Adenoid Cystic Carcinoma

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Introduction   

Adenoid cystic carcinoma (ACC) is a rare malignancy originating from secretory glands, most often affecting the salivary glands [1]. Although the malignancy makes up 1% of head and neck cancers, adenoid cystic carcinoma accounts for almost 10% of salivary gland tumors [2]. ACC is the most common tumor of the minor salivary glands and the second most common of the major salivary glands [3]. Beyond the salivary glands, ACC can also arise in other sites such as the lungs and breasts. 

Presenting between the sixth and seventh decades of life, ACC shows a slight tendency for females, with a reported female-to-male ratio of 3:2 [4]. The tumor is slow-growing and often asymptomatic in its initial stages [1][2]. Advanced disease stages manifest with symptoms including pain and altered sensation, primarily due to the tumor’s inclination for perineural invasion (PNI) [5]. PNI is a distinctive feature of ACC that facilitates local and systemic spread, contributing to high relapses and recurrence rates of 50% [1][5]. 

The etiopathogenesis of ACC remains unclear [6]. However, researchers identified mutations and biomarkers, suggesting roles in its initiation and progression. These molecular abnormalities drive research into targeted therapies, including multitargeted tyrosine kinase inhibitors, to inhibit tumor growth and metastasis. 

Diagnosing ACC is often challenging and necessitates a multidisciplinary approach combining clinical examination, imaging studies, and histopathological analysis [1]. The primary management strategy is wide surgical excision, with neck dissection indicated for cases involving positive lymph nodes [7]. Although radiotherapy improves local control, in cases of microscopic residual disease, it shows limited success in treating recurrent or metastatic tumors, whether used alone or combined with chemotherapy [1]. Given the complexities and challenges associated with ACC in advanced stages the focus will be on the latest management approaches and emerging future trends in the treatment of salivary adenoid cystic carcinoma, with the goal of enhancing understanding and improving patient outcomes. 

Case Study: Adenoid Cystic Carcinoma (ACC) 

A 62-year-old female presented to the clinic with a three-month history of a painless growing lump near her left parotid gland. She also reported mild discomfort during mastication and occasional numbness on the left side of her face. On physical examination, there was a palpable, firm, non-tender mass approximately 3 cm in diameter in the infra-auricular region. The examination revealed no overlying skin changes or lymphadenopathy. 

The patient’s medical history was unremarkable, and she had no prior history of salivary gland disease or significant family history of malignancies. She denied recent weight loss, fever, or other systemic symptoms. 

Imaging Studies: 

• • Ultrasound: Identified a hypoechoic, well-circumscribed mass in the left parotid gland. 

• • CT scan: Revealed a heterogeneously enhancing lesion with no bony involvement but slight extension into adjacent soft tissues. 

• • MRI with contrast: Highlighted perineural invasion (PNI) along the facial nerve. 

Fine Needle Aspiration Biopsy (FNAB): 

• • Cytological examination suggested malignancy with features consistent with adenoid cystic carcinoma.
  • Histopathology confirmed a cribriform pattern, characteristic of ACC. 

Surgical Intervention: 

• • The patient underwent wide surgical excision of the mass with preservation of facial nerve branches, given the absence of gross nerve involvement.
  • Margins were negative for malignancy. 

Postoperative Radiotherapy: 

• • Delivered to the surgical bed and adjacent tissues at risk, using Intensity-Modulated Radiotherapy (IMRT) to achieve precise targeting. 

Follow-Up and Monitoring: 

• • Regular imaging and clinical assessments to monitor for local recurrence or distant metastasis, with particular attention to the lungs, which are common metastatic sites. 

Prognosis and Expected Outcomes 

• • The aggressive nature of ACC and the substantial risk of recurrence or distant metastasis created a guarded prognosis.
  • A multidisciplinary team provided close follow-up. 

Epidemiology  

Adenoid cystic carcinoma (ACC) is a histopathological subtype of epithelial malignancies that primarily affects the exocrine glands in the head and neck region [1]. ACC involves the salivary glands but can also occur in organs such as the esophagus, cervix, lungs, and breasts [1][8]. ACC that originates in the salivary glands carries the name salivary gland adenoid cystic carcinoma (SACC) or adenoid cystic carcinoma of the salivary glands (ACCSG) [1]. SACC arises from both major and minor salivary glands. ACC affects the minor salivary glands, often involving the palate [1]. Among the major salivary glands, the parotid gland is most often involved, followed by the submandibular gland [1][8]. 

SACC represents a rare disease, comprising 1% of all head and neck malignancies and about 10% of salivary gland neoplasms [1]. Despite its rarity, it is one of the most common malignant tumors of the salivary glands [1][8]. Alongside established predictors of late mortality in ACC, such as tumor location, stage, and treatment modalities, research indicated that unmarried status and residence in the West region can be independent factors influencing late mortality in multivariable analysis [9]. A retrospective study conducted in the United States, which analyzed 30 years of data from the National Cancer Institute, indicated a higher incidence in the white Caucasian population and reported a female-to-male ratio of 3:2 [9] [10].  

SACC affects individuals across all age groups but most often occurs during the sixth and seventh decades of life [1] [10]. Estimates place the number of new SACC cases in the United States between 1,450 and 1,660. Of note, the incidence of the disease showed a significant decline between 1973 and 2007 [1] [10]. 

Due to its rarity, research into the incidence of SACC is challenging and often incorporated into broader studies of salivary gland cancers. A recent systematic review of 141 multicentric, international clinical studies—including more than 25,800 patients—found that adenoid cystic carcinoma was the second most common tumor after pleomorphic adenoma and the most common malignancy of the salivary glands [1]. This highlights the importance of SACC within the spectrum of salivary gland neoplasms and underscores the need for continued research and awareness. 

Clinical Presentation 

Adenoid cystic carcinoma (ACC) presents as a slow-growing lesion in the affected salivary gland, often with an unsuspicious clinical appearance. This lack of distinctive features means that many lesions go unnoticed for extended periods. In rare cases, the clinical presentation may raise suspicion of malignancy, but these signs are not specific to ACC. 

A thorough clinical assessment of the site is the first step in diagnosis. Normal overlying mucosa can obscure underlying clinicopathological features of ACC, creating challenges for diagnosis through physical examination alone. Clinicians should include ACC in the differential diagnosis when signs suggestive of malignancy appear, such as abnormal soft tissue presentation, bleeding, necrosis in the mouth, or symptoms related to perineural invasion (PNI), until confirmed otherwise [1][11].  

ACC shares clinical behaviors with other salivary gland malignancies, often presenting without detectable signs or symptoms for prolonged periods, sometimes spanning years. It is an insidious tumor that may remain unrecognized until reaching advanced stages in cases involving the minor salivary glands, which take longer to diagnose. ACC manifests as a lump associated with difficulty in chewing or swallowing [1]. It can also involve the tongue and the floor of the mouth [1][8]. When the primary lesion involves minor salivary glands of the upper aerodigestive tract, patients may present with dysphagia, dyspnea, cough, wheezing, hoarseness, or hemoptysis [1][12]. 

Among the major salivary glands, the parotid gland experiences the highest incidence, followed by the submandibular gland [1][8]. Tumors in these glands cause enlargement in the form of a lump or nodule in the periauricular and/or infra-auricular areas, or significant swelling on the affected side of the face, which can reach extensive sizes if neglected. SACC of the parotid gland has been associated with odontogenic-like pain referring to the maxillary sinus and sialolithiasis [1][13]. 

SACC of the submandibular gland may present as a slow-growing swelling in the floor of the mouth, often interfering with speech and mastication [1]. It may also appear as a lump in the submandibular area or along the posterior lower border of the mandible on the affected side [1]. Other clinical features linked to SACC of the submandibular gland include hyposalivation due to sublingual gland obstruction and first bite syndrome—a sequela of parapharyngeal space surgery associated with denervation of the parotid gland rather than the submandibular gland [1][14][15]. 

Common clinical features associated with SACC include dull pain, altered sensation of the tongue, palate, maxilla, or face, and facial nerve palsy [1]. These symptoms indicate perineural invasion (PNI) of local nerves, a sign encountered in advanced stages of the disease [16][17]. 

Despite its slow growth, SACC invades surrounding structures with significant aggressiveness [1][17]. PNI is a distinctive feature of SACC, allowing tumor cells to travel along nerves and cause distant metastasis [17]. A systematic review of 22 studies found PNI in more than 40% of 1,332 patients diagnosed with SACC and reported it as being associated with poor prognosis regardless of age group [1][18]. 

Factors that may increase the likelihood of distant metastasis include solid histological patterns, tumor size greater than 3 cm, and involvement of regional lymph nodes [19][20]. Researchers hypothesize that SACC cells differentiate into Schwann-like cells, facilitating migration along nerves, avoiding host immune detection, and evading recognition for prolonged periods [21]. 

Moreover, SACC can spread via the conventional perivascular route, metastasizing to the lungs, followed by the bone, liver, skin, and breasts [19][20]. Intracranial metastasis can occur through PNI or by direct invasion of the skull base by an adjacent primary lesion [1][22]. 

Differential Diagnosis  

The differential diagnosis of adenoid cystic carcinoma (ACC) involves a comprehensive approach that includes clinical examination, histopathological evaluation, and, when necessary, immunohistochemical staining. Although the clinical spectrum for differentiating ACC is narrow, the presence of a swelling or lump in a suspected site necessitates a thorough assessment using a surgical sieve to exclude other potential pathologies. Clinicians must distinguish ACC from various neoplasms, ranging from common to rare [1][23][24]. These include: 

• Pleomorphic Adenoma 
• Mucoepidermoid Carcinoma 
• Adenoid Basal Cell Carcinoma 
• Polymorphous Adenocarcinoma 
• Acinic Cell Carcinoma 
• Myoepithelial Carcinoma 

Accurate differentiation among these lesions is crucial, as each has distinct management protocols and prognostic implications. 

Furthermore, a case report identified increased plasma levels of immunoglobulin G4 (IgG4) in patients with adenoid cystic carcinoma, suggesting a link between IgG4-related disease (IgG4-RD) and ACC [25]. 

Metastatic Disease Presentation 

Adenoid cystic carcinoma (ACC) is known for its aggressive nature, exhibiting both local invasion and systemic metastasis to various organs. Several studies document the liver as a singular site of systemic spread, while less common metastatic sites include the breast and larynx [26]. In rare cases, ACC metastasizes to the pituitary gland, sternum, dorsal spine, choroid, toe bones, and pericardium [19][20][26]. Numerous factors contribute to the tumor’s invasive and metastatic processes, leading to clinical trials of targeted chemotherapeutic agents aimed at suppressing disease spread. 

Researchers identify several elements that promote ACC invasiveness: 

• CXCR5 Overexpression: Overexpression of CXCR5 correlated with increased proliferation and migration of tumor cells. Blocking CXCR5 expression resulted in suppressed tumor cell migration and metastasis [27]. 
• Fatty Acid Synthase (FASN): FASN promotes epithelial-mesenchymal transition (EMT), invasion, and metastasis of SACC cells. Inhibiting FASN led to a noticeable reduction in tumor cell migration and EMT activities [28]. 
• Long Noncoding RNA MRPL23-AS1: Patients with SACC exhibit elevated plasma levels of MRPL23-AS1, which correlate with increased EMT and microvascular permeability [29]. 
• Claudin-7 (CLDN7): Overexpression of CLDN7 attenuated these activities, highlighting its importance in suppressing SACC progression and metastasis [30]. 
• NR2F1 Protein: NR2F1 may play a role in recurrence and metastasis of SACC [31]. 
• Interstitial Fluid Pressure (IFP): Studies indicated a positive correlation between elevated intertumoral pressure and enhanced proliferation and migration activities of tumor cells [32]. 

These findings underscore the complex mechanisms behind ACC metastasis and highlight potential therapeutic targets. The scarcity of detailed etiological information in the literature calls for further clinical and immunohistochemical studies to elucidate the exact mechanisms driving ACC development and spread. 

ACC of the submandibular gland shows a greater tendency to metastasize compared to the parotid gland [1]. The submandibular tumor generates additional tumor-associated blood vessels and promotes angiogenesis, contributing to this tendency. ACC is notable for its locoregional aggressiveness and capacity for distant metastasis. The tumor can disseminate via the conventional perivascular route or through perineural invasion (PNI)—a characteristic that sets it apart from other malignancies in comparable sites [33].  

Despite the well-documented impact of PNI on ACC prognosis, the specific mechanisms underlying its development remain unclear. Numerous in vivo and in vitro studies have explored the biological and pathological mechanisms of ACC metastasis, linking certain biomarkers to the disease’s unique metastatic patterns and how they may influence nerve invasion or lymphovascular spread [34]. Understanding these mechanisms could pave the way for new diagnostic and therapeutic approaches. 

Etiology (Genetic Influences) 

The etiology of adenoid cystic carcinoma (ACC) without definitive evidence identifying the exact factors that trigger tumor development. Researchers have not clarified the precise pathogenesis of the disease. However, they conduct extensive studies using approaches similar to those in other cancer research, focusing on potential factors driving disease progression and metastasis. Key areas of investigation include genetics, the role of biological biomarkers, spreading mechanisms, and, to a lesser extent, the involvement of viruses and bacterial biofilms in the disease process. 

Genetic Involvement in Adenoid Cystic Carcinoma 

Research into the genetic factors of ACC has concentrated on examining mutations known to play roles in the pathogenesis of other cancers. While genetic factors may initiate ACC, researchers have not identified a specific gene type or mutation as the cause. 

• Beta-Calcitonin Gene-Related Peptide (β-CGRP): This gene may increase the risk for SACC, as SACC patients show elevated serum levels of CGRP and β-CGRP peptides [35]. 
• KDM6A and KRAS Mutations: Researchers identified a KRAS gene mutation in two cases of ACC affecting Bartholin’s salivary glands in the lip [36]. 
• NOTCH Signaling Pathway: detected evidence of upregulation in the NOTCH signaling cascade, a well-known pathway contributing to various human cancers [37].  
• Gene Expression Profiles: The upregulation of 119 and downregulation of 263 expressed genes (DEGs) in ACC indicate a genetic link in ACC development [38]. 

Genetic Links from Other Adenoid Cystic Carcinoma Studies 

• MYB and MYBL1 Genes: Studies suggests a genetic involvement, identifying MYB or MYBL1 genes in all tracheobronchial ACC samples and concluding that these genes may serve as hallmarks of tumor occurrence [39]. 

Top of Form / Bottom of Form 

The etiology and pathogenesis of ACC involve a complex interplay of genetic factors, specific genes, peptides, and proteins. Although researchers have not identified a definitive cause, numerous studies indicate that genetic mutations and protein dysregulation influence tumor initiation, progression, and metastasis. Ongoing research in these areas remains crucial for understanding ACC and developing targeted therapies to improve disease management and treatment. 

Diagnostic Radiology 

The initial imaging modality for suspected neoplastic growth in a major salivary gland is ultrasound [40]. This non-invasive technique aids in identifying the nature of any lump, delineating its approximate borders, and assessing its internal contents. Clinicians also use ultrasound as a three-dimensional guidance tool during diagnostic or interventional procedures, such as conducting a fine needle aspiration biopsy (FNA) or cytology screening for ACC as an initial biopsy technique. 

Computed Tomography 

Computed Tomography (CT contrast-enhanced cervical computed tomography – CECCT) is crucial for detecting bone involvement and determining tumor boundaries. The CT features of ACC are variable and depend on the tumor’s location, disease stage, and extent of bone involvement. Reported findings of bone destruction involving the palatine, maxillary, and nasal bones, enlargement of the greater palatine foramen (GPF), and involvement of the pterygopalatine fossa, foramen rotundum, and cavernous sinus [41]. 

Magnetic Resonance Imaging 

Magnetic Resonance Imaging (MRI), including contrast-enhanced MRI (CEMRI), is essential for diagnosing ACC. MRI provides detailed images of tumor characteristics and their effects on surrounding structures, bones, and soft tissues. utilized both CECCT and CEMRI to study perineural invasion (PNI) of adenoid cystic carcinomas in the oral and maxillofacial region [42].  

The use of Positron Emission Tomography (PET) combined with MRI or CT (PET-MRI or PET-CT) is critical when evaluating metastasis of ACC throughout the body [43]. Studies found no significant difference in diagnostic accuracy between PET-CT and PET-MRI, both achieving an accuracy of 94% in detecting local lesions [43]. 

Fine Needle Aspiration Biopsy 

Fine Needle Aspiration Biopsy (FNAB) is a valuable diagnostic tool used as an initial, non-invasive procedure when clinical and radiographic features do not suggest advanced disease [44]. The technique aims to examine the nature and origin of cells within a lesion. Clinicians perform FNAB under local anesthesia for accessible cystic lesions or under regional or general anesthesia with ultrasound guidance for deeper lesions.  

Management Approaches and Expected Outcomes 

There is no standardized comprehensive treatment protocol for managing all cases of adenoid cystic carcinoma (ACC). The management of ACC depends on factors such as the size of the primary lesion, presence of metastasis, disease grade, and the patient’s overall health [45]. Treatment often involves a combination of surgery, postoperative radiotherapy (PORT), and chemotherapy [46]. 

Surgical Treatment 

Surgery remains the first-line treatment for resectable ACC tumors [1] [47]. The surgical approach involves tumor resection with clear margins, with or without reconstruction. Surgical planning should consider the size and location of the lesion to ensure that the tumor is both accessible and resectable. 

In cases where complete tumor resection with negative margins is not possible, PORT is often employed to address residual disease. Poor prognosis and an increased likelihood of recurrence occurs in patients with high rates of postoperative positive margins who do not receive PORT [1] [48]. Therefore, combining surgery with PORT can lead to improved outcomes. 

In ACC cases with lung metastasis, surgical removal of metastatic lesions reduces disease progression and increases overall survival rates [49]. The success of this procedure depends on factors such as lung condition, metastasis size, and the patient’s general health. Performing elective neck dissection (END) alongside surgery improves the metastasis-free period, though recommendations suggest limiting END to lymph node levels I to III [50].  

Radiotherapy 

Clinicians reserve radiotherapy alone to treat ACC for advanced stages and unresectable cases [51]. However, clinicians use PORT as an adjunct to surgery to manage ACC. Patients who do not receive PORT show a 13-fold higher likelihood of developing local recurrence compared to those who receive it [48]. 

Clinicians deliver radiation doses to tissues affected by ACC using various techniques, including [1]: 

• 3D Conformal Radiation Therapy (3D-CRT) 
• Image-Guided Radiotherapy (IGRT) 
• Brachytherapy 
• Intensity-Modulated Radiotherapy (IMRT) 

Clinicians employ all these modalities in PORT and associate them with improved outcomes, but evidence remains insufficient to determine which technique achieves the best results.  

Clinicians use brachytherapy to eliminate recurrent lesions, including cases of recurrent ACC of the tongue. Combined radiotherapy and chemotherapy in patients with unresectable ACC have achieved complete remission in 80% of cases [1]. Concurrent chemoradiotherapy following surgery was effective in controlling local recurrence but did not improve overall survival rates.  

Chemotherapy 

Chemotherapy alone has limited effectiveness in treating ACC [1] [52]. However, results have been inconsistent, and the effectiveness of chemotherapy in ACC management remains uncertain, necessitating further research with innovative approaches and novel agents. Most ongoing clinical trials are in phase I and II, investigating antiangiogenic agents. 

Prognosis 

Recurrent and metastasized adenoid cystic carcinoma (R/M ACC) often resists treatment over extended periods, making disease management challenging. The aggressive nature of ACC, characterized by local/regional invasion and perineural invasion (PNI), contributes to high recurrence rates and resistance to treatment. Recurrence is common, with the risk believed to be as high as 50% after initial treatment in some cases [1] [17]. This high recurrence risk, coupled with the lack of comprehensive treatment options, leads to a poor prognosis. Patients may require multiple surgeries and postoperative radiotherapy. This underscores the need for more clinical, pathological, and genetic studies to understand the carcinogenesis and pathogenesis of ACC. Such research could lead to new treatments that target the disease’s etiological mechanisms and improve patient outcomes. 

Conclusion

Adenoid cystic carcinoma (ACC) is a rare cancer but stands as one of the most common malignancies of the salivary glands [1]. Despite its relative prevalence in this context, the disease is not widespread overall, and its etiopathogenesis remains poorly understood. Although researchers have identified several genetic patterns and biomarkers influencing its initiation and progression, they have not determined definitive causative factors. 

Diagnosing ACC is complex and often requires specialized investigations to reach a definitive conclusion. Management of the disease is challenging due to its frequent recurrence after treatment. Surgical resection of metastases combined with adjuvant radiotherapy continues to be the first-line treatment [1][47]. While chemotherapy has limited effectiveness, it can achieve some disease stability in incurable cases and plays a role in palliative management [1][46]. 

Future advancements in the diagnosis and management of ACC depend on uncovering specific elements related to the disease’s oncogenesis. However, the rarity of ACC hinders extensive research and clinical trials needed to explore novel approaches and novel therapies. The insidious clinical behavior, poor prognosis, and aggressiveness of ACC highlight the necessity for increased focus on laboratory and clinical studies to investigate its etiology and development further. 

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