Salivary Gland Adenoid Cystic Carcinoma

Introduction

Adenoid cystic carcinoma (ACC) is a type of cancer that affects glandular tissue, like the lacrimal glands, trachea and most commonly, the salivary glands.¹

Importance of understanding ACC
Though salivary gland tumours are rare, ACC is the second most common type of cancer that affects the major salivary glands, and the most common that affects the minor salivary glands, and it overall represents about 1% of head and neck cancer cases.¹ 10% of salivary gland cancers are adenoid cystic carcinomas.¹ It is, therefore, of the utmost importance to be informed about it. In this article we will discuss specifically adenoid cystic carcinoma of the major and minor salivary glands, what causes it, signs and symptoms to look out for, and treatment and management of this type of cancer.

Causes and risk factors

Genetic factors and mutations

Adenoid cystic carcinoma (ACC), unlike other types of oral cancer such as squamous cell carcinoma, is not related to smoking or consuming alcohol:¹ it has been linked, however, to a few genetic mutations. Deletion of region 1p35-36, a part of chromosome 1, has been suggested as an ACC-specific mutation.¹

Another mutation is the one affecting the MYB gene.²

• When a translocation of chromosomes 6 and 9 occurs, that is, a piece of chromosome 6 breaks off and is fused to chromosome 9, the MYB gene is fused with the NFIB gene. These two genes, when together, activate the MYB gene abnormally, causing excessive cell proliferation.² This mutation is found in about 85% of cases of ACC, making it the most common finding¹
• Alternatively, the MYB gene is activated by either having another copy of itself attachedor by being close to an enhancer sequence of DNA, causing similar results²

The MYB gene is responsible for regulating cell growth and proliferation. It is known as an oncogene once it presents itself as mutated or expressed excessively: it causes uncontrolled proliferation of the cells - in other words, cancer.

Another gene related to adenoid cystic carcinoma is MYBL1: it is closely related to MYB in functions, and also in how it works as an oncogene.³ When paired with NFIB, for instance, MYBL1 also promotes excessive cell proliferation.³

Both genes are said to be oncogenes.³ But what does that mean exactly? An oncogene is a gene, a part of our genetic code, that can potentially cause cancer.⁴ In a normal cell, these genes exist as proto-oncogenes, their normal variations: they control cell growth and proliferation, but also apoptosis, the cell's death.⁴ Once a normal cell grows old and its DNA is damaged beyond repair, it is "killed" by an internal process called apoptosis, and new, healthy cells replace it.⁴

A cancerous cell, however, is a heavily damaged cell that suffered mutations in one or more genes that control the cell's cycle of life.⁴ Instead of being destroyed once its cycle reaches the end, a cancer cell continues to proliferate towards infinity. These cells grow and take away resources like oxygen and nutrients from normal, healthy cells, without completing the functions they should be doing (like producing saliva, in the case of salivary glands cells). They multiply and can take over locally the tissue or organ, and can even spread through blood vessels or lymphatic vessels to distant organs - a process called metastasis.⁵

Environmental factors

Environmental factors also play a role in this type of cancer.⁸ Previous history of head and neck radiation therapy increases the risk of salivary gland cancer, because radiation can promote DNA mutation of cells.⁸ Occupational exposure  to radiation, as well as to nickel compounds or alloys, and rubber industry products (especially those containing nitrosamines) have also been listed as risk factors that can increase the chance of developing ACC, and also to a poorer prognosis.⁸

One interesting environmental factor that is being studied is diet: though with a small sample of 150 patients with ACC, a study done by Horn-Ross and Ljung has found that dietary intake of vitamin C was associated with a 60% decrease in risk of developing salivary gland cancer, as well as a 51% decrease of risk with fibre intake.⁹ According to the same study, a higher cholesterol intake was associated with an increased risk of salivary gland cancer.⁹ Those findings suggest that, although a huge part of ACC risk is associated with genetic factors and mutations, dietary changes that are also beneficial in preventing chronic illnesses have a positive impact on reducing the risk of salivary gland cancer.⁹

Symptoms and diagnosis

Common symptoms and signs

Signs and symptoms can vary depending on the site of the tumour. Most commonly it causes a hard, slowly growing mass in the head and neck region.¹ While initially painless, this type of tumour can cause pain or paresthesia (loss of sensation): although of slow growth, it is a locally aggressive and infiltrative neoplasm that is known for perineural infiltration - when cancer cells engulf a nerve.¹ This type of tumour is notorious for it, having the highest rate of perineural invasion in parotid gland tumours.¹

Nervous symptoms are important to notice because they can show where the tumour is located and where it is spreading:

• Nose bleeding (epistaxis) and nasal stenosis can point to a nasopharyngeal tumour¹
• Facial nerve palsy is possible if the parotid gland is involved
• Horner syndrome, a condition that causes ptosis (drooping) of the eye, miosis (contraction of the pupil) and anhidrosis (lack of sweating) in one side of the face has been reported as a consequence of a salivary gland adenoid cystic carcinoma (ACC)¹

Metastasis of ACC can also cause symptoms. Although this type of cancer grows slowly and is known to be locally aggressive, long-distance metastasis has been reported in one-third of cases.¹ When it happens, it most frequently affects the lungs, bones and liver.¹

Diagnostic methods

Any hard mass in the head and neck area should be investigated by a physician. Image exams like a CT scan or an MRI can find an accurate location of the neoplasm, but only a biopsy can tell for sure what kind of tumour this mass is.¹

A biopsy of the tumour will take a piece of it and look at it under a microscope to evaluate the cells and structures of the tissue. Immunohistochemistry (IHC) is a type of staining that is frequently used to diagnose tumours: it stains specific molecules, like proteins, and only these specific molecules. Some of the most common IHC stains used to test for adenoid cystic carcinoma are MYB and smooth muscle actin.¹ If a tissue sample is positive for these molecules and the overall aspect of the sample is befitting of ACC, diagnosis is confirmed.

As mentioned, a biopsy can confirm or not if a tumour is positive for ACC, but other conditions can present similarly and be confused with salivary gland adenoid cystic carcinoma. Other possible diagnoses are mucoepidermoid carcinoma, basaloid carcinoma, pleomorphic adenoma, and polymorphous adenocarcinoma, though any salivary gland tumours can be considered.¹

Types and staging

Variants of ACC

Microscopically, we also look for different variants of adenoid cystic carcinoma, and different variants greatly influence prognosis.⁷ There are three known patterns: tubular, cribriform and solid.⁷ These names refer to the actual structure of the tissue: tubular and cribriform patterns resemble normal salivary gland tissue, with duct formation, while solid tumours are a compact mass of cancerous cells.⁷ A three-grade classification of ACC has been widely used, proposing Grade 1 (low grade) as a tumour without any solid parts, Grade 2 (intermediate grade) as having up to 30% of solid areas, and Grade 3 (high grade) as having more than 30% of solid components. Recently, the classification of variants has been discussed and suggestions to simplify it into Grade 1 (no solid component) and Grade 2 (solid component present) have been made.⁷ Either way, solid components (high grade) indicate a poorer prognosis.⁷

Staging systems

A staging system is something that helps medical professionals to understand how serious the disease is and to plan for a better treatment.¹⁰ The most commonly used staging system for cancer is the TNM system: it is an acronym for Tumour, (lymph) Nodes, and Metastasis.¹⁰ In this system, there is a number attached to the letter to indicate what it means.

• T: the primary tumour
  • T1 to T4 indicates the size of the tumour; the bigger the number, the larger it is¹⁰
  • T0 means there is no visible tumour¹⁰
  • TX means there is a tumour that cannot be found or measured¹⁰
• N: the regional lymph nodes affected
  • N1 to N3 indicates the number of lymph nodes that have been affected by cancer; the bigger the number, the larger number of lymph nodes have been involved¹⁰
  • N0 means there is no lymph node affected¹⁰
  • NX means the lymph nodes cannot be measured¹⁰
• M: metastasis
  • M0 means there is no distant metastasis¹⁰
  • M1 means there is distant metastasis¹⁰
  • MX means metastasis cannot be accesed¹⁰

In practice, saying a patient has a T2N1M0, for example, means that this patient has a  small to moderate-sized tumour, with lymph node involvement present to a smaller extent, and no long-distance metastasis. This sort of classification creates a standard for communication between medical professionals, simplifying it.

Another staging system is the 0 to IV staging.¹⁰ It is a more simplified approach:

• Stage 0: represents a carcinoma in situ, that is, abnormal/mutated cells that have not proliferated through surrounding tissue; though not cancer, it can become cancer¹⁰
• Stage I: localised cancer¹⁰
• Stage II: locally advanced cancer with early stages of spreading¹⁰
• Stage III: locally advanced cancer with late stage of spreading¹⁰
• Stage IV: metastatic cancer¹⁰

Treatment options

Surgery

Surgical removal of the tumour, with a wide margin of resection, is usually the first choice of treatment whenever possible¹. In some cases, affected lymph nodes can be removed, usually the whole chain of lymph nodes, to avoid recurrence or further spreading.¹

Operating is not always possible. Due to its prevalence of perineural invasion, the cancerous cells can follow along nerves and form secondary smaller tumours not connected to the primary tumour¹. Besides, the complicated anatomy of the head and neck region and risk of running into vital structures might discourage a surgical approach: a tumour that extends to the paranasal sinuses or nasal cavity can easily infiltrate the orbit, cavernous sinus, pterygopalatine fossa, or Meckel cave, and therefore continue to proliferate and reach the base of the cranium or the intracranial space.⁶ Surgical errors, even if millimetric, affecting these areas, can result in greater damage than the risk of not removing the tumour at all.

Radiation therapy

Radiation therapy is usually advised even when surgery has been done, as an adjuvant therapy to minimise the risk of recurrence.¹ Without surgery, radiation therapy is still used but has a poorer outcome.¹

Systemic therapies

Immunotherapy has been considered recently as a treatment option. Although there are promising treatments targeting genes and proteins expressed by ACC tumours, there is currently no consensus on them, as studies are still being held to analyse outcomes, and immunotherapy still has a long way to go before becoming a first option treatment.⁶ Some of the molecules being studied as targets are EGFR, VEGF, histone deacetylase (HDAC) inhibitors and C-Kit: tumours have responded partially to treatment of these targets, but a complete response has yet to be achieved.¹¹

Palliative care

Palliative care is suggested for advanced stages, with recurring ACC tumours or inoperable metastasis.¹¹ In these cases, chemotherapy has been used to treat secondary tumours accordingly: however, concomitant chemotherapy and radiotherapy have not been recommended as clinical practice and have  long been discontinued.¹¹ More important than a pharmaceutical approach, giving the patient psychological and emotional support, fulfilling their needs and taking care of pain and discomfort can and should be done regardless of clinical outcome.

Prognosis and survival rates

Factors influencing prognosis

Prognosis of ACC depends highly on many factors. How big the tumour is, if it is surgically possible to remove it entirely with a clean margin if it is infiltrating vital structures (that cannot or should not be removed), if there are lymph nodes affected, if there is distant metastasis, how well differentiated the tumour is under microscopical examination, among many other factors that should be accessed individually.⁶ Other factors that point towards a poor prognosis are older age, female sex, tumours located in the sinonasal area, lymphovascular invasion, intraneural invasion, and high-grade  transformation of cells.⁷

Survival rates

Survival rates are greater at first, but the recurrence risk undermines it. Recurrence reaches 75% in 5 to 10 years after initial diagnosis, and survival rates (which are about 75% in 5 years) drop to 20% in 10 years.¹ It has a poor prognosis in the long run because even if the tumour is entirely removed and radiation therapy is done, distant metastasis can still develop or the tumour can recur from the remaining cells of the original.¹

Follow-up care and surveillance

Importance of regular monitoring

Due to its high recurrence rate, it is extremely important to monitor the patient closely for, ideally, the rest of their life.¹ Recurrence reaches 75% in 5 to 10 years after initial diagnosis, and a patient will likely  deal with ACC for the rest of their life.¹

Surveillance techniques

Frequent physical exams, as well as image exams, can help diagnose earlier any metastasis or recurrence of the primary tumour: CT scans of the lungs, the usual site of metastasis, can show secondary tumours, and MRI scans can help determine if a primary tumour has grown and infiltrated through surrounding tissue even after surgery with clear margins.¹¹

Fluorodeoxyglucose positron emission tomography (FDG) is a type of CT scan that injects a modified glucose (sugar) compound with a radioactive fluorine ion as a contrast agent.¹¹ This molecule is absorbed much like a regular sugar molecule would be, and is visible during the scan: since cancer cells consume a lot of resources to sustain themselves, it is presumed that they would consume most of the modified sugar as well. However, low absorption of FDG is common due to the salivary gland cells’ naturally lesser affinity for sugar, resulting in a false negative in some cases.¹¹ The use of FDG as a diagnostic means has been debatable because of it.

Summary

Salivary gland adenoid cystic carcinoma is a rare type of cancer that affects the salivary glands. Though uncommon, it represents 10% of all salivary gland tumours, affecting mostly females over the age of 50, and usually presents as a hard mass or swelling that may or may not be painful. Surgical resection is considered the best approach, along with adjuvant radiotherapy, but other alternatives have been and are being studied, like immunotherapy. Although with a tendency to have a good prognosis at first, it is important to do regular follow-ups to decrease chances of recurrence and distant metastasis, as this type of tumour is known for its high mortality rate after 10 years.