Diagnosis and Staging of Adenoid Cystic Carcinoma

Introduction to adenoid cystic carcinoma (ACC)

Definition and Overview of ACC

Adenoid Cystic Carcinoma (ACC) is a rare and puzzling cancer, comprising only 1% of head and neck tumours. Its unique histological patterns pose diagnostic challenges, often misinterpreted as benign lesions due to its slow growth.¹ ACC typically occurs in individuals aged 50 to 60 years, with no significant gender-based differences.² 

The tumour's location in the head and neck region complicates surgical resection (removal), and its tendency of perineural (close proximity to nerves) invasion contributes to long-term recurrence. Multidisciplinary collaboration is essential for treatment optimization, involving surgeons, radiation oncologists, medical oncologists, and supportive care specialists. 

ACC can lead to distressing symptoms impacting patients' quality of life. Limited clinical trial data make evidence-based treatment decisions difficult, emphasising the need for ongoing research. Recent progress in genomic profiling and precision medicine offers potential for targeted therapies, raising hope for improved outcomes in patients with this rare malignancy.³

Prevalence and risk factors

ACC remains a captivating field of study in oncology due to its enigmatic nature and limited prevalence. As an uncommon malignancy, ACC represents only a small fraction of all head and neck tumours and tumours in other locations. The rarity of this cancer poses challenges in understanding its underlying biology, risk factors, and optimal treatment strategies. However, ongoing research is shedding light on key aspects of ACC, offering hope for improved patient outcomes.

Prevalence

• ACC comprises approximately 1% of all head and neck tumours, making it a relatively uncommon cancer
• It can also occur in other areas, including the breast, lung, and minor salivary glands (10%), but its occurrence in these sites is infrequent¹

Risk factors

The precise causes of ACC remain largely unknown, but several potential risk factors have been suggested:

• Previous exposure to radiation in the head and neck region, such as prior cancer treatments, may increase the risk of developing ACC
• Certain occupational exposures, such as exposure to certain chemicals or industrial pollutants, have been hypothesized to contribute to ACC development in some cases
• In rare instances, familial clusters of ACC have hinted at possible genetic predisposition in certain individuals
• Hormonal factors, for instance, hormonal changes during pregnancy, have been suggested as potential contributors, particularly for ACC tumours in the breast⁴

Clinical presentation of ACC

Signs and symptoms

Though there are variations in the symptoms of ACC patients, some of the common symptoms have been outlined below:

• Slow-growing mass or lump in the affected area
• Painless or mildly painful lump
• Facial weakness or paralysis due to involvement of the facial nerve
• Difficulty swallowing or changes in speech
• Pain or discomfort in the affected area
• Perineural invasion leading to nerve-related symptoms (e.g., pain, numbness, tingling)
• Airway obstruction in rare cases with tumours in the upper airway or trachea.
• Systemic symptoms in advanced stages or with distant metastasis (e.g., fatigue, weight loss, decreased appetite)

It's important to note that these symptoms can vary depending on the location and size of the tumour. If you or someone you know experiences any persistent symptoms or finds an unusual lump, it's essential to seek medical evaluation for proper diagnosis and management.^5,6

Common affected sites

ACC can arise in various locations throughout the body, but certain sites are more commonly affected than others, like the ones listed below:

1. Salivary Glands: ACC most frequently originates in the salivary glands, with the parotid gland (located in front of the ears) being the most common site. It can also occur in other major salivary glands, such as the submandibular and sublingual glands, as well as in the minor salivary glands located in the mouth and throat.
2. Head and Neck Region: Apart from the salivary glands, ACC can develop in other areas of the head and neck, such as the nasal cavity, sinuses, throat, and base of the skull.
3. Breast: ACC can also occur in the breast, although it is relatively less common than in the salivary glands.
4. Lung: While rare, ACC can develop in the lungs, typically originating from the bronchial glands.
5. Trachea: ACC can affect the trachea, leading to potential airway obstruction and breathing difficulties.
6. Other Sites: In rare cases, ACC has been reported in other locations, including the skin, lacrimal glands (tear glands), and certain organs of the digestive system.

It's important to remember that ACC's occurrence in different sites may present with varying symptoms and challenges in diagnosis and treatment. The management of ACC requires a multidisciplinary approach involving specialists familiar with the affected site to optimize patient care and outcomes.^{7, 8}

Diagnostic procedures for ACC

Medical history and physical examination

As ACC is a rare malignancy with varied clinical presentations, these initial steps are essential for guiding further diagnostic investigations and determining the most appropriate management plan.

The patient's medical history is assessed to identify any relevant risk factors, previous exposure to radiation in the head and neck region, or a family history of ACC or other cancers. The duration and progression of symptoms, if present, are carefully evaluated to understand the timeline and severity of the disease. A thorough review of the patient's past medical conditions and treatments is conducted to rule out any other potential causes of the presenting symptoms.

Additionally, a comprehensive physical examination is performed, with particular attention to the affected area, such as the head and neck region, breasts, or other potential sites of ACC. The presence of a palpable mass, its size, location, and consistency are noted. Any signs of facial nerve involvement, such as facial weakness or asymmetry, are carefully assessed, especially in cases affecting the salivary glands.

Based on the medical history and physical examination findings, further diagnostic tests may be recommended, including imaging studies (e.g., ultrasound, CT scan, MRI) to visualize the tumour’s extent and location and a biopsy to obtain a tissue sample for histological examination.⁹

Imaging tests

Computer tomography (CT)

• CT scans use X-rays to produce detailed cross-sectional images of the body
• CT is particularly useful in evaluating the size, location, and local spread of ACC tumours
• It provides clear images of bony structures and is commonly used to assess the involvement of the skull base or bones in the head and neck region
• CT can help in determining if ACC has spread to nearby lymph nodes or surrounding tissues¹⁰

Magnetic resonance imaging (MRI)

• MRI uses powerful magnets and radio waves to create detailed images of soft tissues
• MRI is well-suited for visualizing the soft tissues of the head and neck, making it useful in evaluating ACC in this region
• It provides detailed information about the tumour's relationship with nearby structures, such as nerves, blood vessels, and surrounding organs
• MRI is sensitive to differentiating tumour tissues from normal tissues, aiding in accurate tumour characterization¹¹

Positron emission tomography (PET)

• PET scans use a radioactive tracer to highlight areas with increased metabolic activity
• PET detects metabolic changes associated with cancer cells, providing information about tumour activity and aggressiveness
• It is commonly used to determine if ACC has spread to distant organs or sites (metastasis)
• PET can complement CT and MRI findings, offering valuable insights into the overall disease status¹¹

A combination of CT, MRI, and PET imaging is often used in ACC diagnosis and staging.

Biopsy

Fine needle biopsy (FNB)

FNB involves inserting a thin, hollow needle into the suspicious tissue to obtain a small sample. This minimally invasive procedure is often performed under image guidance, such as ultrasound or CT, to target the specific area of concern. FNB is useful for obtaining cellular material for initial evaluation, such as identifying if the lesion is cancerous or benign. However, FNB may not always provide enough tissue for a comprehensive assessment of the tumour’s architecture and characteristics, potentially leading to inconclusive results.^11,12

Core needle biopsy (CNB)

CNB is a more extensive biopsy technique that uses a larger, hollow needle to extract a larger tissue core from the lesion. The larger tissue sample obtained through CNB allows for a more detailed evaluation of the tumour's histological features and architecture. CNB is especially useful when a more definitive diagnosis is required, and FNB is inconclusive or when there is a suspicion of malignancy based on imaging.¹²

Surgical Biopsy

Surgical biopsy involves the removal of the entire tumour or a substantial portion of it for examination. It is often performed when other biopsy techniques are inconclusive or when a definitive diagnosis and comprehensive tumour evaluation are necessary. Surgical biopsy allows for complete histopathological analysis, providing critical information about the tumour's type, grade, and extent of invasion. Additionally, it may be performed as part of the initial treatment to remove as much tumour tissue as possible.^11,12

Histopathological examination

Pathological characteristics of ACC

• Three typical growth patterns; tubular, cribriform, and solid; are evident under a microscope and aid in identifying the tumour as ACC
• The characteristic "Swiss-cheese" appearance is due to the cribriform pattern, with small gland-like spaces separated by solid sheets of cells
• Perineural invasion is a prominent feature of ACC, wherein tumour cells infiltrate along nerve sheaths, contributing to its locally aggressive nature
• High-grade areas within ACC may show increased cellularity (more cells), nuclear atypia (abnormal cell appearance), and increased mitotic activity (increased division of cells)¹³

Immunohistochemistry (IHC)

• IHC is a vital tool used to analyse the specific protein expression profile of tumour cells, helping to confirm the diagnosis of ACC and distinguish it from other tumours that may have similar appearances
• ACC typically shows a characteristic IHC staining pattern, including positive expression for certain markers, such as cytokeratins (e.g., CK7, CK14), S100 protein, and CD117 (c-Kit)¹⁴

Molecular testing

• Molecular testing of ACC may involve identifying specific genetic mutations or chromosomal rearrangements associated with the disease
• The most common genetic alteration in ACC involves a gene fusion called MYB-NFIB, which is detected in a significant portion of cases and is considered a specific molecular marker for ACC
• Other genetic alterations, such as MYBL1-NFIB fusion and mutations in TP53 and PIK3CA genes, have also been identified in some ACC cases^{12, 14}

Staging of ACC

Overview of staging systems

ACC is staged using the TNM (tumour, node, metastasis) system, which is specific to salivary gland tumours. The TNM system assesses the size and location of the primary tumour (T), the involvement of regional lymph nodes (N), and the presence of distant metastasis (M). The results are combined to determine the cancer stage, which is essential for treatment planning and prognosis prediction. ACC can be staged from 0 to IVB, based on the extent of the tumour and its spread.¹⁵

TNM staging

Tumour (T)

• TX: Primary tumour cannot be evaluated
• T0: No evidence of a tumour
• T1: Small tumour ≤ 2 cm, non-invasive
• T2: Larger tumour> 2 cm and ≤ 4 cm, non-invasive
• T3: Tumour > 4 cm but not larger than 6 cm, with limited spread beyond the salivary gland
• T4a: Tumour invades nearby structures like the skin, jawbone, ear canal, or facial nerve
• T4b: Tumour invades the skull base and/or nearby bones and encases arteries

Node (N)

• NX: Lymph nodes cannot be evaluated
• N0: No regional lymph node involvement
• N1: Cancer spread to a single lymph node on the same side as the primary tumour, ≤ 3 cm
• N2a: Spread to a single lymph node, > 3 cm but ≤ 6 cm, on the same side as the primary tumour
• N2b: Spread to multiple lymph nodes on the same side as the primary tumour, none > 6 cm
• N2c: Spread to multiple lymph nodes on either side of the body, none > 6 cm.
• N3: Spread to lymph nodes > 6 cm

Metastasis (M)

• MX: Distant metastasis cannot be evaluated
• M0: No distant metastasis
• M1: Distant metastasis is present

Based on the TNM system, ACC is staged from I to IVC, and recurrent ACC is classified as recurrent. Staging helps doctors plan the best treatment approach and predict outcomes.^{15, 16}

Prognostic factors

Key prognostic factors include histological grade, tumour stage, perineural invasion, tumour location, molecular markers, and treatment response. 

Low-grade tumours and early-stage disease generally have a more favourable prognosis. The presence of perineural invasion and ACC in certain locations may indicate a poorer outcome.

Specific genetic alterations, such as the MYB-NFIB gene fusion, can also influence prognosis. Understanding these factors allows doctors to tailor treatment plans and provide more accurate prognostic information for individual ACC patients. However, each patient's prognosis is unique and influenced by multiple factors.¹

Additional diagnostic tools and considerations

Biomarkers and genetic markers

Biomarkers and genetic markers in ACC provide vital information about the disease's presence, progression, and treatment response. Key markers, like the MYB-NFIB gene fusion, aid in ACC diagnosis and classification. They distinguish ACC from other tumours and guide treatment choices effectively.¹¹

Molecular imaging techniques

Molecular imaging techniques employ specialized agents to visualize specific molecular and cellular processes in the body. In ACC, these techniques non-invasively visualize and characterize tumours, including size, location, and metabolic activity. Positron Emission Tomography (PET) with specific tracers is particularly useful in staging ACC and detecting distant metastasis.^{10, 11}

Genetic testing and counselling

Genetic testing analyzes a patient's DNA to identify cancer-related genetic mutations or alterations. In ACC, this testing helps identify the MYB-NFIB gene fusion and other alterations for precise diagnosis and personalized treatment. Genetic counselling is crucial for ACC patients and families to understand disease risk, implications for relatives, and preventive measures.¹⁷

Differential diagnosis of ACC

Distinguishing ACC from other salivary gland tumours

Distinguishing ACC from other salivary gland tumours can be challenging due to similar appearances. However, key features to differentiate ACC include its triphasic growth pattern (cribriform, tubular, and solid structures), perineural invasion, and specific molecular markers like MYB-NFIB gene fusion. Clinical behaviour, IHC staining, and tumour location also play a role in distinguishing ACC from other tumours. A comprehensive approach involving histopathological examination, molecular testing, and expert consultation is essential for accurate diagnosis and appropriate management.¹⁸

Other conditions with similar clinical presentation

ACC can have similar clinical features to various other conditions, including benign salivary gland tumours (e.g., pleomorphic adenoma), mucoepidermoid carcinoma, other metastatic tumours, inflammatory conditions, and salivary duct carcinoma. Accurate differentiation is crucial for appropriate treatment. A comprehensive evaluation, including histopathological examination and imaging, is necessary to distinguish ACC from these conditions. Seeking expert consultation is essential for accurate diagnosis and management.^{1, 18}

Summary

Diagnosis, management & treatment of ACC is challenging because of its rarity. Accurate diagnosis and staging are important for better treatment, which can be done using molecular markers, genetic testing, and imaging techniques.