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2000-01-03-12 Introduction to fetal tumors © Meizner www.thefetus.net/


Introduction to fetal tumors

Israel Meizner, MD 

The prenatal diagnosis of fetal tumors by ultrasound is a new aspect of fetal pathology, that has been described only in the last two decades, making possible an understanding of the antenatal natural history and pathophysiology of most commonly detected fetal tumors. The introduction of ultrasonic techniques in obstetrics has opened new horizons in prenatal detection of tumors arising in the unborn child. Fetal tumors are rare, but are associated with serious illness or even death in the fetal or neonatal period. Therefore, the prenatal diagnosis of fetal tumors has significant implications on the well-being of both mother and fetus, as well as on perinatal and neonatal outcome. 

Prenatal detection of fetal tumors may alert the obstetrician not only to the fetus at risk, but also to the potential of maternal risk. For example, fetal goiter may cause obstruction of labor due to the size of the tumor and associated hyperextension of the fetal neck. Once a fetal tumor has been detected, close surveillance by a multidisciplinary team is mandatory, with anticipation and early recognition of problems during pregnancy, labor and immediate postnatal stage. In rare cases, intrauterine treatment of the affected very compromised but salvageable fetus may be contemplated.

Etiology and mechanisms of carcinogenesis

For many years, it has been the hope, expressed in many epidemiological studies, to identify the cause or causes of malignancies that occur in early life. In particular, the limited temporal nature of intrauterine development provides a unique opportunity to identify carcinogenic stimuli. Fetal and/or maternal exposure to exogenous factors, including ionizing irradiation, drugs and viruses, may start the biological mechanisms responsible for tumor formation[1].

Developmental errors during embryonal and fetal maturation may result in embryonic tumors. Durante and Cohnheim have introduced the “cell rest” theory that may be adopted to embryonic tumors[2],[3]. These authors believed that more cells are produced than are required for the formation of an organ or tissue and the origins of embryonic tumors rest in developmental errors in these surplus embryonic rudiments. Embryonic tumors developing after infancy are explained by the persistence of cell rests or developmental vestiges[4]. Developmentally anomalous tissue, i.e. hamartomas and dysgenic gonads, is a source of neoplasms in older children and adults. When any of this developmentally abnormal tissue is present at birth, it is inferred that the cells failed to mature, migrate or differentiate properly during intrauterine life.

Neoplastic transformation of cells in tissue culture and in vivo carcinogenesis are dynamic, multistep and complex processes that can be separated artificially into three phases: initiation, promotion and progression[5]. These phases may be applied to the natural history of virtually all human tumors, including embryonic ones. Initiation is the result of exposure of cells or tissues to an appropriate dose of a carcinogen; an initiated cell is permanently damaged and has a malignant potential. The initiated cells can persist for months or years before becoming malignant. During the promotion phase initiated cells clonally expand. Promotion may be modulated or reversed by a variety of environmental conditions. In the last phase, progression, the transformed cells develop into a tumor, ultimately with metastasis. Embryonic tumors can therefore, be regarded as defects in the integrated control of cell differentiation and proliferation.

A genetic model of carcinogenesis has also been introduced in an attempt to clarify the pathogenesis and behavioral peculiarities of certain embryonic tumors[6]. According to this hypothesis, embryonal neoplasms   arise as a result of two mutational events in the genome. The first mutation is prezygotic in familial cases and postzygotic in non-familial; the second mutation is always postzygotic.

Benignity of fetal and infantile neoplasms       

It is a fact, that some neonatal and infantile tumors bear a benign clinical behavior despite clear malignant histological picture. Examples include congenital neuroblastomas, hepatoblastomas below I year of age, congenital and infantile fibromatosis, and sacrococcygeal teratomas in infants under 4 months of age. This regressive tendency of neonatal tumors was explained by Bolande as an “oncogenic period of grace” which starts in utero and extends through the first few months of extrauterine life. The factors contributing to the existence of this phenomenon are obscure[7].

Association of neoplasia and congenital malformations

The concept that teratogenesis and oncogenesis have shared mechanisms is well documented by numerous examples. Probably, there is simultaneous or sequential cellular and tissue reaction to specific injurious agents. The degree of cytodifferentiation, the metabolic or immunological state of the embryo or fetus, and the length of time of exposure to the agent will determine whether the effect is teratogenic, oncogenic, both, or neither. Many biological, chemical and physical agents known to be teratogenic to the fetus or embryo are carcinogenic postnatally[8]. Alternatively, a teratogenic event during intrauterine life may predispose the fetus to an oncogenic event later in life. This would explain Neoplastic transformation occurring in hamartomas, developmental vestiges heterotopias and dysgenetic tissues. It is postulated that the anomalous tissues harbor latent oncogens which, under certain environmental conditions, are activated resulting in malignant transformation of a tumor.

Classification

A formal classification of fetal tumors does not exist. Apart from distinguishing solid from cystic lesions, probably the best classification should be by location.  The main compartments of fetal tumors include the following:

  • Head and brain
  • Face and neck
  • Thorax (including cardiac)
  • Abdomen and retroperitoneum
  • Other :
  • Extremities
  • Genitalia
  • Sacrococcygeal region
  • Skin

Sonographic  diagnostic approach

The diagnostic approach for diagnosing fetal tumors in-utero should be based on three sets of ultrasound signs:

1. General signs

2. Organ specific signs

3. Tumor specific signs

The cardinal principle behind the sonographic diagnosis of fetal tumors is recognizing the general signs indicating departure from normal fetal anatomy.  The general sonographic criteria include:

1. Absence of a normal anatomic structure

2. A disruption of contour, shape, location, sonographic texture or size, of a normal anatomic structure.

3. Presence of an abnormal structure.

4. Abnormal fetal biometry.

5. Abnormal fetal motion.

6. Polyhydramnios.

7. Hydrops fetalis.

Each of the above listed general criteria should raise the suspicion of an underlying fetal tumor.

Polyhydramnios is an important general sign for fetal tumors. Almost 50% of fetal tumors are accompanied by severe polyhydramnios. Potential causes for polyhydramnios in such cases include mechanical obstruction i.e. GIT tumors, interference with swallowing i.e. goiter or myoblastoma, excessive production of liquor i.e. sacrococcygeal teratoma, and decreased resorption by lung tissue in lung pathology. Since in intracranial tumors polyhydramnios appears in as much as 50% of cases, a central brain effect may also be encountered.

Tumor specific signs include pathologic changes within the tumor mass, displaying specific sonographic appearance. These include: calcifications, liquification, organ edema, internal bleeding, neovascularization and rapid changes in size and texture. It should be remembered that fetal tumors may metastasize.

Organ specific signs are rare but some sonographic pictures are highly suspicious of being associated with fetal tumors i.e. cardiomegaly with huge solid or cystic mass occupying the entire heart suggesting intrapericardial teratoma.

It should be emphasized that pitfalls in diagnosis may exist. In some cases normal and abnormal sonographic findings may mimic fetal tumors. Examples may vary from severe cases of bladder extrophy where the protruding bladder mass appears as a solid tumor like structure, to rare cases of fetal scrotal inguinal hernia where bowel loops occupy the scrotum appearing as huge masses.

Apart from ultrasound, other diagnostic tests may be used. Imaging techniques may include x-ray and MRI. X-ray methods will not provide superior information that sonography has not provided. Even brain CT, in cases of brain tumors is not superior to the detailed sonographic imaging. Magnetic resonance imaging, as a noninvasive nonionizing imaging modality is the primary choice when an alternative to ultrasound is required[9]. However, MRI usage is limited to the third trimester and in cases of polyhydramnios (as in neoplastic cases) fetal motions restrict to a minimum visualization of both normal and abnormal anatomy.

Rapid karyotype should be evaluated in all cases of suspected fetal tumors since, malignant tumors tend to acquire chromosome changes[10]. Fetal tissue biopsy may be carried out in cases where the ultrasonic diagnosis is uncertain and histology will provide the ultimate diagnosis.    

Prognosis and obstetric management

Apart from intracranial tumors, where the chances for the fetus are poor, other tumor location do not give a poor prognosis in advance. The prognosis mainly rely on other factors, such as the size of the tumor’ involvement of other organs, associated mechanical problems and proximity to vital organs or structures.

Every case of a fetal tumor should be managed by a multidisciplinary team  capable of dealing with such problems. The team should consider the following :

1.   Is there a place for termination of pregnancy? The question of “how" and “when” should be discussed if the answer to this question is yes.

2.  Preventing preterm delivery.

3.  Preventing lung hypoplasia.

4.  Is there a need for other diagnostic tests? If yes, which and when?

5.           Is there a place for therapeutic measure by puncture or via new approaches i.e. fetoscopy? In the presence of a fetal tumor, time place and mode of delivery must be chosen carefully. The risk of preterm delivery should be weighted against need for urgent relief of vitally compressed organs or surgical intervention.

References
[1] Court Brown W.M., Doll, R., Hill, A.B. Incidence of leukemia after exposure to diagnostic radiation in utero. BMJ 1960; 2:1539

[2] Durante F. Nesso fisio-patologico tra la struttura dei nei materni e la genesi di alcuni tumori maligni. Arch Memor Observ Chir Prat  1874;11:217

[3] Cohnheim J.  Lecture on general pathology, Vol. 2. The New Syndenham  Society, London, 1889

[4] Bolande R.P. Cellular aspects of developmental pathology. Lea & fabriger, Philadelphia, 1967, pp. 88-143

[5] Scott R.E., Wille J.J. Jr., Wier M.L. Mechanisms for the initiation and promotion of carcinogenesis. A review and a new concept. Mayo Clin Proc 1984; 59:107

[6] Knudson A.G. Mutagenesis and embryonal carcinogenesis. Natl Cancer Inst Monogr 1979; 51:19

[7] Bolande R.P. Benignity of neonatal tumors and concept of cancer regression in early life. Am J Dis Child 1971; 122:12

[8] DiPaolo J.A., Kotin P. Teratogenesis-oncogenesis: a study of possible relationships. Arch Pathol 1966; 81:3

[9] Hricak, H. Obstetrics. in Magnetic Resonance imaging of the body. Higgins C.B. and Hricak H., Editors, Raven Press, New York, 1987, p. 525

[10] Hecht, F., Grix, A. JR., Hecht, B.K. Direct prenatal chromosome diagnosis of a malignancy. Cancer Genet. Cytogenet. 1984; 11:107

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