Polymorphous adenocarcinoma

by Jason Wasserman MD PhD FRCPC
June 27, 2024

Polymorphous adenocarcinoma (previously known as polymorphous low-grade adenocarcinoma) is a type of cancer that arises in the salivary glands. It typically occurs in the minor salivary glands found throughout the mouth and throat. This tumour is most commonly seen in the palate, but it can also occur in other areas such as the lip, buccal mucosa (inside of the cheek), and floor of the mouth. It is characterized by various cellular patterns and structures, which is why it is called “polymorphous.”

What are the symptoms of polymorphous adenocarcinoma?

Patients with polymorphous adenocarcinoma may notice a painless mass or swelling in the mouth or throat. Other symptoms can include difficulty swallowing, changes in speech, or a sore that does not heal. Because it is a slow-growing tumour, symptoms may develop gradually over time.

What causes polymorphous adenocarcinoma?

The exact cause of polymorphous adenocarcinoma is not well understood. Like many cancers, it is believed to result from genetic mutations that cause cells to grow and divide uncontrollably. Various factors, including environmental exposures and genetic predispositions, may influence these mutations. However, no specific risk factors have been definitively identified for polymorphous adenocarcinoma.

Histologic subtypes of polymorphous adenocarcinoma

Pathologists classify polymorphous adenocarcinoma into two main histologic subtypes: conventional and cribriform. This classification is based on the microscopic appearance and structural patterns of the tumour cells.

Conventional subtype

The conventional subtype of polymorphous adenocarcinoma commonly arises in the palate, but it can also be found in other parts of the oral cavity. It is characterized by various growth patterns, including tubular, trabecular, papillary, and solid formations. These tumours often display a diverse and sometimes confusing array of architectural patterns within the same tumour, which is why the term “polymorphous” is used. Cells in this subtype are generally uniform in appearance, with minimal cellular atypia. They tend to be low grade, meaning they have a slower growth rate and a lower potential for aggressive behaviour.

Cribriform subtype

The cribriform subtype of polymorphous adenocarcinoma is more likely to arise in the floor of the mouth or base of the tongue. It also features a distinct growth pattern. The tumour cells form sieve-like (cribriform) structures with numerous small, round spaces. This pattern resembles other salivary gland tumours, such as adenoid cystic carcinoma, but cribriform polymorphous adenocarcinoma typically lacks the high grade features seen in those more aggressive tumours. While the cribriform subtype can be slightly more aggressive than the conventional subtype, it still generally behaves as a low grade malignancy.

Why is the subtype important?

Identifying the subtype of polymorphous adenocarcinoma is important for several reasons:

• Prognostic information: Knowing whether a polymorphous adenocarcinoma is of the conventional or cribriform subtype can help predict the tumour’s behaviour. Although both subtypes are generally low grade, the cribriform subtype may have a slightly higher risk of local invasion, recurrence, and metastatic spread.
• Treatment decisions: The subtype can influence treatment decisions. For example, tumours with a cribriform pattern might require closer follow-up and more extensive surgical margins to ensure complete removal due to their potential for slightly more aggressive behaviour.
• Differential diagnosis: Properly identifying the subtype helps differentiate polymorphous adenocarcinoma from other salivary gland tumours with similar histologic patterns, such as adenoid cystic carcinoma. This differentiation is crucial as it impacts the overall treatment approach and prognosis.

Microscopic features

Conventional subtype

When examined under the microscope, the conventional type consists of a uniform population of tumour cells arranged in various patterns, including single cells, tubular, trabecular, cystic, and solid. A few mitotic figures (cells dividing to create new cells) may be seen. The tumour cells in this type frequently surround nerves and blood vessels in a circular pattern that pathologists describe as targetoid or ‘eye of the storm’ because it resembles the eye of a hurricane.

Cribriform subtype

The cribriform type of polymorphous adenocarcinoma shares many microscopic features with the conventional type. However, the tumour cells in the cribriform type are more likely to show cribriform or papillary growth patterns. Distinctive round structures, characterized as glomeruloid because they resemble the glomerulus in the kidney, are also often seen.

What other tests may be performed to confirm the diagnosis?

Immunohistochemistry

Immunohistochemistry (IHC) is a test that allows pathologists to see the expression of specific proteins inside the tumour cells. Cells that express protein are called positive or reactive. Cells that do not express a protein are called negative or non-reactive. The tumour cells in polymorphous adenocarcinoma are typically positive for cytokeratin 7 (CK7), S100, SOX10, and p63. Some tumours are positive for epithelial membrane antigen (EMA), smooth muscle actin (SMA), and muscle-specific actin (MSA). The tumour cells should be negative for p40. However, not all of these markers will be ordered for every case.

Next-generation sequencing

Next-generation sequencing (NGS) may be ordered to look for one of the genetic changes or fusions commonly seen in polymorphous adenocarcinoma (PRKD mutations or translocations). The results will describe any fusions or other genetic changes identified.

Grade

Polymorphous adenocarcinoma is typically graded based on its histological features. The World Health Organization (WHO) uses a three-tier system to classify polymorphous adenocarcinoma into low, intermediate, and high-grade categories. This grading system helps to predict the tumour’s behaviour and guide treatment decisions.

• Low grade: Most polymorphous adenocarcinomas are considered low grade. These tumours tend to show very little cytologic atypia, minimal mitotic activity, and no necrosis. They tend to grow slowly and have a low risk of metastasis.
• Intermediate grade: These tumours show more marked cytologic atypia and increased mitotic activity. Focal tumour necrosis may also be seen. Most cribriform subtype tumours are best categorized as intermediate grade.
• High grade: These tumours tend to show significant cytologic atypia, high mitotic activity, and necrosis. They are more likely to grow rapidly and metastasize.

Why is the tumour grade important?

The grade of polymorphous adenocarcinoma is important because it provides information about the tumour’s likely behaviour, including its growth rate, potential to spread, and overall prognosis. Higher-grade tumours generally have a worse prognosis and may require more aggressive treatment.

Perineural invasion

Perineural invasion (PNI) is the process by which cancer cells spread along or around nerves. This phenomenon is significant in head and neck cancers, including polymorphous adenocarcinoma. Cancer cells can travel along the nerve fibres to reach areas beyond the primary tumour site when they invade the perineural spaces. Perineural invasion is an important pathological feature because it can indicate a higher risk of local recurrence and can be associated with a more aggressive disease course. Symptoms related to perineural invasion may include pain or nerve dysfunction, depending on the nerves involved.

Lymphovascular invasion

Lymphovascular invasion (LVI) refers to the presence of cancer cells within the lymphatic system or blood vessels. This type of invasion is a critical step in the metastatic spread of cancer, as it allows tumour cells to travel through the lymphatic system or bloodstream to distant sites in the body. In polymorphous adenocarcinoma, lymphovascular invasion is important in determining the prognosis and guiding treatment decisions. The presence of lymphovascular invasion typically suggests a higher likelihood of metastasis, particularly to regional lymph nodes or other organs, which can affect the overall treatment approach and outcome.

Margins

In pathology, a margin is the edge of tissue removed during tumour surgery. The margin status in a pathology report is important as it indicates whether the entire tumour was removed or if some was left behind. This information helps determine the need for further treatment.

Pathologists typically assess margins following a surgical procedure, like an excision or resection, that removes the entire tumour. Margins aren’t usually evaluated after a biopsy, which removes only part of the tumour. The number of margins reported and their size—how much normal tissue is between the tumour and the cut edge—vary based on the tissue type and tumour location.

Pathologists examine margins to check if tumour cells are present at the tissue’s cut edge. A positive margin, where tumour cells are found, suggests that some cancer may remain in the body. In contrast, a negative margin, with no tumour cells at the edge, suggests the tumour was fully removed. Some reports also measure the distance between the nearest tumour cells and the margin, even if all margins are negative.

Lymph nodes​

Small immune organs, known as lymph nodes, are located throughout the body. Cancer cells can travel from a tumour to these lymph nodes via tiny lymphatic vessels. For this reason, doctors often remove and microscopically examine lymph nodes to look for cancer cells. This process, where cancer cells move from the original tumour to another body part, like a lymph node, is termed metastasis.

Cancer cells usually first migrate to lymph nodes near the tumour, although distant lymph nodes may also be affected. Consequently, surgeons typically remove lymph nodes closest to the tumour first. They might remove lymph nodes farther from the tumour if they are enlarged and there’s a strong suspicion they contain cancer cells.

Pathologists will examine any removed lymph nodes under a microscope; the findings will be detailed in your report. A “positive” result indicates the presence of cancer cells in the lymph node, while a “negative” result means no cancer cells were found. If the report finds cancer cells in a lymph node, it might also specify the size of the largest cluster of these cells, often referred to as a “focus” or “deposit.” Extranodal extension occurs when tumour cells penetrate the lymph node’s outer capsule and spread into the adjacent tissue.

Examining lymph nodes is important for two reasons. First, it helps determine the pathologic nodal stage (pN). Second, discovering cancer cells in a lymph node suggests an increased risk of later finding cancer cells in other body parts. This information guides your doctor in deciding whether you need additional treatments, such as chemotherapy, radiation therapy, or immunotherapy.