Residual Germ Cell Tumors Research Articles

Outcomes and surgical approaches for pineal region tumors in children: 30 years' experience.

Pineal region tumors account for 2.7%-11% of all CNS tumors in children. In this series, the authors present their surgical results and long-term outcomes from a pediatric pineal region tumor cohort. A total of 151 children aged 0-18 years were treated from 1991 to 2020. Tumor markers were collected in all patients; if positive, chemotherapy was performed, and if negative, biopsy was performed, preferably endoscopically. Resection was performed when there was a residual germ cell tumor (GCT) lesion after chemotherapy. The distribution based on histological type, as verified by markers, biopsy, or surgery, was germinoma (33.1%), nongerminomatous GCT (NGGCT) (27.2%), pineoblastoma (22.5%), glioma (12.6%), and embryonal tumor (atypical teratoid rhabdoid tumor) (3.3%). A total of 97 patients underwent resection, and gross-total resection (GTR) was achieved in 64%; the highest GTR rate (76.6%) was found in patients with GCTs, and the lowest (30.8%) was found in those with gliomas. The supracerebellar infratentorial approach (SCITA) was the most common, performed in 53.6% of patients, followed by the occipital transtentorial approach (OTA), performed in 24.7% of patients. Lesions were biopsied in 70 patients, and the diagnostic accuracy was 91.4. The overall survival (OS) rates at 12, 24, and 60 months as stratified by histological type were 93.7%, 93.7%, and 88% for patients with germinomas; 84.5%, 63.5%, and 40.7% for patients with pineoblastomas; 89.4%, 80.8%, and 67.2% for patients with NGGCTs; 89.4%, 78.2%, and 72.6% for patients with gliomas; and 40%, 20%, and 0% for patients with embryonal tumors, respectively (p < 0001). The OS at 60 months was significantly higher in the group with GTR (69.7%) than in the group with subtotal resection (40.8%) (p = 0.04). The 5-year progression-free survival was 77% for patients with germinomas, 72.6% for patients with gliomas, 50.8% for patients with NGGCTs, and 38.9% for patients with pineoblastomas. The efficacy of resection varies by histological type, and complete resection is associated with higher OS rates. Endoscopic biopsy is the method of choice for patients presenting with negative tumor markers and hydrocephalus. For tumors restricted to the midline and with extension to the third ventricle, a SCITA is preferred, whereas for lesions with extension toward the fourth ventricle, an OTA is preferred.

A case of vasculogenic mesenchymal tumor in the mediastinum: whole-exome sequencing reveals origin from pre-existing germ cell tumor

Vasculogenic mesenchymal tumor (VMT), a primitive mesenchymal neoplasm enriched by various-sized atypical vessels, is a new entity that develops in mediastinal germ cell tumors (GCTs) with yolk sac tumor (YST) components after chemotherapy. Notably, patients with VMT in the residual GCT have increased risk of developing sarcomas or hematopoietic malignancies. Here, we report a late-teenage male patient with residual teratoma and high-grade VMT after chemotherapy for a mediastinal mixed GCT, including YST. Whole-exome sequencing revealed biallelic inactivation of TP53 and extensive copy number alterations that suggested whole-genome doubling. The biopsy tissue of the mixed GCT before chemotherapy exhibited overlapping genetic alterations to those in the VMT. Immunohistochemical analyses of the VMT showed that the abnormal vessels were positive for cytokeratin, glypican 3, EZH2, and IMP3. The findings that VMT inherits the genetic alterations of pre-existing mixed GCT and exhibits a partly YST-like immunophenotype might contribute to its clinical aggressiveness.

Morphologic Changes in the Thymus Following Chemotherapy for Anterior Mediastinal Germ Cell Tumors: A Study of 91 Cases Emphasizing Pseudoneoplastic Features.

The interpretation of postchemotherapy resections of anterior mediastinal germ cell tumors plays a critical role in determining future patient management and prognosis. Treatment-related changes in the thymus may mimic residual teratoma or microcystic-pattern yolk sac tumor. There is limited extant information concerning therapy-related pseudoneoplastic thymic alterations. To provide diagnostic assistance to distinguish nonneoplastic thymic abnormalities secondary to chemotherapy from residual germ cell tumor. We retrospectively reviewed 91 resections of primary anterior mediastinal germ cell tumors with recognizable thymic gland following cisplatin-based chemotherapy. The cohort included 90 men and 1 woman (median age, 29 years). A spectrum of thymic epithelial alterations occurred, including cystic change (macrocysts [n = 21] or microcysts [n = 20]); hyperplasia with reactive atypia (n = 8); ciliated, mucinous, or columnar cell metaplasia (n = 3); and mature squamous metaplasia (n = 2). These changes were similar to so-called acquired multilocular thymic cysts, were often contiguous with and adjacent to normal thymic epithelium, and lacked the neoplastic-type atypia seen in teratomatous elements in this setting. In 1 case, confluent microcysts closely mimicked the appearance of yolk sac tumor but lacked other distinctive features of that neoplasm and its characteristic immunoreactivity. Recognition of therapy-induced thymic changes is important to avoid misinterpretation as residual teratoma or yolk sac tumor. Continuity with and proximity to benign thymic epithelium, absence of neoplastic-type atypia, and awareness of this phenomenon are important in avoiding this pitfall.

Optimization of serum miR-371a-3p for the detection of chemotherapy-naïve minimal residual germ cell tumor.

423 Background: Currently used serum tumor markers exhibit middling sensitivity and specificity for the detection of germ cell tumors (GCTs). Circulating miRNAs, particularly miR-371a-3p, have exhibited strong performance characteristics in the pre-orchiectomy setting. However, the ability of miR-371a-3p to detect chemotherapy-naïve occult disease is less clear. We previously reported in a small cohort of patients that miR-371a-3p outperforms conventional markers in the context of chemotherapy-naïve minimal residual disease. Here, we expand upon that experience and further refine the assay, including the recommendation of an indeterminate range. Methods: We examined over 250 assays to compare performance between classification based on raw Cq, Cq normalized to miR-30b-5p (∆Cq), or relative quantification to normal serum (RQ). We prospectively collected pre-surgical serum samples and clinical information from GCT patients undergoing primary retroperitoneal lymph node dissection (RPLND) at our institution. Patients were classified based on histology as “Control” (pure teratoma or no GCT) or “GCT”. RNA was extracted from these samples, and miR-371a-3p (target) and miR-30b-5p (reference gene) were detected by qPCR. Performance was assessed by calculation of sensitivity, specificity, and area under the ROC curve (AUC). Results: Sensitivity, specificity, and AUC did not significantly change based on thresholding metric (Cq, ∆Cq, or RQ). We found a 25% chance that any given control sample would return a false positive result, and to combat this, estimated an indeterminate range of Cq 28-35. Repeating any indeterminate sample once improved performance. We then compared the performance of this updated process to a simple binary threshold in a cohort of patients with occult disease. 32 patients were enrolled in the study (15 Control, 17 GCT). 12 samples were indeterminate on first run (6 Control, 6 GCT). 8 remained indeterminate on a second run, all of which harbored teratoma or viable GCT. Inclusion of a second run prevented 3 false positives, improving specificity from 86% to 100% and yielding a sensitivity of 92% and AUC of 0.96 (95% CI: 0.89-1). Conclusions: The use of Cq instead of RQ to classify results for the miR-371a-3p test would eliminate the need for a normal sample in each run without injuring assay performance. In the context of chemotherapy-naïve minimal residual germ cell tumor, consideration of an indeterminate range may improve the performance of the miR-371a-3p test.

Balanced Steady-State Free Precession Techniques Improve Detection of Residual Germ Cell Tumor for Treatment Planning.

Identification of a partial/complete chemotherapy response in pediatric patients with intracranial germ cell tumors is clinically important for radiation treatment and management. Partial/complete response is conventionally determined on postcontrast MR imaging sequences. The purpose of this study was to assess the diagnostic utility of a balanced steady-state free precession sequence as an adjunct to standard MR imaging sequences for the detection of residual tumor in pediatric patients on postchemoreduction pre-radiation planning MR imaging. This was a retrospective study of pediatric patients with intracranial germ cell tumors undergoing postchemotherapy, preradiotherapy MR imaging. Patients underwent 1.5T or 3T MR imaging with pre- and postcontrast T1WIs, T2WIs, and a balanced steady-state free precession sequence. Two neuroradiologists independently reviewed standard MR imaging sequences without the balanced steady-state free precession sequence, then with the balanced steady-state free precession sequence 1 week later. Assessment for partial/complete response was determined using Response Assessment in Neuro-Oncology criteria. A 5-point Likert scale scored the diagnostic confidence of the neuroradiologist rating each study without/with the balanced steady-state free precession sequence. Rates of residual disease concordance and diagnostic confidence levels without/with the balanced steady-state free precession sequence were calculated. Thirty-nine patients were included with 31 males and 8 females (mean age, 14.15 ± 4.26 years). Thirty-one patients had single-site disease; 8 patients had multisynchronous disease (47 sites in total). Compared to review of the standard MR sequences alone, the addition of the balanced steady state free precession sequence resulted in higher rates of tumor partial response categorization and greater diagnostic confidence levels (P < .001, P < .001). The balanced steady-state free precession sequence improves detection of residual chemotherapy-reduced intracranial germ cell tumors and increases diagnostic confidence of the neuroradiologist. The balanced steady-state free precession sequence may be an important adjunct to the standard MR imaging protocol for radiation planning.

Management of Residual Mass in Germ Cell Tumors After Chemotherapy.

The purpose of this review is to educate medical oncologists on the management of patients with residual germ cell tumors and the role of surgical resection after platinum-based chemotherapy. Patients with non-seminomatous testicular cancer and residual enlarged retroperitoneal lymph nodes > 1cm following induction chemotherapy with normal tumor markers should undergo a post-chemotherapy retroperitoneal lymph node dissection. All patients with primary mediastinal non-seminoma should undergo surgical resection of the mediastinal mass post-chemotherapy. These are complex surgeries and require expert surgeons in high-volume centers. Patients with advanced testicular seminoma who have residual masses less than 3cm after chemotherapy can be observed without further intervention. Patients with a residual mass > 3cm should be evaluated with PET scan after 6weeks of chemotherapy. Residual mass with negative PET scan can be followed by surveillance while a positive PET scan requires further work up to rule out active disease.

Zugang zu retrokruralen Tumoren des Mediastinums

Retrocrural tumors of the lower posterior mediastinum are rare. Most tumors in this region involve lymphatic metastasis of germ cell tumors. Formerly these tumors were resected through a combined thoracoabdominal approach, with division of the diaphragm and effecting an at least partial phrenic paresis. The ventral approach via bilateral subcostal incision with cranial extension avoids this problem and allows a bilateral access to the retrocrural space. From November 1999 to December 2005, using this approach we operated on 12 patients with residual germ cell tumors after chemotherapy. In all cases radical resection was obtained. Intra- or postoperative complications did not occur. All patients are still alive and free of disease.

“BURNT-OUT” TESTICULAR GERM CELL TUMORS

Infrequently males are found to have extragonadal germ cell neoplasms without testicular symptoms or clinical evidence of a primary testicular tumor. Germ cell tumors arising in the mediastinum or pineal region without clinical evidence of a testicular primary are likely to represent primary extragonadal germ cell tumors arising in misplaced germ cells. However, there is considerable evidence that retroperitoneal germ cell tumors arising in the absence of a clinically evident testicular neoplasm are less likely to have arisen primarily at that site, and are more likely to represent metastases from a regressed (burnt-out) primary testicular germ cell tumor.1 The phenomenon of spontaneous primary germ cell tumor regression in a setting of metastatic cancer was documented in an autopsy study several decades ago.2 The probability of this occurrence appears roughly to parallel the tendency of an individual tumor type to undergo necrosis; consequently, choriocarcinoma is most likely to burn out followed in frequency by embryonal carcinoma and mixed germ cell tumors. Regression is uncommon with testicular seminoma and probably does not occur in teratoma, a neoplasm that seems resistant to spontaneous necrosis as well as being resistant to therapy induced necrosis. In a setting of known retroperitoneal germ cell tumor with palpably normal testes ultrasound may be helpful in detecting the presence of a subtle mass lesion. Examination of orchiectomy specimens may disclose no apparent gross abnormalities or may demonstrate the presence of scarring, which may be ill-defined and poorly demarcated, or may be circumscribed and relatively easy to identify in the background of normal adjacent tissue (fig. 1). Small cysts or small hard cartilaginous nodules may be evident, reflecting the presence of zones of residual teratoma. Microscopically, the testicular germ cell neoplasm may be entirely or partially burnt-out. In the former case the zone of complete regression is represented by a residual deposit of collagen that typically is infiltrated by hemosiderin laden macrophages, scant lymphocytes and lipid laden macrophages (fig. 2). Intratubular germ cell neoplasia may be evident in the surrounding testicular parenchyma. Dystrophic calcification and necrotic material may be seen within the zone of scarring, arrayed in such a way as to suggest necrotic intratubular germ cell tumor. In cases of incomplete regression small foci of residual invasive germ cell tumor are present, most commonly of teratomatous type. Residual germ cell tumor in the testis may be histologically different from the metastatic cancer. This may reflect selective regression of only discrete elements of a primary testicular mixed germ cell tumor; alternatively, it may reflect transformation of tumor types in the metastatic malignancy.

Residual Masses Post Chemotherapy in Germ Cell Tumors: Role of Fluorodeoxyglucose Positron Emission Tomography Scans

Background: The standard treatment for patients with advanced germ cell tumor is 3–4 cycles of chemotherapy. Post therapy a significant number of patients have residual radiographic abnormalities. Resection of this mass depends on the histology. Those patients with viable cancer will require additional chemotherapy. An imaging study that may identify viable cancer in residual tumor is being evaluated with a Fluro-2-deoxy-D-glucose positron emission tomography (FDG PET) scan. Methods: Thirteen patients with metastatic germ cell tumors who were treated with chemotherapy who had residual abnormalities on CT scan were evaluable. They underwent a PET scan and had surgical resection. The pathological specimens were correlated with the findings on the PET scan. Results: Five patients had a positive PET scan, and eight had no uptake on a PET scan. Ten patients had pathological tissue available for correlation. The overall sensitivity and specificity of a PET scan in evaluating residual masses were 62 and 100%, respectively. Conclusion: PET imaging has limited utility in the management of patients with residual germ cell tumors.

Detection of tumor cells in peripheral blood samples from patients with germ cell tumors using immunocytochemical and reverse transcriptase-polymerase chain reaction techniques.

The aim of this study was to establish sensitive techniques for the detection of residual germ cell tumor cells in peripheral blood and progenitor cell harvests. For this purpose, we used immunocytochemical staining for cytokeratin filaments and reverse transcriptase-polymerase chain reaction (RT-PCR) for epidermal growth factor receptor (EGF-R) and germ cell alkaline phosphatase (GCAP). Germ cell tumor lines Tera-1 and Tera-2 were titrated into normal peripheral blood. Immunocytochemical staining allowed detection of one cytokeratin-positive tumor cell in 10(5) cells. RT-PCR for EGF-R revealed one tumor cell in 10 cells for Tera-1 and one tumor cell in 10(3) cells for Tera-2, while RT-PCR for GCAP displayed a sensitivity of one tumor cell in 10(6) cells for Tera-1, one tumor cell in 10(4) cells for Tera-2, and no positivity in normal mononuclear cells (n = 20) and progenitor cell harvests (n = 5). The analysis of peripheral blood and progenitor cell harvests from 20 patients with germ cell tumors revealed tumor cell contamination in three patients using immunocytochemical staining and in seven patients by RT-PCR for GCAP. We conclude that RT-PCR for GCAP appears to be suitable for the sensitive detection of residual germ cell tumor cells in peripheral blood and progenitor cell harvests.

The unique association of malignant histiocytosis and a primary gonadal germ cell tumor

Previous reports of the association between hematologic malignancies and germ cell tumors have been limited to patients with nonseminomatous tumors, exclusively of mediastinal origin. Among the various hematologic disorders, a large proportion have involved histiocytic tumors, either acute monocytic leukemia or malignant histiocytosis. We now report the first case of simultaneously occurring malignant histiocytosis and testicular embryonal carcinoma. The patient, an 18-year-old male, presented with hepatosplenomegaly due to malignant histiocytosis and was found on further evaluation to have a stage I testicular cancer consisting of teratocarcinoma with endodermal sinus elements. Despite aggressive chemotherapy, the patient died of malignant histiocytosis 6 months after the original diagnosis. The autopsy revealed widespread organ involvement with malignant histiocytosis and no evidence of residual germ cell tumor. This case demonstrates that germ cell tumors associated with hematologic malignancy do not arise solely in extragonadal sites.