Women and their doctors talk about advanced biomarker testing
High-risk HPV-positive woman with normal Pap cytology
39 years old
Sees her practitioner on a regular basis
No prior abnormal cytology results
No prior HPV testing
Sooner rather than later
Pooled high-risk HPV-positive woman with normal Pap cytology
Claudia’s doctor recently became part of a regional pilot program to evaluate primary screening for high-risk HPV (hrHPV).
Her doctor explains that hrHPV testing is much more sensitive than Pap cytology. When a woman has a negative hrHPV test result, doctors can be very confident that cervical disease is not present. Cytology, on the other hand, is known to miss disease in some cases, and while many doctors rely on the technique, they know a negative Pap cytology result may not always be a reliable indicator of the absence of disease.
Claudia agrees to have the hrHPV test. Her doctor collects a liquid-based cytology (LBC) specimen for the hrHPV testing. Claudia’s hrHPV test results are positive for pooled hrHPV. Her doctor also receives hrHPV genotyping results as part of the pilot program; Claudia is negative for the HPV 16 and HPV 18 genotypes most strongly associated with the development of pre-cancerous lesions. To determine if any cervical cytologic abnormalities are present, the laboratory subsequently runs a Pap cytology test on Claudia’s liquid-based cytology specimen. The Pap cytology results are normal.
Claudia’s doctor is presented with inconclusive test results that make it difficult to make a clear plan to help manage her patient. In a hrHPV primary screening program, women like Claudia with a positive pooled hrHPV test and a negative Pap cytology test would be managed by more frequent follow up, possibly culminating with a colposcopy. This can mean additional visits for the patient and additional anxiety about test results. A colposcopy could help provide more clarity about any changes to her cervical tissue, but the procedure ultimately turns out to be unwarranted for most women. This is because most hrHPV infections do not persist and lead to precancerous dysplasia, but rather resolve on their own over time.
The pilot program protocol stipulates that women like Claudia, who have a positive hrHPV result and normal (negative) Pap cytology result, return for follow-up hrHPV testing at 12 months.
How biomarkers could help
Using a dual-stain p16/Ki-67 biomarker test instead of a Pap cytology test to triage Claudia’s initial HPV test result could potentially spare her the anxiety of protracted retesting and even the need for colposcopy. Because Pap cytology can sometimes miss disease, Claudia’s doctor would be much more confident in prescribing a plan to manage her.
The co-expression of p16 and Ki-67 is strongly linked to pre-cancerous changes in the cervix, so a negative result can indicate that such changes are not present. In this case, colposcopy would be unnecessary, and the patient can be followed up according to appropriate guideline screening intervals.
A positive p16/Ki-67 result, conversely, would warrant immediate colposcopy. This would also help Claudia and her doctor avoid retesting and the anxiety associated with inconclusive results.
Woman with ASC-US cytology
São Paulo, Brazil
42 years old
Last Pap cytology test 2 years ago; no prior abnormal Pap cytology results
Fewer steps to a definitive answer
Abnormal Pap cytology (ASC-US) without hrHPV test results
Mariana sees her doctor for a routine Pap cytology test, results of which show ASC-US cytology (atypical squamous cells of undetermined significance).
The doctor explains that this finding is ambiguous, a type of abnormal cytology result that should be monitored with additional follow up and testing. The best plan to manage Mariana is not immediately clear.
In some countries, one course of action to gather more information about a patient with ASC-US cytology is to run a pooled high-risk HPV DNA test (hrHPV), and perhaps test specifically for the HPV 16 and HPV 18 genotypes. HPV DNA test results can give doctors additional insights about the potential for more serious abnormalities, and even the presence of pre-cancerous lesions.
In many parts of the world, hrHPV testing is not readily available. This is the circumstance where Mariana and her doctor live. Mariana’s doctor recommends that she return regularly for repeat Pap cytology testing at a shorter interval than her normal screening exams. This is the best way that her doctor can monitor Mariana for any cervical changes.
Mariana is uncomfortable with the prospect of having to undergo so many Pap cytology tests. Her doctor says the only alternative is colposcopy with cervical biopsy, an invasive procedure that ultimately may not be necessary and thus create more uncertainty about her situation.
How biomarkers could help
Using a dual-stain p16/Ki-67 biomarker test to triage Mariana’s Pap cytology result means her doctor receives immediate feedback about how to best manage her patient without the need for retesting or colposcopy. Because p16 and Ki-67 are co-expressed simultaneously in the same cell only in the presence of transforming disease, a negative biomarker test result would help rule out pre-cancerous lesions, even with abnormal cytology.
Conversely, if the p16/Ki-67 biomarker test yielded a positive result, Mariana’s doctor could confidently refer her to colposcopy to confirm the presence of pre-cancerous lesions. Additionally, Mariana would not have to wait for results because the dual-biomarker test can be performed on the same sample collected during a Pap cytology exam.
Woman of child-bearing age with LSIL cytology
27 years old
Plans to have a child in the next year
Sees her OB/GYN regularly
Last Pap cytology result was normal but she has had a prior history of abnormal Pap cytology results
Preventing unnecessary risk to pregnancy
Woman of child-bearing age with low-grade Pap abnormality (LSIL)
At Laura’s most recent routine OB/GYN visit, her doctor recommended a Pap cytology test. Although the interval since her last exam did not mandate it was time for another, Laura and her doctor agreed it would be a pre-emptive safeguard given her plans to begin a family.
Unfortunately, her Pap cytology result comes back from the lab as LSIL (low-grade squamous intraepithelial lesion). Laura is distraught when her doctor explains that LSIL is a diagnosis of potential pre-cancerous disease, which warrants immediate evaluation by colposcopy and potential biopsy should a cervical lesion be identified. She offers some consolation, explaining that, in most cases, LSIL does not progress to high-grade pre-cancerous disease. But to be sure, they need to be vigilant.
Laura and her doctor discuss the situation in the context of her interest in becoming pregnant. Her doctor explains that colposcopy is necessary to identify any lesions on the cervix and, should a lesion be found, a biopsy would need to be taken for further evaluation. If a high-grade lesion is confirmed on the biopsy, an excisional procedure will be necessary. The doctor explains to Laura that excisional procedures could introduce complications associated with pre-term birth. Laura asks if follow-up evaluation or treatment could wait, but her doctor advises that it is best to act quickly and investigate despite the potential risks should treatment be necessary.
How biomarkers could help
Dual-stain p16/Ki-67 biomarker testing could help Laura’s doctor come up with a definitive plan to manage her without generating additional anxiety or intrusive testing.
Because Laura’s Pap was done using liquid-based cytology, the same sample could be used to run p16/Ki-67 immunocytochemistry. The simultaneous expression of these two biomarkers within cervical cells is highly predictive of underlying high-grade disease, so a negative biomarker test result would help rule out the immediate concern that Laura’s LSIL abnormality was, in fact, a precursor to cervical cancer. While her doctor would continue to monitor her, she could do so with repeat testing instead of colposcopy.
A positive p16/Ki-67 result would cause Laura to be referred to colposcopy and biopsy. Because the biomarker test has already indicated the possible presence of pre-cancerous disease, the biopsy performed during colposcopy could confirm the presence of pre-cancerous lesions and thus conclusively resolve Laura’s specific situation. This is one example in which a biomarker guided result could prevent a woman from being referred unnecessarily to colposcopy.
Now the conversation between Laura and her doctor can include biomarker test results to inform the best treatment options. Laura can be more confident she is making the right choice for herself and her future family.
Woman with discordant cytology and histology results
Amsterdam, The Netherlands
28 years old
Sees her OB/GYN regularly
Confirming the presence of cervical pre-cancer with advanced biomarker technology
Woman of child-bearing age with an abnormal cytology result
At her recent OB/GYN visit, Anjelika receives a routine Pap cytology examination. Her doctor calls when the results come back and tells her the unfortunate news that her cytology result revealed significant abnormalities in her cervix that could progress to cervical cancer.
Anjelika is confused and upset. She follows her doctor’s orders and makes an appointment as soon as possible for a colposcopy and biopsy. Her doctor explains that these procedures are warranted due to the severity of the cytologic findings.
The colposcopy identifies a suspicious lesion on the cervix. Anjelika’s doctor explains that he will need to take a biopsy and send the tissue to the lab for confirmatory diagnosis. He will use this information to help guide her management plan.
The laboratory stains Anjelika’s cervical tissue specimen using hematoxylin and eosin (H&E). The pathologist interprets the H&E slide and renders a diagnosis of “normal” for Anjelika’s cervical biopsy specimen. H&E diagnoses are based on the interpretation of cellular structure and sometimes small lesions within the biopsy tissue may be missed.
Because Anjelika’s cytology result was abnormal and the initial biopsy result was negative, Anjelika’s doctor indicates that he wants to closely monitor her to ensure cervical pre-cancer is not missed or does not develop. Her doctor asks her to return to the office in 6 months for repeat cytology along with colposcopy. Anjelica is visibly upset and concerned but agrees that this is the most prudent approach to ensure her health.
How biomarkers can help
p16 immunostaining of cervical biopsy specimens may identify overexpression of p16 due to transforming high-risk HPV (hrHPV) infections. p16 overexpression in cervical biopsy specimens is highly correlated with oncogenic transformation and cervical pre-cancer. In histologic samples, adjunct p16 immunostaining along with conventional H&E morphological interpretation can provide additional information about the status of the cervical specimen, and can also help identify occult lesions that may be missed by the H&E interpretation alone.
By requesting p16 immunostaining of the cervical biopsy specimen, Anjelika’s doctor would be more confident that disease was not missed on tissue biopsy − without the need for generating additional anxiety due to lengthy follow up and retesting.