Testicular cancer

Testicular cancer is the most common solid cancer in men aged 15-35 years.

The incidence is 2.5 to 20 times higher in patients with cryptorchidism, even when the undescended testicle has been surgically descended. Cancer can also develop in a normally descended testicle. The cause of testicular cancer is unknown.

Epidemiology

Testicular cancer accounts for 0.5% of all malignancies in men, occurs most frequently between the ages of 15 and 44, and is the leading cause of death among malignancies in this age group.

Approximately 90-95% of primary testicular tumors are germ cell (non-seminoma and seminoma) tumors, 5-10% are non-germinoma (leydigoma, sertolioma, gonadoblastoma, etc.). Testicular cancer, like cryptorchidism, occurs somewhat more often in the right testicle. Primary testicular tumors are bilateral in 1-2% of cases. Approximately 50% of patients have a history of uni- or bilateral cryptorchidism. Primary bilateral tumors can occur both synchronously and metachronously, but, as a rule, belong to the same histological type. Of the primary testicular tumors, the most common bilateral is seminoma, and of the secondary ones, lymphoma.

There is currently a steady increase in testicular cancer incidence. Over the past 5 years, according to world statistics, it has increased by an average of 30%.

[ 1 ], [ 2 ], [ 3 ], [ 4 ], [ 5 ], [ 6 ], [ 7 ]

Causes testicular cancer

Factors that in one way or another lead to testicular atrophy ( cryptorchidism, chemical factors, trauma, idiopathic testicular atrophy, as well as various infectious diseases) can also provoke testicular cancer. Men with testicular hypotrophy have an increased risk of developing testicular cancer.

In normally functioning cells, the p53 protein is practically not detected. It is an important factor influencing cell proliferation and apoptosis. In many malignant neoplasms, a mutation of the p53 gene is detected. As a rule, the detection of a mutant functionally inactive p53 is an indicator of a poor prognosis and resistance to the treatment. In germ cell tumors of the testicle, increased formation of normal p53 protein is noted, which may explain the unique sensitivity of these tumors to chemo- and radiation therapy.

Most testicular cancers arise in the primordial germ cells. Germ cell tumors are classified as seminomas (40%) or nonseminomas (tumors containing any nonseminomatous elements). Nonseminomas include teratomas, embryonal carcinomas, endodermal sinus tumors (yolk sac tumors), and choricoarcinomas. Histologic combinations are common; for example, teratocarcinoma may include teratoma and embryonal carcinoma. Functional interstitial testicular cancers are rare.

Even patients with apparently localized tumors may have occult regional or visceral metastases. The risk of metastasis is highest for choriocarcinoma and lowest for teratoma.

Tumors arising in the epididymis, epididymis, and spermatic cord are usually benign fibromas, fibroadenomas, adenomatous tumors, and lipomas. Sarcomas, most often rhabdomyosarcomas, are rare and occur more frequently in children.

[ 8 ], [ 9 ], [ 10 ], [ 11 ]

Risk factors

• Cryptorchidism is the main risk factor for testicular cancer. If the testicle does not descend to the scrotum, the risk of the disease increases by 5 times compared to the general population. The risk becomes significantly higher (more than 10 times) in men with bilateral cryptorchidism. Cryptorchidism is the cause of 7-10% of testicular tumors, most often seminoma. However, in 5-10% of cases, the tumor occurs in a normally descended testicle, on the opposite side.
• Toxicosis of pregnancy suffered by the mother due to hypersecretion of estrogens, or prolonged use of estrogens during pregnancy increases the risk of testicular cancer in sons.
• Excess estrogen in the environment due to pesticide pollution (dioxin, polychlorinated diphenols, phytoestrogens) also leads to an increased incidence of testicular cancer.
• Genetic risk factors. A study of familial cases of testicular cancer confirms their importance in the etiology of neoplasms. With a family history of the disease, the risk of developing testicular cancer for fathers and sons of patients is increased by 2-4 times, and for brothers of patients - by 8-10 times compared to the general male population. The possibility of recessive inheritance of testicular cancer is also considered.
• Klinefelter syndrome.
• Contact with tin.
• Infertility.

[ 12 ]

Pathogenesis

Factors that in one way or another lead to testicular atrophy (cryptorchidism, chemical factors, trauma, idiopathic testicular atrophy, as well as various infectious diseases) can also lead to the development of testicular cancer. Men with testicular hypotrophy have an increased risk of developing testicular cancer.

In normally functioning cells, the p53 protein is practically not detected. It is an important factor influencing cell proliferation and apoptosis. In many malignant neoplasms, a mutation of the p53 gene is detected. As a rule, the detection of a mutant functionally inactive p53 is an indicator of a poor prognosis and resistance to the treatment. In germ cell tumors of the testicle, increased formation of normal p53 protein is noted, which may explain the unique sensitivity of these tumors to chemo- and radiation therapy.

[ 13 ], [ 14 ], [ 15 ], [ 16 ], [ 17 ], [ 18 ], [ 19 ]

Symptoms testicular cancer

Most patients present with a scrotal mass that is painless or occasionally mildly painful. In a few patients, bleeding into the mass may cause acute local pain. Many discover testicular cancer on their own, either through self-examination or after minor trauma.

Symptoms of testicular cancer consist of signs caused by the primary tumor and metastases. The earliest symptoms of testicular cancer are: enlargement of the testicle, a feeling of heaviness in the scrotum, a palpable tumor in the corresponding part of the scrotum.

About 10% of patients seek medical attention due to acute pain in the testicle. It is usually caused by hemorrhage or infarction of the testicle. Pain rarely occurs in the initial stages of the disease and appears with a significant increase in intratesticular pressure, ingrowth of the scrotum or spermatic cord, which corresponds to common forms of the disease.

Approximately 10% of patients seek medical attention with complaints caused by metastases (most often, this is lower back pain due to compression of the spinal roots by metastases in the lumbar lymph nodes). Obstruction of urine outflow through the ureters can lead to complaints associated with the development of renal failure. In addition, cough and shortness of breath may occur with metastases in the lungs, loss of appetite, nausea and vomiting with metastases in the lymph nodes located behind the duodenum, bone pain, complaints associated with intestinal obstruction, as well as swelling of the legs with compression of the inferior vena cava.

Rarely, the first symptom of a testicular tumor is hemospermia. In about 10% of patients, the disease is asymptomatic. In this case, the tumor is usually detected by chance by the patient himself, his sexual partner, or during an examination for a testicular injury.

Non-germinogenic testicular tumors may cause symptoms of testicular cancer associated with hormonal imbalances. In approximately every third case of these neoplasms, gynecomastia occurs, caused by the production of a significant amount of chorionic hormone by the tumor tissue.

In addition, in adults, decreased libido, impotence and feminization are possible due to hyperestrogenism, and in children, masculinization (macrogenitosomia, pubic hair, voice change, hirsutism, premature development of the skeletal and muscular systems, frequent erections) due to increased production of androgens by the tumor.

Forms

Histological classification of testicular tumors

• Germ cell tumors (develop from the seminal epithelium).
  • Tumors of the same histological structure:
    • seminoma;
    • spermatocytic seminoma;
    • embryonic cancer;
    • yolk sac tumor (infantile-type embryonic carcinoma, endodermal sinus tumor):
    • polyembryoma;
    • choriocarcinoma;
    • teratoma (mature, immature, with malignant transformation).
  • Tumors of more than one histologic type:
    • teratocarcinoma (embryonic cancer and teratoma);
    • choriocarcinoma;
    • other combinations.
• Sex cord stromal tumors.
  • Well differentiated forms:
    • leydigoma;
    • sertolioma;
    • granulosa cell tumor.
  • Mixed forms.
  • Incompletely differentiated tumors
• Tumors and tumor-like lesions containing germ cells and sex cord stromal cells.
  • Gonadoblastoma.
  • Others.
• Various tumors
  • Carcinoid.
• Tumors of lymphoid and hematopoietic tissue.
• Secondary tumors.
• Tumors of the rectal tubules, rete testis, epididymis, spermatic cord, capsule, supporting structures, rudimentary formations.
  • Adenomatous tumor.
  • Mesothelioma.
  • Adenoma.
  • Cancer.
  • Melanotic neuroectodermal tumor.
  • Brenner tumor.
  • Soft tissue tumors:
    • embryonal rhabdomyosarcoma;
    • others.
• Unclassifiable tumors.
• Tumor-like lesions.
  • Epidermal (epidermoid) cyst.
  • Non-specific orchitis.
  • Nonspecific granulomatous orchitis.
  • Specific orchitis.
  • Malakoplakia.
  • Fibromatous periorchitis.
  • Spermatocyte granuloma.
  • Lipogranuloma.
  • Adrenal remnants.
• Others.

The most common forms of testicular tumors

• Seminoma. Seminoma accounts for 35% of germ cell tumors of the testicle. Three histological variants have been described, although the prognosis for tumors of the same stage does not depend on the histological variant. Classic seminoma is detected in 85% of all cases of seminoma. It most often occurs at the age of 30-40 years. In seminoma, secretion of chorionic gonadotropin is detected in 10-15% of cases. Anaplastic seminoma is less differentiated compared to classical seminoma and accounts for 5-10% of seminomas. However, as already noted, the prognosis for anaplastic or classical seminoma of the same stage is the same. Spermatocyte seminoma is diagnosed in 5-10% of cases. In more than 50% of cases, spermatocyte seminoma occurs at the age of over 50 years.
• Embryonal testicular cancer accounts for almost 20% of germ cell tumors of the testicle. It is characterized by pronounced polymorphism of cells and unclear boundaries between them. Mitoses and giant cells are common. They can be arranged in sheets or form acinar, tubular or papillary structures. Extensive areas of hemorrhage and necrosis can occur.
• Teratoma. Teratomas account for 5% of germ cell tumors of the testicle. It can occur in both children and adults, and can be mature or immature. This tumor consists of derivatives of two or three germ layers. Macroscopically, it has cavities of varying sizes filled with gelatinous or mucous contents. Mature cystic teratomas (dermoid cysts), typical of the ovaries, are extremely rare in the testicle.
• Choriocarcinoma of the testicles. Choriocarcinoma is extremely rare in its pure form (less than 1% of cases). This tumor is usually small and located in the thickness of the testicle. A hemorrhage is often visible in the center of the tumor when cut. Choriocarcinoma is an aggressive tumor prone to early hematogenous metastasis. Extensive dissemination is possible even with a small primary tumor.
• Yolk sac tumor is sometimes called endodermal sinus tumor or embryonal carcinoma of the immature type. It is the most common testicular germ cell tumor in children. In adults, it is usually found in mixed germ cell tumors. The tumor secretes AFP
• Polyembryoma is another extremely rare testicular tumor. It contains embryoid bodies that resemble a two-week-old embryo.
• Mixed germ cell tumors account for 40% of testicular germ cell tumors. In most cases (25% of testicular germ cell tumors), they are a combination of teratoma and embryonic cancer (teratocarcinoma). Up to 6% of testicular germ cell tumors are mixed tumors containing elements of seminoma. These tumors are treated as non-seminomatous tumors.
• Intratubular germ cell tumors. In one study, in patients with unilateral testicular germ cell tumor, intratubular germ cell tumors (carcinoma in situ) were found in the other testicle in 5% of cases. This is more than twice the incidence of bilateral lesions in primary testicular tumors. The clinical course of intratubular testicular germ cell tumors has not been studied. Some patients develop invasive germ cell tumors.

The most important clinical distinction is the division of all germ cell testicular tumors into seminomas and non-seminomas, which significantly influences the choice of treatment approach. Further subdivision of non-seminoma testicular tumors does not play a major role.

The WHO classification (1977), which examined in detail the various histological variants of germ cell tumors of the testicle, did not take into account the unity of their origin and the possibility of further differentiation into other morphological types in the process of carcinogenesis.

A new histological classification proposed in 1992 is based on the idea of a single origin of all germ cell tumors of the testicle from carcinoma in situ. All germ cell tumors, with the exception of spermacytoma, are proposed to be called gonocytomas. The latter are subdivided into seminoma (classical and anaplastic, characterized by a more aggressive course), teratogenic gonocytoma and anaplastic germ cell tumor. having features of both seminoma and teratogenic gonocytoma.

The stem cell of teratogenic gonocytoma is pluripotent and capable of differentiating into various types of teratomas (mature and immature), epiblastoma (in the old classification - embryonic cancer) and extraembryonic elements, which include yolk sac tumor and choriocarcinoma.

[ 20 ], [ 21 ]

International Germ Cell Tumor Group Classification

[ 22 ], [ 23 ]

Non-seminomatous germ cell tumors

• Good prognosis (if all signs are present):
  • AFP level in blood serum less than 1000 ng/ml;
  • serum human chorionic gonadotropin level less than 5000 mIU/ml;
  • serum LDH activity less than 675 U/l;
  • absence of extragonadal mediastinal tumor;
  • absence of metastases in the liver, bones, brain.
• Moderate prognosis (if all signs are present):
  • AFP level in blood serum 1000-10,000 ng/ml;
  • serum chorionic gonadotropin level 5000-50,000 mIU/ml;
  • LDH activity in blood serum 675-4500 U/l;
  • absence of extragonadal mediastinal tumor;
  • absence of metastases in the liver, bones, brain.
• Poor prognosis (if at least one sign is present):
  • serum AFP level over 10,000 ng/ml;
  • serum beta-human chorionic gonadotropin level greater than 50,000 mIU/ml;
  • LDH activity in blood serum is more than 4500 U/l;
  • presence of extragonadal tumor of the mediastinum;
  • the presence of metastases in the liver, bones, and brain.

Seminomas

• Good prognosis: no metastases to the liver, bones, or brain.
• Moderate prognosis: presence of metastases in the liver, bones, brain.

Due to the emergence of new cytostatics and the development of new polychemotherapy regimens, survival rates for testicular tumors have increased statistically significantly. Five-year survival rates have increased from 78% in 1974-1976 to 91% in 1990-1995.

Diagnostics testicular cancer

During examination, asymmetry of the scrotum is often determined. Sometimes the second testicle is not visible due to a sharp increase in the other one affected by the tumor. In case of inguinal retention, the testicular tumor looks like a dense or spherical protrusion in the inguinal region. As a rule, tumors are defined as dense formations with a smooth, bumpy surface.

In secondary hydrocele, the tumor has a soft elastic consistency when palpated. It is also necessary to palpate the spermatic cord; sometimes it is possible to determine the transition of the tumor from the testicle to the spermatic cord. Most often, testicular tumors are painless when palpated.

Laboratory diagnostics of testicular cancer

Currently, three main indicators have practical significance in the diagnosis of testicular germ cell tumors: AFP, beta-hCG and LDH.

Determining the level of tumor markers allows us to predict the histological structure of the germ cell tumor.

Groups of testicular neoplasms depending on the concentration of markers.

• A group of tumors that do not produce AFP and the beta subunit of hCG. These include seminomas, mature teratomas, and pure embryonal carcinomas. Embryonic cancer cells may contain giant syncytiotrophoblast cells, which produce insignificant amounts of hCG.
• A group of marker-producing tumors. These include about 80% of germ cell tumors (yolk sac tumors that produce AFP, choriocarcinomas that secrete hCG, mixed tumors that produce AFP and/or hCG).

Given the significant differences in the treatment approach to seminoma and non-seminomatous testicular tumors, determination of AFP and hCG levels is of great practical importance. Tumor markers are often more indicative than routine histological examination of the tumor.

An increase in the serum AFP level in a patient with seminoma without liver metastases should be regarded as a sign of the presence of yolk sac elements in the tumor. An increase in the hCG concentration is detected in 15% of patients with seminoma due to the presence of non-seminomatous elements in the tumor or, much less frequently, the presence of giant syncytiotrophoblast cells.

If the hCG level at stage I-II seminoma does not exceed 1.5 times the upper limit of the norm, the treatment approach should not be changed. However, if the serum hCG level increases with a small primary tumor or with a number of giant syncytiotrophoblast cells in the tumor that is incomparable with its level, the disease should be assessed as a tumor of mixed structure and the treatment regimen should be changed.

In addition, an increase in the level of AFP and hCG in the presence of unchanged testicles allows one to suspect an extragonadal germ cell tumor in the early stages.

Determination of the concentration of tumor markers in blood serum before and 5-6 days after removal of the primary tumor allows for clarification of the clinically established stage of the disease, which reduces the error rate by 35%.

The level of tumor markers is determined in all patients with germ cell tumors during treatment and observation at certain intervals depending on the extent of the disease. After radical removal of the tumor, the level of markers should decrease to normal values in accordance with their half-lives (AFP less than 5 days, hCG - 1-2 days).

If the concentration of AFP and hCG remains elevated and the half-life of the markers increases after removal of the primary tumor, even in the absence of radiological data indicating dissemination of the process, the presence of distant metastases should be considered and appropriate treatment should be carried out.

An increase in the concentration of AFP and hCG may indicate disease progression 1-6 months before the clinical appearance of a relapse and serves as a basis for initiating treatment. The diagnostic sensitivity of AFP and hCG in relapses of germ cell tumors is 86% with a specificity of 100%.

Normal marker levels do not allow to definitely exclude disease progression. A recurrent tumor can acquire new biological properties, for example, become marker-negative. False-negative results of a study of tumor marker concentration in blood serum can be obtained with a small tumor size or the presence of a mature teratoma.

Rarely, false-positive results in determining the level of AFP and hCG are due to lysis of tumor cells in response to intensive chemotherapy. An increase in the concentration of AFP, not associated with disease progression, may also be due to liver failure.

[ 24 ], [ 25 ], [ 26 ], [ 27 ]

Instrumental diagnostics of testicular cancer

In order to verify the diagnosis of "testicular cancer" in complex diagnostic cases, aspiration biopsy with cytological examination of the puncture is performed, although this carries the risk of implantation metastases. If there is doubt about the correctness of the established diagnosis, an exploratory operation with urgent histological examination is performed.

The main methods for diagnosing testicular tumor metastases include chest X-ray, ultrasound, CT of the abdominal cavity, retroperitoneal space and chest.

When planning retroperitoneal lymphadenectomy in patients with large residual tumor masses involving the main vessels, angiographic studies are performed (aortography, lower one- and two-projection cavography).

Differential diagnosis

Hydrocele can complicate the diagnosis of testicular cancer. Diaphanoscopy and ultrasound help to distinguish hydrocele from a tumor.

Recently, great hopes have been placed on PET, which allows for a high degree of reliability in differentiating viable tumors from sclerotic tissues.

[ 28 ], [ 29 ], [ 30 ], [ 31 ], [ 32 ], [ 33 ]

Treatment testicular cancer

Radical inguinal orchiectomy, the cornerstone of treatment, provides important histopathologic information, especially the proportion of histologic types and the presence of intratumoral vascular or lymphatic invasion. Some patients may be candidates for sparing (partial) orchiectomy. Information obtained during surgery helps to plan further treatment and can accurately predict the risk of occult lymph node metastases. It thus helps to identify which low-risk patients with normal radiographic and serologic findings, especially those with nonseminomas, may be candidates for surveillance with frequent serologic markers, chest radiography, and CT.

Seminomas recur in approximately 15% of these patients and can usually be cured with radiation therapy if small or chemotherapy if large. Non-seminoma recurrences are rapidly treated with chemotherapy, although delayed retroperitoneal lymph node dissection may be an appropriate approach for some.

Standard treatment for seminoma after unilateral orchiectomy is radiation therapy, usually 20–40 Gy (higher doses are used for patients with node-positive disease) to the para-aortic areas up to the diaphragm, usually excluding the ipsilateral ilioinguinal area. Sometimes the mediastinum and left supraclavicular area are also irradiated, depending on clinical stage. For nonseminomas, many consider retroperitoneal lymph node dissection to be the standard treatment; for early tumors, plexus-sparing dissection is possible. Alternatives include observation for stage I tumors without factors predicting recurrence.

At the time of orchiectomy, up to 30% of patients with nonseminomas have microscopic retroperitoneal lymph node metastases. Intermediate-sized retroperitoneal lymph nodes may require retroperitoneal lymph node dissection and chemotherapy (eg, bleomycin, etoposide, cisplatin), but the optimal sequence has not been established.

Laparoscopic lymph node dissection is under study. The most common adverse effect of lymph node dissection is impaired ejaculation. If the tumor volume is small and sparing dissection is possible, ejaculation is usually preserved. Fertility is often impaired, but no risk to the fetus has been identified in ongoing pregnancies.

A cosmetic testicular prosthesis can be implanted during orchiectomy, but these are not widely available due to the known problems with silicone breast implants. However, a saline-based implant has been developed.

Lymph node involvement larger than 0.1 cm, metastasis to lymph nodes above the diaphragm, or visceral metastasis require initial platinum-based combination chemotherapy followed by surgery for the remaining lymph nodes. This treatment usually controls tumor growth for the long term.

Treatment of seminoma tumors at stage I

Approximately 15-20% of patients with stage I seminoma already have metastases, most often in the retroperitoneal space, which are the cause of relapse of the disease.

• Surgical treatment of testicular cancer. Retroperitoneal lymphadenectomy is not indicated for stage I seminoma due to the high risk (9.5%) of retroperitoneal recurrence.
• Radiation therapy
  • Since seminoma cells have unique radiosensitivity, adjuvant radiotherapy to the para-aortic zones up to a total dose of 20 Gy is indicated, which allows reducing the recurrence rate to 1-2%.
  • After radiation therapy, relapse is possible primarily outside the irradiated area (in the supra-diaphragmatic lymph nodes or lungs). Adjuvant radiation therapy to the para-aortic zones is a standard treatment for patients with stage I testicular seminoma, as well as T1-T3 and unaffected lymph nodes. The incidence of relapse in the iliac lymph nodes is 2% when only the para-aortic zones are irradiated. Adjuvant radiation therapy to the supra-diaphragmatic lymph node zone is not indicated for stage I seminoma.
  • Moderate gastrointestinal complications occur in 60% of patients. Five-year relapse-free survival is about 80%. In a multifactorial prognosis analysis, the most significant factors for relapse are a tumor size of more than 4 cm and invasion of the testicular membranes. The relapse rate is 15-20%. Most often, relapse occurs in the subdiaphragmatic lymph nodes. In 70% of patients with relapse, only radiation therapy can be performed. After radiation therapy, only 20% of patients subsequently develop a relapse requiring chemotherapy. Overall cancer-specific survival for stage I seminoma is 97-100%. Although 70% of relapses occur in the first 2 years after orchiectomy, 7% of patients relapsed 6 years after diagnosis.
• Chemotherapy
  • No significant differences were found between carboplatin chemotherapy and radiotherapy in terms of recurrence rate, time to recurrence, and survival at a median follow-up of 3 years.
  • Thus, adjuvant chemotherapy with carboplatin is an alternative to radiation therapy in stage I seminoma in terms of survival. Two courses of carboplatin may reduce the recurrence rate.

Treatment of seminoma tumors at stages IIA and IIB

• Radiation therapy is the standard treatment option for stage IIA and IV seminoma (radiation dose of 30 and 36 Gy, respectively). The irradiation zone, compared to the standard one for stage I, includes the ipsilateral iliac zone. For stage IIB, the irradiation zone includes the area of the metastatic lymph node with a safety zone of 1.0-1.5 cm. This technique allows achieving 6-year relapse-free survival of 95 and 89% for stages IIA and IIB, respectively. Overall survival reaches 100%.
• Chemotherapy
  • At stage IIB, chemotherapy may be administered according to the 3rd course of BEP or the 4th course of EB in patients with a good prognosis as an alternative to radiation therapy if the patient refuses it.
  • Platinum-containing salvage chemotherapy regimens may be effective in 50% of patients who relapse or are unresponsive to first-line chemotherapy.
  • Main chemotherapy regimens:
    • 4 courses of the PEI VIP regimen, including cisplatin, etoposide, ifosfamide.
    • 4 courses of VelP, including vinblastine, ifosfamide, cisplatin.

PEI regimen every 3 weeks

Preparation	Dose	Day	Course duration
Cisplatin	20 mg/ m2	1-5	21 days
Etoposide	75-100 mg/ m2	1-5
Ifosfamide	1.2 g/ m2	1-5

VelP regimen every 3 weeks

Preparation	Dose	Day	Course duration
Vinblastine	0.11 mg/kg	1-2	21 days
Ifosfamide	1.2 g/ m2	1-5
Cisalatin	20 mg/ m2	1-5

Further management

Patients treated with chemotherapy or radiation therapy for stage I testicular seminoma require long-term follow-up.

Dynamic observation of testicular seminoma stage I after chemotherapy or radiotherapy

Procedure	Year
	1	2	3	4-5
Clinical examination	6 times	4 times	3 times	2 times a year
Chest X-ray	6 times	4 times	3 times	2 times a year
Research of markers	6 times	4 times	3 times	2 times a year
CT scan of the abdominal cavity	1 time	1 time	According to the readings	According to the readings
Ultrasound of the abdominal cavity	1 time*	1 time*	1 time	According to the readings

* Possibly instead of abdominal CT

Dynamic observation of testicular seminoma stage I with close observation tactics

Procedure	Year
	1	2	3	4-5	6-10
Clinical examination	6 times	4 times	3 times	2 times a year	Once a year
Chest X-ray	6 times	4 times	3 times	2 times a year	Once a year
Research of markers	6 times	4 times	3 times	2 times a year	Once a year
CT scan of the abdominal cavity	4 times	4 times	According to the readings	According to the readings	According to the readings
Ultrasound of the abdominal cavity		1 time	1 time	According to the readings	According to the readings

Dynamic observation of stage IIA-IIB seminoma after radiation therapy.

Procedure	Year
	1	2	3	4-5	6-10
Clinical examination	6 times	4 times	3 times	2 times a year	Once a year
Chest X-ray	6 times	4 times	3 times	2 times a year	Once a year
Research of markers	6 times	4 times	3 times	2 times a year	Once a year
CT scan of the abdomen and pelvis	According to the readings	According to the readings	According to the readings	According to the readings	According to the readings
CT scan of the chest	According to the readings	According to the readings	According to the readings	According to the readings	According to the readings

Treatment of non-seminomatous tumors at stage I

In patients with stage I non-seminomatous testicular tumors, subclinical metastases exist in 30% of cases and relapses may develop after orchiectomy.

Using a number of prognostic features, patients can be divided by the degree of risk of developing metastases. The main indicator of relapse in patients with stage I is vascular invasion by tumor cells in the primary tumor. The low-risk group includes patients without vascular invasion and tumor growth into the vaginal tunic of the testicle. In the group of patients with vascular invasion, with a proliferation level of more than 70% and a tumor cellular composition of more than 50% embryonic carcinoma in the tumor, the risk of developing metastatic lesions is 64% (high-risk group).

• Chemotherapy
  • If careful dynamic observation in low-risk patients is impossible, nerve-sparing retroperitoneal lymphadenectomy or 2 courses of chemotherapy according to the BEP regimen (cisplatin, etoposide, bleomycin) are indicated. If metastatic lymph node involvement is detected during retroperitoneal lymphadenectomy, the patient is indicated 2 courses of adjuvant chemotherapy according to the BEP regimen (cisplatin, etoposide, bleomycin).
  • Patients with a poor prognosis are indicated for active treatment of testicular cancer: 2 courses of neoadjuvant chemotherapy according to the BEP regimen (cisplatin, etoposide, bleomycin)
• Surgical treatment of testicular cancer. If chemotherapy is impossible or the patient refuses it, nerve-sparing retroperitoneal lymphadenectomy or dynamic observation with surgical treatment of testicular cancer in case of relapse are indicated.

80% of relapses are detected during the first year of observation, 12% during the second year and 6% during the third year. The frequency of relapses decreases to 1% during the fourth and fifth years, occasionally they occur later. In one third of patients with relapse, the level of serological markers is normal. 60% of relapses occur in the retroperitoneal space.

Treatment of non-seminomatous tumors at stage II

Three courses of chemotherapy according to the BEP regimen (cisplatin, etoposide, bleomycin) are indicated.

Patients with stage IIA and IIB non-seminomatous tumors and elevated serologic markers should be treated for testicular cancer according to prognosis groups. Patients in the moderate and good prognosis groups are recommended to undergo 3 or 4 courses of neoadjuvant chemotherapy according to the BEP regimen, followed by resection of the residual tumor. Approximately 30% of patients fail to achieve complete tumor regression during chemotherapy, so retroperitoneal lymphadenectomy is indicated for them.

Patients who refused chemotherapy at the first stage are indicated for nerve-sparing retroperitoneal lymphadenectomy followed by 2 courses of adjuvant chemotherapy according to the BEP regimen if metastatic lesions of the lymph nodes are detected.

• Chemotherapy. At the first stage, chemotherapy is administered to patients in accordance with the prognosis groups according to the IGCCCG classification, the 3rd or 4th course according to the BEP scheme. This regimen is more effective compared to PVB (cisplatin, vinblastine, bleomycin) in patients with widespread forms of the disease. The three-day scheme of drug administration has similar effectiveness, but is associated with higher toxicity.

Scheme VER every 3 weeks

Preparation	Dose	Day	Course duration
Cisplatin	20 mg/ m2	1-5	21 days
Etoposide	100 mg/ m2	1-5
Bleomycin	30 mg/ m2	1-8-15

Chemotherapy depending on the prognosis of the disease.

• Good prognosis group. Standard therapy is considered to be 3 courses according to the BEP scheme or 4 courses of RE (if bleomycin is contraindicated). The drugs are used every 22nd day without reducing the dose. Delay in the start of the next course is possible only in the presence of fever, the number of blood neutrophils less than 1000 in 1 ml, platelets less than 100,000 in 1 ml on the 1st day of the corresponding course. Granulocyte colony-stimulating factor is not prescribed for prophylactic purposes. However, in the event of infectious complications during chemotherapy, it is recommended to prescribe granulocyte colony-stimulating factor prophylactically during subsequent
• Moderate prognosis group. Standard therapy is considered to be 4 courses according to the VER scheme
• Poor prognosis group. Four courses of chemotherapy are prescribed according to the BEP scheme. The scheme of the 4th course PEI (cisplatin, etoposide, ifosfamide) has the same effectiveness, but significantly higher toxicity. Five-year relapse-free survival is 45-50%. Improvement of results when prescribing drugs in high doses has not yet been proven.

Surgical treatment of testicular cancer

In complete remission of non-seminomatous tumors after chemotherapy, removal of residual tumors is not indicated. In the presence of residual masses greater than 1 cm in transverse size in CT examination and normalization of marker levels, surgical treatment of testicular cancer is indicated. At the end of initial chemotherapy, only 10% of residual masses contain viable tumor cells, 50% - mature teratoma and 40% - necrotic masses. Thus, removal of residual masses after initial chemotherapy is considered mandatory for non-seminomatous tumors.

After completion of two courses of chemotherapy, a repeated assessment of the detected formations and the level of serological markers is necessary. If the marker level is normal and tumor manifestations stabilize or regress, chemotherapy must be completed (3rd or 4th course, depending on the initial stage of the process). If the marker level is normalized, but metastases progress, it is necessary to remove residual formations after the initial chemotherapy is discontinued. "Salvage" chemotherapy is indicated only if there is a proven increase in the marker level after completion of two courses of chemotherapy.

Final chemotherapy (2 courses of platinum-containing drugs) is indicated after surgical treatment of testicular cancer if viable tumor cells or mature teratoma are detected during a planned pathomorphological examination.

“Salvage” chemotherapy is carried out in case of tumor resistance to the first line of therapy or relapse after “salvage” surgery (4 courses according to the PEI/VIP scheme).

Further management

The absence of vascular invasion has a negative predictive value of approximately 80%, allowing stage I patients to be kept under close observation.

Patients who refused chemotherapy at the first stage, after nerve-sparing retroperitoneal lymphadenectomy with subsequent 2 courses of adjuvant chemotherapy according to the BEP regimen, if metastatic lesions of the lymph nodes are detected, dynamic observation is indicated.

Dynamic observation of non-seminomatous testicular tumors stage I after retroperitoneal lymphadenectomy or adjuvant chemotherapy

Procedure	Year
	1	2	3-5	6-10
Clinical examination	6 times	3 times	2 times a year	Once a year
Chest X-ray	6 times	3 times	2 times a year	Once a year
Research of markers	6 times	3 times	2 times a year	Once a year
CT scan of the abdominal cavity	2 times	1 time	According to the readings	According to the readings
Ultrasound of the abdominal cavity*	2 times	2 times	2 times a year	Once a year

* Possibly instead of abdominal CT.

Dynamic observation of non-seminomatous tumors of stage IIA-IIB after retroperitoneal lymphadenectomy or chemotherapy

Procedure	Year
	1	2	3-5	6-10
Clinical examination	1 time in 2 months	4 times	2 times a year	Once a year
Chest X-ray	1 time in 2 months	4 times	2 times a year	Once a year
Research of markers	1 time in 2 months	4 times	2 times a year	Once a year
CT scan of the abdominal cavity	2 times	2 times	According to the readings	According to the readings
Ultrasound of the abdominal cavity*	2 times	2 times	According to the readings	According to the readings

*- Possibly instead of CT scan of the abdominal cavity.

Forecast

Testicular cancer has a variable prognosis, which depends on the histological structure and extent of the tumor. The 5-year survival rate is greater than 95% for patients with seminoma or non-seminoma localized to the testicle, or with non-seminoma and small metastases in the retroperitoneal space. The 5-year survival rate for patients with extensive retroperitoneal metastases, with pulmonary or other visceral metastases ranges from 48% (for some non-seminomas) to more than 80%, depending on the area, volume, and histological structure of the metastases. However, even patients with advanced disease can be cured if they seek treatment.

For prognosis and standardization of treatment approaches, there are several classifications according to the degree of spread of the disease (European Organization for Research and Treatment of Bladder Cancer, etc.).

In 1995, a new classification of the International Germ Cell Tumor Group was proposed, dividing disseminated testicular germ cell tumors into prognostic groups, recognized by most major centers treating disseminated testicular tumors. In the IGCCCG classification, the concentration of tumor markers in the blood serum is used as a prognostic factor for testicular germ cell tumors.

[ 34 ], [ 35 ], [ 36 ]