Adenoid Cystic Carcinoma: Symptoms, Types, Causes and Treatment

Adenoid cystic carcinoma (ACC) is a rare and enigmatic form of cancer that most often arises from the secretory glands, particularly the salivary glands in the head and neck region, but can also develop in other sites such as the breast, respiratory tract, and various mucosal tissues. Despite its relatively slow growth, ACC is notorious for its persistent nature, tendency for recurrence, and potential for distant metastasis—even many years after initial diagnosis. Understanding its symptoms, types, causes, and treatment options is critical for patients, caregivers, and clinicians navigating this challenging disease.

Symptoms of Adenoid Cystic Carcinoma

The symptoms of adenoid cystic carcinoma can be subtle, often leading to delayed diagnosis. Unlike many cancers that present with dramatic or specific signs, ACC’s symptoms are generally unspecific and depend on the tumor's anatomical location. This makes early detection challenging, underscoring the importance of awareness and vigilance.

Symptom	Frequency/Significance	Typical Locations	Source(s)
Dyspnea	Most common presenting symptom in laryngeal ACC	Larynx (subglottic)	1
Hoarseness	Frequently reported, especially with laryngeal tumors	Larynx	1
Pain	Often due to perineural invasion	Head/neck, oral cavity	2 3 6 12
Palpable Mass	May be present in accessible glands (e.g., salivary, breast)	Salivary glands, breast	2 12
Numbness	May occur if nerves are affected	Head/Neck, oral cavity	2 3 6
Late Recurrence	Recurrences can happen years after treatment	Multiple	3 13

Table 1: Key Symptoms

Symptom Overview

ACC’s clinical manifestations are highly variable:

• Dyspnea and Hoarseness: In cases where ACC arises in the larynx or respiratory tract, patients may present with difficulty breathing (dyspnea) or changes in voice (hoarseness). These symptoms often reflect submucosal tumor growth, which can delay presentation until the tumor is advanced 1.

• Pain and Numbness: A distinguishing feature of ACC is its tendency for perineural invasion, where the tumor infiltrates nerves. This can cause persistent pain or numbness, especially in the head and neck region 2 3 6 12. In some cases, involvement of cranial nerves may lead to facial weakness or sensory changes.

• Palpable Mass: Tumors arising in accessible salivary glands or the breast can manifest as a slowly enlarging, often painless, lump. Because ACC grows indolently, these masses may go unnoticed for months or years 2 12.

• Late Recurrence: ACC is infamous for recurrent disease, sometimes many years after initial treatment. This indolent but relentless course requires extended follow-up—often beyond 15 years post-diagnosis 3 13.

Symptom Details By Location

Head and Neck

Most ACCs arise in the minor or major salivary glands of the head and neck. Here, patients might notice a mass inside the mouth, jaw pain, or numbness due to nerve involvement. Tumors in the paranasal sinuses or nasal cavity may cause nasal obstruction or bleeding 12.

Larynx and Trachea

In the larynx, submucosal growth leads to symptoms only when the tumor is large enough to interfere with breathing or voice. Dyspnea and hoarseness are common initial complaints 1.

Other Sites

ACC can also develop in the breast, tracheobronchial tree, and even in the skin or reproductive organs. Symptoms in these sites are dictated by local effects—such as a breast lump or cough in tracheal involvement 12.

Types of Adenoid Cystic Carcinoma

Adenoid cystic carcinoma exhibits a spectrum of histological and molecular subtypes, influencing disease behavior, prognosis, and, increasingly, treatment strategies. Understanding these types is vital to tailoring management plans.

Type/Variant	Key Features	Clinical Significance	Source(s)
Cribriform	Classic “Swiss cheese” pattern; basaloid cells	Most common, intermediate prognosis	3 10 12
Tubular	Glandular/tubular structures	Often indolent, favorable prognosis	3 10 12
Solid	Sheets of basaloid cells, less gland formation	More aggressive, higher recurrence	3 4 5 12 15
Molecular Subtypes	MYB-NFIB, MYBL1 fusions, NOTCH1 mutations	Impact prognosis and therapy options	4 5 7 8 9 11
Anatomical Types	Head/neck, breast, tracheobronchial, others	Symptoms and outcomes vary by site	1 2 12

Table 2: Main Types and Variants

Histological Subtypes

Three primary histological patterns are recognized:

• Cribriform: This classic type features basaloid tumor cells arranged in a “Swiss cheese” pattern with pseudocystic spaces. It is the most common form and has an intermediate clinical course 3 10 12.
• Tubular: Characterized by true glandular and tubular structures, this variant generally has the best prognosis and slowest progression 3 10 12.
• Solid: Composed of dense sheets of basaloid cells with fewer gland-like spaces, the solid form is associated with more aggressive behavior, a higher rate of recurrence, and worse survival outcomes. It is also more likely to metastasize 3 4 5 12 15.

Molecular Subtypes

Recent genomic studies have helped clarify the molecular landscape of ACC:

• MYB-NFIB Fusions: The majority of ACCs harbor chromosomal translocations that fuse the MYB gene to NFIB, driving abnormal cell signaling and growth 8 10 11 14.
• MYBL1 Rearrangements: A subset of tumors are driven by MYBL1 fusions, which behave similarly to MYB-driven cancers 11.
• NOTCH1 Mutations: Especially prevalent in solid-type ACC and certain aggressive subtypes, NOTCH1-activating mutations are now recognized as markers of poor prognosis and potential therapeutic targets 4 5 7 9 15.
• Other Genetic Alterations: Mutations in chromatin regulators (e.g., CREBBP, KMT2C), DNA damage response genes, and tyrosine kinase pathways (e.g., FGFR2, PIK3CA) have also been described, adding complexity to ACC’s biology 8 9.

Anatomical and Organ-specific Types

While ACC most often arises in the salivary glands, it can develop in a wide range of tissues:

• Head and Neck: Includes salivary glands, nasal cavity, paranasal sinuses, and larynx 1 2 12.
• Breast: Shows both classic and solid variants; solid-type ACC in the breast is a distinct molecular entity with unique mutations 4 5.
• Other Sites: ACC is reported in the trachea, lungs, skin, prostate, uterine cervix, and even Bartholin’s gland 12.

Causes of Adenoid Cystic Carcinoma

The precise causes of ACC remain largely unknown, but advances in molecular genetics are beginning to shed light on the mechanisms that drive its development. Unlike many cancers, ACC is not strongly associated with environmental risk factors or inherited syndromes; rather, it appears to arise from a series of molecular events within secretory gland cells.

Factor	Description	Relevance	Source(s)
Genetic Fusions	MYB-NFIB and MYBL1 rearrangements	Fundamental driver events	8 10 11 14
Chromatin Mutations	Mutations in CREBBP, KMT2C, SMARCA2, etc.	Aberrant gene regulation	8 9
NOTCH Pathway	Activating NOTCH1 mutations, SPEN alterations	Aggressive disease, therapy	4 5 7 9 15
PI3K/FGFR2 Pathway	Mutations in PI3K, FGFR2, etc.	Potential therapy targets	8 9 15
Environmental	No clear risk factors identified	Unclear etiology	2 12

Table 3: Key Causes and Molecular Mechanisms

Molecular Drivers

MYB-NFIB Fusion

• The hallmark genetic event in ACC is a chromosomal translocation resulting in the fusion of the MYB gene with NFIB. This fusion leads to overexpression of MYB, a transcription factor that promotes oncogenic growth and survival 8 10 11 14.
• The presence of MYB-NFIB or MYBL1 fusions is now considered a defining feature of most ACCs, though not all tumors possess these alterations 11 14.

Other Genetic Mutations

• Chromatin Regulators: Mutations in genes like CREBBP, KMT2C, and SMARCA2 suggest that disruption of normal chromatin structure and gene expression is an important step in ACC development 8 9.
• NOTCH Pathway: Activating mutations in NOTCH1 and alterations in regulators like SPEN have been linked to more aggressive forms, particularly in solid-type ACC and metastatic disease 4 5 7 9 15.
• PI3K/FGFR2 Pathway: Some ACCs harbor mutations in growth factor signaling pathways, such as PI3K and FGFR2, which may provide new targets for therapy 8 9 15.

Environmental and Lifestyle Factors

• Unlike squamous cell carcinomas or many other cancers, ACC has not been linked to smoking, alcohol, viral infections, or other common environmental risks 2 12.
• No clear familial or inherited syndromes have been associated with increased risk of ACC.

Summary

ACC is primarily driven by specific genetic rearrangements and mutations within secretory gland cells. Ongoing research into these molecular pathways holds promise for new diagnostic tools and targeted treatments.

Treatment of Adenoid Cystic Carcinoma

Treating ACC is challenging due to its unpredictable behavior, resistance to standard chemotherapy, and potential for late recurrence and distant metastasis. Management is best tailored to the individual, considering tumor type, stage, site, and molecular profile.

Treatment	Description/Approach	Clinical Notes	Source(s)
Surgery	Mainstay for localized tumors	Achieves best local control	1 3 6 13
Radiotherapy	Often post-operative or for inoperable cases	Improves local control; not curative	1 3 6 13
Chemotherapy	Limited efficacy; palliative role	Used in metastatic/recurrent cases	6 7 13 15
Targeted Therapy	Agents against c-KIT, EGFR, NOTCH, etc.	Limited results, ongoing trials	7 14 15
Immunotherapy	Immune checkpoint inhibitors under study	Experimental and investigational	6 14 15
Surveillance	Long-term follow-up due to late recurrence	Essential for all patients	3 13

Table 4: Main Treatment Approaches

Surgery

• Primary Modality: Surgical removal of the tumor with clear margins offers the best chance of local disease control, especially for localized ACC 1 3 6 13.
• Challenges: Complete resection can be difficult due to perineural invasion and the tumor’s tendency to spread along nerves and tissue planes, sometimes into inaccessible areas like the skull base 6.

Radiotherapy

• Adjuvant Therapy: Postoperative radiotherapy is often recommended to reduce the risk of local recurrence, particularly when margins are close or perineural invasion is present 1 3 6 13.
• Definitive Radiotherapy: In inoperable cases, radiotherapy alone may be used but is generally less effective than surgery 6.

Systemic Therapies

• Chemotherapy: Standard cytotoxic chemotherapy has shown only modest or minimal benefit in ACC and is usually reserved for advanced, recurrent, or metastatic disease 6 7 13 15.
• Targeted Therapy:
  • Several targeted agents have been studied, including those against c-KIT, EGFR, and, more recently, molecular targets such as NOTCH1 and MYB. Thus far, results have been limited, but ongoing clinical trials are selecting patients based on tumor molecular profiles, such as the presence of NOTCH1-activating mutations 7 14 15.
  • Novel agents targeting the PI3K pathway, FGFR2, and chromatin regulators are in various stages of research 8 9 14.
• Immunotherapy: Immune checkpoint inhibitors are being explored but remain investigational due to the unique immune environment of ACC tumors 14 15.

Surveillance and Follow-up

• Long-Term Monitoring: Due to ACC’s propensity for very late recurrence—sometimes decades after initial treatment—patients require extended, often lifelong, surveillance 3 13.
• Management of Metastatic Disease: The lungs are the most common site of distant metastasis. Management is often palliative, focusing on quality of life 15.

Conclusion

Adenoid cystic carcinoma is a complex, rare cancer that challenges both patients and clinicians with its indolent yet relentless behavior, unpredictable recurrences, and limited treatment options. However, advances in molecular understanding are opening new avenues for targeted therapies and more personalized care.

Key Takeaways:

• Symptoms are often subtle and variable, depending on tumor location, with pain, mass, numbness, and sometimes breathing or voice changes as common features 1 2 3 6 12.
• Three main histological types exist—cribriform, tubular, and solid—with solid type being more aggressive. Molecular subtypes (MYB-NFIB, MYBL1, NOTCH1) are increasingly important for prognosis and treatment 3 4 5 7 8 9 11 12 14 15.
• Causes are primarily genetic, with hallmark MYB and MYBL1 fusions, chromatin regulator mutations, and NOTCH pathway alterations as major drivers 8 9 10 11 14 15.
• Surgery and radiotherapy remain the mainstays of treatment for localized disease, while systemic therapies are largely investigational, and long-term surveillance is essential due to the risk of late recurrence and metastasis 1 3 6 7 13 14 15.

The landscape of ACC management is evolving, with hope on the horizon as molecular insights translate into more effective, individualized therapies.