HPV associated endocervical adenocarcinoma

by Jason Wasserman MD PhD FRCPC
February 3, 2025

HPV associated endocervical adenocarcinoma is a type of cervical cancer. It starts in the glandular cells that line the endocervical canal, the part of the cervix that connects the uterus to the vagina. These cells normally produce mucus, but when they become cancerous, they grow abnormally and can spread into surrounding tissues.

This cancer is called HPV associated because it is caused by high-risk types of human papillomavirus (HPV), a virus that can lead to cancer over time.

Cervix anatomy and histology

What are the symptoms of HPV associated endocervical adenocarcinoma?

The symptoms of HPV associated endocervical adenocarcinoma can vary but may include:

  • Unusual vaginal bleeding, especially after sex, between periods, or after menopause.
  • Watery or bloody vaginal discharge that may have a strong odor.
  • Pelvic pain or discomfort, especially during or after sexual intercourse.

In some cases, early-stage cancers may not cause any symptoms and are found during routine Pap tests or HPV screening.

Why is this type of cancer called HPV associated?

HPV stands for human papillomavirus, a common virus that infects skin and mucosal cells. Some types of HPV are considered high risk because they can cause cervical cancer.

HPV associated endocervical adenocarcinoma is most often caused by HPV types 16 and 18, which are responsible for the majority of HPV-related cervical cancers. When a pathologist describes a tumour as HPV associated, it means that HPV infection played a role in the development of the cancer.

HPV spreads through direct person-to-person contact, most commonly during sexual activity. While most HPV infections clear on their own, in some cases, the virus stays in the cells of the cervix and causes abnormal growth, which can develop into cancer over many years.

How common is HPV associated endocervical adenocarcinoma?

HPV associated endocervical adenocarcinoma is less common than squamous cell carcinoma of the cervix, which is another type of cervical cancer caused by HPV. However, the number of cases of HPV associated endocervical adenocarcinoma has been increasing over time. This may be because Pap tests are better at detecting squamous cell carcinoma than glandular cell cancers like adenocarcinoma.

HPV associated endocervical adenocarcinoma is most often diagnosed in women between the ages of 30 and 50, but it can occur at any age.

How is this diagnosis made?

The diagnosis of HPV associated endocervical adenocarcinoma is usually made through a combination of:

  • Pap test (Papanicolaou test): A Pap test is a routine screening test that looks for abnormal cells in the cervix. If abnormal glandular cells are found, further testing is needed.
  • Cervical biopsy: In a biopsy, a small sample of tissue is removed for examination.
  • Endocervical curettage: Cells are scraped from inside the cervix to check for cancer.
  • Cone biopsy or LEEP procedure: A larger sample of tissue is removed to determine how far the cancer has spread.

A pathologist examines the tissue sample under a microscope to confirm the diagnosis.

What does HPV associated endocervical adenocarcinoma look like under the microscope?

Hallmarks of HPV associated endocervical adenocarcinoma include increased mitotic activity (cell division), visible as apical mitoses (cells dividing at the top of the gland) and karyorrhexis (cell death). These features are easily seen at low magnification under the microscope. The tumour cells have enlarged, elongated, and hyperchromatic (dark) nuclei. Well to moderately differentiated tumours have glandular structures lined by pseudostratified columnar epithelium with smooth luminal borders.

What other tests are used to confirm the diagnosis?

Immunohistochemistry (IHC)

Immunohistochemistry (IHC) is a test that uses special dyes to detect specific proteins in tumour cells. It is performed by applying an antibody solution to the tissue sample, which binds to the target protein and produces a color reaction under the microscope.

For HPV associated endocervical adenocarcinoma, pathologists test for p16, a protein that becomes overexpressed in HPV-related cancers. A strong and continuous staining pattern for p16 suggests that HPV is driving the cancer.

In situ hybridization (ISH) for high-risk HPV

In situ hybridization (ISH) is a molecular test that detects HPV DNA or RNA in the tumour cells. It involves applying a special probe to the tissue that binds to HPV genetic material.

This test confirms that the tumour is caused by high-risk HPV, helping to distinguish HPV associated adenocarcinomas from other types of cervical or endometrial cancers.

Silva classification (growth pattern)

Under the microscope, HPV associated endocervical adenocarcinoma can show different patterns of invasion into the surrounding tissue. Some tumours grow in a non-destructive pattern, resembling adenocarcinoma in situ (AIS), while others show destructive invasion, where the cancer cells break apart and spread irregularly into the cervical tissue.

Pathologists use a system called the Silva pattern-based classification to categorize these tumours based on their invasive pattern. This system helps predict the risk of the cancer spreading to lymph nodes, coming back after treatment, and overall survival. The Silva system classifies tumors into three patterns of invasion.

Pattern A (non-destructive invasion):

  • Glands are well-formed and closely packed.
  • No cancer cells in blood vessels or lymphatic vessels.
  • Difficult to distinguish from AIS because the cancerous glands remain well-organized.

Pattern B (early / focally destructive invasion):

  • Small groups of tumour cells separate from the main glands.
  • Some areas of destruction in the surrounding cervical tissue.
  • May or may not have cancer cells in lymphatic or blood vessels.

Pattern C (diffusely destructive invasion):

  • Tumour cells invade in an irregular and aggressive manner.
  • Cancerous glands appear angulated and distorted.
  • Desmoplastic response (a fibrous tissue reaction around the tumour) is often seen.
  • Cancer cells are more likely to spread to lymph nodes.

Silva patterns

Tumours with Pattern A behave more indolently (less aggressive) and have a low risk of spreading. Patterns B and C are more aggressive, with a higher chance of lymph node involvement and recurrence. The tumour is considered destructive if cancer cells are found in blood or lymphatic vessels (Pattern B or C).

How is the tumour measured, and why is depth of invasion important?

When a HPV associated endocervical adenocarcinoma is diagnosed, the tumour is measured in three dimensions: length, width, and depth of invasion. These measurements help determine the pathologic tumour stage (pT), an important factor in deciding the best treatment approach and predicting prognosis.

  • Length – The tumour is measured from top to bottom to determine how far it extends along the surface of the cervix.
  • Width – The tumour is measured from side to side, showing how wide it has grown across the cervix.
  • Depth of invasion – This measurement is particularly important because it indicates how deeply the cancer cells have spread into the cervical stroma, the supportive connective tissue beneath the surface of the cervix.

Invasion refers to the movement of cancer cells from the epithelium (the thin layer of cells that covers the cervix) into the stroma below. A tumour that remains entirely within the epithelium is called adenocarcinoma in situ (AIS) and has not yet developed the ability to spread. However, the tumour is considered invasive once cancer cells break through the basement membrane (the barrier between the epithelium and stroma).

The depth of invasion is measured from the surface epithelium down to the deepest point where cancer cells are found. This measurement is crucial because tumours that invade deeper into the stroma are more likely to spread to lymph nodes or nearby tissues.

  • Superficial invasion (less than 3 millimetres deep) is often associated with early-stage disease and a low risk of spread.
  • Deeper invasion (more than 5 millimetres deep) increases the risk of lymphovascular invasion, lymph node involvement, and cancer recurrence.

For small, early-stage tumours, measuring the depth of invasion is particularly important in distinguishing stage IA1, IA2, and IB cancers. Tumours that invade less than 3 millimetres deep are classified as IA1, while those that invade between 3 and 5 millimetres are classified as IA2. Tumours that invade deeper than 5 millimetres are considered stage IB or higher, which may require more aggressive treatment.

Has the tumour spread outside of the cervix?

All HPV associated endocervical adenocarcinomas start in the cervix. However, larger tumours can grow to involve nearby organs such as the endometrium, vagina, bladder, or rectum or supporting tissues such as the parametrium. Pathologists use the term tumour extension to describe how far the cancer cells have travelled from their starting point in the cervix into surrounding organs and tissues. Tumour extension into other organs or the parametrium around the cervix is important because it is associated with a worse prognosis and is used to determine the pathologic tumour stage (pT).

What does lymphovascular invasion mean?

Lymphovascular invasion (LVI) means that cancer cells have entered the small blood vessels or lymphatic channels that run through the cervix. The lymphatic system is a network of vessels that helps drain fluid from tissues and is also a pathway for immune cells to travel throughout the body. When cancer cells invade these vessels, they have a higher chance of spreading to nearby lymph nodes or distant parts of the body.

Lymphovascular invasion

The presence of lymphovascular invasion is considered an important risk factor for cancer spread. In HPV associated endocervical adenocarcinoma, tumours with Pattern B or Pattern C invasion are more likely to show lymphovascular invasion, while Pattern A tumours typically do not. Studies have shown that when lymphovascular invasion is present, patients may require more aggressive treatment, such as lymph node removal and additional therapies like radiation or chemotherapy.

If lymphovascular invasion is found in an early-stage tumour, such as stage IA2, treatment may include radical hysterectomy with lymph node dissection to address any potential spread. In some cases, fertility-sparing options may still be possible, but close monitoring is required.

What does perineural invasion mean?

Perineural invasion (PNI) means that cancer cells have grown around or into the small nerves within the cervical tissue. Nerves act as pathways that allow signals to travel between different body parts, and some cancers can use these pathways to spread.

Perineural invasion

 

Perineural invasion is less common in HPV associated endocervical adenocarcinoma compared to lymphovascular invasion, but when present, it is considered a sign of a more aggressive tumour. Tumours with Pattern C invasion are more likely to show perineural invasion than those with Pattern A or B invasion.

Perineural invasion may also be linked to higher recurrence rates and poorer survival outcomes. When found in a tumour, doctors may recommend more intensive treatment, including radiation therapy, to target any remaining cancer cells along nerve pathways.

What are margins, and why are they important?

Margins refer to the edges of the tissue that is removed during surgery. When a tumour is surgically removed, the pathologist examines the margins under the microscope to see if any cancer cells are present at the edge of the tissue.

  • A negative margin means that no cancer cells are found at the edge, suggesting that the tumour was removed entirely.
  • A positive margin means that cancer cells are still present at the edge, which increases the risk that some cancer remains in the body and could lead to recurrence.

In HPV associated endocervical adenocarcinoma, margins are particularly important in procedures such as a cone biopsy (removal of part of the cervix) or radical hysterectomy (removal of the uterus and cervix).

For early-stage tumours, such as stage IA1 or IA2, a clear margin from a cone biopsy may be enough to avoid additional surgery. However, if the tumour extends to the margin, a second surgery or further treatment may be needed to ensure complete removal of the cancer.

In cases where a radical hysterectomy is performed, margins include not just the cervix but also the uterus, vaginal cuff, and sometimes surrounding connective tissues. If cancer cells are found at these margins, doctors may recommend radiation therapy or chemotherapy to reduce the risk of recurrence.

The presence of lymphovascular invasion or a destructive growth pattern (Pattern B or C) also influences margin assessment. For example, even if the margins are negative, doctors may recommend additional treatment if these high-risk features are present.

Lymph nodes

Lymph nodes are small immune organs found throughout the body. They help fight infections and filter harmful substances. Cancer cells can spread from the tumour to lymph nodes through tiny channels called lymphatic vessels. When cancer cells move from the tumour to another part of the body, such as a lymph node, it is called a metastasis.

Lymph node

How are lymph nodes examined?

During surgery, lymph nodes near the cervix may be removed and sent to a pathologist for examination under the microscope. These lymph nodes are usually grouped based on their location:

  • Pelvic lymph nodes are found in the lower abdomen near the cervix.
  • Para-aortic lymph nodes are located near a large blood vessel called the aorta, higher up in the abdomen.
  • Ipsilateral lymph nodes are on the same side of the body as the tumour.
  • Contralateral lymph nodes are on the opposite side.

Your pathology report will describe:

  • The total number of lymph nodes examined.
  • The location of the lymph nodes.
  • The number of lymph nodes containing cancer cells, if any.

How is cancer in a lymph node measured?

If cancer is found in a lymph node, the size of the affected area is measured. The results are classified as follows:

  • Isolated tumour cells: Cancer cells are present, but the area is less than 0.2 millimetres in size.
  • Micrometastasis: Cancer cells form a cluster between 0.2 and 2 millimetres in size.
  • Macrometastasis: Cancer cells form a cluster larger than 2 millimetres.

Why is the examination of lymph nodes important?

Checking the lymph nodes is important for two reasons:

  1. Determining the cancer stage: The presence or absence of cancer in the lymph nodes helps determine the pathologic nodal stage (pN).
  2. Guiding treatment decisions: If cancer is found in a lymph node, it is more likely to spread elsewhere. In these cases, doctors may recommend additional treatment, such as chemotherapy, radiation therapy, or immunotherapy, to lower the risk of recurrence.

What does it mean if a lymph node is “positive” or “negative” for cancer?

Pathologists use the term “positive” to describe a lymph node that contains cancer cells. For example, a report may say “positive for malignancy” or “positive for metastatic carcinoma”.

A “negative” lymph node does not contain any cancer cells. In this case, the report may say “negative for malignancy” or “negative for metastatic carcinoma”.

The number and size of positive lymph nodes help doctors decide on the best treatment plan and predict how the cancer may behave in the future.

What pathologic stage is HPV associated endocervical adenocarcinoma?

The pathologic stage of HPV associated endocervical adenocarcinoma is determined using the TNM staging system, an internationally recognized system created by the American Joint Committee on Cancer (AJCC).This system classifies the cancer based on:

  • T (Tumour) – The size of the tumour and how far it has spread within the cervix and surrounding structures.
  • N (Nodes) – Whether cancer cells are found in nearby lymph nodes.
  • M (Metastasis) – Whether cancer has spread to distant parts of the body.

Your pathologist examines the tissue removed during surgery and assigns a stage to each category. Based on these findings, the overall stage is then determined. In general, a higher stage means a more advanced cancer that may require more aggressive treatment.

Tumour stage (pT) for HPV associated endocervical adenocarcinoma

The T stage describes how deeply the cancer has grown into the cervix and whether it has spread beyond it.

  • T1a – The tumour is small and only detected under the microscope. It has grown no more than 5 millimetres deep and 7 millimetres wide.
  • T1b – The tumour is large enough to be seen by the doctor during an exam or has grown deeper than 5 millimetres or wider than 7 millimetres.
  • T2a – The tumour has spread beyond the cervix and uterus but has not invaded the parametrium (the connective tissue next to the cervix).
  • T2b – The tumour has spread into the parametrium.
  • T3a – The tumour has grown into the lower part of the vagina.
  • T3b – The tumour has spread to the pelvic wall (the bony structure that encloses the reproductive organs) or has blocked the ureters, leading to kidney problems.
  • T4 – The tumour has spread into the bladder or rectum or has extended beyond the pelvis into the abdomen.

Nodal stage (pN) for HPV associated endocervical adenocarcinoma

The N stage describes whether cancer has spread to lymph nodes, small immune organs that help filter harmful substances. Lymph node involvement increases the risk that cancer may spread to other parts of the body.

  • NX – No lymph nodes were removed for examination.
  • N0 – No cancer cells were found in the lymph nodes.
  • N0(i+) – Only isolated cancer cells (less than 0.2 millimetres in size) were found in a lymph node.
  • N1 – A larger group of cancer cells (greater than 0.2 millimetres) was found in at least one lymph node.

The stage of the cancer plays a key role in determining the best treatment plan and predicting prognosis. Early-stage tumours (T1a, T1b) without lymph node involvement (N0) are typically treated with surgery alone, while more advanced stages (T2 and higher, or N1) may require additional treatments such as radiation or chemotherapy.

FIGO staging for HPV associated endocervical adenocarcinoma

The FIGO staging system is another method used to classify the extent of cervical cancer. FIGO, which stands for the International Federation of Gynecology and Obstetrics, developed this system specifically for cervical cancer. It is widely used by doctors to guide treatment decisions and predict outcomes. Unlike the TNM system, which considers tumour size, lymph node involvement, and metastasis separately, the FIGO system focuses on how far the cancer has spread beyond the cervix. Understanding the FIGO stage helps determine whether a patient may need surgery, radiation, chemotherapy, or a combination of treatments.

Stage I: Cancer is confined to the cervix

At this stage, the tumour has not spread beyond the cervix. The depth of invasion (how deep the tumour has grown into the cervix) is an important factor.

  • Stage IA: Cancer is only visible under a microscope and has not formed a tumour that can be seen with the naked eye.
    • Stage IA1: Cancer has grown 3 millimetres or less into the cervical tissue.
    • Stage IA2: Cancer has grown between 3 and 5 millimetres into the cervical tissue.
  • Stage IB: The tumour is larger than 5 millimetres and can be seen without a microscope but is still confined to the cervix.
    • Stage IB1: Tumour is 2 centimetres or smaller.
    • Stage IB2: Tumour is between 2 and 4 centimetres.
    • Stage IB3: Tumour is larger than 4 centimetres.

Stage II: Cancer has spread beyond the cervix but not to the pelvic wall or lower third of the vagina

At this stage, the tumour has extended into nearby structures, but it has not reached the pelvic wall or lower vagina.

  • Stage IIA: The cancer has spread to the upper two-thirds of the vagina but has not invaded the parametrium (the connective tissue next to the cervix).
    • Stage IIA1: Tumour is 4 centimetres or smaller.
    • Stage IIA2: Tumour is larger than 4 centimetres.
  • Stage IIB: The tumour has spread into the parametrium (the tissues next to the cervix) but has not reached the pelvic wall.

Stage III: Cancer has spread to the lower third of the vagina, the pelvic wall, or nearby lymph nodes

At this stage, the tumour has extended further into surrounding structures.

  • Stage IIIA: Cancer has spread to the lower third of the vagina but has not reached the pelvic wall.
  • Stage IIIB: Cancer has spread to the pelvic wall or is blocking the ureters, which can cause kidney dysfunction.
  • Stage IIIC: Cancer has spread to nearby lymph nodes, regardless of tumour size.
    • Stage IIIC1: Cancer is found in pelvic lymph nodes only.
    • Stage IIIC2: Cancer has spread to para-aortic lymph nodes (lymph nodes near the aorta in the abdomen).

Stage IV: Cancer has spread beyond the pelvis or to distant organs

Stage IV is the most advanced stage, meaning the cancer has spread beyond the pelvic region.

  • Stage IVA: Cancer has spread to nearby organs, such as the bladder or rectum.
  • Stage IVB: Cancer has spread to distant body parts, such as the lungs, liver, or bones.

Why is FIGO staging important for HPV associated endocervical adenocarcinoma?

FIGO staging helps doctors choose the best treatment plan and predict how the cancer may behave over time. Early-stage cancers (Stage I and some Stage II) are often treated with surgery alone, while more advanced stages (Stage IIIB and beyond) usually require a combination of radiation therapy and chemotherapy. The presence of lymph node involvement (Stage IIIC) is also important, as it increases the risk of cancer recurrence, which may lead to additional treatments. Your pathology report will include the FIGO stage, along with other important features such as tumour size, depth of invasion, lymph node involvement, and the presence of metastases. Your doctor will use this information to create a personalized treatment plan.

What is the prognosis for a person diagnosed with HPV associated endocervical adenocarcinoma?

The prognosis for HPV associated endocervical adenocarcinoma depends on several factors, including the stage of the cancer at diagnosis, the pattern of invasion, the presence of lymphovascular invasion, and the patient’s overall health.

The stage of the cancer is the most important factor in determining prognosis. In early-stage disease, survival rates are very high. For example, patients with stage IA1 disease, which is the earliest stage, have nearly a 100% survival rate. For stage IA2, the survival rate is around 93%. However, as the cancer progresses, survival rates decrease significantly. For stage III disease, the survival rate drops to about 34%, and for stage IV, it is only 3%.

The Silva pattern of invasion also plays a significant role in prognosis. Tumours with Pattern A invasion, where the cancerous glands remain well-defined and do not invade destructively, have a very low risk of spreading to lymph nodes or recurring after treatment. In contrast, Pattern B and Pattern C tumours are more aggressive. Pattern B tumours, which show early or focal destructive invasion, have about a 4% risk of lymph node spread, while Pattern C tumours have a much higher risk of spread (around 25%). Among Pattern C tumours, those with micropapillary growth tend to have a greater risk of lymph node involvement. In comparison, tumours with diffuse destructive and confluent growth have a higher risk of recurrence and poorer survival outcomes.

Some genetic changes have been linked to prognosis. Mutations in the KRAS and PIK3CA genes are frequently found in HPV-associated endocervical adenocarcinomas, especially those with destructive invasion, and these mutations have been associated with a worse prognosis. However, overall, HPV-associated endocervical adenocarcinoma has a better prognosis than HPV independent endocervical adenocarcinoma, which is a different type of cervical cancer that is not caused by HPV.

Certain subtypes of HPV associated endocervical adenocarcinoma also have different prognoses. Villoglandular adenocarcinoma, a subtype that grows in finger-like projections, typically has an excellent prognosis as long as it remains confined to the cervix. However, if it invades deeply into the surrounding tissue, its behaviour becomes similar to that of other HPV associated adenocarcinomas. Some mucinous subtypes, such as stratified mucin-producing carcinoma, may have a worse prognosis compared to other HPV associated tumours.

For early-stage, non-destructively invasive tumours, conservative treatment with a cone biopsy (removal of part of the cervix) is often sufficient, and additional surgery is not needed. However, some studies have reported that even early-stage adenocarcinomas with an AIS-like appearance may, in rare cases, spread to the ovaries, meaning careful follow-up is required if a conservative treatment approach is chosen.

For more advanced tumours, treatment typically includes radical hysterectomy with lymph node removal and/or chemoradiation therapy. More aggressive treatment is often necessary if the tumour has lymphovascular invasion or is larger in size. Fertility-preserving options, such as radical trachelectomy (removal of the cervix while preserving the uterus), may be considered for stage IA tumours with lymphovascular invasion or for selected stage IB1 tumours, but only if lymph nodes remain cancer-free.Overall, the prognosis for HPV associated endocervical adenocarcinoma is good when diagnosed early, but survival decreases significantly if the cancer has spread beyond the cervix. Regular screening, early detection, and appropriate treatment are essential for improving outcomes.

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