Germ cell tumors

Germ cell tumors are neoplasms that develop from the primary germ cells of the human embryo, from which sperm and eggs are normally formed.

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Epidemiology

Germ cell tumors are considered rare: they make up 3% of all registered malignant tumors in childhood. At the same time, in the first year of life, teratomas and teratoblastomas make up 20% of all registered neoplasms. Their frequency is 1 case per 26,000-34,000 births. The second peak of incidence is observed in adolescents aged 15-19 years.

As a result of the migration of germ cells, germ cell tumors develop not only in the gonads, but also in other organs and tissues of the fetus and child.

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Frequency of germ cell tumors of various localizations

• Sacrococcygeal region - 42
• Mediastinum - 7
• Retroperitoneal space - 4
• Testicle - 9
• Ovary - 24
• Pineal gland area - 6
• Other areas - 6

This article only discusses extracranial germ cell tumors.

Histogenesis of germ cell tumors

Germ cell tumors develop from pluripotent germ cells. They arise in the endoderm of the yolk sac and normally migrate from there along the hindgut toward the urogenital ridge on the posterior abdominal wall, where they become part of the developing gonads. Depending on where they stop along the migration path, embryonic germ cells can give rise to tumor growth in one or another area along the midline of the body. Therefore, germ cell tumors are found in various parts of the body; they can have gonadal and extragonadal localizations.

Due to the fact that during embryogenesis the germ cells in the caudal part of the urogenital ridge persist longer compared to the head, teratomas and teratoblastomas are more often found in the pelvic region, sacrococcygeal region, retroperitoneal space than in the mediastinum, in the neck region and intracranial region.

Germ cell tumors originate from a plurilotent germ cell and may therefore consist of derivatives from all three germ layers. As a result, they may contain tissues that are not typical for the anatomical site in which the tumor arises.

The type of tumor that develops depends on the migration route and the degree of maturity of the ectopic cells.

Histological classification

Histologically, germ cell tumors are divided into germinomas and non-germ cell tumors. The latter include teratomas, yolk sac tumors, embryonic cancer, choriocarcinoma, and mixed germ cell tumors.

• Germinomas are germ cell tumors that arise in extragonadal areas (pineal region, anterior mediastinum, retroperitoneal space). A neoplasm that is histologically identical to a germinoma but develops in the testicle is called a seminoma, and in the ovaries, a dysgerminoma.

Germ cell tumors are divided into those that secrete (alpha-fetoprotein, beta-chorionic gonadotropin) and those that do not.

• Teratomas are embryonic tumors containing tissues of all three germ layers: ectoderm, endoderm, and mesoderm. They arise in the sacrococcygeal region, mediastinum, ovaries, and are divided into mature teratomas (benign variant), immature teratomas (intermediate variant), and malignant tumors - teratoblastomas. According to their structure, teratomas are divided into cystic and solid.
• Yolk sac neoplasms (endodermal sinus) are extragonadal germ cell tumors that occur in young children in the sacrococcygeal region, and in older children in the ovaries. Two age-related types are typical for localization in the testicles - in younger children and in adolescents. It is possible to have foci of yolk sac tumor in teratoblastomas. Yolk sac tumors are classified as highly malignant.
• Embryonic cancer (embryonic carcinoma) can be found both in pure form and as a component of teratoblastoma. It is localized in the testicles and ovaries. It occurs more often in adolescence.

How do germ cell tumors manifest themselves?

Germ cell tumors manifest themselves in different ways. Their symptoms depend on the localization of the neoplasm.

• Lumbar-sacral region - Deformation and enlargement of this region due to neoplasm.
• Mediastinum - Respiratory distress when the tumor reaches large sizes.
• Retroperitoneal space - Symptoms characteristic of this localization.
• Testicle - Enlargement of the testicle due to a dense, tuberous formation.
• Ovary - Palpable tumor of the abdominal cavity and pelvis; if the tumor stalk is twisted - abdominal pain.
• Pineal gland region - Focal and general cerebral symptoms.

Sacrococcygeal teratomas are usually detected at birth and are diagnosed without much difficulty. Manifestation of germ cell tumors of the testicles has two peaks of incidence: up to 4 years (most cases) and in the period over 14-15 years. At the same time, biology in early childhood and adolescence is different: in the younger age group, yolk sac neoplasms and mature teratomas are encountered, while in adolescents - teratoblastoma and seminoma. In contrast to the well-visualized localization in the testicle, other extracranial germ cell tumors (mediastinal, abdominal cavity, small pelvis) in children usually appear at stage III-IV of the process. Manifestation of ovarian dysgerminoma occurs in the prepubertal and pubertal periods (8-12 years). Germ cell tumors of the mediastinum are detected in early childhood and in adolescents. At the same time, at the age from 6 months to 4 years, they are represented by teratoblastomas, yolk sac tumors, and embryonic cancer. In adolescence, the germ cell tumor type of the mediastinum predominates among germ cell tumors.

Symptoms of metastatic lesions depend on the localization and degree of development of the metastatic process and have no specific signs compared to other malignant neoplasms. A tumor symptom complex can develop with teratoblastoma in the case of massive disintegrating neoplasms.

Classification (clinical staging)

The POG/CCSG study group uses separate postoperative staging systems for testicular, ovarian, and extragonadal germ cell neoplasms.

I. Germ cell tumors of the testicle.

• Stage I - the tumor is limited to the testicle, completely removed by high inguinal or transscrotal orchofuniculectomy. There are no clinical, radiological or histological signs of tumor spread beyond the organ. The content of tumor markers, studied taking into account the half-life (alpha-fetoprotein - 5 days, beta-hCG - 16 hours), is not increased. In patients with normal or unknown initial values of tumor markers, the retroperitoneal lymph nodes are not affected.
• Stage II - transscrotal orchiectomy is performed. Microscopically, the presence of a neoplasm in the scrotum or high in the spermatic cord (less than 5 cm from its proximal end) is determined. Retroperitoneal lymph nodes are affected by the tumor (size less than 2 cm) and/or the content of tumor markers is increased (taking into account the half-life).
• Stage III - the tumor affects the retroperitoneal lymph nodes (size more than 2 cm), but there is no tumor damage to the abdominal organs and no spread of the tumor beyond the abdominal cavity.
• Stage IV - distant metastases, including the liver.

II. Germ cell tumors of the ovaries.

• Stage I - the tumor is limited to the ovary (ovaries), lavage fluid from the peritoneum does not contain malignant cells. There are no clinical, radiological or histological signs of tumor spread beyond the ovaries (the presence of peritoneal gliomatosis is not considered a basis for changing stage I to a higher one). The content of tumor markers is not increased given their half-life.
• Stage II - microscopically detect tumor lesions of the lymph nodes (size less than 2 cm), lavage fluids from the peritoneum do not contain malignant cells (the presence of peritoneal gliomatosis is not considered a basis for changing stage II to a higher one). The content of tumor markers is not increased given their half-life.
• Stage III - lymph nodes are affected by a tumor (size more than 2 cm). After surgery, a massive tumor remains or only a biopsy is performed. Tumor damage to adjacent organs (e.g. omentum, intestine, bladder), lavage fluid from the peritoneum contains malignant cells. The content of tumor markers may be normal or elevated.
• Stage IV - distant metastases, including the liver.

III. Extragonadal germ cell tumors.

• Stage I - complete removal of the neoplasm at any of its locations; if localized in the sacrococcygeal region, the coccyx is removed, histologically, resection is within healthy tissues. The content of tumor markers is normal or increased (but decreases taking into account their half-life). Regional lymph nodes are not affected.
• Stage II - malignant cells are microscopically identified along the resection line, lymph nodes are not affected, the content of tumor markers is normal or elevated.
• Stage III - after surgery, a massive neoplasm remains or only a biopsy is performed. Retroperitoneal lymph nodes may or may not be affected by the tumor. Tumor marker levels are normal or elevated.
• Stage IV - distant metastases, including the liver.

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How are germ cell tumors recognized?

Diagnostics of the primary lesion in germ cell tumors includes ultrasound, radiography, CT and/or MRI, ultrasound Doppler angioscanning. Diagnostics of possible metastases includes chest radiography, ultrasound of the abdominal cavity and regional zones, myelogram examination. To exclude a neoplasm of a neurogenic nature in the case of neoplasm localization in the mediastinum, retroperitoneal space, presacral region, excretion of catecholamines and their metabolites should be studied.

Germ cell tumors of the sacrococcygeal region require identification (if any) of the presacral component of the neoplasm. This requires a rectal examination and careful evaluation of ultrasound and CT or MRI data.

Germ cell tumors are distinguished by the fact that it is possible to assess the degree of malignancy before receiving a histological conclusion using the Abelev-Tatarinov reaction - a study of the concentration of alpha-fetoprotein protein in the blood serum. This protein is normally synthesized by cells of the yolk sac, liver and (in small quantities) the gastrointestinal tract of the fetus. The biological role of alpha-fetoprotein is that, penetrating through the placenta into the blood of a pregnant woman, it inhibits the immunological reaction of rejection of the fetus by the mother's body. The alpha-fetoprotein protein begins to be synthesized in the early stages of intrauterine development. Its content reaches its maximum at a pregnancy term of 12-14 months, dropping to the level of an adult by the age of 6-12 months of postnatal life. Malignant germ cell tumors are capable of synthesizing alpha-fetoprotein, therefore, the study of the Abelev-Tatarinov reaction allows us to assess the degree of malignancy of the neoplasm. In a child under 3 years of age, with a severe condition that makes any surgical intervention undesirable, even in the volume of biopsy, a high titer of alpha-fetoprotein can serve as a basis for starting antitumor treatment without morphological verification of the diagnosis. When determining the dynamics of the alpha-fetoprotein content in the blood serum, the half-life of this protein and the dependence of this indicator on age should be taken into account.

In the diagnostics of teratoblastoma and other germ cell tumors, other tumor markers also play an important role - cancer embryonic antigen (CEA), beta-human chorionic gonadotropin (beta-hCG) and placental alkaline phosphate. An increase in the latter indicator is associated with the presence of syncytiotrophoblasts in the tissue of the neoplasm. The half-life of beta-hCG is 16 hours (in children under one year - 24-36 hours).

In a smaller proportion of cases, teratoblastoma may progress without an increase in alpha-fetoprotein and other tumor markers. On the other hand, an increase in alpha-fetoprotein does not necessarily indicate the presence of a germ cell tumor. This indicator also increases in malignant liver tumors.

Mandatory and additional studies in patients with suspected germ cell tumors

Mandatory diagnostic tests

• Complete physical examination with assessment of local status
• Clinical blood test
• Clinical urine analysis
• Blood biochemistry (electrolytes, total protein, liver function tests, creatinine, urea, lactate dehydrogenase, alkaline phosphatase, phosphorus-calcium metabolism)
• Coagulogram
• Ultrasound of the affected area
• Ultrasound of the abdominal organs and retroperitoneal space
• CT (MRI) of the affected area
• X-ray of the chest organs in five projections (straight, two lateral, two oblique)
• Tumor marker research
• Study of catecholamine excretion
• Bone marrow puncture from two points
• ECG
• EchoCG
• Audiogram
• In children over 3 years of age and with normal and questionable values of alpha-fetoprotein or beta-hCG
• The final stage is a biopsy of the neoplasm (or complete removal) to verify the cytological diagnosis. It is advisable to make prints from the biopsy for cytological examination.

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Additional diagnostic tests

• If metastases to the lungs are suspected - CT of the chest organs
• If metastases to the brain are suspected - EchoEG and CT of the brain
• Ultrasound color duplex angioscanning of the affected area

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How are germ cell tumors treated?

Treatment of benign germ cell tumors is surgical, while malignant tumors are treated in a combined and comprehensive manner. Radiation therapy and course chemotherapy using platinum, ifosfamide, and etoposide are used. In case of dysgerminomas, chemoradiotherapy is prescribed initially for unresectable tumors and after surgery - at postoperative stages II-IV. In case of other histological variants of malignant germ cell tumors (e.g., yolk sac tumor, choriocarcinoma, embryonic cancer), treatment at all stages consists of surgery and postoperative chemotherapy.

If a resectable neoplasm is detected, the first stage of treatment is radical surgery. In case of unresectable primary tumor, biopsy should be enough. Radical surgery is performed after neoadjuvant chemotherapy and the tumor's acquisition of signs of resectability against its background. In cases of neoplasm detection in children under 3 years of age and undesirability of surgery even in the volume of biopsy due to the severity of the patient's condition, a high titer of alpha-fetoprotein or B-hCG serves as a basis for refusing diagnostic surgery and starting chemotherapy without morphological confirmation of the diagnosis.

Congenital teratoid tumor of the sacrococcygeal region should be removed as early as possible. It should be borne in mind that this neoplasm may have two components: sacrococcygeal, removed through the perineal approach, and presacral, removed through the laparotomic approach. Thus, in such cases, an operation through a combined abdominoperineal approach is necessary. An undetected and unremoved presacral component becomes a source of recurrent growth, while in the case of an initially benign variant of the neoplasm, its malignancy with the development of a malignant relapse is possible. Before the operation, in order to avoid injury to the rectum, a tube is inserted into it to control its position. It is imperative to resect the coccyx, and in case of widespread lesions - the sacrum. During the operation, the tumor type (cystic, solid) should be taken into account. In the first case, it is necessary to avoid opening cystic cavities.

If morphological data on the benign nature of the process are obtained after removal of the sacrococcygeal tumor, the tumor is assessed as a mature teratoma, and treatment is terminated. The picture of malignancy in histological preparations becomes the basis for the diagnosis of teratoblastoma, which requires chemoradiation therapy. In the case of immature teratomas, patients are left under observation after surgery, chemotherapy is carried out only if a relapse of the neoplasm is diagnosed.

Ovarian germ cell tumors, like other neoplasms of the retroperitoneal space, are removed through a laparotomic approach. Salpingo-oophorectomy with the tumor is performed. In case of unilateral ovarian damage, along with its removal, a biopsy of the opposite ovary should be performed. Also, when removing an ovarian tumor, it is necessary to resect the greater omentum (the latter, due to the mechanism of contact metastasis, can be affected by metastases) and perform a biopsy of the retroperitoneal lymph nodes. The presence of ascitic fluid is an indication for its cytological examination. Bilateral tumor damage is an indication for removal of both ovaries.

A feature of ovarian teratomas is the possibility of seeding the peritoneum with tumor cells (the so-called peritoneal gliomatosis). Peritoneal gliomatosis may be a microscopic or macroscopic lesion. In cases of peritoneal gliomatosis, it is advisable to prescribe postoperative chemotherapy.

Germ cell tumors of the mediastinum

If the tumor is localized in the mediastinum, thoracotomy is performed. In some cases, depending on the localization, sternotomy is possible.

Germ cell tumors of the testicle

In case of tumor damage to the testicle, orchofuniculectomy is performed from the inguinal access with high ligation of the spermatic cord. Removal or biopsy of the retroperitoneal lymph nodes is performed (from the laparotomic access) as a second-look operation, after program chemotherapy as indicated.

If pulmonary metastases present before the start of treatment persist on radiographs and CT scans and are considered resectable, their surgical removal is necessary.

What is the prognosis for germ cell tumors?

Malignant extracranial germ cell tumors had an extremely unfavorable prognosis before effective chemotherapy. With the use of chemotherapy, a 5-year survival rate of 60-90% has been achieved. The prognosis depends on the histological variant, age, localization and prevalence of the neoplasm, as well as the initial level of tumor markers. In case of teratomas of the sacrococcygeal region, the prognosis is better in patients up to 2 months. In case of teratomas of the mediastinum, the prognosis is better in patients up to 15 years. Favorable histological germ cell tumors (terminomas, teratomas without foci of tumor tissue of unfavorable histological variants) have a better prognosis compared to unfavorable ones (embryonic carcinoma, yolk sac tumor, choriocarcinoma). The prognosis is worse with a higher level of tumor markers before the start of treatment compared to patients with a lower level.

Non-germinocyte tumors of the gonads

Non-germinogenic tumors of the gonads are rare in childhood, but they do occur in children. This type of pathology requires differential diagnostics with such neoplasms as germinogenic tumors, as well as appropriate treatment.

Sertolioma (sustenocytoma, androblastoma) is usually benign. It is detected at any age, but is more common in infant boys. Clinically, sertolioma is manifested by a tumor formation of the testicle. The neoplasm consists of sustenocytes that form tubular structures.

Leydigoma (interstitial cell tumor) originates from glandulocytes. Usually benign. Occurs in boys aged 4 to 9 years. As a result of hypersecretion of testosterone and some other hormones, premature sexual development begins in affected boys. Histologically, the neoplasm is indistinguishable from ectopic tissue of the adrenal cortex. In both cases, inguinal orchofuniculectomy is performed (as an option - orchiectomy from the scrotal approach).

Benign ovarian cysts account for 50% of all ovarian tumors. Cysts can be detected by accidental ultrasound, as well as by laparotomy performed for "acute abdomen" with torsion or twisting of the cyst. Such patients must undergo tumor marker testing before and after surgery.

Other ovarian tumors are extremely rare. Granulosa cell tumors (thecomas) are benign neoplasms of stromal origin. The tumor manifests itself as premature sexual development. Cystadenocarcinoma is distinguishable from other tumors only histologically. In isolated cases, the primary manifestation of non-Hodgkin's malignant ovarian lymphoma has been described.

Gonadoblastomas are detected in patients with gonadal dysgenesis (true hermaphroditism). Female phenotype with signs of virilization is present in 80% of patients. The remaining 25% of patients have male phenotype with signs of cryptorchidism, hypospadias and/or presence of internal female genital organs (uterus, fallopian tubes or their rudiments). Histological examination reveals a combination of germ cells and elements of immature granulosa, Sertoli or Leydig cells. These neoplasms should be surgically removed together with stroke gonads due to high risk of malignancy of the latter. Cytogenetic karyotype examination is performed to establish the true sex of the patient.