Adenoid cystic carcinoma (ACC) is a rare malignancy arising from the secretory glands, most commonly seen involving the salivary glands. It accounts for approximately 1% of all malignancies of the head and neck region. However, it is the most common tumor of the minor salivary glands and the second most common tumor of the major salivary glands. Overall, it accounts for 10% of all salivary gland tumors. The tumor is typically slow-growing compared to other carcinomas and has a tendency for perineural invasion as well as hematogenous spread to distant organs and is most commonly seen in the elderly. Due to its rarity, limited data is available regarding the predisposing risk factors and the management of patients with advanced disease.
Owing to the low prevalence of this malignancy, scarce data in the form of a few single-center population-based studies is available regarding its etiology. Unlike other carcinomas of the head and neck region like squamous and basal cell carcinoma, smoking and the use of alcohol have not been linked as potential risk factors for the development of ACC. Several genetic mutations have been found during the chromosomal analysis and sequencing of over 80 ACC genomes, with age being an independent predisposing risk factor.
ACC exhibits a slight predominance in females (60% vs 40% in males) with an overall age-adjusted rate of 4.5 cases per 100,000 individuals. Although it predominantly arises from secretory cells of the salivary glands, it can also originate in other areas like the hard palate, nasopharynx, lacrimal glands, tongue as well as the external auditory canal. Apart from the head and neck region, cases of ACC arising from glands in the breast, reproductive tract, skin, and trachea, have also been reported. The malignancy has a preponderance for the elderly, with the highest incidence of cases of ACC in the head and neck area seen in the fifth to sixth decade of life.
The pathophysiology of ACC is an understudied area because of the rarity of the condition. Few studies looking at the molecular pathogenesis have provided vital information regarding the genes associated with dysregulation of cellular proliferation leading to this cancer. Nonrandom loss or gain of specific chromosomal segments has been seen in the tumor cells, particularly the most frequently encountered deletion of chromosome 1p35-36, which might be an ACC-specific chromosomal trait. Another ACC specific chromosomal abnormality is the translocation between chromosome 6q and 9p, which is found in greater than 85% of these tumors. This translocation creates the MYB:NFIB gene fusion, which leads to the overexpression of the MYB oncoprotein, which in turn promotes tumorigenesis. This is suggestive that the dysregulated MYB plays a key role in the pathogenesis and proliferation of ACC. Interestingly, important oncogenes and tumor suppressor genes that are frequently mutated in other cancers like the p53 tumor suppressor, RAS, and phosphatidylinositol-3-kinase (PI3K) growth factor signaling proteins are rarely altered in these tumors. Much remains to be understood regarding the specific mutations associated with ACC as they would pave the way for novel targeted immunotherapy, particularly in patients with advanced disease.
ACC was initially named ''cylindroma'' by Billroth, who initially described it in 1859, owing to the cylindrical arrangement of tumor cells in the hyaline stroma. The tumor cells have angulated hyperchromatic nuclei and minimal cytoplasm, which is usually clear or eosinophilic. Three distinct histological patterns are associated with ACC: tubular, cribriform, and solid, which are seen in varying degrees, often mixed, with the cribriform subtype being the most common. It derives its name from the multiple variably sized cyst-like spaces interspersed between small islands of basaloid cells. These cysts are not true cysts, as they do not represent a true glandular lumen, but are rather contiguous with the surrounding stroma. In the tubular pattern, tubular-shaped nests of malignant cells are found in surrounding hyalinized stroma. In the solid subtype, basaloid cells are arranged solid sheets, often having prominent mitotic activity and central necrosis.
Immunohistochemistry greatly aids in the diagnosis of ACC as the tumor cells stain positive for smooth muscle actin, S100, vimentin, as well as for MYB and CD 117 (receptor tyrosine kinase c-KIT) which helps differentiate it from other tumors.
The contribution of the solid component is a factor of the aggressiveness of the tumor. A grading strategy is used to describe the histology. The higher the solid parts, the higher the grade, while grade 1 tumors are mostly tubules or cribriform areas.
The prolonged asymptomatic clinical course of ACC may cause a delay in seeking medical attention. ACC is commonly locally aggressive, however distant metastasis can also occur. The most common presentation of ACC is a slow-growing, hard painless swelling in the head and the neck region, though pain and paresthesia are not uncommon as the tumor is notorious for perineural infiltration with the highest rates of perineural involvement seen in tumors arising from the parotid gland. The clinical features depend on the site of the primary tumor and the nerve infiltrated. For instance, in the case of a nasopharyngeal tumor, frequent epistaxis and worsening nasal stenosis are seen along with dysfunction of the eustachian tube. Tumors originating close to the skull base may cause ocular dysmotility, and cranial nerve palsies involving IX, X, XI, and XII. Cases of Horner's syndrome have also been reported. More than one-third of the cases progress to metastatic disease. The most common site of metastases via hematogenous spread is the lungs, followed by bone and liver. Rarely intracranial metastases can occur, though usually intracranial disease results from direct extension of the tumor or invasion along cranial nerves.
Radiological investigations like computerized tomography (CT) and magnetic resonance imaging (MRI) are the imaging of choice to help delineate the extension of the primary tumor as well as for staging purposes. A biopsy of the tumor is needed for definitive diagnosis where the characteristic histological features along with the immunohistochemical markers like smooth muscle actin, S100, vimentin, as well as for MYB and CD 117 (c-kit) confirm the diagnosis.
Complete resection of the tumor via surgery, if possible, is the mainstay for treatment. For localized ACC of the head and neck, care is taken to avoid accidental severance of nerve tissue in the adjoining area and to ensure clean surgical margins. In patients with the spread of disease to the cervical lymph nodes, modified radical neck dissection is the preferred route. However, despite good surgical techniques, the 5 to 10-year recurrence rate is roughly 75%. Surgically resectable cases with positive margins, perineural invasion, and positive lymph nodes carry a poor prognosis. Although there are no defined guidelines, most centers prefer patients to undergo postoperative radiation therapy in the presence of the poor prognostic factors, as studies have shown that it can significantly lower the rate of local recurrence compared to surgical resection alone. Whether postoperative radiation therapy leads to an overall increase in survival is still debatable as the evidence is confounded by the need for long-term follow-up as recurrence of malignancy is seen after 5 years in nearly 50% of the cases. Furthermore, radiation may prevent local recurrences, but patients may develop recurrences in distant sites outside the radiation field. Despite the lack of clarity in data, patients with intermediate or high-grade ACC or any grade tumor with positive surgical margins are recommended to have postoperative radiation treatment to 60 Gy or more. Patients with an irresectable tumor are generally offered radiation therapy with or without systemic treatment but have poorer outcomes.
Depending on the location of the tumor, the differential diagnosis includes both malignant and benign tumors of the affected organ. In cases where the primary tumor is located in the head and neck region, particularly the major salivary glands, important differential diagnoses to consider include pleomorphic adenoma, polymorphic adenocarcinoma, basaloid carcinoma, or mucoepidermoid carcinoma.
Because ACCs do not have a fast turnover rate, systemic chemotherapy does not confer benefit generally, and therefore a standard chemotherapy regimen is not a part of treatment for ACCs. However, the consensus remains to reserve chemotherapy for palliative purposes in patients with symptomatic metastatic disease, recurrent disease, or rapidly progressing tumors not amenable to surgery. Studies have also been done to look at possible molecular targets for immunotherapy agents, but results have been disappointing. Clinical trials looking at c-KIT (an onco-receptor overexpressed by ACCs) as a potential target for the c-KIT inhibitor, Imatinib, showed disappointing results. Similarly, drugs targeting the EGFR and HER-2 receptor families did not show any clinical benefit. However, a recent phase II trial looking at the tyrosine kinase inhibitor axitinib in patients with incurable recurrent/metastatic ACC showed that 66.7% of patients had tumor shrinkage and 9.1% of patients had a partial response suggesting that patients with 4q12 amplified ACCs may benefit from tyrosine kinase inhibitors. NTRK inhibitors such as larotrectinib should be considered in NTRK mutations in the absence of other available options in recurrent or metastatic tumors, as approved by the FDA.
ACCs generally carry a favorable prognosis with a 5-year survival rate of around 75%, but the 10-year survival rate drops acutely to 20%. Features associated with poor prognosis include the size of >4 cm of the primary tumor and a solid subtype histological pattern. Other features like perineural invasion and bone involvement are also associated with unfavorable outcome and increased mortality. Unfortunately, as the tumor mainly originates in the head and neck region, often at times a complete resection of the tumor is not without complications because of the surrounding neurovascular bundles, which greatly increase the chances of local recurrence.
Depending on the region where the tumor originates, it can cause complications such as facial pain and paralysis, particularly if it involves the facial nerve. Apart from intraoperative surgical complications that occur during the removal of the tumor, the most common complication seen is the recurrence of the malignancy which is more commonly seen in patients with large, bulky tumors with lymphovascular infiltration and/or positive nodal status. Furthermore, even in patients where ACC was diagnosed and resected in the early stage, there is a high risk of distant metastases, particularly in patients with age >45 years, lymph node involvement, and high-grade solid subtype histological features.
Upon diagnosis, the patient should be counseled regarding the slow-growing and locally aggressive nature of the tumor. The treatment depends on the stage, but largely involves surgical resection followed by radiation therapy in the presence of high risk features. The patient should, however, be educated about the possibility of recurrence of the malignancy even as late as more than 5 years after the initial surgery, so periodic medical follow up should be reinforced.
The slow-growing kinetics, along with the rarity of the condition, often hinders in early diagnosis of ACC. While the treatment is mainly surgical, it is important to consult with an interprofessional team that includes a radiologist, radiation oncologist, and a medical oncologist to tailor the best possible treatment for the patient. The radiologist plays a pivotal role in studying the images for staging purposes, which are crucial to deciding the surgical technique. The radiation oncologist can weigh in on the benefit of postoperative radiation, which plays a crucial part in the overall management of the patient. Lastly, although there is no defined role of systemic chemotherapy in the treatment of localized ACC, in unresectable, recurrent, and metastatic cases, chemotherapy and targeted agents are the only options. Therefore, a medical oncology consult is also advised. Although there are no strict guidelines for the overall management of the ACC, a multidisciplinary approach can improve outcomes and quality of life. [Level 2]
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