Hyalinizing clear cell carcinoma

by Jason Wasserman MD PhD FRCPC
November 5, 2024

Hyalinizing clear cell carcinoma (HCCC) is a slow-growing type of head and neck cancer. A genetic alteration involving the EWSR1 gene is found in most tumours. This type of cancer is typically found in minor salivary glands in the lip, tongue, buccal mucosa (inner cheeks), gingiva (gums), hard and soft palate (the roof of the mouth), floor of the mouth, or oropharynx (tonsils and base of tongue). Less common sites include the nasal cavity, paranasal sinuses, parotid gland, and larynx.

What are the symptoms of hyalinizing clear cell carcinoma?

The symptoms of hyalinizing clear cell carcinoma often include a painless lump or swelling in the mouth, gums, or throat, depending on where the tumour is located. People may experience discomfort, numbness, or mild pain if the tumour presses on nearby tissues or nerves. A doctor should evaluate any persistent lump or unusual changes in the mouth or throat.

What causes hyalinizing clear cell carcinoma?

The exact cause of hyalinizing clear cell carcinoma is not fully understood, but most of these tumours have a specific genetic change. Nearly all hyalinizing clear cell carcinomas contain a translocation, a type of genetic rearrangement involving two genes called EWSR1 and ATF1. This translocation typically results in a fusion between parts of these genes—specifically, EWSR1 exon 11 and ATF1 exon 3—creating a new gene fusion that may lead to tumour growth. Other, less common fusions involving EWSR1 (such as fusions with ATF1 exon 5 or with a different gene, CREM) have also been identified in hyalinizing clear cell carcinoma. While this genetic change is common in this type of cancer, it is still unclear why it occurs or what triggers it in the first place.

How is this diagnosis made?

To diagnose hyalinizing clear cell carcinoma, your doctor will typically start with an imaging test, such as an ultrasound, CT scan, or MRI, to assess the size and location of the tumour. If a suspicious area is found, a biopsy will be performed to take a small tissue sample. A pathologist will then examine this sample under a microscope to confirm the diagnosis. Sometimes, additional tests are done to help confirm that the tumour is hyalinizing clear cell carcinoma and to rule out other types of salivary gland cancers.

Microscopic features of this tumour

Under the microscope, hyalinizing clear cell carcinoma comprises clear or eosinophilic (pinkish) cells. Although it is called “clear cell carcinoma,” completely clear cell tumours are rare, and some tumours have no clear cells at all. The tumour cells are often arranged in nests, cords (long strands), and trabeculae (beam-like structures), with small ducts and cysts also present. Squamous cells (flat cells) and mucocytes (cells that produce mucus) are commonly seen as part of the tumour’s structure.

One unique feature of hyalinizing clear cell carcinoma is that it often infiltrates or spreads into nearby tissues, including muscle. In cases where the tumour starts in the mouth, it may connect with the surface lining (epithelium) and spread in a pagetoid pattern, meaning the tumour cells spread along the surface layer. The surrounding tissue (called the stroma) has a mix of dense, hyalinized areas and looser, fibrous areas. This combination of tissue types is a characteristic feature of this type of cancer.

What other tests may be performed to confirm the diagnosis?

Most HCCCs harbour a genetic alteration involving the EWSR1 gene. Your pathologist may order tests such as fluorescence in situ hybridization (FISH) or next-generation sequencing (NGS) to look for this genetic change. A test called immunohistochemistry may also be performed. By immunohistochemistry, the tumour cells are usually positive (or reactive) for the markers CK5, p40, p63, and CK7. They are generally negative (or non-reactive) for the markers S100 and SOX-10. Other immunohistochemical markers may also be ordered, although they are not required to make the diagnosis.

Tumour size

After the tumour has been completely removed, it will be measured, and its size will be described in your report. Tumour size is important because it determines the pathologic tumour stage (pT).

Extraparenchymal extension

In the context of a salivary gland tumour such as hyalinizing clear cell carcinoma, extraparenchymal extension (EPE) is the spread of the tumour beyond the salivary gland into the surrounding tissues. This condition is often associated with a more aggressive form of cancer, indicating that the tumour can invade beyond its original site. The presence of extraparenchymal extension is associated with more aggressive tumours and a worse prognosis.

Extraparenchyma, extension impacts the pathologic stage but only for tumours arising from one of the major salivary glands (parotid, submandibular, and sublingual). Tumours with extraparenchymal extension are generally classified at a higher stage, reflecting their advanced nature and the associated challenges in treatment and management.

Lymphovascular invasion​

Lymphovascular invasion occurs when cancer cells invade a blood vessel or lymphatic vessel. Blood vessels are thin tubes that carry blood throughout the body, unlike lymphatic vessels, which carry a fluid called lymph instead of blood. These lymphatic vessels connect to small immune organs known as lymph nodes scattered throughout the body. Lymphovascular invasion is important because it spreads cancer cells to other body parts, including lymph nodes or the liver, via the blood or lymphatic vessels.

Perineural invasion​

Pathologists use the term “perineural invasion” to describe a situation where cancer cells attach to or invade a nerve. “Intraneural invasion” is a related term that specifically refers to cancer cells inside a nerve. Nerves, resembling long wires, consist of groups of cells known as neurons. These nerves, present throughout the body, transmit information such as temperature, pressure, and pain between the body and the brain. Perineural invasion is important because it allows cancer cells to travel along the nerve into nearby organs and tissues, raising the risk of the tumour recurring after surgery.

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 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 entirely removed. Some reports also measure the distance between the nearest tumour cells and the margin, even if all margins are negative.

Lymph nodes​

Lymph nodes are small immune organs 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 lymph nodes removed under a microscope, and 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.

Pathologic stage

Pathologic staging is a system doctors use to describe the size and spread of a tumour. This helps determine how advanced the cancer is and guides treatment decisions. The pathologic stage is usually determined after the tumour is removed and examined by a pathologist, who analyzes the tissue under a microscope. For hyalinizing clear cell carcinoma, staging is based on the “TNM” system, where “T” stands for the size and extent of the primary tumour, “N” refers to lymph node involvement, and “M” indicates whether the cancer has spread to other parts of the body.

Tumour stage (pT)

The tumour stage describes the size of the tumour in the salivary gland and whether it has spread into nearby tissues.

• T0 means there is no evidence of a primary tumour in the salivary gland.
• Tis refers to carcinoma “in situ,” meaning the cancer cells are limited to where they started and have not invaded deeper tissues.
• T1 means the tumour is 2 cm or smaller and has not spread beyond the salivary gland.
• T2 refers to a tumour larger than 2 cm but not larger than 4 cm, still confined to the salivary gland.
• T3 means the tumour is larger than 4 cm or has spread to nearby soft tissues.
• T4 describes more advanced tumours. T4a means the tumour has spread to the skin, jawbone, ear canal, or facial nerve. T4b indicates very advanced cancer that has spread to the base of the skull, nearby bones, or major blood vessels.

Nodal stage (pN)

The nodal stage indicates whether the cancer has spread to the lymph nodes, which are small glands that help the body fight infection. Lymph node involvement can increase the risk of cancer spreading further.

• N0 means there is no spread to nearby lymph nodes.
• N1 indicates the cancer has spread to a single lymph node on the same side of the neck, measuring 3 cm or smaller.
• N2 describes more extensive lymph node involvement:
  • N2a: A single lymph node on the same side of the neck is affected, measuring up to 6 cm, or smaller nodes that show signs of cancer outside the node.
  • N2b: Multiple lymph nodes on the same side of the neck are affected, none larger than 6 cm.
  • N2c: Cancer has spread to lymph nodes on both sides of the neck or on the opposite side, none larger than 6 cm.
• N3 indicates more advanced lymph node involvement. N3a means a node larger than 6 cm is affected. N3b involves multiple nodes or any nodes where cancer has spread outside the lymph node into nearby tissues.

What pathologic factors are associated with prognosis?

The prognosis, or expected outcome, for hyalinizing clear cell carcinoma depends on several factors. Small tumours confined to one area typically have a better prognosis. Larger tumours or those that have spread into surrounding tissues or nerves may require more aggressive treatment. High grade transformation, which means the tumour cells become more aggressive and show signs such as increased cell division, atypia (more abnormal cell shapes), or areas of necrosis (dead cells), is associated with a poorer prognosis and may require additional therapy.