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Adenoid Cystic Carcinoma (ACC)

A. JABBAR DENTAL CLINIC KARACHI

Sadia Khan

Overview

Adenoid cystic carcinoma (ACC) is a rare malignant neoplasm that develops in the secretory glands. It can affect the throat, mouth, and other areas of the body, including the tear and sweat glands. 
Adenoid cystic carcinoma (ACC) is a kind of cancer that typically originates in the salivary glands or other areas of the head and neck. Other locations of the body where ACC can develop include the breast, skin, cervix in females, and the prostate gland in males. 
&nbsp;

ACC tumors are distinguished by the presence of aberrant &quot;nests&quot; or cords of the epithelial cells that surround and/or infiltrate ducts or glandular systems inside the diseased organ. Typically, these formations are filled with a mucous-like fluid or have aberrant fibrous membranes. These abnormal nests can be seen when tumor cells from a biopsy sample are examined under a microscope.

It&#39;s usually classified as low-grade cancer with a history of slower development. However, in rare cases, ACC can be highly invasive and infiltrate neighboring lymph nodes as well as the perineural spaces. It recurs later at the location where it originally appeared and, in roughly 50% of individuals, ACC spreads to distant body regions, mainly the lungs that can cause life-threatening problems<a href="#accordion">[1]</a>.

ACC is most commonly diagnosed in adults between the ages of 40 and 60; however, it can also affect children and adolescents<a href="#accordion">[1]</a>. This condition affects an estimated 200,000 people worldwide, with approximately 60% being female. Around 1,300 people are diagnosed with ACC each year in the United States alone<a href="#accordion">[2]</a>.

Late ACC recurrence is frequent and can occur several years after the first therapy. Recurrences of ACC are identified at the metastatic stage around half of the time, which means it has already spread to other regions of the body. Survival rates begin to decline after 10 years<a href="#accordion">[4]</a>. 
&nbsp;

Based on histological tumor growth patterns ACC is categorized into the following<a href="http://#accordion">[1]</a>: 
&nbsp;

1.&nbsp;Cribriform: The most frequent development pattern is cribriform, which shows as a &quot;Swiss cheese&quot; pattern in histological stains.

2.&nbsp;Tubular: This type is often less aggressive and has the best prognosis<a href="#accordion">[8]</a>.

3.&nbsp;Solid: Tumors with a solid pattern are more likely to spread and have a worse prognosis. 
&nbsp;

Signs and Symptoms

The majority of the cases occur in adults, but it can develop in children, too. And even though ACC is generally less aggressive in children, symptoms vary from one individual to the next, depending on the location, size, type, and progression of the tumor. 
&nbsp;

<h5>ACC Of The Salivary Gland</h5>

<ul>
	<li>Facial pain</li>
	<li>Facial drooping</li>
	<li>Facial numbness, especially numb lips 
	&nbsp;</li>
</ul>

<h5>ACC Of The Lacrimal Gland</h5>

Adenoid cystic carcinoma occurs in the gland that generates tears in certain persons. (Among the possible symptoms are:

<ul>
	<li>Vision changes</li>
	<li>Bulging eye</li>
	<li>Swelling and pain 
	&nbsp;</li>
</ul>

<h5>ACC Of The Skin</h5>

Adenoid cystic carcinoma usually affects the scalp or the external ear canal when it originates in the skin. Symptoms include:

<ul>
	<li>Pain</li>
	<li>Pus</li>
	<li>Bleeding</li>
	<li>Increased sensitivity</li>
	<li>Hair loss in the afflicted region 
	&nbsp;</li>
</ul>

<h5>ACC Of The Lower Respiratory Tract</h5>

Adenoid cystic carcinoma of the lower respiratory tract typically develops in the tracheal mucous glands. This can gradually clog the windpipe, resulting in:

<ul>
	<li>Difficulty breathing</li>
	<li>High-pitched, wheezing sound when breathing in&nbsp;</li>
	<li>Hoarseness 
	&nbsp;</li>
</ul>

<h5>ACC Of The Larynx</h5>

The region right below the glottis &mdash; the slit-like hole between the vocal cords &mdash; can be affected by ACC malignancies of the larynx. This illness can cause a variety of symptoms, including:

<ul>
	<li>Dyspnea or shortness of breath</li>
	<li>Difficulty breathing while exercising</li>
	<li>Hoarseness</li>
	<li>Voice change</li>
	<li>Pharyngitis or throat discomfort</li>
	<li>Difficulty swallowing</li>
	<li>A mass in the neck</li>
	<li>Neck pain 
	&nbsp;</li>
</ul>

<h5>ACC Of The Esophageal</h5>

Even though it&rsquo;s not a common occurrence, adenoid cystic carcinoma can develop in the esophagus. When this happens, symptoms can include:

<ul>
	<li>Difficulty swallowing liquids, soft foods, and even saliva</li>
	<li>Indigestion</li>
	<li>Unintended weight loss 
	&nbsp;</li>
</ul>

<h5>ACC Of The Breast</h5>

ACC of the breast is unlikely to spread in most circumstances. This kind of adenoid cystic carcinoma can be identified by:

<ul>
	<li>A movable mass in one breast, generally around the areola&nbsp;</li>
	<li>Breast tenderness and pain</li>
	<li>Nipple discharge in rare instances 
	&nbsp;</li>
</ul>

<h5>ACC Of The Cervical</h5>

Adenoid cystic carcinoma of the cervix can occur in women, commonly after menopause. It is extremely aggressive and is distinguished by a massive cervical tumor. Symptoms include:

<ul>
	<li>Vaginal discharge</li>
	<li>Vaginal bleeding</li>
	<li>Vaginal pain 
	&nbsp;</li>
</ul>

<h5>ACC Of The Prostate</h5>

When ACC develops in the prostate, it is classified as a kind of prostate adenocarcinoma. Symptoms include:

<ul>
	<li>Frequent urination</li>
	<li>Poor urine flow</li>
</ul>

In rare cases, adenoid cystic carcinoma can spread to other parts of the body. 
&nbsp;

Causes

Till date, there is uncertainty regarding the cause of adenoid cystic carcinoma. Research points towards several genetic mutations identified during the chromosomal analysis and sequencing of over 80 ACC genomes, with age being an independent predisposing risk factor.

According to some studies, MYB-NFIB, a protein formed by the fusion of two transcription factor genes, has a role in the formation of ACC malignancies, especially since it has been detected in 90-95% of cases<a href="#accordion">[1]</a>. 
&nbsp;

Moreover, the inactivation of the p53 tumor suppressor gene rarely occurs, except for the aggressive types of ACC. This gene is necessary to limit cell growth; mutation causes it to lose its tumor-suppressive activities and, at the same time, to gain oncogenic functions that support cancer growth. The same holds true for the PI3K growth factor signaling proteins and RAS; they&rsquo;re rarely altered in ACC<a href="#accordion">[5]</a>. However further research is needed. 
&nbsp;

Diagnosis

Numerous tests are performed to determine the presence of ACC. Not every test listed here will be applied to every individual. When selecting a diagnostic test, the doctor will take these things into account: 
&nbsp;

<ul>
	<li>The part of the body where it started</li>
	<li>Symptoms</li>
	<li>Patient&rsquo;s age and overall health&nbsp;</li>
	<li>The findings of previous medical testing 
	&nbsp;</li>
</ul>

<h5>Self-Check And Physical Exam</h5>

While ACC is not a common type of cancer and given that the tumors grow slowly, it&rsquo;s important that the individual is consciously aware of any changes their body undergoes. Any abnormalities that they can pinpoint and bring their doctor&rsquo;s attention to can help with early diagnosis. 
&nbsp;

For instance, in most cases, ACC initially affects the salivary glands, which are located in the head and neck, and then spreads to other parts of the body (liver, lungs, and bones). Check for any signs of change in terms of color or lumps under the tongue, inside the cheeks, on the floor and roof of the mouth, and on the lips. Also, check the lymph nodes for tenderness.

The ENT will thoroughly examine the ear, nose, and throat. The examination can also reveal neurologic symptoms, like facial numbness. and order a biopsy and further tests if they suspect ACC. 
&nbsp;

Note: Routine lab tests are not diagnostic tests because there&rsquo;s no blood test for ACC; they just help to rule out other causes of the symptoms<a href="#accordion">[9]</a>. A complete blood count test is often performed along with a comprehensive metabolic panel, tumor blood markers, gene testing, and circulating tumor cell test<a href="#accordion">[9]</a>. 
&nbsp;

Direct Laryngoscopy: A flexible, tube-like instrument is used to obtain direct visual examination of the larynx, especially if it&rsquo;s ACC of the larynx. Small samples of the laryngeal tissue may also be removed during the procedure for further microscopic examination<a href="#accordion">[1]</a>. 
&nbsp;

Barium X-Ray: If the doctor suspects ACC of the esophagus, this test is ordered. The patient is asked to swallow a mixture containing barium (a metallic chemical) and water. Barium is impenetrable by X-rays; therefore, subsequent imaging reveals the extent of the esophageal tumor. 
&nbsp;

Mammogram: This procedure is typically recommended for ACC of the breast. It&rsquo;s followed by fine-needle biopsy and microscopic evaluation of tumor tissue to categorize the nature of the tumor. Some researchers are of the opinion that surgical removal and microscopic evaluation of the malignancy should be conducted during the diagnosis and initial treatment only. However, given that involvement of the regional lymph nodes is rare in ACC of the breast, routine sampling of the regional lymph nodes during the initial stages may not be necessary. 
&nbsp;

Cervical Smear Test: This is a specialized test to locate abnormal cell changes in the cervix. It may be followed by colposcopy and biopsy. 
&nbsp;

Pyelography: In addition to a clinical examination of the prostate, pyelography, ultrasonography, biopsy, and blood studies may be considered to confirm ACC of the prostate gland. 
&nbsp;

Differential Diagnosis: With ACC of the skin, it&rsquo;s imperative to eliminate the diagnosis of other possible skin cancers, including primary cutaneous cribriform apocrine carcinoma and basal cell carcinoma. 
&nbsp;

Biopsy: A biopsy can help make a definite diagnosis of cancer. A tiny sample of tissue is taken for microscopic analysis. However, salivary gland pathology can be challenging. For this reason, it&rsquo;s imperative that the tissue is analyzed by an experienced head and neck pathologist who deals with disorders of the salivary glands. 
&nbsp;

Imaging Assessments: Before doing surgery, imaging techniques, such as CT scans or MRIs, allow surgeons to examine the tumor&#39;s size and position.

<ul>
	<li>Ultrasound: The test uses soundwaves to create pictures of the inside of the body. The patient lies down and a gel is spread over the affected part of the body. The transducer is then moved over that part. It&rsquo;s a painless procedure. 
	&nbsp;</li>
	<li>Magnetic Resonance Imaging (MRI): An MRI creates precise pictures of the body using magnetic fields. A special dye called a contrast medium is administered to provide a sharper image. This dye can be administered intravenously or as a tablet or liquid for ingestion. MRIs are used to determine the tumor size, but they can also be used to check tumor growth along nerve branches. 
	&nbsp;</li>
	<li>Computed Tomography (CT&nbsp;Or CAT&nbsp;Scan): A CT scan uses X-rays captured at various angles to create a detailed, 3-D image of the inside of the body that reveals any anomalies or malignancies. A CT scan can also be used to assess tumor size. Again, a contrast medium is administered either intravenously or orally before the scan. 
	&nbsp;</li>
	<li>Positron Emission Tomography (PET)&nbsp;Or PET-CT Scan: Sometimes, a PET scan is combined with a CT scan. A tiny quantity of a radioactive sugar compound is administered intravenously to the patient. Cells that consume the most energy absorb this sugar molecule. Since cancer cells consume energy aggressively, they&rsquo;re highlighted by a scanner. 
	&nbsp;</li>
</ul>

NOTE: The radiation level is too low to be dangerous so it&rsquo;s a safe procedure. 
&nbsp;

The TNM staging system for salivary gland tumors is used for ACC<a href="#accordion">[2]</a>.

If the tumor comes from a major salivary gland, then the staging for a major salivary gland tumor is utilized. For instance, if the tumor originates from the salivary gland, then the TNM staging technique for the oral cavity will be used. 
&nbsp;

TNM stands for:

<ul>
	<li>Tumor (T): Where is the tumor located and how large is it?</li>
	<li>Node (N): Is the tumor spreading to the lymph nodes? If yes, then where and how many are affected?</li>
	<li>Metastasis (M): Is the primary tumor spreading to other parts of the body? If yes, where and how much?</li>
</ul>

Staging is either clinical or pathological. Overall, there are 5 stages, beginning with Stage 0 and going from Stage 1-4. 
&nbsp;

Tumor (T)

The &ldquo;T&rdquo; describes the location and size of the tumor.

<ul>
	<li>TX: The primary tumor cannot be assessed.</li>
	<li>T0: There&rsquo;s no evidence of a tumor.</li>
	<li>T1: It&rsquo;s a small tumor (2 cm max), which is non-invasive.</li>
	<li>T2: The tumor has grown and is now 2-4 cm big; it&rsquo;s still non-invasive, though.</li>
	<li>T3: The tumor is 4-6 cm big; it&rsquo;s spreading beyond the salivary gland but does not have any effect yet on the seventh nerve.</li>
	<li>T4a: The tumor has spread to the skin, ear canal, jawbone, and/or facial nerve.</li>
	<li>T4b: The tumor has spread to the skull base and/or the arteries or nearby bones. 
	&nbsp;</li>
</ul>

Node (N)

The &ldquo;N&rdquo; is for lymph nodes.

<ul>
	<li>NX: The neck has undergone an intervention that prevents the evaluation of lymph nodes.</li>
	<li>N0: There&rsquo;s no evidence of cancer in the regional nodes, i.e., lymph nodes near the head and neck.</li>
	<li>N1: Cancer&rsquo;s 3 cm or smaller and is spreading to a single node on the same side as the primary tumor.</li>
	<li>N2a: Cancer&rsquo;s 3-6 cm large and has spread to a single lymph node on the same side as the primary tumor.</li>
	<li>N2b: The tumor is as big as 6 cm and is spreading to more than one lymph node on the same side as the primary tumor.</li>
	<li>N2c: The tumor is not larger than 6 cm and is spreading to more than one lymph node on either side of the body.</li>
	<li>N3: Cancer is larger than 6 cm. 
	&nbsp;</li>
</ul>

Metastasis (M)

The &ldquo;M&rdquo; refers to the fact that cancer has spread to other parts of the body.

<ul>
	<li>MX: Distant metastasis cannot be evaluated.</li>
	<li>M0: Cancer has not spread to other parts of the body.</li>
	<li>M1: Cancer has spread to other parts of the body. 
	&nbsp;</li>
</ul>

Using the TNM system, the doctor grades ACC accordingly:&nbsp;

<ul>
	<li>Stage I: A noninvasive tumor (T1 or T2) with no spread to lymph nodes (N0) and no distant metastasis (M0).</li>
	<li>Stage II: It depicts an invasive tumor (T3) with no spread to lymph nodes (N0) or distant metastasis (M0).</li>
	<li>Stage III: A smaller tumor (T1 or T2) that has expanded to regional lymph nodes (N1) but displays no signs of metastasis (M0).</li>
	<li>Stage IVA: This stage describes any invasive tumor (T4a) that either has no lymph node involvement (N0) or has spread to only a single, same-sided lymph node (N1), but with no metastasis (M0). Additionally, it can refer to any tumor (any T) with severe nodal involvement (N2) but no metastasis (M0), as well as a T3 tumor with one-sided nodal involvement (N1) but no metastasis (M0).</li>
	<li>Stage IVB: This stage describes any cancer (any T) with more extensive spread to lymph nodes (N2 or N3) and no metastasis (M0).</li>
	<li>Stage IVC: This stage describes any cancer (any T, any N) with distant metastasis (M1). 
	&nbsp;</li>
</ul>

Treatment

While the major objective of treatment is to eradicate cancer, it&#39;s also essential to maintain the function of the neighboring nerves, organs, and tissues. Doctors consider a patient&#39;s quality of life, including how they feel, look, talk, eat, and breathe when planning therapy. 
&nbsp;

<h5>Surgery</h5>

The best course of therapy for ACC, provided it can be carried out safely and is likely to provide positive results, is surgical excision of the tumor.

A margin is a region of healthy tissue that surrounds the tumor that will be removed by the surgeon during surgery. The margin of the tumor that is removed after surgery is said to have been &quot;clean&quot; if there are at least 2 mm of cancer-free tissue surrounding it. The surgery&#39;s scope changes depending on the location of the tumor and the body part involved. 
&nbsp;

Side Effects Of Surgery For ACC

Facial drooping due to severing of the facial nerve is a potential negative effect of surgery, A permanent facial drooping is usually associated with ACC of the parotid gland. Consequently, the individual will require another reconstructive surgery to treat facial drooping. 
&nbsp;

<h5>Radiation Therapy</h5>

If the doctor is unable to remove the entire tumor without endangering crucial organs or if they are concerned that cancer has spread undetected, they will opt for radiation treatment. The three most common types are: 
&nbsp;

<ol>
	<li>&nbsp;External beam radiation concentrates high-energy X-rays or protons on the target tissue to kill cancer cells.</li>
	<li>&nbsp;Brachytherapy is another name for internal radiation therapy. Small radioactive &quot;seeds&quot; are injected into or around the tumor. It is usually done when cancer has progressed to the lungs. The radioactivity of the seeds decreases after a few weeks.</li>
	<li>&nbsp;Neutron therapy targets tiny malignancies while allowing the healthy cells around them to regenerate. 
	&nbsp;</li>
</ol>

The Side Effects Of Radiation Therapy

This includes dry mouth, nausea and vomiting, swallowing issues, hair loss, deterioration of teeth, or pain in the treated region. 
&nbsp;

<h5>Chemotherapy</h5>

Drugs are used in chemotherapy to either kill or halt the development of cancer cells.

Chemotherapy is rarely applied to treat ACC. However, it can be considered as part of palliative care or a clinical study when cancer has reached an advanced stage. 
&nbsp;

<h5>Palliative Care</h5>

Palliative care usually includes medication, relaxation techniques, nutritional changes, emotional support, and other therapies, and works to enhance the quality of life of the patient by relieving cancer symptoms. In addition to alleviating pain and assisting in the management of other symptoms, palliative care can help stop the progression of ACC.&nbsp; 
&nbsp;

The complication of the disease depends upon the region where the tumor emerges: 
&nbsp;

<ul>
	<li>It causes facial pain and paralysis in case it involves facial nerves.</li>
	<li>Intraoperative surgical complication while removing the tumor. This might result in relapsing the malignancy.</li>
	<li>Metastasis is a very common complication which is common in patients above 45 years of age.</li>
	<li>A severe complication is the high death rate that is associated with oral (part of head and neck) cancers, not because it couldn&rsquo;t be diagnosed; rather, it&rsquo;s because the cancer was discovered later after it had spread to other parts of the body. 
	&nbsp;</li>
</ul>

According to the Oral Cancer Foundation, overall survival rates are 76% and 63% at 5 and 10 years respectively. Later-stage discovery and, consequently complications, occur frequently because there is no option for early screening<a href="#accordion">[9]</a>. 
&nbsp;

Currently, risk factors for ACC remain obscure, since the results of&nbsp; scientific research have been inconsistent<a href="#">[4]</a>. 
&nbsp;

There is presently no known strategy to lower the chance of developing adenoid cystic carcinoma. Additionally, there is no known mechanism to prevent a relapse<a href="#accordion">[4]</a>. 
&nbsp;

A review of nearly 40 Phase II clinical studies with a focus on ACC patients or salivary gland cancer patients with a sizable ACC patient population concluded<a href="#accordion">[7]</a>: 
&nbsp;

<ul>
	<li>Regulatory authorities have not yet approved any chemotherapies, immunotherapies, or targeted medications for ACC because none have shown that they can appreciably reduce tumors or lengthen lives in a significant number of ACC patients. Fortunately, improved outcomes from targeted medications and immunotherapies are being achieved as a result of a better understanding of the biology of ACC malignancies. 
	&nbsp;</li>
	<li>Lenvatinib and Apatinib (Rivoceranib), have shown the best rates of objective responses in ACC patients in recent studies. Axitinib and sorafenib, two comparable targeted medications, also appear to stabilize ACC tumors in a significant majority of ACC patients. While the medications do not treat the disease, they may slow down its progression for six months or longer, which is a significant advantage for individuals with progressive disease. Some oncologists also prescribe Vorinostat for their patients who are making progress. 
	&nbsp;</li>
	<li>Only a tiny percentage of ACC tumors respond significantly to treatment. Medical oncologists, however, frequently turn to chemotherapy when their ACC patients are faced with few treatment options, quick progression, severe symptoms, or central nervous system involvement. The most frequently prescribed chemotherapy is cisplatin, which is frequently given in combination with vinorelbine or with doxorubicin, cyclophosphamide, and/or doxorubicin. Sometimes low-dose chemotherapy is used to decrease tumor-related pain or to make tumors more sensitive to radiation. 
	&nbsp;</li>
</ul>

Key Points

<ul>
	<li>Adenoid cystic carcinoma (ACC) is a rare malignant neoplasm that develops in the secretory glands. It can affect the throat, mouth, and other areas of the body, including the tear and sweat glands.</li>
	<li>ACC tumors are distinguished by the presence of aberrant &quot;nests&quot; or cords of the epithelial cells that surround and/or infiltrate ducts or glandular systems inside the diseased organ.</li>
	<li>ACC is classified as low-grade cancer with a history of slower development. However, in rare cases, it can be highly invasive and infiltrate neighboring lymph nodes as well as the perineural spaces.</li>
	<li>Imaging techniques, such as CT scans or MRIs, allow surgeons to examine the tumor&#39;s size and position.</li>
	<li>The best course of therapy for ACC, provided it can be carried out safely and is likely to provide positive results, is surgical excision of the tumor. 
	&nbsp;</li>
</ul>

[1] Adenoid cystic carcinoma. NORD (National Organization for Rare Disorders).  Published May 29, 2019. Accessed January 1, 2023.

[2] View all pages. Cancer.Net.

[3] Adenoid cystic carcinoma: Rare form of cancer in saliva glands. WebMD.

[4] Adenoid cystic carcinoma (ACC): Symptoms, pathology, Prognosis & What it is. Cleveland Clinic.

[5] Ammad Ud Din M, Shaikh H. Adenoid Cystic Cancer. [Updated 2022 Jun 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-.