Neuroendocrine carcinoma of the nasal cavity and paranasal sinuses is a rare, fast-growing cancer. It starts in cells with features of neuroendocrine cells, which can release hormones into the blood. Doctors often call it sinonasal neuroendocrine carcinoma. Two main types exist: small cell neuroendocrine carcinoma and large cell neuroendocrine carcinoma.
Sinonasal neuroendocrine carcinoma is a high-grade cancer, meaning the cells look very abnormal and divide quickly. It differs from a neuroendocrine tumor of the sinonasal tract, which has more orderly cells and usually grows more slowly. The two names sound alike, so it helps to check which one appears on your report.
This article explains how small cell and large cell neuroendocrine carcinoma of the nose and sinuses are diagnosed. It also describes what the tests, margins, lymph nodes, and stage in your pathology report mean for your care.
Sinonasal neuroendocrine carcinoma is found mostly in adults, with a typical age at diagnosis in the 50s. In a study of 415 patients from a large US cancer database, the median age was 58 years, and about 6 in 10 patients were men.
About half of these tumors start in the nasal cavity, the space inside the nose. Most of the rest start in the paranasal sinuses, the air-filled spaces in the bones around the nose and eyes. Small cell neuroendocrine carcinoma is more common than large cell neuroendocrine carcinoma at this site.
For most people with sinonasal neuroendocrine carcinoma, the cause is unknown. The cancer develops from genetic changes that build up in the tumor cells during a person’s life. Sinonasal neuroendocrine carcinoma is not known to run in families.
A small group of these tumors is linked to high-risk human papillomavirus (HPV), the same virus that causes cervical cancer and many throat cancers. HPV-associated squamous cell carcinoma of the throat usually has a favorable outlook. HPV-associated neuroendocrine carcinoma does not share that advantage, and it behaves like other neuroendocrine carcinomas.
The symptoms of sinonasal neuroendocrine carcinoma come from a growing mass inside the nose or sinuses. The most common are:
Because sinus infections and nasal polyps also cause these symptoms, the cancer is often large by the time it is found. Very rarely, the tumor cells release hormones into the blood and cause symptoms elsewhere in the body.
The diagnosis of sinonasal neuroendocrine carcinoma is made after a tissue sample is examined under the microscope by a pathologist. The sample is usually removed during nasal endoscopy, either in the clinic or in the operating room. In this procedure, a thin camera is passed into the nose to see the tumor and take a biopsy.
Under the microscope, the pathologist sees sheets of tightly packed, abnormal cells. Many cells are dividing, and these dividing cells are called mitotic figures. By definition, a neuroendocrine carcinoma has more than 10 mitotic figures per 2 square millimeters. There are often large areas of dead tumor cells, called necrosis. The size and shape of the cells tell the pathologist whether the tumor is small-cell or large-cell.
Small cell carcinoma is much more common in the lung than in the nose. For this reason, your doctors will review scans of the chest to make sure the tumor in the nose did not spread from the lung. CT and MRI scans of the face and skull show how far the tumor has grown. A PET scan is often used to look for spread to lymph nodes or distant organs.
Sinonasal neuroendocrine carcinoma looks similar to several other fast-growing cancers of the nose. A panel of special stains is therefore needed to confirm the diagnosis, as described in the next section.
Immunohistochemistry uses antibodies to detect specific proteins inside cells. For sinonasal neuroendocrine carcinoma, it confirms that the tumor cells are neuroendocrine and rules out other cancers that look alike. Your report may list some or all of these results:
Not every sinonasal neuroendocrine carcinoma needs every stain. The pathologist chooses the panel based on what the tumor looks like and which other cancers need to be ruled out.
The World Health Organization (WHO) Classification of Head and Neck Tumors, 5th edition, published in 2022, divides sinonasal neuroendocrine carcinoma into two types. The College of American Pathologists (CAP) protocol for the nasal cavity and sinuses also lists a combined form. Your report will name one of the following:
Small cell and large cell neuroendocrine carcinoma are both high grade and are usually treated similarly. A related diagnosis, called neuroendocrine tumor grade 3, has orderly cells that divide quickly. It is a separate diagnosis and is described in our article on neuroendocrine tumors of the sinonasal tract.
Sinonasal neuroendocrine carcinoma is not divided into well, moderately, or poorly differentiated grades. Both the small cell and the large cell types are high-grade cancers by definition. Older reports sometimes used the term poorly differentiated neuroendocrine carcinoma for the same diagnosis.
Your report may describe the tumor as high-grade, or the grade line may say that grade is not applicable. Either way, the diagnosis itself tells your care team that the tumor grows quickly and is likely to spread. The grade does not need to be assigned separately to guide treatment decisions.
Perineural invasion means cancer cells are seen along or inside a nerve. In sinonasal neuroendocrine carcinoma, nerves near the skull base can give the tumor a path to spread toward the brain. Your report will say whether perineural invasion was identified, not identified, or could not be determined.
Lymphovascular invasion means cancer cells are seen inside a blood vessel or lymphatic channel. In sinonasal neuroendocrine carcinoma, this finding raises concern that tumor cells could travel to lymph nodes or other organs. Your report will say whether lymphovascular invasion was identified, not identified, or could not be determined.
A margin is the edge of tissue the surgeon cuts to remove the tumor. Margins are described only when sinonasal neuroendocrine carcinoma has been removed by surgery, not on a biopsy. Your report will describe them as follows:
Lymph nodes are small immune organs that filter fluid from the tissues. Sinonasal neuroendocrine carcinoma can spread to lymph nodes in the neck. Lymph nodes are removed in an operation called a neck dissection when scans show they may contain cancer.
When lymph nodes are examined, your report will say how many were removed and how many contain cancer cells. It will also give the size of the largest group of cancer cells in a lymph node. The report will also say whether extranodal extension is present, meaning cancer cells have broken through the outer capsule of a lymph node into surrounding tissue. Extranodal extension increases the nodal stage and is one of the findings your care team considers when planning treatment after surgery.
In a large US database study of sinonasal neuroendocrine carcinoma, cancer in several lymph nodes, or in one large node, was linked to shorter survival.
For sinonasal neuroendocrine carcinoma, there is currently no biomarker test that selects a targeted drug made specifically for this cancer. When the cancer has returned or spread, your care team may order broader tests on the tumor. These tests look for rare features that make a patient eligible for drugs approved for any solid tumor, no matter where it started. These approvals are called tumor-agnostic.
Mismatch repair proteins fix mistakes made when a cell copies its DNA. Testing is usually done by immunohistochemistry for four proteins, called MLH1, PMS2, MSH2, and MSH6. Your report will describe the result in one of these ways:
A deficient result can make a patient eligible for immunotherapy. The US Food and Drug Administration (FDA) approved pembrolizumab in 2017 for dMMR or MSI-high solid tumors. The FDA approved dostarlimab in 2021 for dMMR solid tumors. A deficient result can also indicate an inherited condition called Lynch syndrome, so genetic counseling may be offered.
Tumor mutational burden is the number of genetic changes found in the tumor cells. Next-generation sequencing (NGS) measures it. Results are reported as mutations per megabase, or mut/Mb. A result of 10 mut/Mb or more is called TMB-high, and a lower result is called TMB-low. In 2020, the FDA approved pembrolizumab for TMB-high solid tumors that have grown after earlier treatment when no good alternative exists.
NGS can also find rare changes such as an NTRK or RET gene fusion or a BRAF V600E mutation. The FDA has approved targeted drugs for solid tumors carrying each of these changes, regardless of where the cancer started. These changes are uncommon in sinonasal neuroendocrine carcinoma, so a negative result is expected. More information is available in our Biomarkers and Genetic Testing section.
The pathologic stage for sinonasal neuroendocrine carcinoma uses the TNM system in the AJCC Cancer Staging Manual, 8th edition. The pTNM stage combines the tumor stage (pT) and the nodal stage (pN). The metastasis stage (M) is usually decided from scans rather than from the pathology report.
The tumor stage for sinonasal neuroendocrine carcinoma depends on where the tumor started. In a large US database study, about two in three of these tumors had already grown into nearby structures and were classified as T4.
Nasal cavity and ethmoid sinus:
Maxillary sinus:
If the tumor stage cannot be assessed, for example because the tumor was removed in many small pieces, your report may say that the pT stage was not assigned.
Your care team combines the pT stage, the pN stage, and your scans to assign an overall stage group from stage I to stage IV. A tumor that is pT4a is at least stage IVA, and a tumor that is pT4b is stage IVB. Cancer that has spread to distant organs is stage IVC.
The prognosis for sinonasal neuroendocrine carcinoma is guarded, because the cancer tends to grow back and to spread to distant organs. Because the disease is rare, survival figures come from pooled case reports and database studies rather than clinical trials.
A 2016 review pooled 115 published cases of sinonasal small cell carcinoma. About 46 percent of these patients had not died of the cancer five years after diagnosis, which means more than half had. Some recent single-center reports describe better results, but they include only small numbers of patients. Survival figures for the large cell type at this site have not been published in large enough groups to give a reliable number.
Several findings are linked to a worse outcome:
Patients who received more than one kind of treatment did better in the same database study. Your care team can explain how these findings apply to you.
Once sinonasal neuroendocrine carcinoma has been confirmed by pathology, the next steps depend on the type of carcinoma, the stage, and whether the cancer has spread. Your care team will usually include a head and neck surgeon, a radiation oncologist, and a medical oncologist. No single standard treatment exists because the disease is rare.
When the cancer has not spread to distant organs, the team often combines treatments. Options include:
When the cancer has spread, chemotherapy with a platinum drug and etoposide is the usual starting point. For small cell carcinoma, some teams consider the approach used for small cell lung cancer. That approach adds an immunotherapy drug such as atezolizumab, which the FDA approved in 2019 for small cell lung cancer. It is not approved for cancer that starts in the nose, so its use here would be off-label.
No drug has been approved by the FDA specifically for neuroendocrine carcinoma of the nose and sinuses. Clinical trials are testing new drugs for neuroendocrine carcinomas that start outside the lung, and your oncologist can tell you whether any are open to you. After treatment, regular endoscopy and scans are used to watch for the cancer coming back.