NORD gratefully acknowledges Cecelia Barry and Meredith McClain, NORD Editorial Interns from the University of Notre Dame, and Nicole Spardy Burr, PhD, Scientific Program Officer, Adenoid Cystic Carcinoma Research Foundation, for assistance in the preparation of this report.
Adenoid cystic carcinoma (ACC) is a relatively rare form of cancer that most commonly develops in the salivary glands or other regions of the head and neck. ACC can occur in other parts of the body, such as the breast, skin, cervix in females, prostate gland in males, and various other areas. ACC tumors are characterized by a distinctive histological pattern of abnormal "nests" or cords of certain cells (epithelial cells) that surround and/or infiltrate ducts or glandular structures within the affected organ. These structures are typically filled with a mucous-like material or contain abnormal fibrous membranes. Such characteristics are apparent during microscopic evaluation of tumor cells from a biopsy sample. ACC is considered a low-grade malignancy that has a history of slow growth. Rarely, ACC can be aggressively invasive and infiltrate nearby lymph nodes as well as the "sheaths" or coatings surrounding nerve fibers (perineural spaces). This form of cancer may have a tendency to recur later at the site where it first developed (local recurrence) and in approximately 50% of patients, ACC spreads to distant bodily sites, particularly the lungs (metastatic disease), potentially resulting in life-threatening complications. ACC typically occurs during adulthood, around the ages of 40 to 60, but has also been diagnosed in children and adolescents.
There are three histological tumor growth patterns common to ACC: cribriform, tubular, and solid. The cribriform growth pattern is most common and appears as a “Swiss cheese” pattern in histological stains. The cribriform and tubular growth patterns are less aggressive. Tumors exhibiting a solid pattern are more likely to spread and have a worse prognosis.
ACC most commonly arises in the salivary glands or other areas within the head and neck region. Symptoms of ACC of the salivary glands may include numbness of the lower lip and/or other facial areas; nerve impairment causing weakness of certain facial muscles; ongoing pain; and/or other associated abnormalities. The specific symptoms observed vary between patients and depends on both the size of the tumor and specific salivary gland and nerve(s) affected by the malignancy.
The lacrimal gland is the gland that produces tears. Symptoms of lacrimal gland ACC include a bulging eye (proptosis) or changes in vision. Although lacrimal gland ACC appears to occur predominantly during adulthood, there have been some reports of the disease in children and adolescents. Some researchers indicate that this form of ACC assumes a somewhat less aggressive course when it occurs among the young.
ACC may also arise in certain skin regions (primary cutaneous ACC). Such malignancies primarily develop on the scalp and external ear canal, potentially resulting in pain, discharge of pus and/or blood, and/or other symptoms. The development of isolated or multiple reddish (erythematous) nodules or plaques that vary in size typically characterize ACC of the skin. ACC of the skin is due to abnormal cell growth and tends to invade local soft tissue and bone aggressively. Other primary sites of tumor development include the arms or legs, and trunk. Although associated symptoms may vary, findings may include pain, increased sensitivity, or perceiving pain from stimuli not normally associated with pain. In addition, individuals with involvement of the scalp may experience hair loss in the area of tumor growth. ACC of the skin can be aggressive and may be associated with infiltration of nerves and, in rare cases, result in distant metastases. In addition, many affected individuals have local recurrences may develop months or years after surgical removal of the initial lesion.
ACC may also arise within certain organs of the lower or upper respiratory tract, breast, esophagus, cervix (females), and prostate gland (males). Descriptions of these forms of ACC are provided in the following paragraphs.
ACC of the lower respiratory tract most frequently develops in mucous glands of the trachea, particularly the upper third. In individuals with tracheal ACC, tumor growth gradually causes obstruction of the windpipe, resulting in difficult or labored breathing; hoarseness; and/or a high-pitched, respiratory sound upon the intake of breath (stridor). Additional symptoms may include a general feeling of ill health (malaise), weight loss, pain, recurrent inflammation of the lungs (pneumonitis), and/or the coughing up of blood.
In ACC of the lower respiratory tract, the malignancy tends to infiltrate regional lymph nodes and may spread along nerves to bone, particularly the spine (vertebrae). More rarely, sites of metastases may include the lungs, liver, brain, kidneys, or other regions.
In some individuals, ACC may also arise in mucous glands of the voice box (larynx), which lies between the throat and the trachea. ACC of the larynx most commonly arises in the region beneath the glottis, which is the slit-like opening between the vocal cords. In addition, these tumors may regionally invade the vocal cords. Tumor growth in the subglottic region gradually results in difficulty breathing upon exertion, shortness of breath, and eventual airway obstruction. When the malignancy develops above the opening; between the vocal cords, it may eventually result in persistent hoarseness, change in speech, difficulty swallowing, and soreness of the throat. In some individuals with ACC of the larynx, a mass may be seen in the neck area. Because this malignancy tends to infiltrate nerves, some affected individuals may also experience associated pain or discomfort. Laryngeal ACC may spread through the bloodstream, as well as via the nerves. Metastatic disease most typically occurs in the lungs; however, other sites may include bone or the brain.
ACC of the esophagus, which is extremely rare, has the same cellular structure and composition as ACC of the salivary glands and other areas of the body. As with ACC of the salivary gland, esophageal ACC is a slow-growing malignancy that may be prone to perineural invasion, local recurrences, and distant metastases. Initially, affected individuals may have problems swallowing solids. With increasing tumor growth, they may have difficulties swallowing soft foods as well as liquids, including even saliva in some cases. This typically results in regurgitation of food and liquids, with associated weight loss.
ACC may also arise in the breast. However, the disease course may be markedly different from primary ACC in other regions of the body. For example, ACC of the breast is considered a less aggressive malignancy that is not as likely to invade regional lymph nodes, metastasize, or locally recur. Compared to other forms of breast cancer, ACC is low-grade and progresses slowly. Researchers attribute such characteristics to several possible factors, such as slower overall tumor growth, relatively small tumor size, and an increased ability to remove all traces of such malignancies surgically. However, this malignancy tends to invade adjacent tissue and infiltrate nerves. In addition, although considered extremely rare, local recurrences may develop and metastatic disease may occur months or years after surgical removal of the primary tumor. The most common site of metastatic disease is the lung. Other, more rarely reported areas of metastasis include lymph nodes, soft tissue, bone, brain, and kidneys. Incomplete removal of the primary tumor contributes to rare cases of local recurrence and metastasis. Less than 0.1% of all breast carcinomas are diagnosed as ACC.
According to reports in the medical literature, only one breast is affected. To date, no cases have been reported in which both breasts developed ACC. ACC of the breast is characterized by the excessive growth of two specific cell types (luminal and basaloid) in specific patterns.
Patients develop a slowly enlarging, moveable mass that may cause tenderness or pain, unlike some other forms of breast cancer. Tumors tend to develop in the region of the nipple or areola (the pigmented, circular area of skin surrounding the nipple). Findings associated with other malignancies in this region include bloody discharge, indentation of the nipple, and/or tumor invasion of the chest muscle, appear to be uncommon in association with ACC.
In females, ACC may also arise in the cervix, particularly after menopause. Initial symptoms include a watery or bloodstained discharge or vaginal bleeding in association with a relatively large cervical mass. ACC of the cervix frequently recurs locally, spreads to lymph nodes/vessels and perineural spaces, and metastasizes to distant organs. ACC accounts for 0.1% of all cervical cancer cases and is very aggressive.
In males, ACC may arise in the prostate gland. This rare form of ACC is considered a subtype of prostate adenocarcinoma, a common form of prostate cancer. Symptoms may include poor flow of urine, increased frequency of urination, and/or difficulties beginning urination due to enlargement of the prostate gland and associated obstruction of the urinary tract.
Rarely, ACC may arise in other regions of the body. The specific symptoms and clinical course may vary from person to person, depending upon the primary tumor site, size, nature, progression, and other factors.
The exact cause of adenoid cystic carcinoma is unknown. However, current research suggests that genetic changes (mutations) are the underlying basis of cellular malignant transformation in many cancers, including ACC.
Researchers speculate that a protein produced by the fusion of two transcription factor genes, MYB-NFIB, plays a role in the development of ACC tumors. This fusion protein is found in up to 90-95 % of ACC tumors. Mutations in the NOTCH1 gene are also associated with ACC, particularly in patients with recurrent or metastatic disease. Patients with NOTCH1 gene mutations have a worse prognosis.
Every year, about 1,200 individuals are diagnosed with ACC in the United States. 58% of ACC patients exhibit tumors in the oral cavity, salivary glands, and pharynx, 17% in the respiratory system, 12% in the breast, and the remaining 13% of tumors occur in other areas of the body such as on the skin, lacrimal glands, prostate, etc. ACC makes up 10% of all tumors of the head and neck region.
ACC tends to appear more often in individuals between the ages of 40 and 60, with 58 being the median age. About 60% of patients with ACC are females, likely due to the higher prevalence of ACC in female specific primary sites (breast and genital system) compared to male specific primary sites. However, the average age at disease onset may vary from person to person, depending upon the form of ACC present and other factors. ACC primarily affects adults, but some forms, such as ACC of the lacrimal glands, have been reported in childhood and adolescence.
ACC of the salivary glands, the most common form of the disease, is thought to account for approximately 25 percent of malignant salivary gland tumors. It typically develops from early to late adulthood.
ACC of the lower respiratory tract accounts for less than one percent (0.1 to 0.2 percent) of all primary lung tumors. It appears to affect males and females relatively equally, and most commonly occurs during the fifth decade of life.
ACC of the larynx has been reported in individuals ranging in age from 25 to 75 years, with most cases occurring in the fifth to sixth decade of life. Males and females appear to be equally affected.
ACC of the skin generally affects adults with the average age at diagnosis around 59 years. ACC of the skin occurs more frequently in women compared to men and has not shown to affect one racial group more than others.
Primary ACC of the breast is extremely rare, representing less than one percent of all breast cancers (0.1 %). This form of ACC primarily occurs in females. In the few reported cases among males, disease presentation and course have been similar to that seen in affected females. This malignancy tends to become apparent during mid to late adulthood.
ACC of the cervix typically becomes apparent after menopause. However, there are a few reports of the disease in younger females.
ACC of the prostate tends to develop during or after middle age with the average age of patients’ being 50.
The diagnosis of adenoid cystic carcinoma is based upon a thorough clinical evaluation, characteristic symptoms and physical findings, a detailed patient history, and a variety of specialized tests. Such testing includes microscopic evaluation of tumor cells.
Biopsies play a major role in the evaluation and treatment plans of all forms of ACC. A biopsy involves the removal of a small portion of the diseased tissue in order for examination by a pathologist. Biopsies allow for a diagnosis of ACC, making it a more powerful test compared to other laboratory tests that can only evaluate and measure the disease.
In individuals with ACC of the salivary glands, physical examination may reveal the presence of a hard fixed mass, and certain neurologic symptoms, such as facial numbness, weakness, or pain due to involvement of particular nerves. In some cases, a diagnostic technique may be performed in which a thin, hollow needle is used to withdraw small samples of tissue from the salivary glands (fine-needle biopsy).
Specialized imaging techniques may be used to help evaluate the size, placement, and extension of the tumor and to serve as an aid for future surgical procedures, among individuals with ACC of the salivary glands or other regions of the head and neck. Such imaging techniques may include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. Laboratory tests and specialized imaging tests are performed to determine possible infiltration of regional lymph nodes and the presence of distant metastases.
Salivary cancers are hard to diagnose, and careful pathological review of histology combined with analysis of the MYB/MYBL1 genes may be necessary for a correct diagnosis. Identification of fusion between the two transcription factor genes MYB and NFIB may also be associated with ACC and help to confirm the diagnosis.
Among individuals with ACC of the lower respiratory tract, such as tracheal ACC, diagnostic testing often includes the use of a flexible instrument, inserted through the mouth or nose that produces an image of the trachea and the air passages of the lungs. During this procedure, biopsy samples are also obtained for microscopic evaluation. In addition, a series of procedures may be performed to evaluate the function of the lungs, particularly among older individuals being considered as surgical candidates.
Diagnostic testing for ACC of the larynx may include direct visual examination with a flexible, tube-like instrument (direct laryngoscopy) or indirect observation of the larynx’s interior with a mirror. Small samples of laryngeal tissue are also removed for microscopic examination.
In those with ACC of the esophagus, diagnostic testing may include barium x-ray procedures, during which a mixture containing water and a metallic chemical (barium) is swallowed. Because barium is impenetrable by x-rays, subsequent imaging of the digestive tract may help to reveal the nature and extent of the esophageal tumor. Diagnostic procedures may also include endoscopy, during which a flexible, tube-like instrument is used to visualize the esophagus and to obtain biopsy samples. Microscopic evaluation of biopsy samples may help to differentiate between “true ACC” and other forms of esophageal cancer.
In females with ACC of the breast, mammograms are typically performed. Fine-needle biopsy, microscopic evaluation of tumor tissue, and other laboratory techniques may then be performed to confirm ACC and to help characterize the nature of the malignancy. Some researchers suggest that the diagnosis and initial treatment of ACC of the breast should include surgical removal and microscopic evaluation of the malignancy. Unlike with many other forms of breast cancer, routine sampling of regional lymph nodes during initial surgery may be of questionable value, since involvement of regional lymph nodes is thought to be extremely rare with ACC of the breast.
In females with cervical ACC, diagnostic testing may include specialized tests to detect abnormal cellular changes in the cervix (cervical smear test), examination of the cervix with a magnifying instrument (colposcopy), and biopsy.
In males with ACC of the prostate gland, clinical examination of the prostate may reveal the presence of a hard mass. Diagnostic testing may include blood studies, specialized imaging of the urinary tract (pyelography), the use of high-frequency sound waves to create an image of the prostate and other internal organs (ultrasonography), biopsies, and/or other tests.
When diagnosing ACC of the skin, it is important to eliminate the possible diagnosis of other skin cancers such as basal cell carcinoma (BCC) and primary cutaneous cribriform apocrine carcinoma (PCCAC). Metastasis to the skin from primary ACC in another organ must also be ruled out.
The therapeutic management of individuals with ACC may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), specialists in the use of radiation to treat cancer (radiation oncologists), surgeons, oncology nurses, and other specialists (depending upon the primary tumor site).
In many individuals with ACC, standard therapy includes surgical removal of the malignancy and affected tissue followed by radiation. If initial surgery is not an option due to the specific location and/or progression of the malignancy, therapy may include radiation alone. Radiation therapy preferentially destroys or injures rapidly dividing cells, primarily cancerous cells. Various types of radiation may be used, depending on cancer type, location, stage and grade, prior treatments, etc.–including conventional external radiotherapy (e.g., standard photon and/or electron treatments) and/or, in some selected cases, neutron radiation.
ACC is resistant to chemotherapy, and few patients have been shown to benefit from drug treatment. Systemic therapy including chemotherapy has not been approved by the U.S. Food and Drug Administration for the treatment of ACC. However, patients with ACC who have progressive disease may be eligible to participate in a clinical trial of a specific drug therapy (See Investigational Therapies section below).
Tumor profiling (molecular analysis of alterations in DNA, RNA and proteins) is becoming increasingly important in helping physician researchers to select the best systemic therapy. Approximately 15-25% of recurrent/metastatic ACC patients have tumors with alterations in the NOTCH pathway (primarily in the NOTCH1 gene) that tend to be more aggressive. These patients may want to consider participating in a clinical trial of a NOTCH inhibitor.
Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as primary tumor location, extent of the primary tumor (stage), and degree of malignancy (grade), whether the tumor has spread to lymph nodes or distant sites, individual’s age and general health; and/or other elements. Decisions concerning the use of particular interventions are made by physicians and other members of the health care team in careful consultation with the patient, based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks; patient preference, and other appropriate factors.
Long-term follow-up is essential with ACC in ensuring the prompt detection and treatment of local recurrences and metastatic disease. Because the lungs are a common location of metastasis, physicians recommend regular CT scans of the lungs. Other standard therapies for individuals with ACC include symptomatic and supportive measures as required.
Current clinical trials are posted by the Adenoid Cystic Carcinoma Research Foundation here:
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
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