By Scott Baltic
NEW YORK (Reuters Health) - In patients with conjunctival squamous-cell carcinoma (cSCC), distinct clinical and histopathological features associated with human papillomavirus (HPV) status support the theory that HPV has a causal role in at least some of these conjunctival tumors, researchers in Denmark report.
Such characteristics include transcriptionally active HPV in the tumor tissue, as identified by in situ hybridization, but not in the surrounding normal tissue, they report.
The study also shows that patients with an HPV-positive cSCC tumor were significantly younger at the time of diagnosis than their HPV-negative counterparts (mean difference, 11.5 years) and had both a lower comorbidity index and a higher risk of recurrence.
Though rare, cSCC is the world's most common malignancy of the conjunctiva and has seen an increase in incidence, Dr. Ingvild Ramberg of Rigshospitalet, Copenhagen University Hospital, and colleagues note in the British Journal of Ophthalmology, online October 24.
Exposure to solar ultraviolet radiation B is considered to be the primary risk factor for cSCC, along with immunosuppression. The role, if any, of HPV infection in cSCC has been controversial.
The researchers reviewed records on all patients in Denmark diagnosed with conjunctival intraepithelial neoplasia (CIN), conjunctival carcinoma in situ, or cSCC from 1980 through 2016.
In all, they examined 154 cases of primary tumors (112 cCIN and 42 cSCC) and 39 of recurrent tumors (25 cCIN and 14 cSCC) histopathologically. The mean age at diagnosis was 67 years in men and 61 years in women. Males were predominant (72%) with both preinvasive and invasive carcinomas.
One hundred and twelve primary tumors and 33 recurrent tumors contained enough tissue to undergo HPV analyses. Of these, 21% were HPV positive, with HPV16 being the most prevalent type (75%).
The age-adjusted incidence of cCIN and cSCC in Denmark increased from 0.03 per 100,000 in 1980 to 0.12 per 100,000 in 2016, for an average annual percentage change of 3.9 (P<0.05). Throughout this period, a higher incidence was seen for HPV-negative tumors than for HPV-positive tumors.
Within two years of diagnosis, enucleation or exenteration had been performed in three of six patients with an HPV-positive cSCC and in three of 32 patients with an HPV-negative cSCC.
Recurrence was more common in patients with an HPV-positive primary tumor than in patients with an HPV-negative primary tumor (HR, 2.30; P=0.046). All-cause mortality did not differ between the groups.
A non-keratinizing tumor was significantly likelier to be HPV positive.
The large age difference by HPV status, the authors write, "could suggest that HPV infection and exposure to UV radiation act synergistically, and those patients both exposed to sunlight and HPV infection may develop malignancy at an earlier age."
Dr. Ramberg told Reuters Health by email that based on this study, the increasing incidence of these cancers can't be explained by HPV infection, because the incidence of HPV-related cSCC in their cohort remained stable.
Other countries, for example in Africa, have also reported an increase in incidence, which might be due to HIV/AIDS, as immunosuppressed patients have a many-fold higher risk for developing cSCC, she said.
At this stage, there are no specific precautions that should be taken by primary-care physicians or ophthalmologists, Dr. Ramberg said. "Future studies will reveal if (tissue) samples should be routinely screened for HPV."
Dr. Ashish Deshmukh of UTHealth School of Public Health in Houston, Texas, who has studied the rising rates of anal cancers linked to HPV, told Reuters Health by email that cSCC has a U.S. incidence of fewer than 0.08 per 100,000 persons.
"Given the rarity of the disease, it has not been well studied in many countries where cancer diagnosis information is not well documented," he said.
"The increase in incidence is not surprising - it is consistent with the rises that we are observing in the U.S. - although the differences in the HPV-positive and HPV-negative tumors is surprising," said Dr. Deshmukh, who was not involved in the new study.
"These findings further convey the importance of HPV vaccination in both sexes . . . to prevent these malignancies in our future generations," he concluded.
The authors declared no competing interests.
Br J Ophthalmol 2019.