- Design
- Single-institution case series with molecular analysis
- Population
- 201 cervical squamous cell carcinomas; 11 with negative or focal p16
- Primary outcome
- HPV status, MTAP, RB1, p53 and mutation profile in non-diffuse p16 tumours
- Effect
- 4 of 11 high-risk HPV-associated; MTAP lost in 3 of 4 with complete p16 loss
Pathologists reviewed 201 cervical squamous cell carcinomas at one institution and found 11 (5.5%) with negative or focal p16 staining. Four were associated with high-risk HPV, six were HPV-independent and one had low-risk HPV.
In three of the four high-risk HPV cases with complete p16 loss, MTAP was also lost, pointing to deletion of the CDKN2A/MTAP region; the same pattern appeared in two p16-negative high-grade intraepithelial lesions. All six HPV-independent tumours kept MTAP, and they more often carried TERT promoter and PIK3CA mutations. One HPV-independent tumour had a null p53 pattern with a TP53 nonsense mutation.
This matters because HPV-independent cervical carcinoma behaves differently and is classified separately, and p16 is often used alone as a surrogate. A negative p16 can therefore misclassify an HPV-associated tumour.
The practical step, as the authors recommend, is to pair p16 with HPV testing, or with a prior liquid-based HPV result, whenever p16 is not block-positive.
- Do not classify a cervical squamous carcinoma as HPV-independent on negative p16 alone.
- Request HPV testing, or check prior cytology HPV results, when p16 is negative or focal.
- Consider MTAP staining when p16 is completely lost in an HPV-positive tumour.
- Remember that p16 loss can occur in high-grade intraepithelial lesions as well.
Why it matters
HPV-independent cervical carcinoma carries a different prognosis, so a surrogate stain error can change what clinicians tell patients.
Don't overread it
Eleven cases from one institution; the frequency of each pattern elsewhere is uncertain.
The statistics, in plain English
5.5% means about 1 in 18 cervical squamous carcinomas lacked diffuse p16 here. Small subgroups of four and six cases cannot give reliable mutation frequencies.
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