In a brief report in The New England Journal of Medicine, Ayumu Arakawa, MD, of the Department of Pediatric Oncology, National Cancer Center Hospital, Tokyo, and colleagues described identification of lung cancer in two boys that likely resulted from transmission of maternal cervical cancer tumor cells during vaginal delivery.1
As noted by the investigators, transmission of maternal cancer to infants is an extremely rare event (with an estimated incidence of approximately 1 infant per every 500,000 mothers with cancer). The relatively small number of cases in the literature has been presumed to occur through hematogenous transmission via transplacental mother-to-fetus transmission. The reported cases involved mothers with cancers of the blood, skin, lungs, and cervix and often included dissemination of tumor cells to multiple organs in the infant. However, transmission of tumor in the birth canal during vaginal delivery is also possible; in a mother with cervical cancer, the infant can be exposed to tumor cells in fluids in the birth canal and aspirate the cells into the lungs.
The two cases were incidentally identified during routine next-generation sequencing of paired samples of tumor and normal tissue to identify mutations in 114 cancer-related genes as part of the TOP-GEAR trial, a prospective gene-profiling trial involving patients with advanced cancer.
The first boy was diagnosed with lung cancer in both lungs at age 23 months. Although cervical cytology at 7 months before the birth was negative, the mother was diagnosed with squamous cell carcinoma of the cervix 3 months after the birth.
Imaging in the boy showed multiple masses along the bronchi in both lungs, with biopsy showing neuroendocrine carcinoma of the lung with focal glandular differentiation. Examination of a subsequent lung metastasis in the mother showed poorly differentiated carcinoma with neuroendocrine differentiation. Reexamination of her hysterectomy specimen showed that the cervical cancer was predominantly poorly differentiated squamous cell carcinoma with focal neuroendocrine differentiation and a minor component of adenocarcinoma.
Histologic similarities between the tumor samples from mother and child prompted comparison of next-generation sequencing findings. It was found that both tumors had the same pathogenic KRAS (c.G38A: p.G13D) and TP53 (c.G853A:p.E285K) mutations and that 47 exonic single-nucleotide polymorphism alleles carried by the mother but not inherited in the child’s germline were present in the child’s tumor. Fluorescence in situ hybridization showed that the boy’s tumor lacked the Y chromosome. Whole-exome sequencing identified an additional 20 somatic mutations in both tumors. HLA class I alleles that were not inherited by the child were lost in samples from both tumors. Polymerase chain reaction analysis showed that both tumors were positive for human papillomavirus (HPV) type 18.
Spontaneous regression of some lesions in the child were observed during the initial follow-up without treatment (parental decision), suggesting an alloimmune response against the transmitted tumor. However, multiple foci of the tumor were still present in both lungs. At 1 year after diagnosis, the patient received five cycles of cisplatin plus irinotecan and two cycles of carboplatin plus etoposide; regression was observed in some tumors, but others progressed. He then received 14 cycles of nivolumab at 3 mg/kg every 2 weeks, with a major regression of remaining tumors being observed and the response being maintained for 7 months with no appearance of new lesions. Lobectomy was performed to remove a remaining nodule, and the patient had no evidence of disease recurrence during 12 months of follow-up after lobectomy.
The second boy was diagnosed with mucinous adenocarcinoma of the left lung at age 6 years. A cervical polypoid tumor had been found in the mother during pregnancy, but cervical cytology was negative and the tumor was stable without any intervention. Biopsy of the cervical lesion after delivery showed adenocarcinoma. Given the diagnosis at 6 years of age, cervical transmission was not initially suspected. However, the evidence implicating cervical transmission indicated slow growth of the tumor in the boy, again suggesting an alloimmune response against the transmitted tumor.
Tumors in the mother and child had the same KRAS (c.G35A:p.G12D) and STK11 (c.464+1G→A) mutations, and 38 exonic single-nucleotide polymorphism alleles carried by the mother but not inherited in the child’s germline were identified in the child’s tumor. Fluorescence in situ hybridization showed that the tumor lacked the Y chromosome. Whole-exome sequencing identified an additional 14 somatic mutations that were present in both tumors. Loss of HLA class I alleles was not detected in either of the tumor samples. Both tumors were positive for HPV type 16.
The tumor in the boy was considered inoperable. He exhibited a partial response to treatment with five cycles of paclitaxel and cisplatin followed by three cycles of paclitaxel and carboplatin and two cycles of paclitaxel and irinotecan. Disease recurrence was found at 3 months after discontinuation of treatment. After five cycles of gemcitabine and docetaxel and one cycle of paclitaxel and carboplatin, he underwent a total left pneumonectomy. He was free from disease during 15 months of follow-up after pneumonectomy.
The investigators concluded: “These cases indicate that mother-to-infant transmission of uterine cervical cancer is possible during vaginal delivery; therefore, cesarean section should be recommended for mothers with uterine cervical cancer…. Next-generation sequencing of paired samples of tumor and normal tissue may be a useful tool to diagnose cancer that is transmitted from mothers to infants and to understand the prevalence of this transmission.”
DISCLOSURE: The study was supported by the Japan Agency for Medical Research and Development and others. Dr. Arakawa has received research support from Astellas, AstraZeneca, and Chugai.
1. Arakawa A, Ichikawa H, Kubo T, et al: Vaginal transmission of cancer from mothers with cervical cancer to infants. N Engl J Med 384:42-50, 2021.