|Year : 2019 | Volume
| Issue : 3 | Page : 342-349
Clinical and radiographic characterization of primary seminomas and nonseminomatous germ cell tumors
L Gu1, L Zhang1, N Hou2, M Li3, W Shen1, X Xie1, Y Teng4
1 Department of Radiology, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, P. R. China
2 Department of Pathology, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, P. R. China
3 Department of Chest Surgery, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, P. R. China
4 Department of Medical Oncology, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, P. R. China
|Date of Acceptance||21-Nov-2018|
|Date of Web Publication||6-Mar-2019|
Prof. L Zhang
Department of Radiology, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and The Affiliated Cancer Hospital of Nanjing Medical University, 42 Baiziting Road, Nanjing, Jiangsu 210009
P. R. China
Prof. W Shen
Department of Radiology, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and The Affiliated Cancer Hospital of Nanjing Medical University, 42 Baiziting Road, Nanjing, Jiangsu 210000
P. R. China
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Primary malignant mediastinal germ cell tumors (PMMGCTs) including seminomas and nonseminomatous germ cell tumors (NSGCTs) are rare, and sometimes the diagnosis is very difficult. Purpose: The purpose of this study is to compare the clinical characteristics, biomarkers, and imaging findings of seminomas and NSGCTs and to determine whether these features could help distinguish these two types of PMMGCT. Material and Methods: A retrospective study of 24 male patients with histopathologically proven PMMGCT was performed. We collected the information of computed tomography (CT) (the scan area ranged from the apex of lung to the costophrenic angles) and magnetic resonance imaging blood test and histology characteristics of these patients. Results: Twelve of 24 cases were confirmed to be seminomas, whereas the other 12 cases were NSGCTs. Alfa-fetoprotein (AFP) was found to be elevated in all patients with NSGCT, whereas none of the patients with seminomas had elevated AFP level. Beta-human chorionic gonadotropin (β-HCG) level was elevated in all the patients with seminomas (seven/seven), whereas in NSGCT only two of seven patients had elevated β-HCG. Lactate dehydrogenase level was increased in five of the nine patients with seminomas, as well as in the eight patients with NSGCT. CT imaging revealed that 12 masses from the seminoma group were homogeneous, soft tissue opacity and showed minimal contrast enhancement. On the contrary, all 12 NSGCT cases showed cystic and solid masses; on contrast-enhanced CT, heterogeneous enhancement was found on the capsule of the tumor, septum, and solid masses. Conclusion: Seminomas and NSGCT showed different profiles of tumor biomarkers and radiographic features. Evidence from serum test, histopathological analysis, and imaging should be combined to ensure the accurate diagnosis of these two types of PMMGCT.
Keywords: Malignant mediastinal germ cell tumors, nonseminomas germ cell tumor, seminomas, tomography
|How to cite this article:|
Gu L, Zhang L, Hou N, Li M, Shen W, Xie X, Teng Y. Clinical and radiographic characterization of primary seminomas and nonseminomatous germ cell tumors. Niger J Clin Pract 2019;22:342-9
|How to cite this URL:|
Gu L, Zhang L, Hou N, Li M, Shen W, Xie X, Teng Y. Clinical and radiographic characterization of primary seminomas and nonseminomatous germ cell tumors. Niger J Clin Pract [serial online] 2019 [cited 2019 May 21];22:342-9. Available from: http://www.njcponline.com/text.asp?2019/22/3/342/253462
| Introduction|| |
Primary malignant mediastinal germ cell tumors (PMMGCTs) are rare and represent only 1%–4% of all mediastinal tumors. PMMGCT can be divided into two broad groups: seminomas and nonseminomatous germ cell tumors (NSGCTs), and the latter includes yolk sac tumor, immature teratocarcinomas, embryonal carcinoma, choriocarcinoma, and mixed tumors. Sometimes, the patient is asymptomatic, and the only clinical finding is elevation of serum alfa-fetoprotein (AFP) and/or beta-human chorionic gonadotropin (β-HCG) by routine examination. A tissue diagnosis is required for definitive diagnosis of PMMGCT before treatment because the management is different for seminomas and NSGCT. Seminomas are sensitive to both chemotherapy and radiotherapy, with good prognosis regardless of the location. Long-term disease-free survival is achieved in roughly 90% of patients.
However, NSGCTs are relatively aggressive with metastases at presentation, and surgery is difficult. In addition, NSGCT is resistant to radiotherapy, compared with seminomas. Treatment using chemotherapy followed by surgery to resect residual masses has proven to be effective in improving the survival of these patients. Thus, accurate diagnosis is of crucial importance. However, because of its low morbidity, nonspecific clinical symptoms, and scarce reports, both locally and internationally, definitive diagnosis of PMMGCT before treatment is challenging.
In this study, we examined and analyzed the clinical and imaging features of 24 cases of PMMGCTs (12 seminomas and 12 NSGCTs). We aimed to improve the understanding and imaging diagnosis of this disease which might guide selection of appropriate treatment in clinical setting.
| Materials and Methods|| |
In this retrospective study, a medical records' database of 43 patients with PMMGCT between 2008 and 2018 in our department was reviewed with the intent of investigating patients with PMMGCT. Nineteen patients were excluded due to incomplete data information. A total of 24 patients ranging from 17 to 66 years of age with complete medical history and radiographic reports were evaluated at the hospital. A diagnosis of PMMGCT was made by mass biopsy or histopathological analysis after excisional/incisional biopsy. Among them, 12 were seminomas and the other 12 were identified as NSGCT. No primary lesion was identified in extragonadal and extramediastinum organs, confirmed by ultrasound or computed tomography (CT) scan.
CT and MRI examination
CT scan was performed using a multislice spiral CT (Philips MX8000, USA) and 64-slice spiral CT (GE Light Speed VCT, GE Healthcare, Buckinghamshire, UK) with high-pressure injector. Patients were asked to lie in supine position. The scan area ranged from the apex of the lung (root of the neck) to the costophrenic angles. Enhanced images were obtained by injection of nonionic contrast medium (iohexol) at a rate of 2–3 mL/s for a total of 100 mL. Other parameters were as follows: 120 kV tube voltage, 250 mA tube current, 5 mm slice thickness, and 2.5 and 1.25 mm reconstruction thickness. Magnetic resonance imaging (MRI) was performed using Philips Medical System Achieva 1.5T superconducting scanner. MRI sequences included axial T1WI, T2WI, and fat-suppresion T2WI (SPAIR). The parameters included the following: 40 cm × 25 cm field of vision, 5 mm slice thickness, and 6 mm interslice spacing. Enhanced scan was performed by injection of gadopentetate dimeglumine as contrast medium through cubital veins access at a rate of 2 mL/s for 15 mL. Coronal and sagittal T1WI were performed together with cross-sectional scan.
Two experienced radiologists were blinded to the initial diagnosis and reached the consensus after complete discussion. The following mass features were reviewed: location, size (defined as maximal dimension), shape, and border. CT signals included unenhanced and enhanced patterns; low-density areas within the lesion (the ratio between areas of necrosis range to areas of the lesion, classified as <25%, 25%–50%, and >50% respectively); and extent of enhancement, which was defined as the increased signal between enhanced and unenhanced images, classified as mild (≤20 HU), moderate (21–40 HU), and apparent enhancement (>40 HU). Other properties included presence or absence of local invasion or distant metastases and presence or absence of pleural effusion or pericardial effusion.
Biopsy samples obtained during surgery were fixed by 4% paraformaldehyde (PFA) and then embedded with paraffin. A consecutive section was performed followed by hematoxylin and eosin staining and immunohistochemistry analysis of biomarkers, which included CD117, PLAP, and AFP.
| Results|| |
Clinical symptoms, tumor markers, and diagnostic methods
We collected the concentration of the two markers and other five tumor markers. The detailed clinical symptoms, tumor markers, and diagnostic methods of seminoma group (n = 12) and NSGCT group (n = 12) are summarized in [Table 1] and [Table 2], respectively.
|Table 1: Clinical symptoms, tumor markers, and diagnostic methods in seminoma group|
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|Table 2: Clinical symptoms, tumor markers, and diagnostic methods in NSGCT group|
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In this study, seven patients in seminoma group were detected with increased serum β-HCG (12.69–188.9 mIU/mL). All the 12 patients were detected as normal AFP concentrations [Table 1]. High level of lactate dehydrogenase (LDH) was observed in five patients of the nine cases with records, and six of the eight patients had elevated neuronspecific enolase (NSE) level.
All the 12 patients with NSGCT were detected with extremely high concentration of AFP, and only 2 patients were detected with increased β-HCG [Table 2]. Eight of eight patients were detected with elevated LDH level; 9 of 10 had increased NSE; 9 of 10 had high level of CA 125; 7 of 9 had increased carcinoembryonic antigen (CEA).
All the 12 cases in the seminoma group underwent CT examination. Among them, four cases underwent CT and MRI examination. All the masses were located in the anterior mediastinum. Masses in seven patients were located on the right, three on the left, and two in the middle. The maximum diameter of each tumor ranged from 6.5 to 12 cm. Masses in 11 cases were irregular in shape, with lobulated or serrated edges [Figure 1]. Only one case had regular edges and was an elliptical mass [Figure 2].
|Figure 1: Diagnosis of a 19-year-old male seminoma patient. (a) CT plain scan showed a soft tissue mass with more uniform density in the anterior mediastinum, with irregular shape, a serrated edge, calcification points (white arrow), CT value of 44 HU, an infiltrating drill-like growth, the disappearance of the mediastinal fat space, and the encroachment of the large vessels. (b) Enhanced mass scan revealed slightly enhancement, CT value about 57 HU, small patch with low-density shadow (black arrow); tumor invaded the right anterior chest wall pleura (white arrow). Pathological diagnosis was spermatogonial tumor|
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|Figure 2: Diagnosis of a 45-year-old male seminoma patient. (a) CT revealed an anterior mediastinal elliptical mass, with smooth boundary. It had patch-like low-density shadow (white arrow) and the total range is more than 25%. (b) Sagittal reconstruction showed that the mass shape is oval, with smooth boundary. It can be observed with low-density shadow (black arrow) in the mass and enlarged lymph node in the right lung gate (white arrow). (c) H and E staining showed that the tumor cells were round and separated by fibrous vessels. The stroma was infiltrated with a large number of lymphocytes. (d) Immunohistochemical results. PLAP (+). The patient was misdiagnosed as thymic carcinoma before surgery. Operative pathology revealed that there was a mediastinal seminoma and a right hilar lymph node metastasis|
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Unenhanced CT scan revealed soft tissue density; four cases were detected with punctate or strip-shaped calcification [Figure 1]. Enhanced CT scan revealed the feature of more homogeneous enhancement. The masses were all spotted and fissured with low-density shadow, including one case with 25%–50% [Figure 2] and the remaining 11 cases with less than 25% [Figure 3]. Eleven cases displayed infiltrative growth, and the mediastinal large vessels were invaded by the masses. Superior vena caval invasion was most frequent and was detected in eight cases [Figure 1] and [Figure 3]. Six cases displayed perfusion-like growth filling the mediastinal vascular space. Eleven cases had pericardium invasion and two cases were confirmed at surgery. Four cases were accompanied by bronchopulmonary tissue compression [Figure 1]. Two cases had hilar lymph node enlargement, one case had tumor metastasis [Figure 2], and five cases had pleural and pericardial effusion.
|Figure 3: Diagnosis of a 23-year-old male seminoma patient. This patient had superior vena cava compression syndrome. (a) CT plain scan showed the anterior mediastinal mass and lobulated margin (white arrow). The mass twines around mediastinum large vessels. Stenting shadow can be seen in the upper cavity and the left brachial vein (white arrow). (b) The fissured low-density shadow in the enhanced scan was clearer than that in the plain CT scan (white arrow), and the range was less than 25%. (c) MRI revealed that the T2WI inhibitory sequence mainly displayed high signal and patchy displayed even higher signal shadows. White arrow indicated corresponding low density of CT scan, and MRI showed clearer image. (d and e) H and E staining revealed that the cell nucleus displayed thick-dyed and heterotypic morphology. It was easy to be misdiagnosed as spindle cell malignant tumor and soft tissue undifferentiated sarcoma. Immunohistochemical results revealed Desine (−), S100 (−), and CD68 (−), which did not support the diagnosis of soft tissue sarcoma. The elevated serum beta-HCG and positive staining of germ cell tumor marker CD117 (+) and PLAP (+) made the final diagnosis of mediastinal seminoma|
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Unenhanced MRI showed a mass in four cases with slightly low signal in T1WI. The T2WI-SPAIR sequence was mainly hyperintense signal, with small flaky higher signal (corresponding to CT cystic low-density shadow) [Figure 3].
In the NSGCT group, 12 cases underwent CT examination for the first time and 3 cases underwent CT and MRI examination. The masses were all located in the anterior mediastinum, whereas the mass in one case extended to the posterior mediastinum [Figure 4]. Eleven cases showed lateral growth (seven cases left and four right), whereas one case was basically in the middle. The maximum diameter of the mass was about 8–17 cm. The mass shape in seven cases was round; five cases were irregular with an incomplete capsule.
|Figure 4: Diagnosis of a 66-year-old male patient with NSGCT. (a) CT scan revealed that the cystic density in right anterior mediastinum was the main mass. The wall and septum were strengthened, with a honeycomb-like change (black arrow). The right middle lung was detected with atectasis (white arrow). (b) MPR showed that the masses extended to the posterior mediastinum. (c) HE staining revealed that tumor cells are arranged in a sparse reticulate structure and S-D corpuscle can be observed (black arrow), indicating the composition of yolk sac tumor (black arrows). (d) HE staining revealed that the tumor displayed heteromorphic morphology which suggested malignant teratoma. Pathology: NSGCT (yolk sac tumor combined with malignant teratoma)|
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Twelve cases of NSGCT were detected as cystic mass, and no fat and calcification were observed. Enhanced scan in three cases displayed cystic wall and septum enhancement and honeycomb-like change [Figure 4]. The remaining nine cases were irregular flaky and nodular nonuniform intensification [Figure 5] and [Figure 6], as well as enhancement of cyst wall and septum. Unenhanced cystic low-density shadow in 10 cases was more than 50% [Figure 4] and [Figure 5]. Thickening tortuous vascular shadows were seen in 12 cases. Twelve cases had pericardial and mediastinal large vessel invasion, and one case of unknown venous thrombosis was confirmed by surgery. Eleven cases of adjacent pulmonary atelectasis were caused by compression or invasion of the bronchi or lung tissue on the same side [Figure 4]. Eight cases of pleural effusion and pericardial effusion were detected. Two treatment-naive cases were diagnosed as lung metastasis [Figure 6] and one case had pleural metastasis.
|Figure 5: Diagnosis of a 24-year-old male patient with NSGCT. (a) CT scan showed a solid mass in the right anterior mediastinal. (b) Enhanced scan showed marked patched enhancement (black arrow), with a large area of cystic low-density shadow without enhancement, and the area was greater than 50%. (c and d) T1W1 mass showed a mixed signal; the T2WI-SPAIR sequence was detected with unevenly high signal. CT showed no enhanced cystic low density. The corresponding MRI performance: A significant short T1 long T2 signal (black arrow) suggested bleeding; significant long T1 long T2 signal suggested liquefied necrosis in the tumor (white arrow), and a slightly longer T1 and slightly longer T2 signal suggested a thick gelatinous sac component. (e) Tubular structure in HE staining was misdiagnosed as adenocarcinoma (black arrow). Serum AFP was significantly increased (47,839 ng/mL). Immunohistochemical staining of TTF-1 (−) and Napsin (−) excluded the possibility of lung adenocarcinoma. With additional evidence of PLAP (+) and AFP (+), the patient was finally diagnosed as yolk sac tumor. (f) Immunohistochemical staining of TTF-1 (−) and Napsin (−) excluded the possibility of lung adenocarcinoma.|
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|Figure 6: Diagnosis of a 27-year-old male patient with NSGCT. (a) CT scan revealed giant cystic mass in anterior mediastinum, cyst wall and septum enhancement, patch floc and nodular enhancement (long black arrow), large blood vessel compression, left lower lung metastasis (short black arrow); (b) After two courses of TIP chemotherapy, chest CT revealed shrinkage of anterior mediastinal mass. (c) Shrinkage of lower left lung metastasis (black arrow) and a hole-like change (black arrow)|
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Three cases were examined by MRI at the same time. The results showed that the CT cystic low-density shadow showed a variety of manifestations of MRI signal: part of them showed an obviously short T1 and long T2 signal, some showed long T1 and long T2 signal, and others displayed a slightly longer T1 and slightly longer T2 signal [Figure 5].
Of the 24 cases, 5 underwent direct surgery and 19 underwent mass puncture or biopsy. In 10 cases of seminoma with mass puncture, 5 cases were misdiagnosed for the first time, including 4 cases that were misdiagnosed as poorly differentiated cancer and 1 case as undifferentiated sarcoma [Figure 3].
In nine cases of NSGCT with mass puncture, three cases were misdiagnosed for the first time. They were misdiagnosed as one case each of poorly differentiated carcinoma, metastatic carcinoma, and adenocarcinoma [Figure 5].
For the eight cases of misdiagnosis, two cases were diagnosed as spermatogonial tumor and NSGCT, respectively, after operation. The remaining six cases had different puncture pathological results and clinical/radiographic features. Thus, after multidisciplinary discussion, they were managed with re-biopsy and combined with immunohistochemical examination of the related germ cell tumor markers, and the diagnosis was finally confirmed.
Immunohistochemical results of 12 cases of seminoma are as follows: 12 cases of CD117 (+), 10 cases of PLAP (+), 3 cases of SALL4 (+), and 1 case of OCT3/4 (+). Of 12 cases of NSGCT, 7 cases were simple yolk sac tumor, 5 cases were mixed germ cell tumor with yolk sac tumor, 8 cases were AFP (+), 6 cases were PLAP (+), 6 cases were CD117 (+), 4 cases were SALL4 (+), and 1 case was HCG weak (+).
| Discussion|| |
The clinical symptoms of PMMGCTs are not obvious and are relatively rare. They are easy to misdiagnose and mistreat. The clinical and radiographic features of 12 cases of seminoma and 12 cases of NSGCTs were analyzed retrospectively. We found that clinical characteristics, biomarkers, and imaging features of seminoma and NSGCTs are different. These results may play a guiding role in distinguishing the diagnosis of seminomas from NSGCTs.
It has been reported that patients had longitudinal strontium seminomas and NSGCTs were often at the age span of 15–35 years. In this study, the age span of this group of seminoma is from 20 to 45 years, in which there were seven cases with age more than 35 years (53.8%, 7/13), suggesting that seminoma may present at a similar frequency both in young and middle-aged adults. In this group of 12 cases of NSGCT, 10 cases were between 17 and 30 years old, suggesting that NSGCT occurs more frequently in young men. Meanwhile, two other cases occurred in 60 and 66 years old men, which is similar to the reported cases of PMMGCT occurring in elderly men. There are no obvious specific clinical features of PMMGCT, commonly showing as the symptoms caused by the large volume of the tumor and the compression of adjacent structures, such as dyspnea, cough, chest pain, or fever. The incidence of superior vena cava obstruction syndrome in seminoma patients was 33.3% (4/12), which was significantly higher than that reported in literature (10%). One possible reason is the large size of tumor mass in this study, whereas another reason is that a majority of cases (58.3%, 7/12) were inclined to right-side growth which lead to compression of superior vena cava. There was a higher frequency of patients with NSGCT with cough (66.7%, 8/12) and chest pain (58.3%, 7/12) in this group, which was considered to be due to the high rate of NSGCT proliferation, as well as a majority of cases exhibiting biased lateral growth compression because of invasion of the ipsilateral bronchus and lung tissue with obstructive atelectasis.
It was reported that β-HCG was slightly elevated in seminomas and significantly increased in embryonic cell carcinoma and choriocarcinoma. Another case was considered as yolk sac tumor pathologically, and it was likely to be a mixed germ cell tumor. Serum β-HCG and AFP results are of great value not only for the qualitative diagnosis and pathological classification of PMMGCT but also for the evaluation of PMMGCT efficacy and monitoring of tumor recurrence/metastasis. Serum AFP is routinely checked in almost every case, but β-HCG is not a routine clinical indicator in clinical practice, which was not detected at the first diagnosis in nearly half of the patients in this group. Thus, we recommend patients with anterior mediastinal mass at the time of initial diagnosis, especially for male patients; detecting serum β-HCG and AFP at the same time can significantly reduce the scope of differential diagnosis. NSGCT also has increased levels of CA125, CEA, and CA199, which shows signs of malignancy, although no specificity was observed. Once the patient is suspected to have PMMGCT, it is preferable to diagnose the tumor with puncture and guided clinical selection of appropriate treatment. According to the International Germ Cell Carcinoma Collaborative Organization standard, primary mediastinal seminomas without pulmonary and visceral metastases are sensitive to radiotherapy and chemotherapy. With a good prognosis, it can have long disease-free survival. The 5-year overall survival rate was 88%.
Pathological diagnosis of PMMGCT puncture cases has its limitations. Due to limited puncture tissue, necrotic lesions, tissue compression, and other reasons, typical morphological features cannot be observed in some PMMGCT puncture cases. In this group, eight cases of newly diagnosed were misdiagnosed. One of them was a 42-year-old patient with initial pathological diagnosis as poorly differentiated cancer. Surgical resection diagnosed thymic cancer, but postoperative pathology was seminoma. Another 23-year-old patient presented with superior vena cava syndrome, with a relatively homogeneous mass with mild longitudinal enhancement found on CT scans. This was considered to be malignant lymphoma or seminoma, integrating with high serum β-HCG, highly suggestive of seminoma. Thus, the patient was asked to do tumor puncture, with the first pathological diagnosis: the tendency of soft tissue was undifferentiated sarcoma; because of the small tissue, it was recommended that it was the postoperative specimen type. However, after reslicing and further immunocytochemical examination of germ cell tumor markers, a diagnosis of seminoma was made. In a 24-year-old patient with chest pain, CT and MRI showed a large inhomogeneous mass of the mediastinum with obvious hemorrhage and necrosis. Considering the possibility of NGSCT combined with serum AFP greater than 40,000 ng/mL, highly suggestive yolk sac tumor, and puncture pathology showed adenocarcinoma. The final diagnosis of yolk sac tumors was made after reslicing and further immunohistochemical examination. Therefore, accurate diagnosis of PMMGCT puncture cases must be combined with clinical, imaging, serum tumor markers (β-HCG, AFP), pathological morphology, and immunohistochemistry results. When the pathological findings are inconsistent with clinical and imaging findings, it is necessary to conduct multidisciplinary discussions, further pathological consultations, and immunohistochemical examination of relevant markers of germ cell tumors. Imaging examination of PMMGCT not only offers suggestive diagnosis, clinical staging, and evaluation of efficacy but also can guide the selection of biopsy sites to avoid bleeding and necrosis as much as possible to improve the accuracy of pathological diagnosis.
| Conclusion|| |
In summary, seminoma occurs predominantly in young and middle-aged men, and serum β-HCG often increases, AFP is not high, and imaging shows multiple anterior pars with more homogeneous masses, with mild enhancement, and some with gap-like perfusion-like growth. Only malignant lymphomas with large mediastinal masses are more difficult to identify. NSGCT occurs in young men, and the serum AFP often increases significantly. The image often presents as a large heterogeneous mass of the anterior mediastinum. It is often accompanied by a large area of cystic necrosis and hemorrhage. The solid component is significantly heterogeneous and is easily associated with lung metastasis. MRI showed better heterogeneity and complex pathological changes in NSGCT than in CT. For patients suspected of having anterior mediastinal masses, CT is the preferred imaging method, and MRI can be used as an adjunct and for posttreatment follow-up. Once suspected as PMMGCT, surgical treatment should not be the first choice. It is recommended that mass biopsy, diagnosis, and classification or staging be performed. PMMGCT partial biopsy cases are often misdiagnosed due to lack of biopsy, significant necrosis of tumors, or cell compression and should be combined with clinical and laboratory tests, as well as imaging performance comprehensive judgment to reduce misdiagnosis, for better guiding of clinical treatment and prognostication.
Availability of data and materials
The datasets used and/or analyzed during this study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
This entire study was approved by the Ethics Committee of XX Hospital, China. No animal was included in this study.
Consent for publication
All patients agreed to participate in the study and a written consent was obtained.
The authors would like to thank Yiming Li (Tianjin Central Hospital) for proofreading the article.
Financial support and sponsorship
Conflict of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2]