Germ cell tumors

Germ cell tumors originate from pluripotent germ cells. Disruption of differentiation of these cells leads to the development of embryonic carcinoma and teratoma (embryonic lineage) or choriocarcinoma and yolk sac tumor (extraembryonic differentiation pathway). Disruption of development of unipotent primitive germ cells leads to the development of germinoma. The histological structure of these tumors is usually not characteristic of the anatomical region where they are located. Germ cell tumors can occur both in and outside the genital organs. Extragonadal germ cell tumors are localized along the midline, i.e. along the migration route of primordial germ cells.

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Symptoms of germ cell tumors

Symptoms of germ cell tumors largely depend on their location. In ovarian tumors, pain syndrome may become dominant, and differential diagnostics with surgical diseases of the abdominal cavity and pelvic organs is significantly complicated. In case of vaginal lesions, bloody discharge is sometimes observed. Testicular tumors are usually painless and are often detected during external examination. Clinical manifestations of extragonadal tumors depend on the dysfunction of nearby organs. When localized in the mediastinum, respiratory failure and coughing are likely to occur. Sacrococcygeal teratomas may cause dysfunction of the pelvic organs. When any difficult-to-explain clinical manifestations are detected, it is necessary to remember the possibility of a tumor disease.

Stages of germ cell tumors

The stage of the disease is determined by the prevalence of the tumor process and the completeness of surgical excision.

• Stage I. Limited tumor, excised within healthy tissue.
• Stage II. Microscopically incompletely removed tumor; tumor growing into the capsule, or presence of micrometastases in regional lymph nodes.
• Stage III. Macroscopically incompletely removed tumor, involvement of regional lymph nodes (more than 2 cm in diameter), tumor cells in ascitic or pleural fluid.
• Stage IV. Distant metastases.

For ovarian tumors, the International Federation of Gynecological Oncologists (FIGO) staging system is widely used.

• Stage I. Tumor is limited to the ovaries:
  • Ia - damage to one ovary, capsule intact, no ascites;
  • lb - both ovaries are affected, the capsule is intact, there is no ascites;
  • Ic - violation of the integrity of the capsule, tumor cells in peritoneal washings, tumor ascites.
• Stage II. Ovarian tumor limited to the pelvic area:
  • IIa - spread only to the uterus or fallopian tubes;
  • IIb - spread to other pelvic organs (bladder, rectum, vagina);
  • IIc - spread to the pelvic organs in combination with the signs described for stage 1c.
• Stage III. The tumor extends beyond the pelvis or there is lymph node involvement:
  • IIIa - microscopic tumor seeding outside the pelvis;
  • IIIb - tumor nodes less than 2 cm;
  • IIIc - tumor nodes larger than 2 cm or lymph node involvement.
• Stage IV: Distant organ damage, including the liver and/or pleura.

Classification

The histological classification of germ cell tumors was developed by WHO in 1985.

• Tumors of the same histological type.
  • Germinoma (dysgerminoma, seminoma).
  • Spermatocytic seminoma.
  • Embryonic cancer.
  • Tumor of the yolk sac (endodermal sinus).
  • Choriocarcinoma.
  • Teratoma (mature, immature, with malignant transformation, with one-sided differentiation).
• Tumors of more than one histologic type.

Germ cell tumors account for less than 3% of all malignant neoplasms in children. In adolescents aged 15-19, their share is 14%. Germ cell tumors in different age groups have their own biological characteristics.

Extragonadal germ cell tumors are typical for young children, most of which are teratomas. Teratomas contain elements of all three germ layers (ectoderm, endoderm, and mesoderm). Mature teratoma consists of well-differentiated tissues. Immature teratoma is divided into three histological subtypes depending on the content of immature neuroglial or blastemal tissue. Teratoma, both mature and immature, may contain elements of various germ cell tumors, and in rare cases, elements of other tumors (neuroblastoma, retinoblastoma). Teratomas are most often localized in the sacrococcygeal region.

In older children and adolescents, extragonadal germ cell tumors are most often located in the mediastinum.

Often, germ cell tumors of the genital organs are combined with developmental defects (mixed and pure gonadal dysgenesis, hermaphroditism, cryptorchidism, etc.).

Histologically, germ cell tumors of the testicle in children are tumors of the endodermal sinus. Seminomas are typical for adolescents. Germ cell tumors of the ovaries are more often observed in girls during puberty. Histologically, they can be represented by dysgerminoma, teratoma of varying degrees of maturity, yolk sac tumor, or include several histological types.

A characteristic cytogenetic anomaly is the isochromosome of the short arm of chromosome 12, which is found in 80% of cases of germ cell tumors. Germ cell tumors of the testicle are characterized by chromosomal anomalies in the form of deletion of the short arm of chromosome 1, the long arm of chromosome 4 or 6, as well as di- or tetraploidy. Aneuploidy is often found in seminomas.

Children with Klinefelter syndrome (an increase in the number of X chromosomes) have an increased risk of developing mediastinal germ cell tumors.

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Diagnosis of germ cell tumors

A characteristic feature of germ cell tumors is secretory activity. In case of yolk sac tumor, an increase in the concentration of alpha-fetoprotein (AFP) is detected in the blood, and in case of choriocarcinoma, beta-chorionic gonadotropin (beta-CGT) is detected. Germinoma can also produce beta-CGT. These substances are used as markers for diagnosing the disease and dynamically assessing the tumor process. Most germ cell tumors in children contain elements of yolk sac tumor, which causes an increase in the concentration of AFP. Dynamic determination of this marker makes it possible to assess the tumor response to therapy. It is important to remember that the concentration of AFP in children under 8 months is extremely variable, and the indicator must be assessed taking into account age-related changes.

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Treatment of germ cell tumors

The results of treatment of malignant germ cell tumors before the development of effective polychemotherapy regimens were extremely unsatisfactory. The overall three-year survival rate of patients using only surgical or radiation therapy was 15-20%. The introduction of chemotherapy led to an increase in 5-year survival to 60-90%. Standard drugs for the treatment of germ cell tumors are cisplatin, etoposide and bleomycin (REB regimen). In children under 16 years of age, the JEB regimen is used, where cisplatin is replaced by carboplatin, which ensures equal efficacy with less nephro- and ototoxicity (direct comparison of the efficacy of the JEB and REB regimens in randomized trials has not been conducted). Ifosfamide is also effective in the treatment of germ cell tumors and is widely used in modern chemotherapy regimens.

What is the prognosis for germ cell tumors?

The prognosis for germ cell tumors depends on the location of the neoplasm and the stage of the process, as well as on the patient's age (the younger the patient, the more favorable the prognosis) and histological variant (the prognosis is more favorable for seminomas).