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October, 2024
Case of the Month
Clinical History: A 34-year-old man presented with shortness of breath and chest pain. He was a former smoker with a remote history of right orchiectomy for testicular torsion. CT chest showed a 25.8 cm mass in the anterior mediastinum extending to the right of midline, with heterogeneous internal enhancement (Figure 1). Serologic markers revealed elevated AFP (2760 ng/mL). After 2 cycles of chemotherapy, he presented with worsening shortness of breath and acute drop in hemoglobin. He underwent urgent thoracotomy with thymectomy and en bloc resection of pericardium and diaphragm. Microscopic examination showed a partially necrotic and hemorrhagic neoplasm with solid and cystic components (low magnification, Figure 2). The tumor contained different tissue elements including mature cartilage, gastrointestinal epithelium, and glial tissue. The stroma demonstrated areas of hypercellularity with atypical cells, increased mitotic activity, and prominent vascular spaces (Figure 3). Some areas had a papillary “Masson-like” appearance (Figure 4). Other areas showed more complex inter-anastomosing vascular spaces with focal multilayering, cytologic atypia, and necrosis (Figure 5). Immunohistochemical stains revealed the stromal cells expressed variable desmin and CAM 5.2, while the cells lining vascular spaces were positive for ERG (Figure 6). Additional immunostains were negative including SOX10, myogenin, OCT3/4, glypican 3, CD30, beta-HCG, and GATA-3.
Q1. This recently described entity usually arises in germ cell tumors with a component of:
- Choriocarcinoma
- Embryonal carcinoma
- Yolk sac tumor
- Teratoma
Q2. Which of the following is true about the tumor in this case:
- A subset have TP53 alterations
- Stromal cells are positive for MyoD1
- It predominantly occurs in children
- It often presents in the testis
Q3. This tumor is thought to recapitulate which of the following embryologic processes in the splanchnic mesoderm:
- Organogenesis
- Neurogenesis
- Histogenesis
- Vasculogenesis
Answers to Quiz
Q1. C
Q2. A
Q3. D
Q2. A
Q3. D
Diagnosis
Teratoma with high-grade vasculogenic mesenchymal tumor and angiosarcoma
Discussion
This case illustrates an example of primary mediastinal germ cell tumor containing teratoma and vasculogenic mesenchymal tumor (VMT) with progression to angiosarcoma. In addition, the marked elevation in serum AFP before starting chemotherapy suggests there was a preexisting component of yolk sac tumor, although histologic evidence of yolk sac tumor was not found in the resection specimen.
Vasculogenic mesenchymal lesions (VMLs) of germ cell tumor origin include a morphologic spectrum from teratoma with vasculogenic stroma to low and high-grade VMTs, and rarely progress to angiosarcoma. Most cases of VMLs have been described in primary mediastinal germ cell tumors of young men after chemotherapy. Clinical presentation includes chest pain, cough, fever, symptoms of superior vena cava syndrome, or an incidental finding on chest imaging. A majority have elevated serum AFP at initial diagnosis. Histologically, VMLs consist of neoplastic vascular and stromal components with varying degrees of atypia. Endothelial cells line rudimentary to well-formed vessels within a primitive mesenchymal stroma that generates other components of vessels including smooth muscle and pericytes. Immunohistochemical stains show endothelial cells are positive for ERG, CD31 and CD34, while stromal cells are variably positive for smooth muscle markers (desmin, SMA, h-caldesmon) and CD34.
Low-grade VMT is characterized by hypocellular stroma with mild cytologic atypia and rare mitotic figures. High-grade VMT has cellular stroma with markedly atypical stromal cells, numerous mitoses, and atypical cells lining vascular spaces. VMT is considered a precursor lesion to angiosarcoma and other somatic-type sarcomas, although progression is relatively rare. Angiosarcoma is characterized by highly atypical, multilayered endothelium lining complex anastomosing vascular spaces, or solid growth, with high mitotic activity, and overt features of malignancy.
The pathogenesis of vasculogenic lesions arising in mediastinal germ cell tumors is believed to recapitulate a neoplastic form of embryonic vasculogenesis. The formation of vessels from undifferentiated mesenchymal cells begins in the splanchnic mesoderm of the embryonic yolk sac. This may explain why VMLs almost exclusively occur in primary mediastinal germ cell tumors with preexisting or concurrent yolk sac tumor components. TP53 alterations have been described in VMT, and p53 overexpression has been associated with transformation to angiosarcoma and other sarcomas. Immunostaining for p53 may have utility for predicting risk of disease progression in a subset of VMT.
Given the rarity of primary mediastinal germ cell tumors, therapeutic guidelines are similar to gonadal germ cell tumors. Treatment involves either surgical resection or cisplatin-based chemotherapy followed by surgery depending on the biochemical markers and histologic subtype. For poor-risk (non-seminomatous) germ cell tumors such as this case with elevated AFP, first-line therapy usually involves chemotherapy followed by surgical resection.
Take home message for trainees:
Vasculogenic mesenchymal tumor can arise from primary mediastinal germ cell tumors and usually has a preexisting or concurrent yolk sac tumor component. There is a risk of transformation to somatic-type sarcomas such as angiosarcoma. Post-chemotherapy specimens should be thoroughly sampled for microscopic examination.
Vasculogenic mesenchymal lesions (VMLs) of germ cell tumor origin include a morphologic spectrum from teratoma with vasculogenic stroma to low and high-grade VMTs, and rarely progress to angiosarcoma. Most cases of VMLs have been described in primary mediastinal germ cell tumors of young men after chemotherapy. Clinical presentation includes chest pain, cough, fever, symptoms of superior vena cava syndrome, or an incidental finding on chest imaging. A majority have elevated serum AFP at initial diagnosis. Histologically, VMLs consist of neoplastic vascular and stromal components with varying degrees of atypia. Endothelial cells line rudimentary to well-formed vessels within a primitive mesenchymal stroma that generates other components of vessels including smooth muscle and pericytes. Immunohistochemical stains show endothelial cells are positive for ERG, CD31 and CD34, while stromal cells are variably positive for smooth muscle markers (desmin, SMA, h-caldesmon) and CD34.
Low-grade VMT is characterized by hypocellular stroma with mild cytologic atypia and rare mitotic figures. High-grade VMT has cellular stroma with markedly atypical stromal cells, numerous mitoses, and atypical cells lining vascular spaces. VMT is considered a precursor lesion to angiosarcoma and other somatic-type sarcomas, although progression is relatively rare. Angiosarcoma is characterized by highly atypical, multilayered endothelium lining complex anastomosing vascular spaces, or solid growth, with high mitotic activity, and overt features of malignancy.
The pathogenesis of vasculogenic lesions arising in mediastinal germ cell tumors is believed to recapitulate a neoplastic form of embryonic vasculogenesis. The formation of vessels from undifferentiated mesenchymal cells begins in the splanchnic mesoderm of the embryonic yolk sac. This may explain why VMLs almost exclusively occur in primary mediastinal germ cell tumors with preexisting or concurrent yolk sac tumor components. TP53 alterations have been described in VMT, and p53 overexpression has been associated with transformation to angiosarcoma and other sarcomas. Immunostaining for p53 may have utility for predicting risk of disease progression in a subset of VMT.
Given the rarity of primary mediastinal germ cell tumors, therapeutic guidelines are similar to gonadal germ cell tumors. Treatment involves either surgical resection or cisplatin-based chemotherapy followed by surgery depending on the biochemical markers and histologic subtype. For poor-risk (non-seminomatous) germ cell tumors such as this case with elevated AFP, first-line therapy usually involves chemotherapy followed by surgical resection.
Take home message for trainees:
Vasculogenic mesenchymal tumor can arise from primary mediastinal germ cell tumors and usually has a preexisting or concurrent yolk sac tumor component. There is a risk of transformation to somatic-type sarcomas such as angiosarcoma. Post-chemotherapy specimens should be thoroughly sampled for microscopic examination.
References
Fujii H, Yamada Y, Yamamura K. A case of vasculogenic mesenchymal tumor in the mediastinum: Whole-exome sequencing reveals origin from pre-existing germ cell tumor. Virchows Arch 2023;482:923-927.
Levy DR, Agaram NP, Kao CS. Vasculogenic mesenchymal tumor: A clinicopathologic and molecular study of 55 cases of a distinctive neoplasm originating from mediastinal yolk sac tumor and an occasional precursor to angiosarcoma. Am J Surg Pathol 2021;45:463-476.
Youssef R, Ulbright TM, Acosta AM. P53 overexpression may represent an early marker of clinicopathologic progression in vasculogenic mesenchymal lesions of germ cell tumor origin. Virchows Arch 2024;484:939-944.
Contributors
Daffolyn Rachael Fels Elliott, MD, PhD
Assistant Professor
Department of Pathology and Laboratory Medicine
University of Kansas Medical Center
Kansas City, United States
Rashna Madan, MD, PhD |
Professor
Department of Pathology and Laboratory Medicine
University of Kansas Medical Center Kansas City, United States
Ameer Hamza, MD, PhD
Assistant Professor
Department of Pathology and Laboratory Medicine
University of Kansas Medical Center
Kansas City, United States
Acknowledgement: Dr. Anja Roden, MD, Professor, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester for expert consultation in this case.
Assistant Professor
Department of Pathology and Laboratory Medicine
University of Kansas Medical Center
Kansas City, United States
Rashna Madan, MD, PhD |
Professor
Department of Pathology and Laboratory Medicine
University of Kansas Medical Center Kansas City, United States
Ameer Hamza, MD, PhD
Assistant Professor
Department of Pathology and Laboratory Medicine
University of Kansas Medical Center
Kansas City, United States
Acknowledgement: Dr. Anja Roden, MD, Professor, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester for expert consultation in this case.
