HPV Independent Gastric-Type Adenocarcinoma of the Cervix: Understanding Your Pathology Report

by Jason Wasserman MD PhD FRCPC
May 15, 2026

HPV-independent gastric-type adenocarcinoma is a rare type of cervical cancer that develops from glandular cells in the cervix. Glandular cells normally produce mucus and line the inside of the cervical canal. Unlike most cervical cancers, this tumor is not caused by infection with human papillomavirus (HPV). Instead, the tumor cells take on features resembling those of mucus-producing cells in the stomach, particularly in the lower part of the stomach (the pylorus).

Gastric-type adenocarcinoma accounts for about 10 to 15% of all cervical adenocarcinomas worldwide and is more common in some regions than others. Compared with HPV-associated cervical adenocarcinoma, gastric-type adenocarcinoma generally occurs in older patients (typically in their 50s), is less likely to be detected by routine cervical screening, and tends to behave more aggressively.

This article will help you understand the findings in your pathology report, what each term means, and why it matters for your care.

What causes HPV-independent gastric-type adenocarcinoma?

The exact cause of HPV-independent gastric-type adenocarcinoma is not fully understood. Unlike most cervical cancers, this tumor is not caused by HPV infection. Instead, it appears to develop through other genetic and molecular changes in cervical glandular cells. Some cases arise in patients with Peutz-Jeghers syndrome, a hereditary condition caused by mutations in the STK11 gene. People with Peutz-Jeghers syndrome have a higher risk of several types of tumors, including gastric-type adenocarcinoma of the cervix. For this reason, when this diagnosis is made, the gynecologic team may discuss referral for genetic counseling and testing for hereditary cancer risk.

A noncancerous condition called lobular endocervical glandular hyperplasia (LEGH) shows some of the same gastric-type features and has been proposed as a possible precursor for a portion of these cancers. However, most cases of gastric-type adenocarcinoma are identified without a recognized precursor lesion.

What are the symptoms?

The most common symptoms are abnormal vaginal bleeding and a persistent watery vaginal discharge. The watery discharge is a particularly characteristic feature of gastric-type adenocarcinoma and reflects the large amount of mucus produced by the tumor cells. Some patients also experience pelvic pain or notice a mass on the cervix during a gynecologic examination.

Because HPV-independent gastric-type adenocarcinoma often develops deeper inside the cervix, it can be difficult to detect through routine cervical screening with a Pap test alone, and HPV-based screening does not identify it because the tumor is not driven by HPV. As a result, gastric-type adenocarcinoma is more likely than HPV-associated cervical cancer to be diagnosed only after symptoms develop, and it may be more advanced at the time of diagnosis.

How is the diagnosis made?

The diagnosis of HPV-independent gastric-type adenocarcinoma usually begins when symptoms such as bleeding or watery discharge lead to a pelvic examination, or when an abnormal finding is seen on imaging or during a routine examination. Tissue from the cervix is then removed for examination by a pathologist. Common ways of obtaining tissue include a biopsy during colposcopy, endocervical curettage to sample tissue from inside the cervical canal, and a cone biopsy that removes a larger cone-shaped portion of the cervix.

If surgery is performed to treat the cancer, the pathologist also examines the removed tissue to measure the size of the tumor, to determine how deeply it has grown into the cervix, and to assess whether it has spread to nearby structures, the surgical margins, and any lymph nodes that were removed.

To confirm the diagnosis and distinguish gastric-type adenocarcinoma from HPV-associated cervical adenocarcinoma and other cancers that may look similar under the microscope, the pathologist performs several special tests. A protein stain called p16, performed by immunohistochemistry, is usually negative or shows only patchy staining in gastric-type adenocarcinoma. This is one of the most important features that distinguishes it from HPV-associated cervical adenocarcinoma, in which p16 staining is typically strong and continuous. Stains called CK7 and PAX8 are usually positive, supporting a cervical origin. Stains associated with gastric differentiation, such as MUC6 and HIK1083, are often positive and reflect the similarity between the tumor cells and the mucus-producing cells of the stomach. Hormone receptor stains (estrogen receptor and progesterone receptor) are typically negative. In situ hybridization (ISH) for HPV is used in many cases to confirm that the tumor is HPV-independent. In gastric-type adenocarcinoma, HPV ISH shows no signals, confirming that no HPV genetic material is present in the tumor cells.

What does HPV-independent gastric-type adenocarcinoma look like under the microscope?

Under the microscope, HPV-independent gastric-type adenocarcinoma is made up of glands lined by cells that produce large amounts of mucus. The tumor cells often have clear or pale pink cytoplasm and distinct cell borders. The nuclei are typically enlarged and irregular, and visible nucleoli (small structures inside the nucleus where ribosomes are made) may be present.

Some tumors are well-differentiated and form glands that look relatively normal at low magnification but grow in an irregular, haphazard pattern deep within the cervix. Other tumors form irregular glands, clusters of cells, or single cells with more obvious abnormalities. Many tumors show destructive invasion into the surrounding cervical tissue, often accompanied by a dense fibrous reaction in the surrounding tissue called desmoplasia. Lymphovascular invasion is relatively common in gastric-type adenocarcinoma and contributes to its early propensity to spread.

Tumor size and depth of invasion

Once invasive cancer is confirmed, the pathologist measures the tumor to determine its size and how deeply it has grown into the cervix. Tumor size describes the largest dimension of the cancer along the surface of the cervix and is usually reported in centimeters. Depth of invasion describes how far the tumor has grown from the surface lining into the supporting tissue (the stroma) of the cervix and is usually reported in millimeters. Both measurements are important because larger tumors and those that invade more deeply are more likely to spread to lymph nodes and nearby organs. These measurements also determine the tumor stage and influence which surgical and other treatment options the gynecologic team discusses with the patient.

Lymphovascular invasion

Lymphovascular invasion means that tumor cells are seen inside small lymphatic channels or blood vessels in the cervix. These vessels normally carry fluid or blood through the body, and tumor cells that gain access to them can travel to nearby lymph nodes or distant organs. Lymphovascular invasion is relatively common in gastric-type adenocarcinoma and is associated with a higher risk of lymph node spread and recurrence.

Perineural invasion

Perineural invasion means that tumor cells are growing along or around nerves in the cervix. This pattern of growth allows the cancer to extend along nerves into surrounding tissue and is associated with a higher risk of local recurrence after treatment. Its presence may influence the team’s discussion about whether to add radiation therapy after surgery.

Surgical margins

A margin is the cut edge of tissue removed during a surgical procedure, such as a cone biopsy or hysterectomy. After surgery, the pathologist examines the margins under the microscope to determine whether any cancer cells are present at the cut edges.

Negative margin — No cancer cells are present at the cut edge of the tissue. This suggests that the entire tumor was removed, and this is the most reassuring result.
Close margin — Cancer cells are within a few millimeters of the cut edge but not reaching it. A close margin may prompt the team to consider additional treatment, depending on the rest of the pathology findings.
Positive margin — Cancer cells extend to the cut edge of the tissue. This means some cancer cells may still remain in the cervix or surrounding tissue, which increases the risk of recurrence. Positive margins may lead the team to discuss further surgery or postoperative radiation.

Lymph nodes

Lymph nodes are small immune organs that filter fluid as it returns from the body’s tissues to the bloodstream. The cervix drains into lymph nodes in the pelvis, and from there to lymph nodes higher in the abdomen along the aorta (the para-aortic nodes). During surgery for cervical cancer, lymph nodes from these areas may be removed and examined under the microscope.

If tumor cells are found inside a lymph node, the cancer is considered to have spread beyond the cervix, and the pathologic stage is increased. The pathology report describes the number of lymph nodes examined, the number that contain tumor cells, the location of the involved nodes, and the size of the tumor deposit in each node:

Isolated tumor cells — Tiny clusters measuring 0.2 mm or less.
Micrometastases — Tumor deposits larger than 0.2 mm but no larger than 2 mm.
Macrometastases — Tumor deposits larger than 2 mm.

The pathology report may also note whether cancer has broken through the outer wall of a lymph node into the surrounding tissue, a finding called extranodal extension, which is associated with a higher risk of recurrence.

Biomarker and molecular testing

Biomarker testing examines proteins or other molecular features in the tumor to guide treatment decisions. Not every biomarker is tested in every case. Testing is typically performed when the cancer is advanced, recurrent, or metastatic, and the results help determine eligibility for specific therapies.

PD-L1

PD-L1 is a protein that some tumor cells use to evade immune system detection. Testing for PD-L1 is performed by immunohistochemistry on a tumor sample and is reported as the Combined Positive Score (CPS), which reflects PD-L1 expression on tumor cells and on nearby immune cells. For cervical cancer, a CPS of 1 or higher is the threshold that indicates eligibility for immune checkpoint inhibitor therapy with pembrolizumab in advanced, recurrent, or metastatic disease. A PD-L1 result on the pathology report does not, by itself, dictate treatment; instead, it informs the discussion the medical oncology team has with the patient about whether immunotherapy is an appropriate option.

Mismatch repair (MMR) protein testing

Mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6) are part of the cell’s system for correcting small errors that occur in DNA during cell division. When one or more of these proteins is absent from tumor cells, the result is called mismatch repair-deficient (dMMR), also known as microsatellite instability-high (MSI-high). When all four proteins are present, the result is mismatch repair proficient (pMMR). A subset of HPV-independent cervical adenocarcinomas, including some gastric-type tumors, are MMR-deficient. When dMMR is identified, two implications matter: first, dMMR tumors may respond particularly well to immune checkpoint inhibitor therapy with pembrolizumab, which is approved for pan-tumor use for dMMR or MSI-high cancers regardless of where the cancer started; second, MMR deficiency may indicate an inherited condition called Lynch syndrome, and referral for genetic counseling is typically discussed.

HER2

HER2 (human epidermal growth factor receptor 2) testing is sometimes performed in advanced or recurrent disease. A subset of cervical adenocarcinomas show HER2 overexpression, and HER2-targeted therapies are increasingly considered as options in advanced disease across many tumor types. Testing is performed by immunohistochemistry, with confirmatory in situ hybridization in equivocal cases.

Pathologic stage

Staging describes how far the cancer has spread within the cervix and beyond. Stage is the single most important factor in predicting outcome and in shaping the decisions made by the gynecologic and medical oncology teams about further treatment. Cervical cancer is staged using two related systems: the AJCC pTNM system (currently the AJCC 8th edition) and the FIGO system (currently the FIGO 2018 revision). The two systems are aligned and use the same anatomic categories, but FIGO is more commonly used by gynecologic oncologists for treatment planning.

The TNM system describes the size and extent of the tumor in the cervix (T), whether nearby lymph nodes contain cancer (N), and whether the cancer has spread to distant organs (M). The metastasis category (M) is generally determined by imaging studies rather than by examination of the surgical specimen.

Tumor stage (pT)

pT1 — Tumor confined to the cervix.
- pT1a — Invasive cancer that can be identified only under the microscope, with depth of invasion of 5 mm or less. (FIGO 2018 removed the prior 7 mm horizontal width criterion, so pT1a is now defined by depth alone.)
  - pT1a1 — Depth of invasion 3 mm or less.
  - pT1a2 — Depth of invasion greater than 3 mm but no more than 5 mm.
- pT1b — Invasive cancer with depth of invasion greater than 5 mm, still confined to the cervix.
  - pT1b1 — Tumor 2 cm or less in greatest dimension.
  - pT1b2 — Tumor greater than 2 cm but no more than 4 cm.
  - pT1b3 — Tumor greater than 4 cm.
pT2 — Tumor extends beyond the cervix but has not reached the pelvic wall or the lower third of the vagina.
- pT2a — Tumor involves the upper two-thirds of the vagina but not the parametrium. Subdivided into pT2a1 (4 cm or less) and pT2a2 (greater than 4 cm).
- pT2b — Tumor has invaded the parametrium.
pT3 — Tumor involves the lower third of the vagina, reaches the pelvic wall, or blocks a ureter (which can damage the kidney).
- pT3a — Tumor involves the lower third of the vagina without extension to the pelvic wall.
- pT3b — Tumor extends to the pelvic wall, blocks a ureter, or both.
pT4 — Tumor has grown into the lining of the bladder or rectum, or has extended beyond the pelvis.

Nodal stage (pN)

pNX — Regional lymph nodes were not examined.
pN0 — No cancer found in the examined regional lymph nodes.
pN0(i+) — Only isolated tumor cells (clusters 0.2 mm or smaller) are present in regional lymph nodes.
pN1 — Larger tumor deposits are present in regional lymph nodes.
- pN1a — Metastasis to pelvic lymph nodes only.
- pN1b — Metastasis to para-aortic lymph nodes, with or without pelvic lymph node involvement.

Metastatic stage (pM)

The metastasis category is determined by imaging studies and clinical evaluation rather than by examination of the surgical specimen. pM0 means no distant spread has been identified. pM1 means cancer has spread to distant organs such as the lungs, liver, or bones.

FIGO stage

The FIGO stage is reported alongside the TNM stage. It reflects the combined pathologic and imaging findings and is the system most commonly used to guide treatment planning:

Stage I — Cancer confined to the cervix. Subdivided into IA1, IA2, IB1, IB2, and IB3 using the same depth and size cut-offs as the AJCC pT1 categories above.
Stage II — Cancer has spread beyond the cervix but has not reached the pelvic wall or the lower third of the vagina. Subdivided into IIA1 (upper vagina, 4 cm or less), IIA2 (upper vagina, greater than 4 cm), and IIB (parametrial invasion).
Stage III — More extensive spread.
- Stage IIIA — Cancer involves the lower third of the vagina.
- Stage IIIB — Cancer reaches the pelvic wall or blocks a ureter.
- Stage IIIC1 — Cancer is present in pelvic lymph nodes (regardless of tumor size).
- Stage IIIC2 — Cancer is present in para-aortic lymph nodes (regardless of tumor size).
Stage IV — Cancer has spread to nearby organs or distant sites.
- Stage IVA — Cancer invades the lining of the bladder or rectum.
- Stage IVB — Cancer has spread to distant organs such as the lungs, liver, or bones.

What is the prognosis?

HPV-independent gastric-type adenocarcinoma generally has a less favorable outlook than HPV-associated cervical cancers. Several factors contribute to this. The tumor is often diagnosed at a later stage because it is not reliably detected by HPV-based screening and arises deeper in the cervical canal, where it may not be sampled on a routine Pap test. It tends to grow in an infiltrative pattern, often involves lymphovascular and perineural spaces, and is less responsive to standard chemoradiation than HPV-associated cervical cancers.

Stage is the most important factor in predicting outcome at any cancer type, but five-year survival rates for gastric-type adenocarcinoma are lower than for HPV-associated cervical cancers at each comparable stage. Reported survival ranges vary by study but are generally substantially lower than the rates for HPV-associated tumors. Additional pathologic features that influence the chance of recurrence include:

Stage at diagnosis — The single most important prognostic factor. Earlier stages have better outcomes, but outcomes are less favorable than for HPV-associated tumors at any given stage.
Lymph node involvement — The number and location of involved lymph nodes, whether pelvic or para-aortic, all influence prognosis.
Lymphovascular invasion — Increases the risk of lymph node spread and recurrence.
Surgical margin status — Negative margins are associated with a lower risk of local recurrence. Positive margins increase the chance that residual disease is present.
Tumor size and depth of invasion — Larger and deeper tumors are associated with a higher risk of recurrence and worse outcomes.
Perineural invasion — When present, is associated with a higher risk of local recurrence.
Biomarker results — A PD-L1 CPS of 1 or higher or an MMR-deficient result identifies patients who may benefit from immune checkpoint inhibitor therapy in advanced disease, which has improved outcomes in this setting.

What happens after this diagnosis?

Once HPV-independent gastric-type adenocarcinoma is diagnosed, the gynecologic oncology team will discuss the treatment options with the patient. Decisions depend on the stage, the size of the tumor, the patient’s age and overall health, and other findings on the pathology report. Because this tumor type tends to be more aggressive and less responsive to standard chemoradiation than HPV-associated cervical cancers, the team often considers more extensive surgery when possible and pays particular attention to biomarker results in advanced disease.

Options the team may consider include:

Radical hysterectomy with pelvic lymph node assessment — For patients with early-stage disease, radical hysterectomy (removal of the uterus, cervix, parametrium, and upper vagina) combined with sentinel lymph node biopsy or pelvic lymph node dissection is the most commonly considered approach. The pathology report from the surgical specimen guides whether additional treatment is needed afterward. Fertility-sparing surgery is less commonly an option for gastric-type adenocarcinoma than for HPV-associated tumors because of the more aggressive behavior of this cancer.
Chemoradiation therapy — For locally advanced cancer, the team often discusses chemoradiation. Chemoradiation may also be added after surgery when the pathology report shows high-risk features such as positive margins, parametrial invasion, or lymph node involvement. Patients and families should be aware that gastric-type adenocarcinoma generally responds less well to chemoradiation than HPV-associated cervical cancer, which may affect treatment-decision discussions.
Systemic therapy for advanced or recurrent disease — For stage IVB or recurrent disease, the medical oncology team discusses systemic options including chemotherapy and, when applicable, immune checkpoint inhibitor therapy (pembrolizumab) based on PD-L1 or MMR/MSI testing. HER2-targeted therapy and other personalized treatment options based on molecular profiling may also be considered. Enrollment in clinical trials investigating new therapies for HPV-independent cervical cancers is often discussed because the responses to standard treatments are less predictable than for HPV-associated tumors.
Genetic counseling and testing — Because gastric-type adenocarcinoma can occur in the setting of Peutz-Jeghers syndrome or other hereditary cancer predispositions, referral for genetic counseling and germline testing is often discussed, particularly in younger patients or those with a personal or family history that suggests a hereditary syndrome.

After treatment, regular follow-up is essential. Surveillance typically includes physical and pelvic examinations every three to six months for the first two to three years, then less frequently. Imaging and additional tests are added based on the original stage, the pathology findings, and the patient’s overall risk of recurrence.

Questions to ask your doctor

What is the stage of my cervical cancer using both the TNM and FIGO systems?
How large is the tumor, and how deeply has it grown into the cervix?
Was lymphovascular invasion present in my pathology specimen?
Was perineural invasion present?
Were the surgical margins negative, close, or positive?
How many lymph nodes were examined, and were any involved by cancer?
Was PD-L1 testing performed, and what does the result mean for my treatment options?
Was MMR or microsatellite instability testing performed, and what did it show?
Was HER2 testing performed, and could HER2-targeted therapy be an option for me?
Should I be referred for genetic counseling and testing for Peutz-Jeghers syndrome or other hereditary cancer conditions?
What treatment options would you discuss with me based on my pathology findings, and how does my outlook differ from a patient with HPV-associated cervical cancer?
Are there clinical trials available that might be appropriate for my situation?
What follow-up schedule will I have after treatment, and what tests will be used to monitor for recurrence?
What symptoms should prompt me to contact you between scheduled appointments?