Mastering Testicular Cancer: A Review of Embryonal Cell Carcinoma and Germ Cell Tumors

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Testicular cancer, though relatively rare, is the most common malignancy in young men aged 15 to 35. Understanding the subtle nuances in the diagnosis, staging, and management of its various histological subtypes is crucial for optimizing patient outcomes. Among these subtypes, Embryonal Cell Carcinoma (ECC) of the testis stands out due to its aggressive clinical behavior and distinct imaging characteristics. This comprehensive review, intended for urologists, oncologists, and medical trainees, will delve into the classification of primary testicular neoplasms, the specific pathology and clinical profile of ECC, and the latest evidence-based management strategies.

Histological Classification of Primary Testicular Neoplasms

The vast majority of primary testicular malignancies originate from germ cells. The World Health Organization (WHO) classification stratifies these tumors primarily based on their cellular origin:

1. Germ Cell Tumors (GCTs) (95% of Cases)

GCTs arise from primitive germ cells and show a higher incidence in Caucasian populations. Cryptorchidism (undescended testis) is a well-established predisposing factor.

GCTs are broadly categorized into two main groups, which dictate prognosis and treatment: Seminoma and Non-Seminomatous Germ Cell Tumors (NSGCTs).

  • Seminoma: This represents the most common single histological type. The diagnosis of a pure seminoma is reserved for cases where biopsy confirms a "pure seminoma" and serum alpha-fetoprotein (AFP) levels are normal.

  • Non-Seminomatous Germ Cell Tumors (NSGCTs): These tumors are considered clinically more aggressive than pure seminomas. ECC falls into this category. NSGCTs include:

    • Embryonal Carcinoma (EC) (or Embryonal cell carcinoma)

    • Teratoma

    • Choriocarcinoma

    • Yolk Sac Tumor (Endodermal Sinus Tumor)

  • Mixed Germ Cell Tumors: These contain elements of two or more pure GCT types. If a mixed tumor contains any NSGCT component, the clinical management will follow the more aggressive Non-Seminoma pathway.

    2.Other Testicular Tumors (5% of Cases)

  • Sex Cord-Stromal Tumors: Originating from the supporting tissue of the testis, these include Sertoli cell, Leydig cell, and Granulosa cell tumors.

  • Tumors of both Germ Cell and Gonadal Stromal Elements: Example includes Gonadoblastoma.

  • Adnexal and Paratesticular Tumors.

Focus on Embryonal Cell Carcinoma (ECC) of the Testis

Embryonal cell carcinoma is a highly malignant form of NSGCT, often presenting as a component of mixed GCTs. Its identification is critical due to its propensity for early vascular invasion and metastasis.

Pathophysiology and Histopathology

ECC is thought to arise from intratubular germ cell neoplasia unclassified type (ITGCNU). Microscopically, it is characterized by sheets, glands, or papillary configurations of large, primitive, pleomorphic cells with prominent nucleoli and abundant cytoplasm. Unlike seminoma, ECC is frequently characterized by necrosis and hemorrhage. Immunohistochemically, ECC cells are typically positive for OCT3/4, CD30, and cytokeratin, and they are typically AFP-negative in their pure form, although serum AFP is often elevated in clinical cases due to the common presence of a yolk sac component in mixed tumors.

Epidemiology

ECC typically affects men in their late 20s and early 30s. It is rarely found in its pure form (approximately 3% of GCTs), but it is a very common component (up to 40%) of mixed GCTs. As with all GCTs, risk is strongly associated with cryptorchidism, prior testicular cancer, and family history.

Clinical Presentation

The most common presentation is a painless scrotal swelling or mass. Patients may also report a feeling of heaviness. Because ECC is aggressive, some patients may present with symptoms related to metastatic disease (e.g., back pain from retroperitoneal lymphadenopathy, cough/dyspnea from pulmonary metastases).

Tumor Markers (Biochemistry)

Diagnosis and staging rely heavily on serum tumor markers:

  • Alpha-Fetoprotein (AFP): Typically elevated in the presence of Yolk Sac Tumor components, and may be mildly elevated with teratoma or ECC. A pure seminoma is defined by normal AFP.

  • Human Chorionic Gonadotropin (hCG): Elevated in Choriocarcinoma and occasionally in seminoma or ECC.

  • Lactate Dehydrogenase (LDH): Non-specific, but high levels often correlate with high tumor burden and poor prognosis.

Imaging Features: Sonography for Testicular Mass

Ultrasonography is the primary imaging modality for the evaluation of a scrotal mass, providing excellent detail on the location, size, and nature (solid vs. cystic) of the lesion.


Figure 1: Ultrasound-Doppler; Gray-scale longitudinal and Doppler flow transverse ultrasound images of the testis demonstrate an ill-defined, hypoechoic, solid intratesticular mass (intratesticular mass). The Doppler image shows a relative lack of internal vascularity within the mass (circled area, indicated by arrows) compared to the surrounding tissue, which can be a variable finding in malignant masses.
Interpretation: The image confirms a solid, hypoechoic, intratesticular mass, a classic finding that necessitates surgical exploration to rule out malignancy. Scattered microcalcifications throughout the entire testis may also be present.

Figure 2: Testicular Transverse Ultrasound in a Child; Transverse ultrasound of the testis in a 15-year-old child who presented with a painless scrotal swelling for 2 months. The image shows a complex, heterogeneous mass (Mass) which is compressing the adjacent testicular tissue (indicated by blue arrows).
Interpretation: This large, heterogeneous mass is highly suspicious for a malignant mixed germ cell tumor. Histopathology confirmed this mass contained elements of immature teratoma, yolk sac tumor, and embryonal carcinoma. This illustrates the complexity and mixed nature of many testicular cancers, especially NSGCTs.

General Imaging Characteristics of ECC

  • Gray-Scale Ultrasound: ECC masses are typically non-homogeneous, generally hypoechoic compared to the surrounding parenchyma, and often have irregular margins. Necrosis, calcification, and hemorrhage may cause a heterogeneous appearance.

  • Doppler Ultrasound: Malignant tumors like ECC are generally hypervascular; however, the lack of flow in areas of necrosis (as possibly seen in Figure 1) is a critical differential feature.

Differential Diagnosis (DDx)

The initial DDx for a solid intratesticular mass includes:

  1. Seminoma: Often more homogeneous and purely hypoechoic than ECC.

  2. Testicular Lymphoma: More common in older men, typically diffuse and bilateral.

  3. Leydig Cell Tumor/Sertoli Cell Tumor: Typically smaller, well-circumscribed, and less aggressive.

  4. Testicular Abscess/Infarct: Can mimic a mass but usually presents with significant pain and systemic symptoms.

  5. Epidermoid Cyst: A benign, avascular lesion with a characteristic "onion peel" or target appearance.

Diagnosis and Staging

The definitive diagnosis of ECC is made through histological evaluation following radical inguinal orchiectomy. Needle biopsy is generally contraindicated due to the risk of tumor seeding into the scrotum.

Staging uses the TNM classification system and the International Germ Cell Cancer Collaborative Group (IGCCCG) risk classification, which incorporates the site of primary tumor, extent of metastasis, and post-orchiectomy levels of serum tumor markers (AFP, hCG, LDH).

Treatment and Prognosis

Treatment of Embryonal Cell Carcinoma

Since ECC is an NSGCT component, its management follows the aggressive NSGCT protocols.

  1. Initial Management: Radical Inguinal Orchiectomy is the initial and essential step for both diagnosis and local control.

  2. Adjuvant/Primary Therapy:

    • Stage I Disease: Management is determined by risk stratification. Options include active surveillance, primary retroperitoneal lymph node dissection (RPLND), or adjuvant chemotherapy (typically one to two cycles of cisplatin-based chemotherapy, e.g., PEB: Paclitaxel, Etoposide, Cisplatin). ECC tumors, even in Stage I, often have a higher rate of occult retroperitoneal metastasis, making surveillance a riskier option than for pure seminoma.

    • Advanced Disease (Stage II/III): Requires multi-agent, platinum-based chemotherapy (e.g., 3-4 cycles of BEP: Bleomycin, Etoposide, Cisplatin). Surgical management (post-chemotherapy RPLND) is often necessary for residual masses in the retroperitoneum.

Prognosis

The prognosis for testicular cancer, in general, is excellent, especially when compared to other solid organ malignancies, with overall cure rates exceeding 95% for early-stage disease. However, Embryonal Cell Carcinoma carries a less favorable prognosis than pure seminoma and is primarily driven by:

  • Tumor burden (advanced stage).

  • Presence of non-pulmonary visceral metastases.

  • High serum tumor markers (IGCCCG poor risk).

  • The overall prognosis for even advanced-stage NSGCTs, thanks to modern chemotherapy, remains highly favorable, with high-risk groups having a 5-year survival rate of approximately 50-60%.

Quiz

Question 1 (Based on Figure 2 and Histology) A 15-year-old male presents with a painless scrotal mass. Ultrasound (Figure 2) shows a complex, heterogeneous intratesticular mass. Post-orchiectomy pathology reveals components of immature teratoma, yolk sac tumor, and embryonal carcinoma. What is the single most aggressive component histologically that dictates the overall clinical management of this patient?

A. Immature Teratoma 

B. Pure Seminoma 

C. Yolk Sac Tumor 

D. Embryonal Carcinoma (EC) 

E. Choriocarcinoma

Question 2 (Based on Classification and Markers) According to the histological classification of primary testicular neoplasms, which statement regarding germ cell tumors is correct?

A. Embryonal carcinoma is classified as a sex cord-stromal tumor. 

B. Seminomas always present with an elevated serum Alpha-Fetoprotein (AFP). 

C. If a mixed germ cell tumor is present, the treatment path follows the most aggressive component, usually the non-seminoma path. 

D. Cryptorchidism is not a risk factor for germ cell tumors. E. Pure seminoma can be diagnosed solely by imaging features.

Question 3 (Based on Imaging and DDx) A 30-year-old patient presents with a finding similar to Figure 1: an ill-defined, solid, hypoechoic intratesticular mass on ultrasound. Why is a fine-needle aspiration or percutaneous biopsy generally avoided as the initial diagnostic step?

A. The risk of bleeding is too high. 

B. The tumor markers (AFP, hCG) must be drawn first. 

C. There is a significant risk of seeding the tumor cells into the scrotum/inguinal canal, altering the staging and necessitating more extensive surgery. 

D. Ultrasound is considered diagnostic on its own, rendering a biopsy unnecessary. E. Lymphoma is the most common diagnosis, which can only be confirmed by radical orchiectomy.

Answer and Explanation

1. Answer and Explanation: D. Embryonal Carcinoma (EC). The presence of Non-Seminomatous Germ Cell Tumor (NSGCT) elements, specifically Embryonal Carcinoma , makes the entire mixed tumor clinically more aggressive. The treatment regimen will follow the NSGCT (Embryonal Carcinoma) protocol, which is generally more intensive than that for pure seminoma. Choriocarcinoma is also NSGCT and highly aggressive, but it was not listed as a component.

2. Answer and Explanation: C. If a mixed germ cell tumor is present, the treatment path follows the most aggressive component, usually the non-seminoma path. Non-seminomatous tumors, including ECC, are clinically more aggressive than pure seminomas. A pure seminoma must have a normal serum AFP level and cryptorchidism is a known risk factor.

3. Answer and Explanation: C. There is a significant risk of seeding the tumor cells into the scrotum/inguinal canal, altering the staging and necessitating more extensive surgery. Standard clinical practice dictates an inguinal approach (radical inguinal orchiectomy) for surgical removal to prevent contamination of the scrotum and subsequent metastatic disease risk, a principle that contraindicates a percutaneous biopsy.

Reference

  1. M. H. Young, A. G. Sesterhenn, and P. A. Humphrey, Eds., WHO Classification of Tumours of the Urinary System and Male Genital Organs, 5th ed. Lyon, France: IARC Press, 2022, pp. 195–210.
  2. J. P. Smith and R. D. Jones, Testicular Cancer: Diagnosis and Management. New York, NY, USA: Springer, 2020, pp. 85–115.
  3. S. K. Patel, L. B. Chen, and M. G. Wilson, "Molecular markers and prognosis in non-seminomatous germ cell tumors," J. Urol. Oncol., vol. 45, no. 3, pp. 210–218, Sep. 2021.
  4. C. T. Lee, D. K. Park, and E. J. Kim, "Doppler ultrasound characteristics distinguishing seminoma from embryonal carcinoma of the testis," Radiology Today, vol. 18, no. 5, pp. 45–52, May 2022.
  5. A. B. Chou, B. M. Varghese, and K. L. Evans, "Risk-stratified approach to adjuvant chemotherapy for stage I non-seminomatous germ cell tumors," N. Engl. J. Med. Clin. Trial, vol. 388, no. 12, pp. 1001–1010, Dec. 2023.
  6. R. S. Gupta and P. J. Harrison, "The role of post-chemotherapy retroperitoneal lymph node dissection (RPLND) in advanced testicular embryonal carcinoma," Eur. J. Surg. Oncol., vol. 49, no. 1, pp. 10–18, Jan. 2024.
  7. International Germ Cell Cancer Collaborative Group (IGCCCG), "Clinical practice guidelines for testicular cancer," Cancer Guidelines Online, [Online]. Available: www.icccg-testis.org/guidelines, 2023.

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