Ovarian Low Malignant Potential Tumor

Introduction

Teratomas (from Greek terato meaning "a monster" and onkoma meaning "swelling or mass") and other germ cell tumors are relatively common solid neoplasms in children. They may occur in both gonadal and extragonadal locations. Locations and specific tumor types depend on the age of the child. The tumors are grouped together because they all appear to arise from postmeiotic germ cells. Most of the malignant tumors produce markers that can be serologically assessed.

Pathophysiology

Several theories about the origin of these tumors are recognized. The best evidence suggests that most are due to abnormal differentiation of fetal germ cells that arise from the fetal yolk sac. Normal migration of these germ cells may cause gonadal tumors, whereas abnormal migration produces extragonadal tumors. Teratomas are typically found in the midline or gonads. Frequencies of the most common sites are as follows:

  • Sacrococcygeal - 40%
  • Ovary - 25%
  • Testicle - 12%
  • Brain - 5%
  • Other (including the neck and mediastinum) - 18%

By definition, teratomas include components derived from all 3 embryonic layers: ectoderm, endoderm, and mesoderm. These tissues are foreign to the location in which they are found. Teratomas may be classified as mature or immature on the basis of the presence of immature neuroectodermal elements within the tumor. Mature tumors (grade 0) have no immature elements. In grade 1 tumors, immature elements are limited to one low-power field per slide; in grade 2 tumors, less than 4 fields are present per slide; and in grade 3 tumors, more than 4 fields are present per slide.

In the past, survival was linked to the degree of immaturity in the teratoma. Close histologic evaluation of immature teratomas reveals a good correlation between the degree of immaturity and the presence of microscopic foci of frankly malignant elements. These malignant elements are typically yolk sac tumors but may also represent primitive neuroectodermal tumor (PNET). Charoenkwan et al (2002) found overexpression of p53 in the more aggressive immature teratomas at all sites.

The risk of recurrence also appears to be related to the degree of immaturity. Recurrence in a completely resected mature teratoma is less than 10%; in an immature teratoma, recurrence may be as high as 33%. The likelihood of recurrence depends on the site of the tumor as well as the completeness of resection. The German MAKEI trials suggest that the recurrence rate for immature teratomas can be decreased to 9.5% with chemotherapy.Sacrococcygeal teratomas are more likely to recur than those in the ovary or other sites. Molecular biologic and cytogenetic studies are providing a firmer scientific basis to these observations.

n 1965, Teilum first suggested the germ cell origin of gonadal tumors.Since that time, the pathologic classification scheme has evolved to its present state. Germ cells undergo neoplastic transformation as follows:

  • Suppressed differentiation
    • Seminoma
    • Dysgerminoma
  • Differentiation
    • Initial - Embryonal carcinoma
    • Embryonic - Mature teratoma and immature teratoma
    • Extraembryonic - Choriocarcinoma and endodermal sinus tumor (yolk sac tumor)

Mutter describes genetic imprinting as a major factor in the development of some of these tumors.The developmentally expressed genes insulinlike growth factor 2 (IGF II) and its receptor RNA (H-19); small nuclear riboprotein (SNRPN); mas proto-oncogene; and the tumor suppressor genes WT1 and MASH2 are imprinted, depending on their maternal or paternal origin. Mutter suggests that these genes or the cells have only the maternal imprint because many teratomas arise from a parthenogenetically activated egg. Therefore, maternally active genes are present in higher-than-usual concentrations, and maternally inactive products are present at lesser concentrations if at all. These abnormalities may account for the lack of organization of the 3 germ cell layers.

Oosterhuis et al suggest that tumors may be grouped on the basis of their chromosomal abnormalities as follows:

  • Group 1 includes immature teratomas and yolk sac tumors. The immature teratomas are usually diploid, whereas yolk sac tumors may be diploid, tetraploid, or aneuploid. The chromosomal aberrations include overrepresentation of chromosomes X, 1, 3, 8, 12, and 14 and underrepresentation of Y and X. Deletions in 1p and rearrangements of 3q and 6q may be present. Isochromosome 12p (i12p) has been found. An abnormal number of centromeres is frequent in both diploid and aneuploid tumors.
  • Group 2 includes most nonseminomatous malignant germ cell tumors and typically includes numeric abnormalities in X, 7, 8, 12, and 21 as excess and deletions of Y, 11, 13, or 18. Once again, isochromosomes 12p with other aberrations of 12p and 1p are present.
  • Group 3 includes mature teratomas or mature cystic teratomas. Numeric abnormalities, including extra X, 7, 12, and 15, have been found. No chromosomal structural anomalies have been found.
  • Group 4 includes spermatocytic seminoma, a type usually confined to older men. The cytogenetics of this group have not been characterized. As with abnormalities and imprinting patterns, these chromosomal rearrangements can lead to overproduction of certain gene products and underproduction of others; these lead to the abnormal growth characteristics of the tumor.

Hara et al suggest that the MAGE gene family of tumor rejection antigens may also be involved in the pathogenesis of these tumors.These genes appear to be more active in pure seminoma or mixed type of seminomatous elements than in other germ cell tumors. In their limited study of 22 patients, MAGE expression was not correlated with disease progression. It is likely to be only an indicator of maturity or differentiation of the tissues.

The concept of teratoma with malignant transformation indicates the development of non–germ cell malignancies within a teratoma. Among 641 patients in the MAKEI protocols 83/86/89/96, 9 patients were identified with this finding Five patients presented with a carcinoma, 2 patients presented with glial tumors, and 2 patients presented with embryonal tumors. Resection and chemotherapy were typically used. Because these tumors are quite rare, response to treatment is difficult to generalize.

When platinum-based chemotherapy–resistant tumors are evaluated, between one third and one half of tumors exhibit microsatellite instability.



Frequency United States

Sacrococcygeal teratoma occurs in 1 in 30,000-70,000 live births. The female-to-male predominance is 4:1. Ovarian teratomas are almost as common, whereas testicular teratomas are about one third less frequent. The overall incidence of malignant germ cell tumors is approximately 3% of all childhood malignancies, or approximately 3 cases per million population per year. The frequency of all germ cell tumors has increased over the last several decades.

International

No significant geographic predilection is recognized.

Mortality/Morbidity

The mortality rate for congenital teratomas depends on gestational age and the size and location of the tumors. Survival of preterm infants younger than 30 weeks' gestation with sacrococcygeal teratoma is only 7%, whereas the survival for infants older than 30 weeks' gestation is 75%.

Rapid early growth is associated with the yolk-sac phenotype and carries a poorer prognosis.Early tumors are frequently large relative to the size of the infant and may induce congestive heart failure. Cervical teratomas may frequently lead to airway problems and death when they are large.

Prior to recent chemotherapeutic successes, the 10-year survival rate for malignant germ cell tumors ranged from 25% for embryonal carcinoma to 75% for dysgerminoma. Today, overall survival rates are greater than 90%.

Race

No racial predispositions for these tumors are known

Sex

Sacrococcygeal teratoma has a 4:1 female-to-male predominance. In other germ cell tumors, the female-to-male ratio is roughly 2:1 in children

Age
  • Sacrococcygeal teratomas
    • Sacrococcygeal teratomas are congenital.
    • Those with a significant external component are identified at birth. Tumors without an external component (Altman type 4) are discovered later.
    • When the tumors are resected before the patient is aged 2 months, 7-10% are malignant. After that age, the risk of malignancy greatly increases to more than 50% by age one year.
  • Ovarian tumors
    • The incidence of ovarian germ cell tumors increases with age and peaks around age 15-19 years.
    • When girls younger than 15 years were examined, fewer than 10% of tumors occurred in girls younger than 5 years, 20% of tumors were found in girls aged 5-9 years, and more than 70% of tumors were found in girls aged 10-14 years.9
    • Benign ovarian tumors, largely teratomas, predominate.
    • Roughly 70% of malignant ovarian tumors in childhood are germ cell tumors, one quarter are epithelial, and the remainder are stromal tumors. The ratio of germ cell tumors to epithelial malignancies decreases with increasing patient age.
    • Chromosomal abnormalities also appear to be related to age at presentation for teratomas. In girls less than 5 years old, no chromosomal abnormalities were found, whereas older girls often have gains of 12p and chromosomes 7 and 8.
  • Testicular tumors
    • Testicular germ cell tumors in childhood are split between teratomas and yolk sac tumors. They are more common from birth to age 5 years. From age 6 years until puberty, testicular tumors are exceedingly uncommon. Thereafter, the incidence increases, with a more adultlike tumor pattern with seminomas gradually becoming the predominant histology.
    • Both teratomas and yolk sac tumors may be associated with contralateral in situ dysgenesis in 9% of patients compared with 0.5% of otherwise healthy males. Contralateral tumors are often found. These are occasionally synchronous but are more often metachronous. Ongoing surveillance of the contralateral testis is therefore needed.
    • Among malignant germ cell tumors, yolk sac tumors predominate until patients are aged 14 years. Few tumors of any type are diagnosed in children aged 5-9 years. For malignant teratomas, yolk sac tumors, and all germ cell tumors, rates by age group are as follows:
      • Age group 0-4 years - 0.45 case, 3.66 cases, and 4.16 cases per million population
      • Age group 5-9 years - 0.12 case, 0.12 case, and 0.12 case per million population
      • Age group 10-14 years - 0.05 case, 1.30 case, and 1.77 case per million population

Clinical History

The clinical presentation of these tumors depends on the location of the tumor. Sacrococcygeal teratomas may be prenatally diagnosed as an incidental ultrasonographic finding; they may occur in an infant who is large for age, in premature infants, or in infants with fetal hydrops. Fetal hydrops is an ominous sign. It is typically due to high flow through the tumor with high-output cardiac failure and placentomegaly. A teratoma larger than 5 cm is likely to cause dystocia and possible rupture; elective cesarean delivery should be performed. Sacrococcygeal teratomas that are not prenatally diagnosed may be noted at delivery, within the first few weeks after birth, or discovered late.

Ovarian masses typically cause abdominal pain, mass, distention, or emesis. Two thirds of affected girls present with pain as their primary symptom. Acute and chronic pain occur with equal frequency. In situations of acute pain, the diagnosis is often related to torsion of the ovary with consequent compromise of the blood supply. Palpable masses are less frequent and appear later in the clinical course.

Testicular tumors typically occur as a scrotal mass with or without pain. The differential diagnosis may include hydrocele because some cystic teratomas may transilluminate. In some situations, the tumor may cause symptomatic metastasis; this is more common in older patients. The distribution of the patients' age at presentation for testicular tumors is bimodal. In the youngest children (aged 0-4 y), teratomatous lesions and yolk sac tumors are predominant. In children older than 10 years, teratomas are increasingly rare. Yolk sac tumors are still predominant, but other malignant germ cell types start to become clinically relevant.

Causes

The epidemiology of the tumors suggests that they are increasing in frequency. With sacrococcygeal teratomas, no causative agents are known. With respect to ovarian germ cell tumors, a familial predilection may be present. Cases in 7 families have been reported in which female first-degree relatives had germ cell tumors. In an additional 7 families, males had germ cell tumors. This observation suggests that certain genes may be present in these families, predisposing them to germ cell malignancy.

One study that examined the effect of diet on the development of ovarian tumors revealed that diets high in polyunsaturated fat were associated with the development of teratomas.Likely, plant estrogens, and not the polyunsaturated fat, are associated with an increased tumor risk.

The risk factors and epidemiologic features of testicular cancer suggest that cryptorchidism increases the risk of germ cell tumor by a factor of 10. Tumors may appear in the ipsilateral or contralateral testicle. Hernia is similarly associated with germ cell tumors. One study also revealed that a history of pyloric stenosis leads to a 4-fold risk of germ cell malignancy.11 Boys whose father or brother has had a teratoma have a 5-15% increased risk for developing a teratoma. Whether this is due to genetic causes or is a consequence of shared environment is unclear.

Intersex anomalies have also been associated with development of germ cell tumors. Gonadoblastoma is observed in roughly one third of patients with intersex anomalies. Although gonadoblastoma is a carcinoma in situ, it frequently evolves into dysgerminoma; yolk sac tumors, immature teratomas, and choriocarcinomas are possible as well. Turner syndrome is similarly a risk factor for gonadoblastoma. Klinefelter syndrome has been linked with an increased risk of extragonadal malignant germ cell tumors. The highest risk seems to be among patients who carry some Y-chromosome genes in ectopic locations where they may not be normally regulated.

Children with intersex anomalies are typically male pseudohermaphrodites with antigen insensitivity or 5-alpha reductase deficiency. These patients with testicular feminization are sometimes discovered serendipitously during a hernia repair. Debate surrounds the optimal timing for gonadal resection in these situations. Gonadal estrogen production may benefit the patient in terms of growth and development. However, gonadoblastoma has been observed in patients as young as 2 months, and frank tumors have been observed in those younger than 2 years. The decision to leave or remove the gonads early should be made with the family after thorough discussion of these risks and potential benefits.

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