Cancer can be transmitted from a mother with cervical cancer to a newborn when the baby passes through the birth canal.
That’s the conclusion of two ground-breaking cases from Japan in which investigators describe lung cancer in two boys that “probably developed” from their respective mothers via vaginal transmission during birth.
“Transmission of maternal cancer to offspring is extremely rare and is estimated to occur in approximately 1 infant per every 500,000 mothers with cancer,” write Ayumu Arakawa, MD, of the National Cancer Center Hospital in Japan and colleagues in a paper published January 7 in The New England Journal of Medicine.
Previous cases, of which only 18 have been recorded, have been presumed to occur via transplacental transmission, they say.
In the two new cases, genetic analyses and other evidence suggest that both boys’ lung cancers developed after aspirating uterine cervical cancer tumor cells into their lungs during passage through the birth canal.
Tragically, both mothers, each of whom was diagnosed with cervical cancer after the births, died while their boys were still infants.
“Most of the maternal-to-infant cases reported have been leukemia or melanoma,” says Mel Greaves, PhD, of The Institute of Cancer Research, London, England, who was asked for comment. In 2009, Greaves and colleagues published a case study of maternal-to-infant cancer transmission (presumably via the placenta). “It attracted an enormous amount of publicity and no doubt some alarm,” he told Medscape Medical News. He emphasized that the phenomenon is “incredibly rare.”
Greaves explains why such transmission is so rare. “We suspect that cancer cells do transit from mum to unborn child more often, but the foreign (aka paternal) antigens (HLA) on the tumor cells prompts immunological rejection. The extremely rare cases of successful transmission probably do depend on the fortuitous loss of paternal HLA.”
Advances in genetic technology may allow such cases, which have been recorded since 1950, to be rapidly identified now, he said.
“Where there is an adult-type cancer in an infant or child whose mother carried cancer when pregnant, then whole genome sequencing should quickly tell if the infant’s tumor was of maternal origin,” Greaves explained.
“I think we will be seeing more reports like this in the future, now that this phenomenon has been described and next-generation sequencing is more readily available,” added Mae Zakhour, MD, of the UCLA Jonsson Comprehensive Cancer Center in Los Angeles, who was also asked for comment.
In the case of the Japanese boys, both cases were discovered incidentally during an analysis of the results of routine next-generation sequencing testing in a prospective gene-profiling trial in cancer patients, known as TOP-GEAR.
How do the investigators know that the spread happened vaginally and not via the placenta?
They explain that in other cases of mother-to-fetus transmission, the offspring present with multiple metastases in the brain, bones, liver, lungs, and soft tissues, which are “consistent with presumed hematogenous spread from the placenta.” However, in the two boys, tumors were observed only in the lungs and were localized along the bronchi.
That peribronchial pattern of tumor growth “suggested that the tumors arose from mother-to-infant vaginal transmission through aspiration of tumor-contaminated vaginal fluids during birth.”
Additionally, the tumors in both boys lacked the Y chromosome and shared multiple somatic mutations, an HPV genome, and SNP alleles with tumors from the mothers.
“The identical molecular profiles of maternal and pediatric tumors demonstrated by next-generation sequencing, as well as the location of the tumors in the children, provides strong evidence for cancer transmission during delivery,” summarized UCLA’s Zakhour.
The first of the cases reported by the Japanese team was a toddler (23 months) who presented to a local hospital with a 2-week history of a productive cough. Computed tomography revealed multiple masses scattered along the bronchi in both lungs, and a biopsy revealed neuroendocrine carcinoma of the lung.
Notably, the mother’s cervical cancer was not diagnosed during her pregnancy. A cervical cytologic test performed in the mother 7 months before the birth was negative. The infant was delivered transvaginally at 39 weeks of gestation.
It was only 3 months after the birth that the 35-year-old mother received a diagnosis of squamous-cell carcinoma of the cervix. She then underwent radical hysterectomy with pelvic lymphadenectomy, followed by chemotherapy.
Had it been known at she had cervical cancer, she may have been advised to have a cesarean section.
The study authors propose, on the basis of their paper, that all women with cervical cancer should have a cesarean section.
But a US expert questioned this, and said the situation is “a bit nuanced.”
William Grobman, MD, of the Feinberg School of Medicine at Northwestern University in Chicago, said the current standard recommendation for many pregnant women known to have cervical cancer is to have a cesarean section and that “the strength of the recommendation is dependent on factors such as stage and size.”
However, in comments to Medscape Medical News, he added that “it may be premature to make a blanket recommendation for all people based on two reports without any idea of the frequency of this event, and with such uncertainty, it seems that disclosure of all information and shared decision making would be a key approach.”
In this case report, the authors also note that the cancer found in the toddler looked similar to the cancer in the mother.
“Histologic similarities between the tumor samples from the mother and child prompted us to compare the results of their next-generation sequencing tests,” they comment.
The result? “The comparison of the gene profiles in the samples of tumor and normal tissue confirmed that transmission of maternal tumor to the child had occurred.”
The lung cancer in the toddler progressed despite two chemotherapy regimens, so he was enrolled in a clinical trial of nivolumab therapy. He had a response that continued for 7 months, with no appearance of new lesions. Lobectomy was performed to resect a single remaining nodule. The boy had no evidence of disease recurrence at 12 months after lobectomy.
His mother, on the other hand, was also enrolled in a nivolumab trial, but her cervical cancer had spread and she died 5 months after disease progression.
In the second reported case, a 6-year-old boy presented to a local hospital with chest pain on the left side. Computed tomography revealed a mass in the left lung and mucinous adenocarcinoma was eventually diagnosed.
In this case, the mother had a cervical polypoid tumor detected during pregnancy. But, as in the other case, cervical cytologic analysis was negative. Because the tumor was stable without any intervention, the mother delivered the boy vaginally at 38 weeks of gestation.
However, after the delivery, biopsy of the cervical lesion revealed adenocarcinoma. The mother underwent radical hysterectomy and bilateral salpingo-oophorectomy 3 months after delivery. She died of the disease 2 years after the surgery.
The boy received chemotherapy and had a partial response, with a reduction in levels of the tumor marker CA19-9 to normal levels. But 3 months later, the disease recurred in the left lung; after more chemotherapy, he underwent total left pneumonectomy and was subsequently free of disease.
The study authors say that they did not suspect maternal transmission of the cancer when her child received a diagnosis at 6 years of age. They explain that metastatic cervical cancer is typically a fast growing tumor and the slow growth in the child seemed inconsistent with the idea that the cancer had been transmitted to him.
However, the pathology exam showed that the boy had mucinous adenocarcinoma, “which is an unusual morphologic finding for a primary lung tumor, but it was similar to the uterine cervical tumor in the mother,” the authors report.
Samples of the cervical tumor from the mother and from the lung tumor of the child were submitted for next-generation sequencing tests and, say the authors, indicated mother-to-infant transmission.
The study was supported by grants from the Japan Agency for Medical Research and Development, National Cancer Center Research and Development Fund, and the Ministry of Education, Culture, Sports, Science and Technology; and funding from Ono Pharmaceutical.
N Engl J Med. 2021;384:42-50. Summary
Nick Mulcahy is an award-winning senior journalist for Medscape. He previously freelanced for HealthDay and MedPageToday and had bylines in the WashingtonPost.com, MSNBC, and Yahoo. Email: [email protected] and on Twitter: @MulcahyNick.