Yolk Sac Tumors

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Continuing Education Activity

Yolk sac tumors (also known as endodermal sinus tumors) are malignant primitive germ cell tumors; they are histologically similar to the mesenchyma of the primitive yolk sac. Yolk sac tumors can be found in a pure form or mixed with other germ cell tumors. They are common in the pediatrics age group and can be found anywhere in the body. To avoid the high morbidity and mortality associated with this condition, it must be promptly diagnosed and treated. This activity reviews the evaluation and treatment of the yolk sac tumors and highlights the role of the interprofessional team in evaluating and treating patients with this condition.


  • Describe the epidemiology of yolk sac tumors.
  • Review the pathophysiology of yolk sac tumors.
  • Summarize the evaluation and treatment of yolk sac tumors.
  • Explain the evaluation and treatment of the yolk sac tumors and highlight the role of the interprofessional team in evaluating and treating patients with this condition.


Yolk sac tumors (also known as primitive endodermal tumors or endodermal sinus tumors) are malignant primitive germ cell tumors. They are histologically similar to the mesenchyme of the primitive yolk sac.[1][2]

Yolk sac tumor is a type of germ cell tumor. Germ cell tumors commonly arise in the gonads but sometimes can occur outside the gonads and are called extragonadal germ cell tumors.[3] The most common testicular tumor in young children under the age of 3 is yolk sac tumor, and it is also known as infantile embryonal carcinoma. Yolk sac tumors have a good prognosis in this age group.[4]

Compared to pure type in infants and young children, yolk sac tumors in adults are often found in combination with other types of germ cell tumors (e.g., teratoma and embryonal carcinoma).[5][6]


The cause of yolk sac tumors is essentially unknown. Some studies suggest that RUNX3 gene hypermethylation and GATA-4 overexpression may be involved in the pathogenesis of yolk sac tumors.[7][8]


Yolk sac tumors are rare tumors that can occur in both genders and may be found in the ovary, testes, and other body parts. Yolk sac tumors are commonly observed in young children.

Yolk Sac Tumors in Males

Yolk sac tumors of the testis have a bimodal age distribution, young children under the age of 3, and post-pubertal adults.[9]

In children, the yolk sac tumor is the most common testicular neoplasm. It makes up about 30% of the germ cell tumors in this age group, with a median age of diagnosis at 18 months. Usually, children have pure yolk sac tumors, and their prognosis is good. In adults, yolk sac tumors typically present mixed germ cell tumors and present in the second to third decades of life.[4][10]

Yolk Sac Tumors in Females

Yolk sac tumors are uncommon neoplasms in the ovary, and they account for 15% of all ovarian germ cell tumors; they present in early life and rarely after the age of 40. The median age of diagnosis is 19 years, and 40% of patients are diagnosed in the prepubertal period. About 60% of ovarian yolk sac tumors present in a pure form, while 40% present with mixed germ cell tumors.[11]


On gross examination, yolk sac tumors are soft, solid masses, and tan to yellow or grey with a mucoid appearance, notable necrosis, cystic changes, and hemorrhages are common to be present.[12]

On microscopic examination, the tumors consist of primitive tumor cells and have many histological types, including microcystic/reticular, papillary, solid, festoon, polyvesicular-vitelline, glandular, intestinal, endometroid, parietal, tubular and, hepatoid. The reticular microcystic pattern is the most common type formed by vacuolated cytoplasm of tumor cells; it appears like a honeycomb under a microscope.[13]

Schiller–Duval body is pathognomonic for yolk sac tumors, and it appears like a glomerulus in structure with a fibrovascular core. However, Schiller-Duvall bodies are usually present only in two to three-quarters of yolk sac tumors and are only seen in papillary type.[14]

History and Physical

Patients with yolk sac tumors have signs and symptoms depending on the location of cancer.

Testicular tumors have no specific symptoms except testicular mass.

Children with testicular yolk sac tumors are generally present with testicular masses; the mass is painless and solid. Metastasis is not common in the presentation of the disease. It occurs in less than one-tenth of cases. While in adults, testicular yolk sac tumors are mixed with other germ cell components such as embryonal carcinoma, choriocarcinoma, teratoma, and seminoma.[15]

Most patients with ovarian yolk sac tumors have symptoms of abdominal distention and sudden onset of pain at presentation. A pelvic mass may be palpable on examination of the patient. This tumor is described by very rapid growth; the duration of the symptoms in most of the patients is seven days or less.[16]

Other symptoms of ovarian cancer can include:

  • Fatigue
  • Upset stomach (dyspepsia)
  • Back pain
  • Pain during sex (dyspareunia)
  • Constipation
  • Changes in the period, such as more massive bleeding (menorrhagia) or irregular bleeding (metrorrhagia)
  • Abdominal swelling with weight loss

Metastasis develops quickly in ovarian yolk sac tumors and invades the structures around the ovaries. Metastasis can also spread through the lymph nodes.[17]


Diagnosis of yolk sac tumors depends on history, physical examination, imaging studies, and blood chemistry.

Yolk sac tumors were shown as an enhancing large solid cystic mass with intertumoral hemorrhage on CT and MR studies.[18]

Immunohistochemical staining can support the diagnosis of yolk sac tumors because almost all cases stain positive for alpha-fetoprotein (AFP).[19]

Alpha-fetoprotein (AFP) is specific in the yolk sac tumor, but it is not sensitive (overall sensitivity as low as 60%) because it can be seen in other cancers like hepatocellular carcinoma.[19]

In mixed germ cell tumors with small foci of the yolk sac tumors, the biopsy findings may be negative for yolk sac tumors, because yolk sac tumors are usually limited in small malignant foci within a larger tumor, staining positive for AFP will confirm the presence of yolk sac tumors within other germ cell tumors, (e.g., in teratoma the biopsy of cancer may reveal teratoma alone, whereas elevated AFP reveals that yolk sac tumor is also present.)[8]

Alpha-fetoprotein can be measured in tumor tissue, serum, cerebrospinal fluid, urine, as well as amniotic fluid.[20][21]

When yolk sac tumor arises in a small focus only, it may be hard to detect AFP in immunohistochemical staining because staining for alpha-fetoprotein is unequable and often varying throughout the tissue; strong staining is not seen in every tumor, in this situation, yolk sac tumors may be marked with cytokeratin or glypican-3, cytokeratin is present in almost all cases, another immunostaining which is frequently positive in yolk sac tumors is placental alkaline phosphatase.[22][23]

Treatment / Management

Without any treatment, yolk sac tumors can be very dangerous and finally lead to death. The present-day treatment for yolk sac tumors is surgery and chemotherapy. Treatment with cisplatin, etoposide, and bleomycin has shown a good response in most of the patients.[24][25]

The treatment regimen of testicular yolk sac tumors depends on the stage of cancer and age of the patient at the presentation; most children with yolk sac tumors present with stage 1 disease. Orchiectomy and chemotherapy +/- dissection of retroperitoneal lymph nodes with the careful post-orchiectomy measuring of serum AFP values is indicated in most cases. Most pediatric patients with metastasis or recurrence can be treated with a chemotherapy regimen successfully.[26]

Ovarian yolk sac tumors, specifically in post-menopausal patients, need more intensive treatment, and surgical resection of cancer with chemotherapy is indicated in the early stages of the disease. [27]

Testicular Yolk Sac Tumors Treatment by Stage:

Stage 1

Stage 1 disease can be cured in almost all the cases, and radical inguinal orchiectomy is performed in all patients.

Choices for Stage 1A

  • Careful observation (surveillance): this management includes visits every two months during the first year, with computed tomography scans (CT scan) every four to six months, then in the second year, the appointments will be every three months, with computed tomography scans (CT scan) every six to twelve months. If cancer relapses, chemotherapy is indicated to treat the patient.
  • Nerve-sparing retroperitoneal lymph node dissection (RPLND)
  • Chemotherapy: giving the BEP regimen (bleomycin, etoposide, and cisplatin) for one cycle. Chemotherapy decreases the rate of relapse.

Stage 1S

  • Chemotherapy with three cycles of BEP or four cycles of EP (etoposide and cisplatin) is indicated if the alpha-fetoprotein is still elevated after the surgery with no evidence of mass on CT scan.

Stage 2

Surgery must be done first for all the cases.

Stage 2A

Tumor marker values after performing the surgery and the involvement of the retroperitoneal lymph nodes will decide the next step of management in those patients.

Normal tumor marker levels:

  • Retroperitoneal lymph node dissection (RPLND): If the lymph nodes contain cancer, then give two cycles of chemotherapy (BEP or EP). If no lymph nodes are involved, then watch and monitor closely for signs of relapse.
  • Chemotherapy: 4 cycles of EP (etoposide and cisplatin) or three cycles of BEP (bleomycin, etoposide, and cisplatin).

High tumor markers after the surgery should be treated using chemotherapy (EP or BEP). The number of cycles is determined after the risk stratification (good, intermediate, or poor).

Stage 2B

Normal tumor marker levels:

  • Chemotherapy: Four cycles of EP or three cycles of BEP should be given to treat the patients.
  • Retroperitoneal lymph node dissection (RPLND)

High tumor markers after the surgery should be treated using chemotherapy (EP or BEP). The number of cycles is determined on the risk stratification (good, intermediate, or poor).

Stage 3

Patients with stage 3 disease should be treated with radical inguinal orchiectomy, followed by 3 to 4 cycles of the following chemotherapy regimens:

  • EP 4 cycles
  • BEP 3 or 4 cycles
  • VIP (etoposide, ifosfamide, and cisplatin) 4 cycles

High-dose chemotherapy and bone marrow transplant might be indicated in cancer resistance to usual dose chemotherapy.

Ovarian Yolk Sac Tumors Treatment

Usually, treating ovarian cancer is the same for all stages and types, surgery should be performed, and a chemotherapy regimen must be given after the surgery.

Surgery: deciding between radical surgery or conservative surgery depends on the patients' wish to have more children and the involvement of one side or both sides of the ovaries.

Debulking surgery is indicated in patients with cancer metastasis to other orangs.

Chemotherapy: most patients will need at least three cycles of chemotherapy. BEP regimen is the best choice.

Reduction in tumor marker levels after chemotherapy is an indication of an excellent response to chemotherapy.

Differential Diagnosis

There are several other tumors that could present in a similar fashion and need to be distinguished. Following are some important differentials with their distinguishing features:

  • Clear Cell Carcinoma: stains positive for cytokeratin, cytokeratin 7, and epithelial membrane antigen while stains negative for glypican-3 and alpha-fetoprotein. Yolk sac tumors stain negative for both cytokeratin 7 and epithelial membrane antigen.[28][29]
  • Sertoli-Leydig Cell Tumor: positive for inhibin, calretinin, and steroidogenic factor 1 (SF1), negative for AFP, and glypican 3.[30]
  • Juvenile Granulosa Cell Tumor: it has morphological similarities with the yolk sac tumor, but the juvenile granulosa cell tumor is positive for inhibin and negative for SALL4, AFP, and glypican 3.[31]
  • Metastatic Hepatocellular Carcinoma: consider in conjunction with clinical history, negative for (Sal-like protein 4) SALL4, while strongly positive in yolk sac tumors.[32]
  • Dysgerminoma/Seminoma: stains positive for placental alkaline phosphatase (PLAP), CD117, and octamer-binding transcription factor 4 (Oct-4).[33]
  • Embryonal Carcinoma: stains positive for placental alkaline phosphatase (PLAP), cytokeratin, CD30, and octamer-binding transcription factor 4 (Oct-4).[34]
  • Granulocytic Sarcoma: stains positive for CD117, leukocyte common antigen (LCA), and myeloperoxidase (MPO).[35]
  • Melanoma: stains positive for S-100.[36]
  • Lymphoma: stains positive for leukocyte common antigen (LCA).[37]
  • While yolk sac tumors stain negative for CD117, CD30, S-100, leukocyte common antigen (LCA), myeloperoxidase (MPO), and octamer-binding transcription factor 4 (Oct-4).


After the diagnosis of the yolk sac tumor has been established, many tests and evaluations should be done to decide if cancer has spread to the lymph nodes or any parts in the body.

Testicular Tumors

Stage 0 is the earliest stage of testicular cancer (it is also known as neoplasia in situ). Stage 4 is not applicable to testicular cancer.

The TNM system is the most popular system for staging testicular cancer, and the system is based on four elements:

  1. Tumor (T): size and location of the tumor.
  2. Node (N): lymph node involvement.
  3. Metastasis (M): number and site of spread of the tumor.
  4. Serum tumor marker (S): Are the serum tumor markers AFP, beta-hCG, and LDH elevated? If so, how high are they?

Stage 1: there is no evidence of metastasis or lymph node involvement, divided into 1A and 1B depending on the tumor size, and 1S when tumor markers are elevated.

Stage 2: the cancer cells have spread to the lymph nodes, but there is no metastasis to other body parts. It is divided into 2A, 2B, and 2C depending on the number and size of lymph nodes involved.

Stage 3: cancer has metastasized to other organs, and this stage is divided into 3A, 3B, and 3C depending on metastasis location and level of tumor markers.

Ovarian Cancer

The FIGO (International Federation of Gynecology and Obstetrics) system and the AJCC (American Joint Committee on Cancer) TNM staging system are the same, and they are the most used systems for staging ovarian cancers.

Both of the systems contain three elements:

  1. Tumor (T): size and location of the tumor.
  2. Node (N): lymph node involvement.
  3. Metastasis (M): number and site of spread of the tumor.

Stage 1: the cancer is only in the ovary (IA) or both ovaries (IB).

Stage 2: cancer has spread to the pelvis (below pelvic brim) without lymph node involvement, and this stage is divided into 2A (spread to the uterus or the fallopian tubes) and 2B (other pelvic tissues).

Stage 3: cancer has spread to the lymph nodes and/or peritoneum outside the pelvis, and this stage is divided into 3A, 3B, and 3C depending on metastasis location and size.

Stage 4: cancer has spread to other tissues (distant metastasis excluding peritoneal metastasis), and this stage is divided into stage 4A (pleural effusion) and 4B (extra-abdominal metastasis).

Staging systems are essential to decide the next step in the management of any patient because each stage has a unique treatment plan.


Age at the time of diagnosis is not a prognostic factor, but the degree of AFP elevation has a negative prognostic value for the yolk sac tumors. Like all malignancies, staging is vital to prognosis. Early-stage tumors fare better than late-stage malignancies.


The complications of the yolk sac tumors can be related to the tumor itself or the treatment.

Tumor mass effect complications depend on the location and the size of the mass; another tumor complication is metastasis; even if cancer has spread to other parts of the body, many patients might not have symptoms until very late stages.

Treatment complications include chemotherapy side effects, operative complications, and postoperative complications.

Enhancing Healthcare Team Outcomes

Yolk sac tumors can be cured if treated in the early stages. Patients need to be able to do self-examination and need to be educated about the successful management of the early disease.



2/4/2023 3:08:43 PM



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