Lacrimal gland adenoid cystic carcinoma (ACC) is a rare and aggressive cancer that originates in the lacrimal gland, which is responsible for tear production.¹ Characterised by a poor prognosis, ACC often recurs and metastasizes despite treatment. While treatment strategies vary, a combination of surgery and radiotherapy is generally considered the standard approach. However, due to the infiltrative nature of the tumour, it remains difficult to manage and is associated with a challenging long-term outlook.

The lacrimal gland plays a crucial role not only in tear formation but also in eye protection and immune defence through the secretion of antibodies. Tumours of the lacrimal gland account for about 10% of all space-occupying orbital tumours, with 60% of malignant cases being adenoid cystic carcinoma.² In this article, we will address early detection and treatment which are critical to improving outcomes, as ACC’s aggressive behaviour can lead to significant complications, including recurrence and metastasis.

Anatomy and function of the lacrimal gland

Structure of lacrimal gland

The lacrimal glands are located in each eye socket, just beneath the upper eyelid, and are typically symmetrical in a healthy individual.^3,4 These small, almond-shaped glands consist of two lobes: the orbital lobe, which is larger, and the palpebral lobe, which is smaller. The two lobes are connected by a network of ducts, blood vessels, and nerves. The primary role of the lacrimal glands is to produce tears, which are essential for maintaining eye health. The fluid they produce acts as a protective barrier, keeping the eye moist and shielding it from foreign particles like dirt, pollen, and other potential irritants.⁴

Normal function and tear production

The lacrimal gland's primary function is to secrete the watery layer of the eye's tear film, which is composed of water, proteins, vitamins, and electrolytes.⁴ Tears produced by the lacrimal glands are released through small openings called puncta located in the inner corner of the eyelids. From there, the tears spread across the surface of the eye with each blink. Additionally, the lacrimal gland responds to environmental stimuli (such as wind or irritants) by producing reflex tears, which help to protect and lubricate the eye in response to external factors. This tear production is vital not only for comfort but also for maintaining the eye’s health and function.^4,5

Pathogenesis and aetiology

Cellular origin and histopathology

The development of tissues in mammals, including the lacrimal gland, involves complex interactions between two main types of cells, the epithelial and mesenchymal cells. The lacrimal gland is derived from three distinct cell lineages: immune, epithelial, and mesenchymal.^4,5 As a tubular organ, its formation depends on interactions between epithelial and mesenchymal tissues, though these processes are not yet fully understood. During the gland’s development, the protein BMP7 plays a key role in facilitating the branching of the gland, contributing to its structure and function.³

Genetic and molecular factors

Research on the genetic and molecular mechanisms behind ACC remains limited, making it difficult to fully understand why the prognosis of these lesions varies.⁶ However, a common genetic feature of this carcinoma is the t(6,9) translocation, a genetic rearrangement where pieces of chromosomes 6 and 9 fuse. This fusion leads to the creation of the MYB-NFIB gene, which is implicated in the tumour's development. The MYB gene is a proto-oncogene, meaning it can drive cancer development when mutated, and regulates cellular processes such as proliferation and differentiation. Meanwhile, the NFIB gene influences cellular division, differentiation, and viability, contributing to the growth of the cancer.⁶

Risk factors and predisposing conditions

The risk factors for lacrimal gland adenoid cystic carcinoma are not yet well established, though studies suggest that smoking and excessive alcohol consumption may increase the risk.² It is important to note that the presence of these risk factors does not guarantee the development of the condition, but it may elevate the likelihood compared to individuals without such risks. This carcinoma is most commonly diagnosed in middle-aged and older adults, with an average age of around 55 years. The condition is slightly more prevalent in females than males, with a female-to-male ratio of 3:2. No significant predisposition has been noted for any particular ethnic or racial group.^2,7

Clinical presentation and symptoms

ACC is a slow-growing tumour that is often painless in its early stages, which can lead to a delayed presentation of symptoms, sometimes for several months or even years. The tumour may remain asymptomatic for long periods, with individuals only noticing symptoms after it has grown for five years or more.¹ 

In the initial stages, it typically grows slowly, but there may be instances of sudden growth. As the tumour progresses and invades surrounding tissues and nerves, it can cause pain, numbness, and tingling sensations. In later stages, a single mass or swollen lump may be visible, often located above the eye, and usually affecting only one eye. Other symptoms that may arise include:^1,2

• Headaches
• Red eye
• Dry eye due to reduced tear production
• Partial loss of vision
• Pain, numbness, or tingling sensations (paraesthesia)

Large tumours may ulcerate, bleed, and become increasingly painful. Differential diagnoses for adenoid cystic carcinoma include pleomorphic adenoma, a benign but potentially malignant tumour that can present similarly and may involve bony structures upon imaging. Other conditions that must be considered in the differential diagnosis include:²

• Lymphoma
• Chronic dacryoadenitis
• Sarcoidosis
• Reactive lymphoid hyperplasia
• Sjögren’s syndrome
• Lipogranuloma
• Dacryops

and other malignant epithelial tumours of the lacrimal gland.²

Diagnosis

ACC of the lacrimal gland typically affects adults around the age of 40, with a slight predominance in individuals assigned female at birth, although it is rare in children. The diagnosis is usually made within six months of symptom onset, with early signs often being:^1,2

• Proptosis (bulging of the affected eye)
• Inferior eye deviation (more noticeable towards the nose)
• Pain (especially in larger tumours, which distinguishes malignant from benign tumours)
• Nerve invasion (causing sensory loss)
• Other symptoms that may be present include:
  • Blepharoptosis (drooping eyelid)
  • Double vision
  • Difficulty with eye movements

Imaging studies are essential for confirming the diagnosis, with CT and MRI commonly used. These imaging techniques may reveal:^1,2

• A mass in the superior part of the eye socket
• Irregular tumour margins
• Possible bone invasion
• Calcium deposits in the tumour

If malignancy is suspected, an excisional biopsy is performed to prevent the spread of tumour cells, followed by histopathological examination, which is considered the gold standard for diagnosis. Under the microscope, the tumour typically has a bland appearance, with malignant cells clearly separated from surrounding tissue. The most common histological subtype is cribriform, which has a Swiss cheese-like appearance due to lobules and circular pools of mucin.

Staging the tumour is critical to assess the extent of the disease and guide treatment. Key factors in staging include:⁸

• Tumour size (ranging from T1 for tumours ≤ 2 cm to T4 for tumours > 6 cm)
• Lymph node involvement
• Presence of metastasis

ACC is classified into stages 1 through 4, with stage 4 being the most advanced and associated with a more aggressive treatment approach. Larger tumours and the presence of metastasis often indicate the need for more intensive therapy. Additionally, histological features play an important role in determining the tumour's aggressiveness and prognosis.

Management and treatment

Management and treatment of ACC requires a multidisciplinary approach, aiming to preserve the eyeball and maintain reasonable visual function. Treatment typically involves a combination of surgery, radiation therapy, and, in some cases, chemotherapy. This approach has been shown to effectively spare the globe in most patients, leading to satisfactory visual outcomes. A recent study found that the overall survival rate for a cohort of 14 patients was 80% after 27 months of follow-up. Notably, this strategy did not increase the risk of recurrence, metastasis, or death when compared to other treatment methods, making it a promising option for managing the condition.⁹ 

Surgical interventions for ACC are commonly considered the preferred treatment, with two main options: orbital exenteration and globe-sparing resection.² The choice between these procedures depends on the extent of the disease. Orbital exenteration is typically recommended if the tumour has extended beyond the orbit or involves the orbital apex. Globe-sparing resection may be preferred in cases where the tumour is more localized. Bone removal is also considered depending on radiological evidence of bone involvement and may be combined with other therapies, such as:^2,10

• Radiation therapy, which is commonly used in cases of perineural invasion, where tumour cells invade areas adjacent to nerves, often indicating metastasis, and may help prolong survival in the long term
• Systemic therapy, which includes chemotherapy, is typically employed when the tumour has metastasized, often in combination with radiation therapy, depending on tumour progression and staging
• Novel and emerging therapies, such as vaccine treatments, are currently undergoing clinical trials, particularly for advanced stages of cancer. These therapies are considered for patients based on their risk factors and hold the potential for improving clinical outcomes in the future

The decision is tailored to each patient based on tumour progression and specific clinical factors.²

Prognosis and survival rates

ACC generally has a poor prognosis, partly due to its rarity and limited available research.^1,2 A study found that the 5-year survival rate for the histopathological basaloid variant was only 21%, compared to 71% for other variants. Prognostic factors largely depend on the tumour’s histological classification, with younger patients typically having a better prognosis, possibly due to less aggressive variants and fewer instances of neural invasion, which often indicates a worse outcome. Tumours with neural invasion are more likely to recur and metastasize, even with aggressive treatment.^1,2 

Follow-up and surveillance

Post-treatment monitoring is crucial for patients with ACC due to the risk of local recurrence, regional spread, and metastasis, even after treatment.² Regular follow-ups, including blood tests and imaging such as MRI, PET scans, and CT scans, are recommended throughout the patient’s life. Long-term complications may include recurrence, metastasis to distant sites like the liver, lungs, and bones, as well as other issues like tumour ulceration, nerve compression, and damage to muscles and blood vessels. The frequency of follow-ups and scans may increase based on the progression of the disease and the patient's specific needs.² 

Supportive care and patient resources

Psychological support is crucial for cancer patients, as they often face emotional challenges, including anxiety, anger, and depression. Therefore, palliative care is focused on supporting individuals in the final stages of life, ensuring they live as comfortably as possible, whether in a hospital or at home. Coping strategies and resources are available online, with organisations like Macmillan offering guidance. Many patients find talking to counsellors, and clergy members, or joining support groups beneficial in managing the emotional and social impact of their diagnosis. These resources help patients access the support they need during their journey.

Summary

Lacrimal gland adenoid cystic carcinomas (ACC) is a rare, aggressive tumour often affecting the lacrimal gland.

• Symptoms: Eye bulging, pain, and nerve-related issues
• Diagnosis: Based on physical exams, imaging (CT, MRI), and biopsy
• Treatment: Surgery, radiation, chemotherapy, and emerging therapies like vaccines
• Prognosis: Poor overall, but younger patients with less aggressive tumours have better outcomes
• Monitoring: Lifelong follow-up for recurrence or metastasis
• Support: Palliative care and psychological support through organisations like Macmillan

While challenging, treatment can improve outcomes and quality of life.