Adenoid cystic carcinoma (ACC) is a rare form of cancer that typically arises in the salivary glands, though it can also originate in other secretory gland sites like the trachea or lacrimal gland. This malignancy is characterized by a relatively slow growth pattern but a relentless tendency to recur and spread over many years. A diagnosis of Stage 4 indicates that the cancer has metastasized, meaning it has spread from the original site to distant organs in the body. Managing this advanced stage requires a comprehensive strategy that combines whole-body systemic treatments with targeted local interventions.
Defining Metastatic Adenoid Cystic Carcinoma
Stage 4 ACC is defined by distant metastasis, meaning cancer cells have traveled through the bloodstream or lymphatic system to establish new tumor sites far from the primary location. Unlike many other cancers, ACC uncommonly spreads to regional lymph nodes, occurring in only about 5% to 10% of cases. The most frequent distant sites for ACC metastasis are the lungs, often appearing as multiple, slow-growing nodules, followed by the liver and bone.
ACC is characterized by a high propensity for perineural invasion, where cancer cells migrate along nerve fibers. This microscopic spread makes complete surgical removal challenging and explains the high local recurrence rate and eventual distant spread. Pathologically, ACC is often associated with the MYB-NFIB fusion gene, a chromosomal rearrangement present in a large percentage of cases that drives the cancer’s growth. The diagnosis of distant spread shifts the treatment goal from curative local therapy to long-term systemic disease control and symptom management.
Current Systemic Treatment Approaches
Systemic treatment focuses on therapies that can reach cancer cells throughout the body to control the overall tumor burden. Traditional cytotoxic chemotherapy has shown modest effectiveness in ACC, with objective response rates generally not exceeding 20% to 33%, even with platinum-based combinations. Chemotherapy regimens, such as those including a platinum agent like cisplatin, are typically reserved for patients with rapidly progressing or highly symptomatic disease, serving a palliative rather than a curative purpose.
Targeted therapies aim to interrupt specific molecular pathways driving ACC growth. While the MYB-NFIB fusion protein and the C-KIT receptor are common targets, clinical responses to agents targeting these pathways have been variable. Tyrosine Kinase Inhibitors (TKIs) that target the Vascular Endothelial Growth Factor Receptor (VEGFR), such as lenvatinib or axitinib, are preferred options. These agents interfere with the blood vessel formation tumors need to grow and have demonstrated activity in controlling disease progression for some patients.
The NOTCH signaling pathway is relevant in metastatic ACC, with activating NOTCH1 mutations found in a subset of cases. These mutations are associated with more aggressive disease behavior, making them a therapeutic target. Inhibitors designed to block NOTCH signaling have shown promise in clinical trials, resulting in disease control—either a partial response or stable disease—for a significant number of patients. Given the rarity of ACC and the lack of a single standard-of-care systemic agent, participation in clinical trials evaluating novel targeted agents or immunotherapy combinations is often recommended.
Targeted Localized Management
Localized treatments play an important role in controlling specific tumor sites and alleviating symptoms. These interventions are not intended to cure Stage 4 disease but rather to improve quality of life and prevent local complications. Stereotactic Body Radiation Therapy (SBRT), which delivers high doses of radiation with extreme precision over a few sessions, is frequently used. SBRT treats isolated, slowly growing lung metastases or painful bone lesions, offering high rates of local tumor control while sparing surrounding healthy tissue.
Surgery may be considered in highly selected cases, particularly for patients with oligometastatic disease (only a few isolated metastatic sites). Pulmonary metastasectomy, the surgical removal of lung metastases, is a viable option when a complete resection is achievable and the patient had a long disease-free interval before metastasis appeared. Surgery may also be necessary to address urgent local problems, such as removing a tumor causing severe airway obstruction or spinal cord compression.
Prognosis and Supportive Care
The prognosis for Stage 4 ACC is highly variable, largely due to the cancer’s characteristically slow growth rate, which distinguishes it from most other metastatic malignancies. While five-year survival rates can be relatively high, long-term survival diminishes over time. The median survival time after the appearance of distant metastases can range significantly, but many patients live for several years with controlled disease.
The primary focus of care for metastatic ACC is maintaining the highest possible quality of life alongside anti-cancer treatment. Comprehensive supportive care, also known as palliative care, should be introduced early in the disease course, as it is not reserved only for end-of-life care. A supportive care team, including specialists in pain management, nutrition, and mental health, addresses the physical and emotional burdens of the disease.
Managing pain is important, particularly due to the cancer’s tendency for perineural invasion, which causes neuropathic pain. This type of pain often requires specialized treatment with adjuvant analgesics, such as anti-seizure medications or certain antidepressants, in addition to standard pain relievers. Psychological support, including counseling and behavioral strategies like relaxation and imagery, helps patients and families cope with the stress and uncertainty associated with an advanced cancer diagnosis.