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 the 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 tend 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.
Adenoid cystic carcinoma (ACC) is an uncommon form of malignant neoplasm that arises within secretory glands, most commonly the major and minor salivary glands of the head and neck. Other sites of origin include the trachea, lacrimal gland, breast, skin, and vulva. This neoplasm is defined by its distinctive histologic appearance.
Causes
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.
Activation of the oncogenic transcription factor gene MYB is the key genomic event of ACC and is seen in the vast majority of cases.[rx][rx] Most commonly, MYB is activated through gene fusion with the transcription factor encoding the NFIB gene as a result of at(6;9) translocation.[rx] Alternatively, MYB is activated by copy number gain or by the juxtaposition of enhancer elements in the vicinity of the MYB gene.[rx] In a subset of ACCs, the closely related MYBL1 gene is fused to NFIB or to other fusion partners.[rx][rx]
Affected Populations
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 been 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.
Diagnosis
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 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, a physical examination may reveal the presence of a hard fixed mass, and certain neurologic symptoms, such as facial numbness, weakness, or pain due to the 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 a careful pathological review of histology combined with an 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 the 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.
Treatment
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 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, the extent of the primary tumor (stage), 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.
The primary treatment for this cancer, regardless of body site, is surgical removal with clean margins. This surgery can prove challenging in the head and neck region due to this tumor’s tendency to show a perineural discontinuous growth, meaning that it follows nerves and different “nests” of the tumor can exist without a connection to the original tumor. Therefore, MRI images should be analyzed following nerve tracts up to the brainstem. Adjuvant or palliative radiotherapy is commonly given following surgery. For advanced major and minor salivary gland tumors that are inoperable, recurrent, or exhibit gross residual disease after surgery, fast neutron therapy is widely regarded as the most effective form of treatment. Chemotherapy is used for metastatic disease. Chemotherapy is considered on a case-by-case basis, as data on the positive effects of chemotherapy are limited. Clinical studies are ongoing, however.
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