PET/CT demonstrated a median SUVmax of 2.52 for recurrences and 4.01 for metastases. The study showed that PSMA PET/CT matched the sensitivity of FDG PET/CT but outperformed it in imaging distant metastases and lesions obscured by physiological uptake or high localised FDG metabolism, particularly in recurrences or metastases near or in the skull base.

PART C: Targeted Therapy

Chapter 7 describes PSMA-radionuclide therapy in six patients with advanced AdCC. The response was limited: two patients experienced stable disease (up to 10 months), while others reported symptom relief despite disease progression. The median survival after initiating therapy was six months.

CONCLUSION

This thesis focuses on the diagnosis and treatment of AdCC by adopting a theranostic approach, contributing to new personalized treatment strategies. The findings offer hope for patients with this difficult-to-treat malignancy, particularly when alternative treatments are exhausted, and contribute to improved prognosis and quality of life. The research highlights the need for large validation studies and lays the foundation for innovations and applications in other salivary gland malignancies.