Oral Cancer: HPV-related Small Cell Carcinoma of the Oropharynx

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HPV-related oropharyngeal cancer is becoming more widely discussed in literature and dental offices. Over the past 30 years, we have learned more about HPV’s role in oropharyngeal cancer. Currently, oropharyngeal cancer is the most common HPV-related cancer in the United States.1

Most of the oropharyngeal cancer caused by HPV are squamous cell carcinomas. However, there are multiple phenotypes that are often overlooked. Some of the various phenotypes associated with HPV are non-keratinized squamous cell carcinoma, basaloid squamous carcinoma, undifferentiated carcinoma, papillary squamous cell carcinoma, adenosquamous carcinoma, spindle cell carcinoma, and small cell carcinoma.2

In most cases, HPV-related oropharyngeal cancers have a good prognosis. There is always an exception to every rule, though. Of the above-mentioned phenotypes of HPV-related cancers, the least talked about, and most deadly, is the small cell carcinoma with a mean survival rate of 10 months with a range from 10 to 48 months overall. Small cell carcinomas mostly occur in the lungs, but they do arise in other sites, most commonly in the larynx.3

Aggressive Cancer

Although HPV-related small cell carcinoma of the oropharynx is a newly recognized variant of HPV-related head and neck cancers, several case studies that have described the progression and prognosis. These case studies report aggressive behavior with a high mortality rate.4-6,8

One such case study reviewed medical records of six patients with a confirmed diagnosis of HPV-related small cell carcinoma of the oropharynx. Of these six patients, 11 cytopathology specimens were identified. Most were acquired through fine needle aspiration, with only one being from a tonsillar imprint performed during surgery.

The patients’ mean age was 61.3 years, with a range from 48 to 81 years of age. Four of the six patients had never smoked, while two had smoking history. Primary lesions were tonsils (four patients) and base of the tongue (two patients).

All patients were treated with chemotherapy and radiation. Two patients also underwent surgical debulking, and two were treated additionally with nivolumab (an immunotherapy drug used to treat a variety of cancers). Unfortunately, all patients died from metastatic disease within 12 to 48 months after diagnosis.5

Immune Checkpoint Inhibitor Therapy

Another case report showed a robust response to the use of immune checkpoint inhibitor therapy. This case was a 69-year-old male patient who presented with left-side neck mass. He underwent neck dissection to reveal glossopharyngeal sulcus carcinoma with mixed squamous cell and small cell pathology. Treating physicians adopted the treatment model for small cell lung carcinomas. This treatment included chemotherapy and radiation; after completion of chemotherapy and radiation minimal progression was observed.

Unfortunately, at the patient’s three-month follow-up, disease progression was observed, which included new pulmonary nodules and a new hepatic metastasis. This was followed by four more cycles of chemotherapy, yet follow-up images revealed worsening pulmonary and hepatic disease.

Combination immunotherapy was implemented with a regimen of ipilimumab and nivolumab. After one dose of ipilimumab and three doses of nivolumab, significant improvement was noted. After an additional dose of ipilimumab, the patient began experiencing multiple autoimmune issues, including immune-related colitis, hypothyroidism, and diabetes mellitus type 1. He was treated for the autoimmune issues, and immunotherapy was withheld.

At a four-month follow-up, scans showed complete resolution of hepatic lesions and pulmonary lesions up to 23mm and a 67% decrease in pulmonary target lesion from 43mm to 14mm. Unfortunately, progression-free survival only lasted six months, at which time the patient had disease progression in the liver and lungs.

The patient underwent four more doses of nivolumab with prophylactic vedolizumab and tolerated treatment well. However, after treatment, he developed tumor-infiltrating lymphocytes, leading to a decline in the patient’s health. The patient was enrolled in hospice two months after finishing treatment and passed away soon after. Disease survival for this patient was 26 months.6

Histological Differences

The main difference in small cell carcinomas and other types of squamous cell carcinoma of the head and neck is the histology. The morphology and IHC (Immunohistochemistry) test results are like that of small cell carcinomas found in other areas such as the lungs rather than that of other HPV-related oropharyngeal squamous cell carcinoma types.7

Small cell carcinoma of the oropharynx, as well as basaloid squamous cell carcinoma of the aerodigestive tract, are quite rare. A significant difference is that basaloid squamous cell carcinomas that are HPV positive have a much higher survival rate than basaloid squamous cell carcinomas that are HPV negative. This is true for many of the other more common phenotypes as well, yet HPV positive status in small cell carcinomas does not increase survival rate.2

Standardized treatment for small cell carcinoma has not been established due to the limited number of cases. Currently, treatment is based off the treatment used for small cell lung cancer. The biggest hurdle is controlling disease metastasis. With proper control of diseases, metastasis prognosis is likely to improve.8

It is important to know HPV-related head and neck cancers are not of just one variety. There are multiple variants with different phenotypes. The importance of this is regarding patient management and prognosis. Treatment varies for different variants of HPV-related oropharyngeal cancers.

Far too often, I see dental professionals downplay the seriousness of HPV-related oropharyngeal cancer, claiming it has a better prognosis than oral cancer associated with alcohol and tobacco use. It is intellectually irresponsible to educate patients in that manner.

Knowing the different phenotypes and their prognosis can help dental professionals better educate their patients and peers. This is a disease we can prevent with proper education, vaccination, and improved treatment options. Dental professionals are on the front lines of this disease. The statistics going forward are going to reflect our ability as health-care providers and prevention specialists. Let’s do our part to prevent this disease from claiming more lives.

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  1. HPV and Cancer. (2023, April 4). National Cancer Institute. https://www.cancer.gov/about-cancer/causes-prevention/risk/infectious-agents/hpv-and-cancer
  2. El-Mofty, S.K. Human Papillomavirus-related Head and Neck Squamous Cell Carcinoma Variants. Semin Diagn Pathol. 2015; 32(1): 23-31.  https://pubmed.ncbi.nlm.nih.gov/25804342/
  3. Bishop, J.A., Westra, W.H. Human Papillomavirus-related Small Cell Carcinoma of the Oropharynx. Am J Surg Pathol. 2011; 35(11): 1679-1684.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3193931/
  4. Misawa, K., Kawasaki, H., Matsuo, R. et al. Human Papillomavirus-associated Small Cell Carcinoma/Neuroendocrine Carcinoma of the Oropharynx: A Report of Two Cases. SpringerPlus. 2016; 5: 1847. https://springerplus.springeropen.com/articles/10.1186/s40064-016-3501-x
  5. Allison, D.B., Rooper, L.M., Mustafa, S., et al. Cytopathologic Characteristics of HPV-related Small Cell Carcinoma of the Oropharynx. Cancer Cytopathol. 2019; 127(1): 35-43. https://pubmed.ncbi.nlm.nih.gov/30468701/
  6. Ho, W.J., Rooper, L., Sagorsky, S., Kang, H. A Robust Response to Combination Immune Checkpoint Inhibitor Therapy in HPV-related Small Cell Cancer: A Case Report. J Immunother Cancer. 2018; 6(1): 33. https://pubmed.ncbi.nlm.nih.gov/29743117/
  7. Ducatman, B.S. The Role of Human Papillomavirus in Oropharyngeal Squamous Cell Carcinoma. Archives of Pathology & Laboratory Medicine. 2018; 142(6): 715-718. https://pubmed.ncbi.nlm.nih.gov/29848036/
  8. Wakasaki, T., Yasumatsu, R., Masuda, M., et al. Small Cell Carcinoma in the Head and Neck. Ann Otol Rhinol Laryngol. 2019; 128(11): 1006-1012. https://pubmed.ncbi.nlm.nih.gov/31161776/