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. 2024 Feb 18;115(4):1039–1047. doi: 10.1111/cas.16102

Cross‐individual cancer transmission to children during the gestational and perinatal periods

Ayumu Arakawa 1,✉, Kayoko Tao 1, Takashi Kohno 2, Chitose Ogawa 1
PMCID: PMC11006992  PMID: 38369705

Abstract

Cancer transmission may rarely occur between individuals. Besides through allogenic transplantation, cancer transmission via the hemochorial placenta, which is permissive for cell traffic, has been described in a few reports. Three etiologies of transplacental cancer transmission include (1) maternofetal transmission of maternal cancer cells, (2) transmission of gestational choriocarcinoma to the fetus, and (3) transfer of preleukemic cells from one monozygotic twin to the other. Additionally, we recently reported two pediatric cases of lung tumors in which the lung‐only distribution of tumors and genomic profiling of both the child's and mother's tumor samples suggested the airway/transbronchial transmission of maternal cervical cancer cells to the child by aspiration at birth. The immune system coordinates the hemostatic balance between effector and regulatory immunity, especially during fetal development. The immunoregulatory properties are shared in both physiological pregnancy‐related and pathological cancer‐related conditions. Mechanistically, the survival and colonization of transmitted cancer cells within a child are likely attributed to a combination of the child's immune tolerance and the cancer's immune escape. In this review, we summarize the current understanding of gestational/perinatal cancer transmission and discuss the possible mechanism‐based immunotherapy for this rare form of pediatric cancer.

Keywords: cross‐individual cancer transmission, infantile choriocarcinoma, next‐generation sequencing, transmission of cancer through the airway, transplacental cancer transmission

The cross‐individual transmission of cancer during the gestational and perinatal periods is an extremely rare phenomenon. In this article, we discuss three forms of transplacental cancer transmission to the fetus during gestation and the transbronchial/airway transmission of maternal cervical cancer to the child, which we recently reported.

graphic file with name CAS-115-1039-g002.jpg

Abbreviations

CHM

complete hydatidiform mole

DNA

deoxyribonucleic acid

GTN

gestational trophoblastic neoplasia

HCT

hematopoietic cell transplant

IC

infantile choriocarcinoma

ICI

immune checkpoint inhibitors

NEC

neuroendocrine carcinoma

NGS

next‐generation sequencing

PHM

partial hydatidiform mole

SNP

single‐nucleotide polymorphism

1. INTRODUCTION

Although the precise prevalence of the condition is unknown, the cross‐individual transmission of cancer is thought to be extremely rare and can occur only in certain circumstances, such as transmission from allogeneic donors to recipients in an organ or hematopoietic cell transplant (HCT) 1 , 2 , 3 and transplacental cancer transmission during gestation. 4 In the latter form of transmission, cancer cells, or precursor cells spread hematogeneously to the body of the fetus. To date, only the following three different etiologies of transplacental cancer transmission have been reported: (1) maternofetal transmission of maternal cancer cells, 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 (2) transmission of gestational choriocarcinoma to the fetus, 23 , 24 , 25 , 26 and (3) the transfer of preleukemic cells from one monozygotic twin to the other (Figure 1 and Table 1). 27 , 28 , 29 , 30 , 31 , 32 Recently, we reported two pediatric cases of lung tumors, in which the lung‐only distribution of tumors and genomic profiling of both the child and mother's tumor samples suggested the transbronchial/airway transmission of maternal cervical cancer to the child through the aspiration of amniotic fluid, secretions, or blood from the cervix during vaginal delivery. 5 The engraftment and survival of transmitted cancer cells within a child are likely attributed to a combination of the child's immune tolerance and the cancer's immune escape. Nonetheless, the precise mechanisms by which allogeneic cancer cells can invade the body of a child have not been fully elucidated.

FIGURE 1.

FIGURE 1

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Patterns of transplacental cross‐individual cancer transmission to the fetus.

TABLE 1.

Classification of transmission pattern of cancer cells from other people to children during the perinatal period.

Types of transmitted cancer Route of transmission Tumor origin Genetic compatibility between host and cancer Reported survival rate References
Host: mother Host: child
Maternal cancer Transplacental Mother's somatic cells Identical Haploidentical Child > mother 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22
Gestational choriocarcinoma Derived from concurrent pregnancy Transplacental Trophoblast cells Haploidentical Identical Mother > child 23, 24, 25, 26
Derived from the previous pregnancy Transplacental Trophoblast cells

Nonidentical (causative pregnancy: CHM)

Haploidentical (causative pregnancy: PHM or nonmolar pregnancy)

 Depends on the chromosomes of cancer cells
Leukemia from another monozygotic twin Transplacental Preleukemic or leukemic cells of another monozygotic twin ‐ Identical – 27, 28, 29, 30, 31, 32
Maternal cervical cancer Transbronchial/airway (aspiration) Mother's somatic cells Identical Haploidentical Child > mother 5
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Abbreviations: CHM, complete hydatidiform mole; PHM, partial hydatidiform mole.

In this review, we aim to provide an overview of cross‐individual cancer transmission occurring during the gestational and perinatal periods, discussing possible cellular and immunological mechanisms and implications of immunotherapy.

2. TRANSPLACENTAL CANCER TRANSMISSION

2.1. Maternofetal transmission of maternal cancer

While cancer coexists approximately once per 1000 pregnancies, 33 mother‐to‐child cancer transmission is estimated to occur in 1 infant per 500,000 mothers with cancer (Figure 1A), 4 indicating it is a rare occurrence. To date, 18 cases of maternofetal transmission (six cases of hematological malignancies, eight melanoma cases, three lung cancer cases, and one case of uterine cancer) have been reported, including the earliest reports dating back to the 1950s. 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 Importantly, the mother's cancer is usually genetically haploidentical (human leukocyte antigen (HLA) half‐mismatched) with the child, which may have an impact on the growth and spread of the tumor and clinical outcome in the child (Table 1). Out of 16 mothers with available data, 15 died of cancer. In contrast, six out of 15 children survived, and spontaneous tumor regression was observed in two children with melanoma. 4 , 15 , 19 In two cases of leukemia, overt leukemia was seen in the mothers, while the involvement of leukemia was limited to the extramedullary site (one in the maxilla and the other in testes) in the children. 4 , 10 , 11 Although there are only a few reported cases, the better survival outcome, spontaneous regression, and localized presence of the tumor in the child may be a result of the elicitation of higher immune response to HLA half‐mismatched maternal cancer.

2.2. Transmission of gestational choriocarcinoma to the fetus

Gestational choriocarcinoma, a malignant neoplasm that originates from the trophoblastic cells of the placenta in the mother's body, has an estimated incidence of 1 in 50,000 pregnancies. 34 The trophoblast, a specialized tissue of embryonic origin that forms the specialized cells of the placenta, plays a major role in immune tolerance at the maternal–fetal interface. 35 Gestational choriocarcinoma can develop from molar and nonmolar pregnancies. Over 50% of choriocarcinomas occur after a complete hydatidiform mole (CHM), while the remaining cases are associated with a partial hydatidiform mole (PHM), normal pregnancy, nonmolar abortion, or ectopic pregnancy. 36 Genetically, choriocarcinomas that result from normal or ectopic pregnancy, abortion, or most PHMs usually have both maternal and paternal chromosomes. However, choriocarcinomas derived from a CHM usually have only paternal chromosomes, that is, they are androgenetic in origin, as most CHMs arise from the ovum in which maternal chromosomes are lost before or after fertilization by one or two sperm cells. 37 Infantile choriocarcinoma (IC) is an extremely rare pediatric malignancy that occurs as a result of the transmission of gestational choriocarcinoma in the placenta or the mother's body to the fetus. There have only been about 40 reported cases, including stillbirths. 23 , 24 , 25 , 26 , 38 In some cases, choriocarcinoma can simultaneously disseminate into both the fetus and the mother. According to the systematic review of Mangla et al., 38 22 cases of gestational trophoblastic neoplasia (GTN) with concurrent metastasis to mother and child have been reported so far. Although genetic analyses of IC have rarely been conducted, many of the cases of IC are presumed to have developed in the concurrent pregnancy, and choriocarcinoma cells in the placenta cross over to the fetus through the umbilical cord. In this condition, the choriocarcinoma cells, which are derived from the trophoblasts of embryonic origin, are genetically identical with those of the fetus (Figure 1B–i).

Gestational choriocarcinoma can also arise from the retained tissue of a previous pregnancy and complicate the course of the following pregnancy. Trophoblast cells reside in the mother's organs (such as the uterus, liver, or lung) after the causative pregnancy and undergo malignant transformation. 39 It is also theoretically possible that choriocarcinoma cells causing IC could have been derived from previous causative pregnancy (Figure 1B–ii). In this case, the choriocarcinoma cells transmitted to the child can be androgenetic or have maternal and male‐derived chromosomes, depending on whether the antecedent causative pregnancy was nonmolar, choriocarcinoma, or hydatidiform mole. Depending on the chromosomes that were inherited from the mother and her male partner to the choriocarcinoma cells, choriocarcinoma cells can even be completely allogeneic for the child. To date, there is no genetic evidence for the origination of IC cancer cells from a previous pregnancy; however, some studies have reported IC in patients whose mothers have a history of hydatidiform mole or choriocarcinoma. 40 Additionally, there was a report that intraplacental choriocarcinoma found during a normal pregnancy had the origin of the previous pregnancy. 39

Gestational choriocarcinoma in the mother is sensitive to anticancer drugs and its five‐year survival rate is 75%–90%, with a relatively good prognosis. 41 In addition, gestational choriocarcinoma cells strongly express PD‐L1, and immune checkpoint inhibitors (ICIs) are reported to be effective. 42 , 43 , 44 On the contrary, the prognosis of IC is poor. Bloom et al. reviewed 30 patients with IC, among whom 23 died due to disease progression or complications, 2 suffered intrauterine fetal death, and only 5 experienced complete remission. Among them, maternal choriocarcinoma was observed in 17 cases, with three mothers having fatal outcomes. 23 According to the review, out of 22 GTN cases with concurrent metastasis to mother and fetus, only 6 (27%) infants survived, while survival was higher in mothers (n = 17; 77%). Although there is limited data, the better response of chemotherapy and ICIs to choriocarcinoma cells and higher survival rate in mothers compared with children could be explained in part by the genetic compatibility between the tumor and the host (HLA mismatched or half‐matched in the mother vs. fully matched in the child in most cases) (Table 1).

2.3. Transfer of preleukemic cells between monozygotic twins

In the case of monozygotic twins, whether the twins share a single (monochorionic) placenta or have separate (dichorionic) placentas is determined by the timing of embryo splitting. When twins share a single placenta, there can be a migration of blood cells between the fetuses through vascular anastomoses within the placenta, and up to 1% of the total twin blood volume is exchanged between them daily. 28 This exchange of blood cells forms the basis for the transfer of preleukemic cells between twins.

Greaves et al. conducted genetic analyses and reported on the phenomenon in which both monozygotic twins develop leukemia after birth due to the transfer of blood cells with preleukemic clones between fetuses (Figure 1C). 27 , 28 , 29 , 30 , 31 They analyzed monozygotic twin pairs with concordant acute lymphoblastic leukemia and revealed that they shared clone‐specific (but not inherited) pre‐acyte lymphoblastic leukemia (ALL) clone founder alterations. 28 , 30 , 31 , 32 Such genomic alterations include ETV6‐RUNX1, hyperdiploid, BCR‐ABL1, and MLL‐AF4. Furthermore, the accumulation of further mutational changes occurring postnatally leads to the clinical manifestation of overt leukemia in each twin patient. For monozygotic twins under 18 months of age sharing preleukemic lesions with the MLL fusion gene, the probability of both of them developing leukemia is 100%. 28 However, for older twins, even when they share the same preleukemic lesion, the concordance rate is 10%–15%. 28

In this mechanism, neither twin inherits germline mutations from their parents. Instead, one twin carries the risk of developing leukemia after birth by receiving cells with the preleukemic genes from the other twin via transplacental transfer.

3. NEW PATHWAY OF MOTHER‐TO‐CHILD CANCER TRANSMISSION: CANCER TRANSMISSION THROUGH THE AIRWAY

We reported two cases in which cervical cancer from the mother was transmitted to the infant and developed into lung cancer. 5 We believe that in these two cases, the mother's cervical cancer cells have been transmitted into the lungs of the infant through the airway during childbirth. Our proposed mechanism is as follows: During childbirth, as the infant passes through the birth canal, blood or contaminated amniotic fluid from the mother's cervical cancer cells may contaminate the infant. When the infant initiates their first breaths, they may inhale, or ingest amniotic fluid or blood present in the oral and pharyngeal cavity, allowing the mother's cancer cells to transmit to the infant's lungs through the airway (Figure 2). During the fetal period, the lungs of the fetus are squeezed and filled with amniotic fluid. With a few first breaths, the newborn's lungs are exposed to strong inspiratory pressure and cancer cell inhalation with air, leading to the spread of cancer cells in the interstitial spaces of the lungs. Although our understanding is difficult to prove and remains speculative, it is worth noting that the clinical characteristics in these two cases differed significantly from those of previous cases involving placental transmission.

FIGURE 2.

FIGURE 2

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Mechanism of transbronchial/airway transmission of maternal cervical cancer to the lungs of the infant.

Case 1 was a boy who was 23 months old at the time of diagnosis. At the initial diagnosis, the boy's CT scan showed multiple lung lesions distributed bilaterally along the course of the trachea. No metastatic lesions were detected in sites other than the lungs. His lung lesions were pathologically diagnosed as neuroendocrine carcinoma (NEC). His mother, who was aged 35, was diagnosed with cervical squamous cell carcinoma 3 months after giving birth to him by vaginal delivery. At the time of relapse, it was confirmed that her cervical cancer partly consisted of neuroendocrine differentiation, which was similar to the histology observed in the boy. Before presenting to our hospital, the boy was observed for approximately one year without intervention according to the parents' wishes. During this period, in some of the pulmonary lesions, spontaneous regression of the tumor without any treatment was observed. After the progression despite two chemotherapy regimens, the boy was treated with nivolumab. Interestingly, his tumors showed remarkable response to nivolumab and achieved pathological complete response after a total of 14 cycles of nivolumab.

Case 2 was a boy who was 6 years old at the time of diagnosis. A polypoid tumor was found in the cervix during his mother's pregnancy; however, the cytology results were negative, and the baby was delivered vaginally. A histological examination of her tumor performed at birth confirmed the presence of cervical adenocarcinoma, and she underwent tumor resection 3 months after delivery. Unfortunately, she died of the disease about 2 years after the surgical operation. Six years after the onset of his mother's cancer, the boy presented to a local hospital with chest pain, and CT revealed a mass 6 cm in diameter in his left lung. His tumor's histopathological diagnosis was adenocarcinoma, and its histopathological features were similar to those of his mother's tumor.

There were clear differences in the site of tumor development and extent of the spread between these two cases compared with cases of IC or hematogenous maternofetal cancer transmission. In these two cases, despite the presence of large or multiple masses in the lungs, there was no metastasis to other parts of the body, and we believe that these findings are consistent with the development of cancer resulting from the inhalation of the mother's tumor (Figure 3).

FIGURE 3.

FIGURE 3

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Clinical characteristics of pediatric cases with lung tumors that are presumably thought to be developed through transbronchial/airway transmission of maternal cervical cancer. 5 HPV, human papilloma virus; NGS, next‐generation sequencing SNP, single‐nucleotide polymorphism.

In fetal blood circulation, the liver is an organ that is susceptible to cancer transmission, as 70%–80% of the blood flowing through the umbilical vein passes through the liver. 45 Meanwhile, since pulmonary vascular resistance is high during the fetal period, 85%–90% of the right ventricular outflow bypasses the lungs, with only 10%–15% flowing through them. 46 Therefore, the direct hematogenous transmission of the mother's cancer into the lungs of the fetus might be rare. In the cases of IC and the maternofetal transmission of solid tumors or melanoma, whereas disseminated metastases to multiple organs (including lung and liver) were observed, 20 , 23 there are few reports of cases with tumors only in the lungs and no metastases in other parts of the body. The radiological findings of our two cases, which showed multiple large tumors in the lungs but no metastases to the liver or other organs, were atypical, and strongly indicated transmission through routes other than the hematogenous route.

Another notable aspect of these two cases is the late onset of cancer. Case 1 presented symptoms at the age of 23 months, while case 2 developed them at the age of 6 years. In reported cases of IC, all cases became symptomatic by 5 months of age, and among the 18 cases of pediatric patients of maternofetal cancer transmission, 17 cases occurred within the first year of life. Therefore, compared with these findings, the onset of symptoms in our two cases was late. In cases of hematogenous transmission, it is presumed that the early onset of cancer happens because the transmission occurs during the fetal period, before birth, and also because the cancer cells receive a steady supply of oxygen and nutrients through the bloodstream, leading to rapid proliferation. However, cancer cells that are inhaled into the lungs during birth would be placed in an isolated state on the surface of the pulmonary epithelium without established blood flow. Thus, cancer cells establish blood flow within the infant's lungs slowly over a long period, requiring time to grow to a size where symptoms appear. Furthermore, one possible factor contributing to the slow growth of the tumor is the existence of an immune response to the HLA half‐mismatched tumors. Spontaneous tumor regression was observed for 1 year in case 1. In case 2, the fact that it took 6 years for the tumor to grow within the lungs may also support the effect of immune reactions suppressing tumor growth.

Next‐generation sequencing (NGS) was useful to prove that the children's tumors were of maternal origin in our cases. In our cases, the genetic panel testing conducted to find treatment options led to the finding that the child's cancer cells were derived from another person. Since the mothers were carriers of cancer, further analyses led to the discovery of this phenomenon. We used an NGS‐based solid‐tumor test in which germline DNA was used as a control, and this led to the realization that the child's cancer cells were not his own but originated from another person. 47 The same pathogenic variants were detected in both the child's and mother's tumors, and SNP alleles carried by the mother but not inherited in the child's germline were detected in the child's tumor using NGS. In addition, polymerase chain reaction (PCR) analyses with a set of pan‐human papilloma virus (HPV) primers revealed that both the child's and mother's tumors tested positive for the same type of HPV (Figure 3).

4. POSSIBLE MECHANISM FOR THE SURVIVAL OF GENETICALLY HAPLOIDENTICAL CANCER CELLS IN THE CHILD

Although there are still many unanswered questions regarding the mechanisms by which genetically haploidentical cancer cells can survive within children, we speculate that it is likely attributed to a combination of the cancer's immune escape and the child's immune tolerance.

One possible mechanism is the immune escape of cancer cells through their subjection to genetic selection. In case 1, HLA class I alleles, which were not inherited by the patient, were lost in the tumors in this child and mother. The same phenomenon has been observed in a case of maternofetal transmission of leukemic cells 10 or in cases of relapsed acute myeloid leukemia after haploidentical stem cell transplantation. 48 As HLA proteins provide major antigenic targets for allograft recognition and rejection, their loss may have contributed to the survival of the cancer cells acquired from another person in the child. This phenomenon corroborates the fact that the recipient might be at a greater risk of transfusion‐associated graft‐versus‐host disease when the recipient would be transfused with one‐way matched blood from donor to recipient. In this case, the recipient's immune system barely recognizes the donors' competent cells, whereas the donors' immune cells can recognize recipients' cells as non‐self and attack them aggressively. 49

Other possible mechanisms include the immune tolerance of the fetus. Cancer cell transmission occurs during the perinatal period when the fetus is in the process of developing immunity. In the fetus, thymic development begins by week 8 of human gestation, and the first T cells begin to populate the periphery by 12–14 gestational weeks. 50 If cancer cells have been transmitted before that period, they may not be recognized as antigens, and an immune response may not occur, possibly hindering the engraftment or growth of the tumors. Moreover, tolerance to self‐inherited and noninherited maternal antigens is important to maintain pregnancy, 51 which is achieved mainly by the function of regulatory T cells. 52 Various factors like intrauterine hypoxia or placental hormones may also contribute to the maternal tolerance through the regulation of T‐cell function. 51 It has been reported that vertically transmitted maternal cells have been observed in fetal tissues 53 and also in children at minimal levels throughout postnatal development. 54 In light of the above findings, fetal immune tolerance possibly contributes to the engraftment and survival of mother‐derived cancer cells in their body. Nonetheless, no mechanistic evidence of such fetal cancer immune tolerance has been demonstrated so far.

5. FUTURE PERSPECTIVES

Our genomic profiling study of 142 pediatric malignancies identified two cases of mother‐to‐child transmission of tumors. 55 Considering the frequency of cancer predisposition syndromes (5%–10% in pediatric cancers), 56 , 57 the prevalence of maternofetal tumor transmission is perhaps higher than we expected. In case the sample has the second signature in the NGS analysis, it is important to suspect the possibility of cross‐individual cancer transmission to the child rather than empirically treat it as a technical issue in the preparation of tumor specimens. Given the widespread use of NGS technology in pediatric oncology, the careful and genuine interpretation of sequencing data will allow this rare childhood malignancy to be identified and not overlooked and its genetic and immunological features to be clarified in the future.

Importantly, one of our pediatric patients (case 1) with pulmonary tumors transmitted from the mother's cervical malignancy responded to anti‐PD‐1 immune checkpoint therapy. This is in line with the findings that ICI monotherapy or combination therapy with chemotherapy has antitumor activity for chemorefractory or relapsed GTN, such as choriocarcinoma in the mother. 42 , 43 , 44 Although the available data are limited to only one case, it is speculated that ICIs may constitute a reasonable option for children whose tumors show evidence of transmission from the mother or another genetically nonidentical or haploidentical individual during the gestational and perinatal period. Further identification of cases and genomic and immunological profiling of tumors will allow us to test the therapeutic implication of ICI‐based therapy in this category of tumors.

AUTHOR CONTRIBUTIONS

Ayumu Arakawa: Writing – original draft. Kayoko Tao: Writing – review and editing. Takashi Kohno: Writing – review and editing. Chitose Ogawa: Writing – review and editing.

CONFLICT OF INTEREST STATEMENT

Chitose Ogawa received a research grant from Ono Pharmaceutical, Co., Ltd. Takashi Kohno received a research grant from Sysmex Corporation. Takashi Kohno is an editorial board member of Cancer Science. Other authors do not have any conflict of interest.

ETHICS STATEMENT

Approval of the research protocol by an Institutional reviewer Board: N/A.

Informed Consent: N/A.

Registry and the Registration No. of the study/trial: N/A.

Animal Studies: N/A.

ACKNOWLEDGMENTS

We thank Takahiro Kamiya and Hirokazu Kanegane of Tokyo Medical and Dental University and Takafumi Kuroda, Akihiro Hasegawa, and Ritsuko Ogasawara of the Department of Obstetrics and Gynecology, The Jikei University School of Medicine for the advice given on how to improve the article.

Arakawa A, Tao K, Kohno T, Ogawa C. Cross‐individual cancer transmission to children during the gestational and perinatal periods. Cancer Sci. 2024;115:1039‐1047. doi: 10.1111/cas.16102

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