HPV independent squamous cell carcinoma of the vagina

by Jason Wasserman MD PhD FRCPC
March 27, 2025

HPV-independent squamous cell carcinoma of the vagina is a type of vaginal cancer that is not related to infection with human papillomavirus (HPV). This cancer develops when squamous cells in the lining of the vagina grow abnormally, forming a tumor that can invade surrounding tissues. To make this diagnosis, your doctors must rule out recent or simultaneous cancers of the cervix or vulva.

What are the symptoms of HPV-independent squamous cell carcinoma?

Symptoms are similar to those seen with HPV-associated squamous cell carcinoma. They can include unusual vaginal bleeding or discharge, bleeding after intercourse, pelvic pain, discomfort or pain during urination, and feeling a mass or foreign body sensation inside the vagina.

What causes HPV-independent squamous cell carcinoma?

The exact cause of HPV-independent squamous cell carcinoma of the vagina is currently unknown. Unlike HPV-associated types, this cancer develops without an HPV infection.

How common is HPV-independent squamous cell carcinoma of the vagina?

Vaginal squamous cell carcinoma overall makes up about 1–2% of all cancers of the female genital tract. HPV-independent cases vary widely, ranging from rare to common in different populations. Most women diagnosed with HPV-independent vaginal cancer are older, typically postmenopausal, with an average age around 73 years.

How is this diagnosis made?

Your doctor will begin by performing a physical examination and may order imaging tests. A definitive diagnosis requires a biopsy, which involves taking a small tissue sample from the affected area. A pathologist then examines this sample under the microscope.

What does HPV-independent squamous cell carcinoma look like under the microscope?

HPV-independent squamous cell carcinoma is made up of atypical squamous cells. It commonly appears as a keratinizing tumor under the microscope, meaning the cancer cells produce keratin, a protein typically found in the skin. Other patterns can also be seen. The cells usually form irregular, infiltrating clusters or sheets, with signs of abnormal cell shapes and frequent cell division.

What other tests may be performed to confirm the diagnosis?

Pathologists usually perform immunohistochemistry for proteins like p16 and p53. HPV-independent tumors typically do not strongly express the p16 protein. However, some HPV-independent tumors can still show weak positivity for p16, making HPV testing useful to confirm the absence of an HPV infection.

Histologic grade

Pathologists divide HPV independent squamous cell carcinoma of the vagina into three grades based on how much the tumor cells resemble normal squamous cells under the microscope. The grade is important because higher-grade tumors (moderately and poorly differentiated) behave more aggressively and are more likely to spread to other body parts.

• Well differentiated (Grade 1) – Tumor cells resemble normal squamous cells.
• Moderately differentiated (Grade 2) – Tumor cells differ from normal squamous cells but are still recognizable as squamous cells.
• Poorly differentiated (Grade 3) – Tumor cells look very abnormal and bear little resemblance to normal squamous cells. These cells may require additional tests like immunohistochemistry for confirmation.

Tumor extension

Tumor extension describes how deeply a tumor has grown into surrounding tissues or organs. Understanding the extent of tumor growth helps doctors determine the cancer stage and choose the most effective treatment options.

Margins

A margin is the healthy tissue surrounding the tumor that is removed during surgery. Margins are examined closely under a microscope to ensure that all cancer cells have been removed. Negative margins (free of cancer cells) lower the chance of the cancer returning.

Lymphovascular invasion

Lymphovascular invasion (LVI) means cancer cells have entered blood vessels or lymphatic vessels within the tumor area. This finding indicates a higher chance of cancer spreading to other parts of the body and can influence treatment decisions.

Lymph nodes

Lymph nodes are small structures that help the body fight infection. Cancer cells can spread from the original tumor to nearby lymph nodes. Pathologists examine lymph nodes removed during surgery under a microscope to determine if cancer has spread, which is crucial for staging and treatment planning.

What is the prognosis for a person diagnosed with HPV-independent squamous cell carcinoma?

The prognosis for HPV-independent squamous cell carcinoma is generally worse compared to HPV-associated types, with lower overall and progression-free survival rates. The prognosis depends on factors such as patient age, tumor stage, and size at diagnosis. Treatment usually includes surgery, radiation therapy, and possibly chemotherapy, depending on the stage and location of the tumor.