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.[2][9] 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.[10] 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.[1]

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.[9] 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%.[11] Surgically resectable cases with positive margins, perineural invasion, and positive lymph nodes carry a poor prognosis.[12] 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.[13] 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.[1]

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.[9]

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.[1] 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.[14][15] Similarly, drugs targeting the EGFR and HER-2 receptor families did not show any clinical benefit.[16][17][18] 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.[19] 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.[10] 

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.[20] 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.[20]

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.[21] [Level 2]