Adenoid Cystic Carcinoma

~Introduction

Adenoid cystic carcinoma (ACC) is a rare, malignant neoplasm originating primarily in the secretory glands, most commonly the salivary glands of the head and neck region. Despite accounting for only 1–2% of all head and neck malignancies and about 10–15% of salivary gland cancers, ACC attracts significant clinical attention due to its unique behavior: slow but relentless growth, early perineural invasion, late distant metastasis, and a high tendency for recurrence even years or decades after the initial therapy.

Unlike many fast-growing aggressive cancers, ACC represents a paradox: patients may live for long periods but remain at constant risk of recurrence and distant spread. Its unpredictable biological behavior makes long-term follow-up essential and often lifelong. This article provides an in-depth exploration of the epidemiology, pathology, clinical presentation, diagnostic work-up, management strategies, prognosis, and emerging research trends in ACC.

~Epidemiology

ACC can occur at any age, but it is most frequently seen between the fourth and sixth decades of life. It affects men and women almost equally, though slight female predominance has been noted in some series. The tumor originates from secretory epithelium, making salivary glands its primary site, especially:

Minor salivary glands (palate is the most common intraoral location)
Submandibular gland
Parotid gland (less common compared to other salivary tumors)

Extra-salivary occurrences include:

Lacrimal glands
Trachea and bronchi
Breast
Bartholin glands
Skin appendages

ACC is not strongly associated with tobacco or alcohol use, setting it apart from most head and neck cancers. Its rarity and diverse anatomical distribution make clinical research challenging, contributing to gaps in understanding its molecular mechanisms.

~Etiology and Pathogenesis

The exact cause of ACC remains unknown, but several molecular and genetic abnormalities have been identified:

1. MYB–NFIB Fusion Gene

The most defining molecular characteristic of ACC is the t(6;9)(q22–23;p23–24) translocation, leading to fusion of the MYB transcription factor with NFIB.
This fusion results in overexpression of MYB, promoting:

Cell proliferation
Anti-apoptotic mechanisms
Angiogenesis

This alteration is found in a majority of ACC tumors, making it a key diagnostic and therapeutic target.

2. MYBL1 Gene Alterations

In some tumors, MYBL1 alterations similar to MYB overactivity have been detected, underscoring the role of this pathway in tumor initiation.

3. Notch Signaling Pathway

Mutations in NOTCH1 have been linked with aggressive behavior, distant metastasis, and poor prognosis.

4. Perineural Tropism

ACC is famous for its ability to invade nerve sheaths, a behavior driven by altered expression of adhesion molecules, neurotrophic factors, and matrix metalloproteinases.
This explains its deep infiltration and high recurrence rates.

~Histopathology

ACC shows distinct microscopic patterns that influence prognosis.

1. Cribriform Pattern

Often described as “Swiss cheese–like,” this is the most characteristic pattern.
Features include:

Rounded nests of malignant cells
Pseudocystic spaces containing mucinous or hyaline material

This pattern is associated with intermediate prognosis.

2. Tubular Pattern

This consists of glandular tubular formations and tends to be the least aggressive pattern with the best outcomes.

3. Solid Pattern

Solid sheets of basaloid cells indicate a high-grade variant.
This pattern correlates with:

Faster recurrence
Higher risk of metastasis
Overall poorer survival

Many ACC tumors show a mixture of these patterns, and the percentage of solid areas can alter the tumor grade.

~Clinical Presentation

ACC’s presentation largely depends on its location, but some characteristics are universal.

1. Slow-Growing Mass

Patients commonly report a painless, slowly enlarging lump.
This often leads to delayed diagnosis.

2. Perineural Invasion Symptoms

Because of nerve involvement, patients may experience:

Pain
Numbness
Facial nerve weakness (if parotid is involved)
Tingling or burning sensations

These neurological symptoms are clinical red flags for ACC.

3. Location-Specific Symptoms

Oral cavity and minor salivary glands:

Palatal swelling
Ulceration
Difficulty chewing or swallowing

Lacrimal gland:

Proptosis
Vision changes
Tearing abnormalities

Respiratory tract:

Wheezing
Hemoptysis
Persistent cough

Breast ACC:

Palpable mass
Often no nipple discharge or skin changes

Despite its low metastatic potential early on, ACC’s capacity for extensive local infiltration leads to significant functional impairment depending on the site.

~Patterns of Spread

Local Spread

ACC infiltrates along tissue planes and nerve pathways, making complete excision challenging.
Skull base involvement may occur in advanced head and neck cases.

Lymph Node Metastasis

ACC rarely spreads to lymph nodes—only about 5–10% of cases show nodal involvement. Therefore, routine neck dissection is often unnecessary unless nodes are clinically or radiologically suspicious.

Distant Metastasis

The lungs are the most common site, followed by:

Bones
Liver
Brain

Metastasis can occur many years after initial therapy, reinforcing the need for lifelong surveillance.

~Diagnostic Work-up

1. Clinical Examination

A detailed head and neck exam, palpation of salivary glands, cranial nerve assessment, and evaluation of oral cavity structures are essential.

2. Imaging Studies

MRI:

Best for assessing soft tissue infiltration
Excellent for detecting perineural spread

CT scan:

Useful for evaluating bone erosion
Helpful in sinonasal or skull base tumors

PET-CT:

Limited sensitivity in slow-growing tumors
Helpful in detecting distant metastasis

3. Biopsy

Core needle biopsy or incisional biopsy is preferred.
Fine-needle aspiration (FNA) is commonly used but may sometimes be inconclusive due to the tumor’s heterogeneity.

4. Histological and Immunohistochemical Analysis

Markers include:

CD117 (c-Kit) – strongly positive in most ACC cases
MYB – indicates MYB–NFIB fusion presence
S100 and p63 – useful in differentiation

These markers help confirm diagnosis and rule out other salivary gland tumors.

~Staging

ACC is staged according to the TNM system, considering:

Tumor size (T)
Nodal involvement (N)
Distant metastasis (M)

However, traditional staging does not always reflect the true biological risk because even small tumors can develop late metastasis.

~Treatment

Treatment strategies aim at long-term disease control due to the tumor’s indolent behavior and high recurrence risk.

1. Surgery

Complete surgical excision with negative margins is the first-line treatment whenever feasible.

For head and neck ACC, this may involve partial or total removal of salivary glands.
Skull base or perineural invasion may require complex resections.
If margins are positive or close, postoperative radiotherapy becomes essential.

Lymph node dissection is not routinely required unless nodes are clinically suspicious.

2. Radiotherapy

Postoperative radiotherapy (PORT) significantly improves local control.

Techniques include:

Intensity-modulated radiotherapy (IMRT)
Proton therapy
Fast-neutron radiotherapy (historically used, less common now)

Radiotherapy is also used as:

Primary definitive treatment when surgery is not possible
Palliation in recurrent or metastatic disease

3. Chemotherapy

ACC is traditionally chemotherapy-resistant.
However, chemotherapy may be used in:

Advanced unresectable disease
Symptomatic metastasis
Palliative scenarios

Common regimens include cisplatin-based combinations, though results are modest.

4. Targeted Therapy and Immunotherapy

Because of limited chemotherapy response, targeted therapy is being explored.

Targeted Agents:

Tyrosine kinase inhibitors (TKIs) such as imatinib, lenvatinib, axitinib
NOTCH inhibitors in selected patients
Agents targeting MYB pathway (in clinical trials)

These show partial responses in some patients but are not yet curative.

Immunotherapy:

ACC generally has low PD-L1 expression and low mutational burden, resulting in limited response to checkpoint inhibitors.
However, ongoing trials aim to identify responsive subgroups.

~Recurrence and Long-Term Follow-Up

ACC has one of the highest recurrence rates among salivary gland cancers. Recurrence may be:

Local (often due to perineural invasion)
Regional (rare)
Distant (lungs most common)

Recurrence can occur even 20–30 years after treatment, making lifelong surveillance mandatory.

Recommended Follow-up:

Imaging every 6–12 months
Annual chest CT for lung metastasis screening
Long-term monitoring of nerve function

~Prognosis

ACC has a paradoxical prognosis:

Short-Term Outlook

Relatively good, because the tumor is slow-growing.

Long-Term Outlook

Challenging, due to persistent risk of metastasis and recurrence.

Survival Rates:

5-year survival: 75–90%
10-year survival: ~55–65%
15-year survival: ~35–40%
20-year survival: ~20%

Prognostic Factors:

Presence of solid histologic pattern
Perineural invasion
Positive surgical margins
Advanced stage
NOTCH1 mutation
Distant metastasis

Although many patients live for years, ACC behaves like a chronic disease requiring continuous observation and management.

~Future Directions and Research

Research in ACC is rapidly evolving, with several promising avenues:

1. Molecularly Targeted Therapies

Efforts focus on:

MYB and MYBL1 gene targets
NOTCH pathway inhibitors
Tyrosine kinase inhibitors

2. Immunotherapy Enhancements

Combination therapies may help overcome ACC’s low immunogenicity.

3. Advances in Radiation Technology

Proton and carbon-ion therapy show improved local control with fewer side effects.

4. Genetic Profiling and Personalized Medicine

Whole-genome and transcriptomic analyses aim to classify ACC into molecular subtypes to tailor treatment.

5. Liquid Biopsy

Detection of circulating tumor DNA (ctDNA) may allow earlier diagnosis of recurrence or metastasis.

~Conclusion

Adenoid cystic carcinoma is a rare but distinct malignancy defined by its slow yet relentless course, marked perineural invasion, and late distant metastasis. Despite advances in surgery and radiotherapy, managing ACC remains challenging due to its unique biology. Long-term survival is possible, but cure remains elusive for many patients, especially those with advanced or recurrent disease.

Ongoing research into molecular pathways, targeted therapeutics, and advanced radiotherapy techniques offers hope for improved outcomes. The future of ACC treatment lies in personalized, biology-driven approaches that target its genetic and molecular underpinnings. Until then, early diagnosis, meticulous surgical excision, adjuvant radiotherapy, and vigilant lifelong follow-up remain the cornerstones of care.

Sunday, November 30, 2025