Transformed Testicular Teratoma to Embryonic-Type Neuroectodermal Tumor With Metastasis to Mediastinum

Abstract

Testicular teratomas may present in both prepubertal and adult men; however, the prognosis differs greatly between these 2 populations. In children, teratomas (prepubertal type) most often occur before the age of 4, are generally seen in their pure form, and behave in a benign fashion. In adults (postpubertal type), teratomas are usually part of a mixed germ cell tumor, and they have the potential to be found at metastatic sites, especially following chemotherapy for non-teratomatous germ cell tumor. Analyses of metastases from germ cell tumors and teratomas from the same patient have demonstrated a high degree of concordance in the observed genetic abnormalities. In rare cases, testicular teratoma can transform into a malignant germ cell tumor. One such type of transformation is into a primitive neuroectodermal tumor. These tumors are malignant and often metastasize to the retroperitoneum but may also metastasize to other sites. A multimodal treatment approach is needed, including surgery and adjuvant chemotherapy. We describe a rare case of malignant transformation of a testicular teratoma into a primitive neuroectodermal tumor with metastasis to the mediastinum. The patient was treated with radical orchiectomy, retroperitoneal lymph node dissection, and adjuvant vincristine, adriamycin, and cyclofosfamide alternating with ifosfamide and etoposide (VAC/IE therapy).

Introduction

Embryonic-type neuroectodermal tumor (ENET) is the term introduced in the fifth edition of WHO Classification of Urinary and Male Genital Tumours (2022), formerly known as primitive neuroectodermal tumor (PNET). ¹ Embryonic-type neuroectodermal tumor represents somatic-type malignancy arising from teratomatous embryonic-type neuroectodermal tissue. Embryonic-type neuroectodermal tumor of testicular origin morphologically resembles embryonal tumors arising in the central nervous system and has no relationship to Ewing sarcoma, which also falls under the name of peripheral PNET. Hence, the term ENET was introduced to avoid confusion with Ewing sarcoma. ²

The type of teratoma is important in elucidating its malignancy potential. Postpubertal teratomas in the testis are associated with isochromosome 12p seen in malignant germ cell tumors and represent most mature spectrum of germ cell neoplasia. ³ Malignant transformation of teratoma into ENETs is rare. Diagnosis can be made with biopsy and treatment involves surgical resection, including retroperitoneal lymph node dissection. ⁴ Conventional cisplatin-based chemotherapy used for germ cell malignancies is ineffective in patients with somatic-type malignancies arising from teratoma.

In some cases, ENETs may metastasize. Metastasis has been described in the retroperitoneum, liver, lung, mediastinum, and kidney.^5,6 Overall, prognosis for ENET arising from teratoma is unfavorable, especially given its resistance to chemotherapy and radiotherapy ⁷ Therefore, it is paramount to use a multimodal treatment approach, including surgery.

We present a case of ENET arising from testicular teratoma. Our case is unique in that the patient developed metastasis to the mediastinum which led to symptoms from compression of nearby structures.

Case Presentation

A 31-year-old man with no significant past medical history presented with right-sided testicular swelling. He underwent radical orchiectomy and pathology showed embryonic-type neuroectodermal tumor, which had arisen from a 6.1-cm teratoma (Figure 1). He subsequently underwent a retroperitoneal lymph node dissection, which was negative for malignancy.

Figure 1.

A representative image from the original testicular tumor, showing the ENET (left side of the image) adjacent to the teratoma (right side of the image). The ENET comprised 80% of the total mass and is shown here to have a vaguely nested growth pattern composed of small round blue cells. A pseudorosette is denoted by the arrow. The teratoma comprised only 20% of the total mass and is shown to contain mature epithelial (asterisks) and cartilaginous tissue (cross). (40× Magnification).

He was monitored with surveillance blood tests, including alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin (beta-hCG) and imaging. Both AFP and beta-HCG remained undetectable. About 15 months after initial diagnosis, surveillance imaging was concerning for disease progression with chest x-ray demonstrating a new lesion. A computed tomography (CT) thorax was performed for better characterization (Figure 2). This demonstrated a left upper lobe lung mass with mediastinal invasion and compression of the left main pulmonary artery and left upper lobe bronchus, with near complete occlusion. The CT abdomen did not demonstrate metastasis. The patient also experienced compressive symptoms from mediastinal mass including hoarseness, likely due to compression of recurrent laryngeal nerve, and shortness of breath on exertion.

Figure 2.

Axial (left) and coronal (right) computed tomographic images of the thorax with contrast demonstrating a large left upper lobe mass. There is mediastinal invasion in addition to hemodynamically significant compression of the left main pulmonary artery and near-occlusion of the left mainstem bronchus.

A fine-needle aspiration and core biopsy of the mass showed small round cell malignant neoplasm, consistent with the previously diagnosed ENET (Figure 3).

Figure 3.

A representative image of the core biopsy of the left mediastinal mass. This mass showed a metastasis of the embryonic-type neuroectodermal tumor arising from a testicular teratoma. This section shows nests of tumor cells (arrows) with surrounding bands of immature neuropil (asterisks). The tumor cells are variably sized and contain hyperchromatic nuclei with minimal to moderate eosinophilic cytoplasm. The morphologic features in this biopsy resemble those seen in the original tumor. No teratoma component was identified in this biopsy. (400× Magnification).

He started chemotherapy with cyclophosphamide and doxorubicin-based regimen alternating with vincristine, ifosfamide, and etoposide. He also received pegfilgrastim support. After 4 cycles of treatment, follow-up chest imaging showed presence of mass, but interval decrease in size (Figure 4). Patient had improvement in his compressive symptoms as well. He is planned for follow-up with urologist and cardiothoracic surgeon to discuss possible surgical options.

Figure 4.

Axial (left) and coronal (right) computed tomographic images of the thorax with contrast demonstrating significant interval decrease in previously visualized left upper lobe mass. This mass is now seen encasing the left mainstem bronchus and the segmental branches of the left pulmonary artery with no hemodynamically significant compression. Interval decrease of mediastinal invasion.

Discussion

There are various types of testicular cancer; the 3 primary types being germ cell tumors, sex cord-stromal tumors, and extragonadal tumors. ⁸ Germ cell tumors are further subdivided into seminoma and non-seminomas, based on histology. ⁸ Risk factors for testicular tumors include, but are not limited to, family history, cryptorchidism, hypospadias, and childhood inguinal hernias. ⁸ Teratoma is a type of non-seminomatous germ cell tumor, comprising structures arising from at least 2 germ cell layers. ⁸

Germ cell tumors, such as teratomas, may undergo malignant transformation. This is rare, occurring in about 3% to 6% of cases.^6,9 Teratoma, or a teratomatous component, is often identified as the tumor type prior to malignant transformation.^9,10 While there is a wide array of possible malignant transformations, adenocarcinoma, neuroectodermal, and rhabdomyosarcoma are more commonly seen (with mesodermal differentiation being the most common).^9,11,12

Histology is essential in making the diagnosis. In ENET, an overgrowth of immature elements is seen, manifesting as neuroepithelium that may form rosette-like tubular structures. ³

Regarding malignant transformation, it has been suggested that there is a progenitor cell located within initial teratoma which then gives rise to the malignant neoplasm.^9,13 Notably, many of these malignant transformations of these testicular germ cell tumors contain 12p gains and may affect genes on this chromosome, notably the oncogene KRAS.^9,13 While this may provide a molecular target for therapy, the mainstay of treatment remains resection and chemotherapy.

Prognosis depends on a variety of factors which include stage and histology. In germ cell tumors that undergo malignant transformation, tumors with sarcomatous component and those of ENET histology are associated with worse prognosis. ⁹ In addition, there is a worse prognosis with incomplete resection, later relapse, a greater number of chemotherapy cycles, and when there is an extragonadal primary. ⁹

Treatment of teratomas transformed to malignant germ cell tumor provides a few challenges. As this disease is rare, it is difficult to ascertain the best treatment modality and factors for determining prognosis. However, there have been studies which have described potential treatment plans. Both surgical resection and systemic chemotherapy are vital, as there is a high risk of relapse after surgery alone.^6-8 Retroperitoneal lymph node dissection is another surgical component which has been shown to have better outcomes. ⁴ Even in those treated with systemic therapy, resistance to chemotherapy is high, and thus repeat resections may be required. ⁴

Regarding systemic options, cisplatin-based adjuvant chemotherapy is the main modality for germ cell tumors.^4,14 While metastatic germ cell tumors are sensitive to cisplatin-based therapy, ENET transformed from teratoma is resistant. ¹⁴ There are cases of successful ENET treatment with chemotherapy regimens, consisting of alternating cyclophosphamide, doxorubicin, and vincristine (CAV) with ifosfamide and etoposide (IE) described in the literature. ¹⁴

Conclusion

Testicular teratomas are a type of non-seminomatous germ cell tumor that in rare cases may undergo malignant transformation. One such possibility is transformation into ENET, which may metastasize to other sites. Treatment includes addressing the primary location with surgical excision. Retroperitoneal lymph node dissection is also recommended due to the high risk of metastasis to that region. Finally, adjuvant chemotherapy is also used as part of the treatment plan. We present a rare case of teratoma transformed into ENET, which was treated with orchiectomy and retroperitoneal lymph node dissection. The patient had recurrence of his disease with mediastinal metastases and thus VAC/IE chemotherapy was added with tumor response.