HPV-Independent Squamous Cell Carcinoma of the Penis: Understanding Your Pathology Report

Section Editor: Trevor Flood MD FRCPC
October 24, 2026

HPV-independent squamous cell carcinoma of the penis is a type of penile cancer that is not caused by human papillomavirus (HPV). It is also called non-HPV squamous cell carcinoma. This cancer starts from the squamous cells that cover the surface of the penis, most often on the glans (the head of the penis) or the foreskin. Most penile cancers are HPV-independent squamous cell carcinomas. The other main type is HPV-associated squamous cell carcinoma, which is caused by a long-lasting HPV infection.

This article explains how HPV-independent squamous cell carcinoma of the penis is diagnosed and what the findings in your pathology report mean. These findings include the tumor type, p16 result, grade, depth of invasion, margins, lymph nodes, and stage.

Who gets HPV-independent squamous cell carcinoma of the penis?

Penile cancer is uncommon in North America and Europe, affecting about 1 in 100,000 men each year. It is much more common in parts of South America, Southeast Asia, and Africa. HPV-independent squamous cell carcinoma usually affects older men, and most are diagnosed after age 50. It is much less common in men who were circumcised as babies.

What causes HPV-independent squamous cell carcinoma of the penis?

HPV-independent squamous cell carcinoma of the penis develops after many years of long-lasting inflammation of the skin of the glans and foreskin. Over time, the inflamed squamous cells can develop genetic changes, often in a gene called TP53, that allow them to grow out of control. Factors linked with this type of penile cancer include:

Phimosis. A tight foreskin that cannot be pulled back traps moisture and secretions under the foreskin. Phimosis is one of the strongest risk factors for invasive penile cancer.
Lichen sclerosus. A long-lasting inflammatory skin condition that causes white, scarred patches on the glans and foreskin. It is commonly found in men with this type of penile cancer.
Chronic inflammation. Repeated inflammation of the glans and foreskin (balanitis) can damage the skin over time.
Smoking. Smoking is linked with a higher risk of penile cancer.

HPV-independent squamous cell carcinoma usually develops from a precancerous change called differentiated penile intraepithelial neoplasia (PeIN). Differentiated PeIN can be hard to see with the eye and can look only slightly abnormal under the microscope.

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

The most common symptom of penile cancer is a sore, lump, or patch on the glans or foreskin that does not heal. The area may bleed, have a bad-smelling discharge, or change color. When the cancer is hidden under a tight foreskin, it may first be noticed as swelling or discharge. Some men notice enlarged lymph nodes in the groin, which can be a sign that the cancer has spread.

How is the diagnosis made?

The diagnosis of HPV-independent squamous cell carcinoma of the penis usually begins with a small sample of tissue from the abnormal area, taken in a procedure called a biopsy. The tumor may later be removed by circumcision, by removing the glans, or by removing part or all of the penis. The choice depends on the tumor’s size and location.

A pathologist examines the tissue under the microscope. The pathologist looks for abnormal squamous cells that have broken through the surface layer and grown into the tissue below, a process called invasion. HPV-independent tumors usually make large amounts of keratin, the tough pink protein normally found in skin, and are described as keratinizing. The skin next to the tumor often shows differentiated PeIN or lichen sclerosus.

To confirm the tumor is not HPV-associated, the pathologist usually stains for a protein called p16, described below. Once cancer is confirmed, the groin lymph nodes are examined, and imaging such as CT, MRI, or ultrasound may be used to check for spread.

p16 and HPV testing

p16 is a protein that builds up in cells infected with high-risk HPV. Pathologists test for p16 using immunohistochemistry, a test that uses antibodies to show which proteins cells make. Current European and American guidelines (EAU-ASCO, 2026) recommend that every penile squamous cell carcinoma report include a p16 result. Your report will describe p16 in one of these ways:

p16 negative. The tumor cells show no staining or only patchy staining. This result supports an HPV-independent squamous cell carcinoma.
p16 positive. The tumor cells show strong, continuous p16 staining, sometimes described as block-type staining. This result supports an HPV-associated squamous cell carcinoma, and the diagnosis would usually be changed.

Some laboratories also test directly for HPV using a method called in situ hybridization (ISH). A negative result supports the diagnosis of HPV-independent squamous cell carcinoma. Not every laboratory performs this test, and p16 alone is usually enough.

What are the different types?

The World Health Organization (WHO) classification, 5th edition (2022), divides HPV-independent squamous cell carcinoma of the penis into several types. The type is based on how the tumor looks under the microscope, and the types behave very differently. Your report may name one of these types:

Squamous cell carcinoma, usual type. This is the most common type of penile cancer. It consists of keratinizing tumor cells that grow in nests and cords into the underlying tissue. Some reports describe patterns within this type, such as pseudohyperplastic or pseudoglandular.
Verrucous carcinoma. This type grows outward as a large, warty mass and pushes into the tissue below with a broad, smooth edge. It grows slowly, and spread to lymph nodes has not been reported in pure verrucous carcinoma.
Papillary squamous cell carcinoma. This type forms finger-like projections on the surface. It usually grows slowly and rarely spreads.
Sarcomatoid squamous cell carcinoma. This rare type consists of long, thin tumor cells called spindle cells that resemble sarcoma. It grows quickly and often spreads, so it has the least favorable outlook.

Some tumors contain more than one type, and the report will list each one. Older reports may call sarcomatoid squamous cell carcinoma spindle cell carcinoma. When p16 or HPV testing is not available, the report may say squamous cell carcinoma, not otherwise specified (NOS).

Histologic grade

The histologic grade of HPV-independent squamous cell carcinoma of the penis describes how different the tumor cells look from normal squamous cells. Pathologists use the three-tier WHO/ISUP grading system and grade the tumor by its least differentiated part:

Grade 1 (well differentiated). The tumor cells look much like normal squamous cells and produce abundant keratin. Verrucous carcinoma is grade 1.
Grade 2 (moderately differentiated). The tumor cells look more abnormal than in grade 1.
Grade 3 (poorly differentiated). The tumor cells look very abnormal. Any amount of grade 3 is noted in the report, and sarcomatoid squamous cell carcinoma is always grade 3.

Grade matters because a grade 3 tumor that is otherwise stage pT1 is staged as pT1b rather than pT1a. Grade can be difficult to judge in a small biopsy, so the grade may change after the whole tumor is removed.

Depth of invasion

Depth of invasion describes how far HPV-independent squamous cell carcinoma has grown below the surface of the penis. The pathologist measures it in millimeters. For tumors that grow outward, such as verrucous carcinoma, the pathologist may measure the tumor thickness instead. The report also names the deepest layer of tissue the tumor has reached:

Lamina propria or dartos. The thin layer of tissue just below the surface of the glans or foreskin.
Corpus spongiosum. The spongy tissue of the glans that surrounds the urethra.
Corpora cavernosa. The two columns of spongy tissue inside the shaft that fill with blood during an erection, surrounded by a tough layer called the tunica albuginea.
Urethra. The tube that carries urine and semen out of the body.

Deeper tumors are more likely to spread to lymph nodes, and the deepest layer reached decides the tumor stage (pT).

Perineural invasion

Perineural invasion means tumor cells were seen along or inside a nerve. Nerves can act as a pathway for tumor cells to spread. Your report will describe perineural invasion as present, not identified, or cannot be determined. In HPV-independent squamous cell carcinoma of the penis, perineural invasion raises the stage of a pT1 tumor from pT1a to pT1b. It is also linked with a higher chance of spread to lymph nodes.

Lymphovascular invasion

Lymphovascular invasion means tumor cells were seen inside a blood vessel or lymphatic channel. Lymphatic channels drain to the groin lymph nodes, so tumor cells within them have a route to spread. Your report will describe lymphovascular invasion as present, not identified, or cannot be determined. Like perineural invasion, lymphovascular invasion upstages a pT1 tumor to pT1b. It is one of the strongest predictors of lymph node spread.

Penile intraepithelial neoplasia (PeIN)

Penile intraepithelial neoplasia, or PeIN, is the precancerous change from which penile squamous cell carcinoma develops. In PeIN, abnormal squamous cells are confined to the surface layer and have not invaded the underlying tissue. The form linked with HPV-independent squamous cell carcinoma is called differentiated PeIN. It is often found in the skin next to the invasive tumor, sometimes together with lichen sclerosus.

PeIN next to the tumor does not change the stage. It matters for the margins, because PeIN left at a cut edge can come back or develop into a new cancer.

Surgical margins

A margin is the cut edge of tissue removed during surgery. For HPV-independent squamous cell carcinoma of the penis, the report describes margins separately for invasive carcinoma and for PeIN. Margins your report may name include the urethral margin, the corpus cavernosum and corpus spongiosum margins, and the skin or mucosal margins. Your report will describe the margins in one of these ways:

Negative margin. No cancer cells are seen at any cut edge. Many reports also give the distance from the tumor to the closest margin, in millimeters.
Positive margin. Invasive cancer cells are present at a cut edge. This raises the chance that the tumor will come back in the same place, and your care team will consider whether further surgery is needed.
PIN at the margin. Precancerous cells, but no invasive cancer, are present at a cut edge. This raises the chance of the precancerous change coming back, and your team may recommend close follow-up or further treatment.

Studies show that the chance of the cancer coming back in the same place rises considerably when the tumor is less than 1 mm from the margin.

Lymph nodes

Lymph nodes are small immune organs found throughout the body. Penile cancer usually spreads first to the lymph nodes in the groin, called the inguinal lymph nodes, and then to the lymph nodes in the pelvis. The lymph node result is the most important factor for prognosis in penile cancer.

When the groin lymph nodes feel normal, the care team may remove only the first one or two lymph nodes that drain the tumor. This is called a sentinel lymph node biopsy. If the lymph nodes are enlarged, the surgeon may perform a larger operation called an inguinal lymph node dissection. The pathologist reports:

Number of lymph nodes. How many lymph nodes were examined, and how many contained cancer, on each side of the groin.
Size of the largest deposit. The size of the largest group of cancer cells in a lymph node.
Extranodal extension. Whether cancer cells have broken through the outer capsule of a lymph node into surrounding tissue. Extranodal extension raises the nodal stage to pN3 and is linked with a higher chance of the cancer coming back.

Our article on sentinel lymph node biopsy reports explains this procedure in more detail.

Biomarker and molecular testing

For most men with HPV-independent squamous cell carcinoma of the penis, no biomarker test currently guides selection of a specific targeted drug. The p16 test described above is used to classify the tumor and to estimate prognosis, not to choose a drug. In advanced penile cancer, comprehensive next-generation sequencing (NGS) testing may be performed. This testing can find changes such as mismatch repair deficiency or a high tumor mutational burden. These are rare in penile cancer, but they can make a patient eligible for treatments approved across many cancer types in some countries. Your oncologist can tell you whether this testing is right for you. Our Biomarkers and Genetic Testing section explains these tests in more detail.

Pathologic stage (pTNM)

The pathologic stage of HPV-independent squamous cell carcinoma of the penis is based on the tumor (pT) and any lymph nodes examined (pN). It uses the TNM staging system in the 8th edition of the AJCC Cancer Staging Manual. Spread to distant organs (M) is usually determined by imaging, not by the pathologist.

Tumor stage (pT)

pTis. Only penile intraepithelial neoplasia (PeIN) is present, with no invasive cancer.
pTa. A noninvasive squamous cell carcinoma that has not grown into the tissue below the surface.
pT1a. The tumor has grown into the tissue just below the surface, with no lymphovascular or perineural invasion, and it is not grade 3.
pT1b. The tumor has grown into the tissue just below the surface and shows lymphovascular invasion, perineural invasion, or grade 3 features.
pT2. The tumor has grown into the corpus spongiosum, with or without growth into the urethra.
pT3. The tumor has invaded the corpora cavernosa, including the tunica albuginea, with or without invasion of the urethra.
pT4. The tumor has grown into nearby structures such as the scrotum, prostate, or pubic bone.

Nodal stage (pN)

pN0. No cancer is found in any of the lymph nodes examined.
pN1. Cancer is found in 1 or 2 inguinal lymph nodes on one side, with no extranodal extension.
pN2. Cancer is found in 3 or more inguinal lymph nodes on one side, or in inguinal lymph nodes on both sides, with no extranodal extension.
pN3. Cancer shows extranodal extension, or cancer is found in the pelvic lymph nodes.
pNX. Lymph nodes were not sent for examination.

What is the prognosis?

The prognosis for HPV-independent squamous cell carcinoma of the penis depends mainly on the tumor type and on whether the cancer has spread to lymph nodes. In large US registry data, about 81 in 100 people with penile cancer limited to the penis are alive five years later. This falls to about 16 in 100 when the cancer has spread to distant organs. In one study, about 62 in 100 men without pelvic lymph node spread were alive five years later. This fell to about 17 in 100 when the pelvic lymph nodes contained cancer.

HPV-independent tumors generally have a less favorable outlook than HPV-associated tumors. In combined studies, about 58 in 100 men with p16-negative tumors had not died of penile cancer five years later. The figure was about 88 in 100 for men with p16-positive tumors. The tumor type also matters a great deal. Verrucous and papillary carcinomas rarely cause death, while sarcomatoid carcinoma has the least favorable outlook of all types. Pathologic features linked with a less favorable outlook include:

Lymph node spread. This is the most important single factor, especially with 3 or more involved nodes, extranodal extension, or pelvic lymph nodes.
Sarcomatoid type. This type often spreads and is difficult to treat.
Lymphovascular invasion. Tumor cells inside vessels can spread to lymph nodes.
Perineural invasion. Tumor cells along nerves can spread.
Grade 3. Poorly differentiated tumors are more likely to spread.
Deeper invasion. Growth into the corpus spongiosum or corpora cavernosa raises the stage.
Positive margin. Tumor at a cut edge raises the chance of the cancer coming back in the same place.

What happens after the diagnosis?

After HPV-independent squamous cell carcinoma of the penis is diagnosed, the next steps depend mainly on the stage, the tumor type, and the lymph node findings. Care is usually planned by a urologist with experience in penile cancer, often at a specialized center. A medical oncologist and a radiation oncologist may also be involved.

Treatment of the tumor aims to remove the cancer while preserving as much of the penis as possible. For small or superficial tumors, the options may include laser treatment, removal of the surface skin of the glans, or removal of the glans. For larger or deeper tumors, part or all of the penis may need to be removed. Radiation therapy, including internal radiation called brachytherapy, is an option for some small tumors. Treating lichen sclerosus and any remaining PeIN may also be part of the plan.

The groin lymph nodes are checked even when they feel normal, because penile cancer can spread there without causing a lump. The choice between surveillance, sentinel lymph node biopsy, and lymph node dissection depends on the pathologic findings in your report. When 3 or more lymph nodes on one side contain cancer, or extranodal extension is present, the pelvic lymph nodes may also be removed. For large or fixed lymph nodes, doctors may give chemotherapy that includes cisplatin before surgery.

For penile cancer that has spread to distant organs, chemotherapy that includes a platinum drug is usually considered. Immunotherapy drugs are being studied in clinical trials, and current guidelines encourage people with advanced penile cancer to ask about trials. Your care team can tell you whether any trials are open to you. Follow-up visits continue for several years and include examination of the penis and groins.

Questions to ask your doctor

Was p16 testing done, and was my tumor p16 negative?
What type of HPV-independent squamous cell carcinoma do I have?
What is the grade of my tumor?
How deep did the tumor grow, and which tissue layers were involved?
Was lymphovascular or perineural invasion present?
Is my stage pT1a or pT1b, and why?
Were the margins clear of invasive cancer and PeIN, and how close was the tumor to the closest margin?
Was lichen sclerosus found, and does it need treatment?
Do I need a sentinel lymph node biopsy or a lymph node dissection?
If lymph nodes were removed, how many contained cancer, and was there extranodal extension?
Which treatment options could preserve as much of my penis as possible?
How will treatment affect urination and sexual function?
How often will I need follow-up visits?