Vaginal transmission of cervical cancer — a phenomenon that has not been previously reported — was detected in two pediatric patients.
A Japanese team said Thursday it had confirmed cases of pediatric lung cancer resulting from a mother-to-baby transmission of cervical cancer during birth for the first time in the world. Two boys were found to have developed lung cancer after swallowing amniotic fluid containing cervical cancer cells in their first cries. The cells mixed into the fluid during birth.
An article on the findings was published in the digital edition of the New England Journal of Medicine. The research team included members of the National Cancer Center.
The team’s analysis found that the DNA arrangements of cancer cells from the boys and their mothers included the same mutations. Also, the cancer cells in the boys did not contain the Y chromosome, usually found in men.
One of the boys was treated with the cancer immunotherapy drug Opdivo, known generically as nivolumab, while the other had his lung cancer surgically removed. Both mothers, however, died after being diagnosed with cervical cancer at or after the time of birth.
Given that only one in a million children develops lung cancer, the two boys “are very rare cases,” said research team member Chitose Ogawa, head of the Pediatric Oncology Department of National Cancer Center Hospital.
“It’s important to prevent mothers from developing cervical cancer,” Ogawa said.
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The main cause of cervical cancer is infection with certain strains of the human papillomavirus, or HPV. Most women infected with the sexually transmitted virus do not develop the cancer.
Vaccination against HPV before turning 17 years old prevents women from developing cervical cancer, and regular checkups make it easier to find the cancer at an early stage.
Ayumu Arakawa, another team member from the same hospital department, believes that cancer cell transmission via amniotic fluid can be prevented through cesarean sections.
Among other types of cancer, skin cancer is known to be transmissible from mothers to babies via blood passing through the placenta.
MedPage Today, an online health magazine, adds: “Two children whose mothers had undetected cervical cancer at delivery went on to develop lung cancer in early childhood, most likely resulting from mother-to-infant transmission of uterine cervical tumor cells,” says Ayumu Arakawa, MD, of the National Cancer Center in Tokyo, and colleagues.
Spontaneous regression of lesions in one child, as well as slow tumor growth in the other, suggested that there was an alloimmune response in the children, they stated in a brief report in the New England Journal of Medicine.
Additionally, immune checkpoint inhibitor therapy with nivolumab (Opdivo) was effective in shrinking tumors in one patient, possibly due to the presence of this alloimmune response, Arakawa’s group noted.
“To our knowledge, this is the first report of vaginal transmission of cancer to infants,” says Arakawa told in an email. “It is also very important that nivolumab showed drastic efficacy to this type of tumor.”
Melissa Frey, MD, an ob/gyn in the gynecologic oncology department at Weill Cornell Medicine in New York City, said that while passing malignancies from mother to baby is rare, this paper challenges how physicians think about transmission.
“I think what is most interesting about this study is that [transmission] is not thought to be hematogenous, which is the way we have previously conceptualized maternal-fetal transmission,” Frey, who was not involved in this research, told MedPage Today. She added that the findings have “tremendous implications for the way we think about delivery.”
While mode of delivery in pregnant cervical cancer patients has previously centered on maternal implications, Frey said that “this paper asks us to think about the fetal implications in the setting of maternal cervical cancer.”
Maternal transmission of cancer to offspring is extremely rare, occurring in around one in 500,000 mothers with cancer. There are 18 previously reported cases of mother-to-infant cancer transmission, all of which were presumably passed transplacentally. Due to the placental barrier and fetal alloimmune response, transplacental cancer transmission is rare, researchers noted.
Vaginal transmission, albeit rare, also has the potential to occur during vaginal birth. If an infant is exposed to tumor cells in the birth canal, they could potentially aspirate those cells into the lungs.
Arakawa’s group detected these two cases of vaginal cancer transmission during routine next-generation sequencing of paired samples of tumor and normal tissues. The researchers found similar histological patterns in both mothers and their children, leading them to suspect uterine transmission. The analysis was a part of the TOP-GEAR trial, a prospective gene-profiling trial of patients with advanced cancer.
The first patient, a boy age 23 months, presented to the hospital with a cough that had persisted for 2 weeks. A CT scan showed several masses along the bronchi in both lungs, and a lung biopsy uncovered neuroendocrine carcinoma of the lung with focal glandular differentiation.
He was delivered vaginally at 39 weeks, after his mother previously tested negative for cervical cancer via Pap test 7 months before. The mother received a diagnosis for squamous cell carcinoma of the cervix 3 months after giving birth.
The child received frequent follow-up, but was not treated until he turned age 3 years. The researchers noticed some spontaneous regression of his tumors, but there was still several spread along the bronchi. After two chemotherapy regimens and further disease progression, physicians enrolled the patient in a clinical trial of nivolumab therapy. He did not inherit HLA class I alleles, a phenomenon that may have led to initial survival of maternal cancer cells, according to Arakawa and colleagues
He received four cycles of nivolumab at a dose of 3 mg per kg every 2 weeks, which resulted in a shrinkage of all lesions. After 14 cycles of nivolumab and lobectomy, researchers noted no evidence of disease recurrence.
The second patient, a boy age 6 years, presented to the hospital with chest pain. Researchers found a mass on the child’s left lung, and he was diagnosed with mucinous adenocarcinoma. Before he was born, physicians detected a cervical polypoid tumor in the mother. However, as a cervical cytologic test was negative and the tumor appeared stable, the mother delivered the boy vaginally at 38 weeks.
After several cycles of chemotherapy and disease recurrence, he underwent total left pneumonectomy and, 15 months later, was free from disease.
Arakawa and colleagues wrote that transmission was demonstrated by the fact that tumors in both pediatric patients lacked the Y chromosome, as well as shared somatic mutations, an HPV genome, and SNP alleles with tumors found in each of their mothers. Additionally, the metastases in both of these cases were localized in the respiratory region, whereas transplacental transmission may result in dispersed metastases throughout the brain, bones, liver, and soft tissues.
This mode of transmission is extremely rare, Arakawa said. But as these reports indicate that vaginal transmission may be possible when infants inhale tumor cells during birth, the researchers recommended that pregnant people with cervical cancer plan for a cesarean section birth.