Stratified mucin producing intraepithelial lesion, usually abbreviated as SMILE, is a rare precancerous condition of the cervix caused by infection with human papillomavirus (HPV). It is described as having features of both squamous cells (flat cells that line the outer surface of the cervix) and glandular cells (mucus-producing cells that line the inside of the cervix). Because it produces mucus and shows a stratified, multilayered appearance, it does not fit neatly into either category.
In the 2020 World Health Organization classification of female genital tumors, SMILE is recognized as a variant of adenocarcinoma in situ (AIS). It is considered a high-grade precancerous lesion, meaning it carries a meaningful risk of progressing to cervical cancer if it is not treated, and it is generally managed similarly to AIS and high grade squamous intraepithelial lesion (HSIL). SMILE is uncommon, identified in approximately 0.5% of cervical biopsies in published studies.
This article will help you understand what this finding means on your pathology report, what each term means, and why it matters for your care.
What causes SMILE?
SMILE is caused by persistent infection with high-risk HPV, the same virus that causes most other cervical precancerous conditions and cervical cancers. Studies of SMILE consistently show that more than 95% of cases are associated with high-risk HPV types, most commonly HPV16, HPV18, and HPV31. SMILE is thought to arise from a particular type of cell in the transformation zone of the cervix called the reserve cell. Reserve cells have the potential to develop into either squamous cells or glandular cells, and SMILE shows a mixture of features from both. This dual character is the reason SMILE looks different under the microscope from HSIL (which shows only squamous features) and AIS (which shows only glandular features).
Several factors increase the risk of developing SMILE or any other HPV-associated precancerous lesion of the cervix:
- Persistent high-risk HPV infection — The single most important risk factor. Most HPV infections clear on their own within one to two years, but infections that persist may lead to precancerous changes.
- A weakened immune system — Conditions such as HIV infection, organ transplantation, or long-term immunosuppressive therapy make it harder for the body to clear HPV.
- Cigarette smoking — Smoking damages the cells of the cervix and makes them more vulnerable to HPV-related changes.
- Lack of regular cervical cancer screening — Without screening, abnormal cells can persist and progress before being detected.
What are the symptoms?
SMILE does not usually cause symptoms. Like most precancerous conditions of the cervix, it is typically found by chance when cervical tissue is examined under the microscope after an abnormal Pap test, a positive HPV test, or a biopsy taken to investigate another concern. Because there are no reliable symptoms, regular cervical cancer screening remains the most important way to detect SMILE and other precancerous lesions early.
How is the diagnosis made?
SMILE is diagnosed by a pathologist after a tissue sample from the cervix is examined under the microscope. The sample is typically obtained through a biopsy during colposcopy, an endocervical curettage that samples tissue from the cervical canal, or a larger excision, such as a loop electrosurgical excision procedure (LEEP) or cone biopsy. Most often, SMILE is identified incidentally in a specimen obtained to investigate HSIL or AIS suspected on a Pap test or earlier biopsy.
Because SMILE can resemble several other cervical conditions, including AIS, HSIL, and a normal but immature pattern of cell growth called atypical immature squamous metaplasia, the pathologist often performs additional tests, such as immunohistochemistry (IHC), to confirm the diagnosis. The typical pattern in SMILE includes:
- Strong, diffuse p16 staining — SMILE almost always shows strong, continuous “block-type” p16 staining, the same pattern seen in HSIL, AIS, and most HPV-associated cervical cancers. This confirms the HPV-driven nature of the lesion.
- High Ki-67 proliferation index — Ki-67 is a marker of cell division. SMILE shows a high percentage of dividing cells, comparable to what is seen in HSIL and AIS.
- Positive squamous markers — Stains such as p40 (or the closely related p63) are positive in some of the cells, reflecting the squamous component of the lesion.
- Positive cytokeratins CK7 and CK19 — These confirm the epithelial origin of the cells.
- Mucin stains — A special stain such as mucicarmine or Alcian blue may be performed to highlight the mucus inside the abnormal cells. The presence of mucus distributed throughout the full thickness of the abnormal area is one of the defining features of SMILE.
HPV testing may also be performed and almost always shows high-risk HPV, most commonly HPV16, HPV18, or HPV31.
What does SMILE look like under the microscope?
Under the microscope, SMILE has a distinctive combination of features that overlap with both HSIL and AIS:
- Stratified, multilayered architecture — The abnormal cells are arranged in many layers, similar to the appearance of HSIL. Importantly, the cells do not form recognizable glands, which separates SMILE from typical AIS.
- Mucin throughout all layers — Unlike HSIL, where the abnormal cells contain no mucus, SMILE shows mucus inside cells at all levels of the abnormal area. The mucus may appear as small clear vacuoles inside the cells or as a wider clear space between the cells.
- Enlarged, darker nuclei — The cell nuclei are larger than normal and appear darker, a feature called hyperchromasia. The genetic material inside the nuclei (the chromatin) may appear coarse or clumped.
- Increased cellular crowding — The abnormal cells are tightly packed, with little space between them.
- Many dividing cells — Mitotic figures (cells in the process of dividing) and apoptotic cells (cells undergoing programmed death) are common throughout the abnormal area.
- No invasion — The abnormal cells stay confined to the surface lining of the cervix and do not invade into the deeper tissue. This is what makes SMILE precancerous rather than cancer.
SMILE is frequently found alongside HSIL, AIS, or both. The pathology report may describe these other findings together with the SMILE diagnosis.
Surgical margins
A margin is the cut edge of tissue removed during a surgical procedure such as a LEEP or cone biopsy. When the tissue is removed, the pathologist examines the margins under the microscope to determine whether any abnormal cells are present at the cut edges.
- Negative margin — No abnormal cells are present at the cut edge of the tissue. This suggests the entire abnormal area was removed and is the most reassuring result.
- Positive margin — Abnormal cells extend to the cut edge of the tissue. This means some abnormal cells may remain in the cervix, increasing the chance that the lesion will recur.
Because SMILE is a glandular type of precancerous lesion and may extend deeper into the cervical canal than purely squamous lesions, margin status is particularly important. When margins are positive, the team often discusses further surgical treatment to confirm complete removal.
What is the prognosis?
SMILE is a high-grade precancerous lesion and carries a meaningful risk of progressing to cervical cancer if it is not treated. Because SMILE is rare and has only been recognized as a distinct entity for a relatively short time, large studies of its long-term behavior are limited. The available evidence suggests that, like AIS, SMILE has the potential to develop into invasive cancer over time, including both squamous cell carcinoma and adenocarcinoma. With complete surgical removal and confirmation of negative margins, the outlook is generally favorable.
Several features influence the chance that SMILE will recur or progress after treatment:
- Margin status — Negative margins on an excision specimen are associated with the best outcomes. Positive margins increase the chance of residual disease and recurrence.
- Persistent high-risk HPV infection — Continued presence of high-risk HPV after treatment is the most important predictor of recurrence.
- Coexisting HSIL or AIS — When SMILE is found together with HSIL or AIS, the overall risk to the cervix depends on all of the abnormal findings combined.
- Immune status — People with weakened immune systems are at higher risk of recurrence or progression and may require closer surveillance.
- Age and reproductive plans — Younger patients who wish to preserve fertility may have ongoing surveillance after excision rather than more extensive surgery.
What happens after this diagnosis?
Because SMILE is considered a high-grade precancerous lesion, complete surgical removal is generally the goal. The discussion between you and your doctor about next steps depends on whether the diagnosis was made on a biopsy alone or on an excisional specimen, and on the margin status and any other findings in the report.
Options that the team may consider include:
- Excisional procedure — When SMILE is identified on a biopsy, the team typically discusses an excisional procedure such as a cone biopsy or LEEP to remove the abnormal area and confirm there is no underlying invasive cancer. Because SMILE has glandular features and may extend deeper into the cervical canal than purely squamous lesions, a cone biopsy is often preferred over LEEP to obtain a larger and more reliably evaluable specimen, although the choice depends on the individual situation.
- Re-excision for positive margins — If the margins of the first excision are positive, the team may discuss a repeat excision to confirm complete removal.
- Hysterectomy — For patients who have completed their families and who have persistent or recurrent SMILE (or related precancerous changes) after excision, hysterectomy may be discussed as a more definitive option. This is particularly relevant when margins remain positive after repeat excision.
- Surveillance after treatment — Following excision with negative margins, the team typically discusses a schedule of follow-up testing that combines Pap testing, HPV testing, and colposcopy at defined intervals to make sure the abnormal area does not recur. Because SMILE may extend higher into the cervical canal, the follow-up plan may include endocervical sampling.
- HPV vaccination — If you have not already received the HPV vaccine, the team may discuss vaccination, which can lower the risk of acquiring new HPV infections and may reduce the risk of future precancerous lesions.
Long-term follow-up is important after treatment of SMILE, similar to the follow-up recommended after treatment of HSIL or AIS. Your doctor will tailor the schedule to your specific situation.
Questions to ask your doctor
- Was SMILE the only abnormal finding, or was it found together with HSIL, AIS, or any other lesion?
- Was high-risk HPV identified, and if so, which type?
- Was p16 staining performed, and what did the result show?
- Was my SMILE found on a biopsy, or on a larger excision specimen such as a cone biopsy or LEEP?
- If an excision was done, were the margins negative or positive?
- What treatment options would you discuss with me, given my findings, age, and plans for the future?
- If I would like to preserve my fertility, what are the safest options for me?
- How often will I need follow-up testing, and what tests will be included?
- What is the chance that SMILE will come back after treatment?
- Should I be vaccinated against HPV if I have not already been vaccinated?
- How will my smoking status, immune health, or medical history affect my risk of recurrence?
- What symptoms should I watch for between routine appointments?
Related articles on MyPathologyReport.com