AT ISPD 2015

WASHINGTON (FRONTLINE MEDICAL NEWS) – When the results of a noninvasive prenatal test are positive for aneuploidy but follow-up fetal karyotype results are normal, an undiagnosed maternal malignancy may be the reason why, Dr. Diana Bianchi reported at the International Conference on Prenatal Diagnosis and Therapy.

The conclusions are based on a study that evaluated several cases of cancers among apparently healthy women who had noninvasive prenatal testing (NIPT) during pregnancy with a cell-free DNA (cfDNA) test, which screens for fetal aneuploidy in chromosomes 13, 18, 21, X, and Y. In these cases, the NIPT results did not match the fetal karyotype results, which were obtained through amniocentesis or chorionic villus sampling.

While uncommon, “occult maternal malignancy is a potential biological explanation for discordant results,” between the fetal karyotype and NIPT, Dr. Bianchi, of the Mother Infant Research Institute at Tufts Medical Center, Boston, and lead author of the study, said at the meeting.

The study findings “underscore the need to perform a diagnostic procedure to ascertain the true fetal karyotype,” she added. The study was published July 13 in JAMA to coincide with Dr. Bianchi’s presentation at the International Conference on Prenatal Diagnosis and Therapy ( doi:10.1001/jama.2015.7120 ).

In the study, she and her associates note that the discordant results are thought to be caused by cfDNA that is “released into the maternal circulation from apoptotic malignant cells.” The first case of a maternal cancer identified as the cause of discordant results between NIPT and fetal karyotype tests was identified in 2013, they said. Other explanations include the death of a twin or having received an organ transplant from a male donor. The researchers examined 125,426 NIPT results from asymptomatic pregnant women, which were processed at one lab between Feb. 15, 2012, and Sept. 30, 2014. Of these tests, 3,757 (3%) were positive for at least one aneuploidy involving chromosomes 13. 18, 21, X, or Y.

Among these cases, 10 women were subsequently diagnosed with cancer after abnormal NIPT results were reported (three cases of B-cell lymphoma and one case each of Hodgkin lymphoma; T-cell leukemia; unspecified adenocarcinoma; leiomyosarcoma; and neuroendocrine, colorectal, and anal carcinomas. Most (seven) had multiple aneuploidies, two had a single trisomy, and one had a single monosomy.

The investigators obtained more information from eight of the women. The other two women were critically ill and did not participate.

The mean age of the eight women was 35 years, and they were diagnosed with cancer while still pregnant or after delivery at a mean of 16 weeks after the first NIPT. Fetal karyotyping had been performed in seven of these cases and showed euploid results. The eight women were asymptomatic when they were screened, and the NIPT results “prompted” the diagnosis in three women, but whether earlier detection of the disease would have made a difference in the outcomes could not be determined, the authors wrote.

The follow-up of these patients was not complete, but the authors estimate that in 20%-44% of cases where multiple aneuploidies are detected and the results are discordant, an occult maternal cancer is the explanation. The study is described by the authors as “preliminary.” Limitations includes the retrospective design and incomplete follow-up information, they wrote.

During her presentation, Dr. Bianchi said that the highest risk group are women with multiple aneuploidies, “or suspiciously, a single autosomal monosomy,” the types of cases that “may warrant more detailed analysis of the whole genome.

“Further studies are needed to determine a recommended medical work-up for women” thought to be at high risk, she added. She referred to a recently published Belgian study , which evaluated a small group of women with the same types of suspicious NIPT results with MRI scans, which picked up evidence of tumors in all three of the women studied.

NIPT, considered an advanced screen not a diagnostic test, involves sequencing of cfDNA in maternal plasma, which contains placental DNA, “used as a proxy for the fetus,” and maternal DNA, the authors explained. NIPT is highly sensitive and specific for detecting trisomies 21, 18, and 13.

The cfDNA tests were manufactured by Illumina and were processed at the company’s clinical laboratory in Redwood City, Calif. Illumina funded the study, and sponsored research funding administered through Tufts Medical Center, which paid for the time that Dr. Bianchi spent working with Illumina employees to design the study, analyze the data, and prepare the manuscript.


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