Disgerminoma

Summarize

1. General remarks

● Overview: Dysgerminoma is a type of malignant germ cell tumor of the ovary, which belongs to germ cell tumors.

● Symptoms: Abdominal distension and pain, which may also be accompanied by menstrual abnormalities.

● Treatment: The main method is the combination of surgery and chemotherapy.

● Prognosis: Dysgerminoma is a type of extracranial (ovarian) malignant germ cell tumor. For children and adolescents, the 5-year survival rate for extracranial germ cell tumors is currently 85%. For patients aged 11 and older with stage IV ovarian malignant germ cell tumors, the long-term disease-free survival rate is approximately 67%.

2. Disease definition

Dysgerminoma is a type of germ cell tumor (Germ Line tumor, GCT) that originates in the ovary. Compared with other malignant ovarian germ cell tumors, bilateral ovarian involvement is more common in dysgerminoma.

3. Epidemiology

Dysgerminoma, a type of ovarian germ cell tumor, accounts for 39% of all malignant ovarian germ cell tumors. It can occur at any age, ranging from 7 months to 70 years, but it is most common in adolescents and young adults. Approximately one-third of malignant ovarian tumors in adolescents and young adults are dysgerminomas.

4. Disease staging

The staging of childhood dysgerminoma is generally based on the staging system for ovarian germ cell tumors developed by the Children's Oncology Group (COG) in the United States:

● Stage I: The tumor is confined to the ovary; no preoperative biopsy was performed; the tumor was completely resected with no ulceration of the capsule, and the margins were negative under microscopic examination; the peritoneum was negative, and no malignant tumor cells were found in the peritoneal lavage fluid; the lymph nodes had a minimum diameter of less than 1 cm on CT or MRI scans, or no cancer was detected in the lymph node tissue samples collected during the biopsy; no lesions outside the ovary were identified by clinical, radiological, or histological examinations.

● Stage II: the tumor is confined to the ovary; the tumor is completely resected without ulceration, and a biopsy is performed before surgery, and the margin is positive under microscopic examination; there are no malignant tumor cells in the peritoneal lavage fluid, and the peritoneal biopsy is negative; no lesions outside the ovary are found by clinical, radiological or histological examination.

● Stage III: gross residual lesions or only biopsy; lymph node involvement, metastatic nodules; visceral involvement (reticulum, intestine, bladder), peritoneal biopsy is positive; malignant tumor cells are detected in ascites or peritoneal lavage.

● Stage IV: distant metastasis, including liver, lung, brain, bone, etc.

Adult anaplastic cell tumors are staged according to the TNM staging system published by the International Federation of Gynecology and Obstetrics (FIGO) in 2017:

● I: The lesion is confined to the ovary.

●IA stage: the lesion is confined to one ovary, the capsule is intact, there is no tumor on the surface, and there is no ascites.

●IB stage: the lesion is confined to both ovaries, the capsule is intact, there is no tumor on the surface, and there is no ascites.

● IC stage: unilateral or bilateral ovarian lesions have penetrated the surface of the ovary, or the capsule has ruptured, or malignant tumor cells have been found in the ascites or peritoneal lavage fluid.

● Stage II: Lesions involving one or both ovaries with pelvic metastasis.

● Stage II A: Lesion extends or metastasizes to the uterus or fallopian tube.

● Stage II B: The lesion extends to other pelvic tissues outside the uterus or fallopian tubes.

● Stage II C: the lesion extends or metastasizes to the uterus, fallopian tubes or other pelvic tissues, the tumor protrudes from the surface of the ovary, or the capsule ruptures, or malignant cells are found in ascites or peritoneal lavage fluid.

● Stage III: Lesions involving one or both ovaries, with extrapelvic implantation or retroperitoneal lymph node metastasis.

● Stage III A: Gross lesion is confined to the pelvis, lymph nodes are negative, but implantation tumor is found on the peritoneal surface of the abdominal cavity under the microscope.

● Stage III B: peritoneal implantation tumor less than 2 cm in diameter, negative lymph nodes.

● III C stage: peritoneal implantation tumor diameter greater than or equal to 2 cm, or with retroperitoneal or inguinal lymph node metastasis.

● Stage IV: distant metastasis of the tumor (excluding peritoneal metastasis).

Epidemiological

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Etiology & Risk Factors

1. General remarks

The cause of dysgerminoma may be related to the abnormal development of primordial germ cells, but the specific hypothesis needs to be further confirmed by relevant studies.

2. Basic etiology

Germ cell tumors are a type of tumor that originates from primitive germ cells. During human development, starting in the embryonic stage, these primitive germ cells gradually migrate along the body's midline to the reproductive glands. After puberty, they mature into mature germ cells, either sperm or eggs. The prevailing hypothesis suggests that some primitive germ cells undergo mutations during embryonic development and reach the ovaries. However, instead of continuing to differentiate, these cells retain their primitive characteristics and proliferate uncontrollably, leading to the formation of dysgerminomas. However, this hypothesis still requires experimental evidence to support it.

3. Triggering factors

Certain genetic disorders may be associated with an increased risk of dysgerminoma. For example, Turner syndrome (also known as congenital ovarian hypoplasia) is associated with an increased risk of dysgerminoma; some patients with malignant ovarian germ cell tumors have an increase in the number of copies of chromosome 12 short arm.

Classification & Staging

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Clinical Manifestations

1. General remarks

Germ cell tumors mainly occur in the ovaries, of which 10-15% involve both ovaries. Common symptoms include abdominal pain, abdominal mass, fever, constipation, precocious puberty, amenorrhea, or irregular vaginal bleeding.

2. Typical symptoms

As a type of ovarian germ cell tumor, dysgerminoma has the following common symptoms:

● Abdominal distension, which may be due to the mass itself, may be due to ascites, or both.

● Abdominal pain due to tumor rupture or torsion. 85% of patients with ovarian germ cell tumors have abdominal pain and abdominal mass at the same time, and the proportion of tumor rupture before or during surgery is about 20%, and the proportion of tumor torsion is about 5%.

● Because of the secretion of human chorionic gonadotropin (hCG) by dysgerminoma, patients may experience precocious puberty, irregular vaginal bleeding, menstrual abnormalities, and even pregnancy-like symptoms. In patients with ovarian germ cell tumors, 10% of patients have fever or vaginal bleeding.

Clinical Department

1. General remarks

When the above symptoms appear, please go to the hospital as soon as possible. After the visit, different tests may be carried out and necessary diagnosis will be made according to the results of the tests.

2. Department of treatment

According to different initial symptoms, the departments for diagnosis may be internal medicine, gynecology, endocrinology, etc. After examination, according to the preliminary diagnosis results, they will be referred to pediatric oncology internal medicine, pediatric oncology surgery, oncology, oncology surgery and other oncology related specialties.

3. Diagnostic process / diagnostic basis

The definitive diagnosis of asomatocytoma is based on histopathological examination, which requires the acquisition of tumor tissue specimens during biopsy or surgical resection. Other laboratory tests and systemic examinations can be used for staging, guiding treatment, and postoperative condition monitoring.

4. Related inspection

1) Medical history inquiry

Understand the patient's previous lifestyle and ask about his medical history and treatments he has received.

2) Physical examination

Observe the state of the body, paying special attention to all signs including diseases, such as the size and location of masses palpated in the abdomen and pelvis.

3) Imaging examination

Imaging techniques commonly used in asynthetic cell tumor examination include CT and magnetic resonance imaging (MRI). Both can be used to scan the tumor area to assist in diagnosis. Ultrasound can also be used to scan primary tumors and lymph nodes to assist in diagnosis.

If metastatic lesions in the chest are suspected, a chest CT should be performed. If brain metastasis is suspected, a brain MRI should be performed. If bone metastasis is suspected, a bone scan should be performed. Imaging studies are essential for determining the location and size of the tumor and whether there is metastasis to adjacent or distant organs.

Cytological examination of ascites by paracentesis is of great value in detecting the presence of peritoneal metastasis.

4) Tumor marker examination

For some specific malignancies, the levels of certain substances called tumor markers rise when the tumor occurs. By detecting tumor markers in the serum, it can help diagnose specific malignancies.

For patients with dysgerminoma, the most common elevated tumor marker is lactate dehydrogenase (LDH). Additionally, 3%-5% of dysgerminoma patients may experience an increase in β-human chorionic gonadotropin (β-hCG) levels. In cases of pure dysgerminoma, alpha-fetoprotein (AFP) levels are typically normal. However, if the dysgerminoma is mixed with yolk sac tumors, a mixed germ cell tumor, AFP levels may slightly increase, reaching a critical level (<16ng/mL).

5) Blood biochemical examination

Blood biochemical tests can help diagnose the function of organs and related diseases by detecting specific chemicals released into the blood from tissues. Abnormal biochemical changes (above or below normal values) may be a sign of an underlying disease.

6) Histopathological examination

Asymptomatic cell tumors can be examined by histopathology through biopsy or surgical sampling. Histopathology results are the final diagnostic basis for diagnosis.

Examination & Diagnosis

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Clinical Management

1. General remarks

Sarcomas are typically treated with a combination of surgery and chemotherapy. For tumors that can be completely removed from one ovary, a unilateral salpingo-oophorectomy is usually performed. The decision on whether to proceed with chemotherapy and the formulation of a corresponding chemotherapy regimen depend on the disease stage, the extent of tumor resection, and the specific pathological diagnosis. For tumors that are difficult to remove completely or for bilateral tumors, neoadjuvant chemotherapy is usually administered before surgery to shrink the tumor, followed by surgery and adjuvant chemotherapy post-surgery.

2. Surgical treatment

1) Surgical plan

Once a diagnosis of dysgerminoma is confirmed, early surgical removal should be performed to prevent complications such as torsion, rupture, or metastasis. Given the rich lymphatic vascular connections between the fallopian tubes and ovaries, patients often require the removal of the ipsilateral fallopian tube. For patients with clinically evident early-stage disease, the unilateral adnexa can be removed while preserving a normally appearing uterus.

Although there is a risk of occult involvement of the contralateral ovary in 5-10% of patients with dysgerminoma, for patients with unilateral tumors, unnecessary surgery or even biopsy of the contralateral normal ovary should be avoided to prevent postoperative adhesion and damage to fertility.

2) Postoperative complications

Because at least one ovary is removed, the menstrual cycle may be affected in patients with dysgerminoma. However, at least 80 percent of patients diagnosed early can have their normal menstrual cycle restored after treatment.

For patients diagnosed before puberty, their sex hormone secretion, secondary sexual development and gonadal development may be affected. After entering puberty, attention should be paid to monitoring sex hormone levels and physical development.

At the same time, fertility can be affected in patients who have had both adnexa removed. Pregnancy can be assisted by freezing their own eggs/ovarian tissue/oocytes or using donated oocytes.

3. Chemotherapy

1) Chemotherapy regimen

In pediatric patients, all patients at all stages typically receive adjuvant chemotherapy after surgery. If the tumor is unlikely to be completely removed, neoadjuvant chemotherapy may also be administered before surgery to shrink the tumor and facilitate its complete removal. However, recent studies have shown that for children meeting the International Federation of Gynecology and Obstetrics (FIGO) IA stage criteria, postoperative monitoring without concurrent chemotherapy may be sufficient.

In adults, for stage IA and IB tumors, a good prognosis can be achieved with surgery alone and postoperative surveillance. For tumors of other stages, systematic adjuvant chemotherapy is required after surgery. If complete resection is unlikely, neoadjuvant chemotherapy is also required before surgery to shrink the tumor.

The adult BEP regimen (Bortezomib + Etoposide + Cisplatin) or the pediatric PEB regimen (Cisplatin + Etoposide + Bortezomib) are the preferred chemotherapy regimens for non-seminomatous tumors. The main difference between these regimens is the dosage and duration of Bortezomib. For patients who cannot tolerate Bortezomib, other chemotherapy regimens can be used as alternatives, typically including Cisplatin and Etoposide. Given the nephrotoxicity and neurotoxicity of Cisplatin, especially its potential to cause irreversible ototoxicity in children, carboplatin can be considered as an alternative for patients who cannot use Cisplatin.

2) Adverse reactions

Common adverse reactions include bone marrow suppression (manifested as leukopenia and neutropenia, thrombocytopenia, anemia, etc.), nephrotoxicity (cisplatin), nausea and vomiting, allergic reaction, hair loss, hearing damage caused by ototoxicity (cisplatin), acute and delayed pulmonary toxicity (bremodin), fatigue, electrolyte disturbance, neurotoxicity, etc.

4. Radiotherapy

Germ cell tumors are sensitive to radiotherapy, but radiotherapy at the primary site of the tumor can damage fertility, so it is rarely used and only considered when the patient cannot be treated with chemotherapy.

5. Other treatments

At present, the combination of high-dose chemotherapy and autologous peripheral blood hematopoietic stem cell transplantation, as well as targeted therapy, are in clinical trial stage.

Prognosis

1. General remarks

Dysgerminoma is a type of malignant ovarian germ cell tumor, and the prognosis for this type of tumor is generally favorable. Factors that influence the prognosis include: the patient's age and overall health, the stage of cancer (whether it has spread to nearby areas, lymph nodes, or other parts of the body), the tumor's response to treatment, whether the tumor can be completely removed through surgery, the pathological type, whether the tumor has recurred, and whether the patient has gonadal dysgenesis. According to European research, the 5-year overall survival rate for malignant ovarian germ cell tumors (including both pediatric and adult patients) is over 95%, and the 5-year event-free survival rate can reach over 90%. The prognosis for different stages is as follows:

● The 5-year overall survival rate of patients in phase I C was 100%.

● The 5-year overall survival rate of stage ● II patients was 85%.

● The 5-year overall survival rate of patients in stage ● III was 79%.

● The 5-year overall survival rate of stage ● IV patients was 71%.

A study by the Children's Oncology Group (COG) showed that the prognosis for children and adolescents with malignant ovarian germ cell tumors at different stages was as follows:

● The 6-year overall survival rate of stage I patients was 95%, and the 6-year event-free survival rate was 95%.

● The 6-year overall survival rate of stage ● II patients was 94%, and the 6-year event-free survival rate was 88%.

● The 6-year overall survival rate of stage ● III patients was 97%, and the 6-year event-free survival rate was 97%.

● The 6-year overall survival rate of stage ● IV patients was 93%, and the 6-year event-free survival rate was 87%.

2. Aftereffects

1) Insufficient sex hormone secretion

Since patients with dysgerminoma may require oophorectomy, for children who develop the disease before puberty, attention should be paid to monitoring sex hormone levels and body development when they reach puberty. If necessary, exogenous sex hormones can be supplemented to maintain the development of secondary sexual characteristics.

2) Early menopause

Platinum-based chemotherapy drugs may increase the risk of ovarian dysfunction or premature ovarian failure, although most patients with dysgerminoma can recover normal ovarian function and fertility after treatment. However, studies have shown that chemotherapy during childhood, adolescence, or young adulthood may be associated with early menopause.

3) Hearing loss

Platinum-based chemotherapy drugs are ototoxic to children and may cause irreversible hearing damage.

4) Secondary tumors

Chemoradiotherapy increases the risk of secondary tumors, especially etoposide, a common chemotherapy drug for dysgerminoma, which increases the risk of secondary leukemia.

3. Recurrence/metastasis

Germ cell tumors are more likely to involve lymph nodes, with lymph node metastasis occurring in approximately 28% of cases (including children and adults).

The recurrence rate of asynthetic cell tumors is not high, but there is a risk of long-term (five years after treatment or more) recurrence.

Follow-up & Review

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Daily Care

1. General remarks

After the completion of treatment for asomatocytoma, it is important to carry out regular review and follow-up, on the one hand to monitor the side effects caused by the treatment, on the other hand to regularly review and monitor whether the disease is recurrent.

2. Review

Patients with non-seminomatous cell tumors should adhere to regular follow-up examinations after surgery. For the first 1-2 years after treatment, a follow-up examination is required every 3 months. In the third year after treatment, a follow-up examination is required every six months. From the fourth to the fifth year after treatment, a follow-up examination is required every six months to one year. After 5 years of treatment, an annual follow-up examination is recommended. Each follow-up examination should include a comprehensive physical examination and imaging tests (usually B-ultrasound; if B-ultrasound is not available, CT can be used as an alternative).

Because of the risk of long-term recurrence of dysgerminoma, it is recommended that follow-up continue for at least 10 years.

3. Daily life management

1) Diet

It is important to provide patients with a nutritious and balanced diet, ensuring the intake of high-quality proteins such as meat, eggs, dairy, poultry, fish, shrimp, soybeans, and soy products. Additionally, patients should consume more whole grains, vegetables, and fruits, and moderately eat dairy products and nuts to ensure the intake of other essential nutrients. Patients can consult clinical nutritionists in the hospital's nutrition department for a suitable nutritional plan. If there is a significant weight loss, consider using tube feeding or parenteral nutrition for nutritional support.

2) Movement

It is important to ensure that patients get enough sleep. Regular and quality sleep is very helpful for physical recovery and immunity. A suitable sleep environment (usually dark, quiet and at a comfortable temperature) may help improve the quality of sleep.

If the patient's physical condition allows, encourage and assist the patient to do some simple activities. Moderate exercise is helpful in preventing muscle atrophy, enhancing physical strength and endurance, and promoting appetite.

3) Lifestyle

If the patient is caused by treatment of neutropenia, attention should be paid to prevent infection. Pay attention to personal and living environment hygiene, do not approach patients with infectious diseases, and do not go to crowded places.

If the treatment causes a decrease in platelets, be careful to avoid bleeding. Stay away from sharp, spiky toys and objects, and avoid strenuous activities such as jumping, soccer, or basketball.

4) Emotional psychology

Germ cell tumors and their treatment can affect a woman's sex hormone secretion and fertility, potentially causing anxiety among patients, especially younger ones. Patients and their families should communicate thoroughly with their primary doctors about these issues early on to understand the potential effects and consider preventive measures. This approach can help minimize side effects and reduce anxiety for both the patient and their family members.

4. Daily disease monitoring

Patients should pay attention to the monitoring of normal ovaries in daily life, and seek medical treatment in time if there is pain. If ovarian torsion occurs, timely treatment can save ovarian function. After entering puberty, patients should monitor estrogen levels to ensure normal growth and development.

5. Special Precautions

Patients with dysgerminoma who have undergone radiotherapy and chemotherapy are at risk of long-term side effects and secondary cancers, which may occur many years after treatment. The risk is related to the treatment regimen and drug dosage used. Therefore, patients should keep all their medical records for future follow-up and reference.

6. Prevention

Because the exact cause of dysgerminoma is not clear, there is no definite way to prevent dysgerminoma. However, regular follow-up and maintaining good healthy lifestyle habits can help prevent and detect early recurrence or long-term adverse reactions.

Cutting-edge therapeutic and clinical Trials

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References

1.PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Extracranial Germ Cell Tumors Treatment. Bethesda, MD: National Cancer Institute. Updated <02/10/2020>. Available at: https://www.cancer.gov/types/extracranial-germ-cell/patient/germ-cell-treatment-pdq. Accessed <07/06/2020>. [PMID: 26389180]

2.Gershenson, DM. Ovarian germ cell tumors: Pathology, epidemiology, clinical manifestations, and diagnosis. In: UpToDate, Goff, B, Pappo, AS, Garcia, RL, Falk, SJ (Ed), UpToDate, Waltham, MA, 2020.

3.Prat J; FIGO Committee on Gynecologic Oncology. Staging classification for cancer of the ovary, fallopian tube, and peritoneum. Int J Gynaecol Obstet. 2014;124(1):1-5. doi:10.1016/j.ijgo.2013.10.001

4.PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Extracranial Germ Cell Tumors Treatment. Bethesda, MD: National Cancer Institute. Updated <05/28/2020>. Available at: https://www.cancer.gov/types/extracranial-germ-cell/hp/germ-cell-treatment-pdq. Accessed <07/06/2020>. [PMID: 26389316]

5.Agarwala S, Mitra A, Bansal D, et al. Management of Pediatric Malignant Germ Cell Tumors: ICMR Consensus Document. Indian Journal of Pediatrics, 2017, 84(6):465-472

6.Gershenson, DM. Treatment of malignant germ cell tumors of the ovary. In: UpToDate, Goff, B, Pappo, AS, Dizon, DS, Vora, SR, Falk, SJ (Ed), UpToDate, Waltham, MA, 2020.

7.PDQ® Fertility Issues in Girls and Women with Cancer. National Cancer Institute. Updated <02/24/2020>. Available at: https://www.cancer.gov/about-cancer/treatment/side-effects/fertility-women. Accessed <07/06/2020>.

8.PDQ® Pediatric Treatment Editorial Board. PDQ Late Effects of Treatment for Childhood Cancer. Bethesda, MD: National Cancer Institute. Updated <03/10/2020>. Available at: https://www.cancer.gov/types/childhood-cancers/late-effects-pdq. Accessed <07/06/2020>. [PMID: 26389365]

9.Murugaesu N, Schmid P, Dancey G, et al. Malignant ovarian germ cell tumors: identification of novel prognostic markers and long-term outcome after multimodality treatment. J Clin Oncol. 2006;24(30):4862-4866. doi:10.1200/JCO.2006.06.2489