Bifocal intracranial germ cell tumor: A diagnostic and therapeutic dilemma for radiation oncologists.

ABSTRACT: An eight-year-old child presenting with increased thirst, raised intracranial tension and visual deterioration was diagnosed with synchronous suprasellar and pineal lesions, for which she underwent partial resection of the suprasellar lesion. Histopathological examination suggested pure germinoma. Tumor marker evaluation showed significantly raised levels of beta human chorionic gonadotropin (ßHCG), favoring a non-germinoma germ cell tumor (NGGCT), leading to a diagnostic dilemma as the histology and ßHCG levels were contradictory. Giving cognizance to the tumor marker levels, the treatment was designed on the lines of NGGCT. Planning of radiotherapy including craniospinal irradiation (CSI) and boost to both lesions was once again a challenge, given the proximity of the lesions to vital organs at risk (OAR). Given the child's age and location of lesions, the target volumes and doses of radiation were designed to optimize between the goals of achieving long-term local control and minimizing late-onset toxicities.

Consensus guidelines for the management of pineal region tumours for low- and middle-income countries.

Pineal region tumours are rare and mainly arise at a younger age. They can be categorized into various types: germ cell tumours (GCT), pineal parenchymal tumours (PPT), meningiomas, gliomas, pineoblastoma, pineal parenchymal tumours of intermediate differentiation, papillary tumours of the pineal region, and SMARCB1- mutant desmoplastic myxoid tumour. Within GCT, germinomas are the most prevalent, comprising the majority of tumours in this region, while nongerminomatous GCTs are also present. In rare instances, metastases from other sites may manifest. These tumours often lead to obstructive hydrocephalus and commonly exhibit symptoms related to mass effect, including headache, nausea, vomiting, and impaired gait stability. Different subtypes of pineal region tumours exhibit distinct radiological characteristics, thus imaging remains the primary diagnostic tool. Histologic diagnosis necessitates biopsy, unless in cases of germ cell tumours, particularly germinomas, which can be identified through elevated levels of tumour markers like alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG) in both cerebrospinal fluid (CSF) and serum. While benign tumours might be effectively treated with radical resection alone, malignant tumours demand additional chemotherapy and radiotherapy following surgical removal.

Robotic left intrapericardial upper lobectomy, pericardial reconstruction and diaphragmatic plication.

Primary mediastinal malignant germ cell tumours are rare, comprising only 1-4% of mediastinal tumours, of which 50-70% are non-seminomatous germ cell tumours. Non-seminomatous germ cell tumours typically demonstrate an excellent response to cisplatin-based chemotherapy. However, in some cases, tumours may persistently enlarge despite normal tumour markers following chemotherapy, leading to a rare condition known as growing teratoma syndrome. This poses a significant challenge for thoracic surgeons, especially when associated with infiltration of neighbouring pulmonary structures. Robot-assisted thoracoscopic surgery is not commonly employed in the resection of large mediastinal tumours. We present a case showcasing the robotic approach to complete resection of a sizeable mediastinal tumour originating from the left/main pulmonary artery, en bloc with a left upper lobectomy, pericardial resection, and reconstruction and diaphragmatic plication.

Undifferentiated embryonal sarcoma of the liver in children: our experience in four difficult cases and three-dimensional practical exploration.

AIMS: To explore rare and difficult cases of undifferentiated embryonal sarcoma of the liver (UESL) in children in a single centre, summarize the diagnosis and treatment experience and analyse the role of a computer-assisted surgery system (Hisense CAS), thus providing a new global vision and three-dimensional perspective. METHODS: We retrospectively collected the clinical data including the diagnoses and treatment processes, of children with UESL confirmed by histopathological examination in our hospital from January 2009 to December 2020. The relationship between the tumour volume and important blood vessels and between the liver volume and tumour volume, as well as other three-dimensional characteristics in the reconstructed three-dimensional model were analysed using Hisense CAS. The findings from this analysis can be used to aid in surgical decision-making and preoperative planning. RESULTS: Four children-3 girls and 1 boy-with UESL were included in the study. The age at onset ranged from 6 to 8 years. All four children presented with symptoms of abdominal discomfort, and abdominal masses were detected during physical examination. Owing to the wishes of their parents and the possibility that the disease was benign, all four children underwent one-stage radical surgery. For patient 1, a three-dimensional reconstruction was created during the initial diagnosis, which made accurate evaluation and planning of the preoperative procedure challenging. In patient 2, the tumour was located in the middle lobe of the liver and involved the first and second hepatic hilum. For patient 3, the pathological diagnosis of the tumour after surgery was challenging, but eventually, the diagnosis was confirmed through histochemistry and consultation with higher-level hospitals. Patient 4 had a giant tumour, which had a preoperative simulated future liver remnant volume (FLV) that was 21.0% of the total volume of the liver and tumour (TLTV). According to the standard liver volume (SLV) for children, the FLV was 77.0% of the SLV, making surgery feasible. All four children underwent complete resection, and only patient 4 experienced recurrence below the diaphragm 19 months after surgery. Currently, the 3-year overall survival rate is 100%, and the 3-year event-free survival rate is 75%. CONCLUSION: UESL in children is rare, and the key to diagnosis and treatment is complete surgical resection. Through individualized three-dimensional surgical planning, accurate and complete resection of difficult and complex UESL in children can be achieved, leading to a favourable prognosis.

Primary lung chordoma: a case report.

BACKGROUND: Chordoma, a rare malignant tumor arising from notochordal tissue, usually occurs along the spinal axis. Only a few published reports of primary lung chordomas exist. Herein, we present a case of primary lung chordoma and discuss important considerations for diagnosing rare chordomas. CASE PRESENTATION: We report a case of primary lung chordoma in a 39-year-old male with a history of testicular mixed germ-cell tumor of yolk sac and teratoma. Computed tomography revealed slow-growing solid lesions in the left lower lobe. We performed wedge resection for suspected germ-cell tumor lung metastasis. Histologically, large round or oval cells with eosinophilic cytoplasm were surrounded by large cells with granular, lightly eosinophilic cytoplasm. Tumor cells were physaliphorous. Immunohistochemistry was positive for brachyury, S-100 protein, epithelial membrane antigen, vimentin, and cytokeratin AE1/AE3, suggesting pulmonary chordoma. Re-examination of the testicular mixed germ-cell tumor revealed no notochordal elements. Although some areas were positive for brachyury staining, hematoxylin and eosin (HE) staining did not show morphological features typical of chordoma. Complementary fluorescence in situ hybridization (FISH) of the lung tumor confirmed the absence of isochromosome 12p and 12p amplification. Thus, a final diagnosis of primary lung chordoma was established. CONCLUSIONS: In patients with a history of testicular mixed germ cell tumors, comparison of histomorphology using HE and Brachyury staining of lung and testicular tumors, and analyzing isochromosome 12p and 12p amplification in lung tumors using FISH is pivotal for the diagnosis of rare lung chordomas.

Effect of delayed diagnosis on neuroendocrine function in individuals with suprasellar germ cell tumors.

Purpose: The impact of delayed diagnosis on tumor-related prognosis appears to be minimal in individuals with intracranial germ cell tumors (iGCTs). However, its effect on neuroendocrine functions remains unclear. We aimed to assess the effects of delayed diagnosis on neuroendocrine function in individuals with suprasellar GCTs. Methods: We conducted a retrospective cohort study of 459 individuals with suprasellar GCTs and categorized them into two groups based on disease duration: delayed diagnosis (> 6 months) and non-delayed diagnosis (≤ 6 months). We compared endocrinological symptoms, neuroendocrine dysfunction and its grading (categorized into 0-3 grades based on severity), and recovery from neuroendocrine dysfunction in both groups. Results: Patients with delayed diagnosis exhibited higher incidences of amenorrhea, slow growth, fatigue, and polyuria/polydipsia. Neuroendocrine dysfunction, including central adrenal insufficiency (CAI), central hypothyroidism (CHT), arginine vasopressin deficiency (AVP-D), growth hormone deficiency, hypogonadism, and hyperprolactinemia, was more pronounced in the delayed diagnosis group at diagnosis, the end of treatment, and the last follow-up. Furthermore, individuals with delayed diagnosis showed higher grades of neuroendocrine dysfunction at diagnosis (OR=3.005, 95% CI 1.929-4.845, p<0.001), end of oncologic treatment (OR=4.802, 95% CI 2.878-8.004, p<0.001), and last follow-up(OR=2.335, 95% CI 1.307-4.170, p=0.005) after adjusting for confounders. Finally, less recovery, particularly in CAI, CHT, and AVP-D, was seen among the group with delayed diagnosis after treatment. Conclusion: Among individuals with suprasellar GCTs, delayed diagnosis is associated with increased, more severe, and less recovered neuroendocrine dysfunction, emphasizing the importance of early diagnosis and treatment to reduce neuroendocrine dysfunction.

Expression of Podocalyxin Potentially Decorated With Low-sulfated Keratan Sulfate in Human Testicular Embryonal Carcinoma.

SummaryWe previously demonstrated that among various histological types of human testicular germinal cell tumors (GCTs), embryonal carcinoma (EC) preferentially expresses low-sulfated keratan sulfate (KS) consisting of repeating N-acetyllactosamine (LacNAc) disaccharide units composed of galactose and 6-O-sulfated N-acetylglucosamine (GlcNAc), which is recognized by the R-10G antibody. Recently, we generated another anti-low-sulfated KS monoclonal antibody, 294-1B1. Immunohistochemical analysis of testicular GCTs (n=83) revealed that the low-sulfated KS recognized by 294-1B1 is also preferentially expressed in EC but minimally in other GCT histological types. Moreover, immunolabeling with R-10G and 294-1B1 antibodies was resistant to peptide-N-glycosidase F digestion, and EC was not stained with the MECA-79 antibody, indicating that low-sulfated KS expressed in EC contains mucin-type core 2 O-glycans carrying GlcNAc-6-O-sulfated oligo-LacNAc. Double immunofluorescence staining showed that R-10G and 294-1B1 antibody signals colocalized with those for podocalyxin (PODXL). Furthermore, western blot analysis of recombinant human PODXL•IgG fusion proteins secreted from low-sulfated KS-expressing human embryonic kidney 293T cells revealed that PODXL functions as a core protein for low-sulfated KS. Taken together, these findings strongly suggest that the PODXL glycoform decorated with low-sulfated KS is preferentially expressed in human testicular EC and may therefore serve as a diagnostic marker for this malignancy.

Pathogenesis and pathobiology of testicular germ cell tumours: a view from a developmental biological perspective with guidelines for pathological diagnostics.

Testicular germ cell tumours (GCT) are divided into three different subtypes (types I-III) regarding to their developmental origin, histological differences and molecular features. Type I GCT develop from disturbed primordial germ cells and most commonly occur in children and young adolescents, which is why they are referred to as prepubertal GCT. Type II GCT develop from a non-invasive germ cell neoplasia in situ (GCNIS) and show an isochromosome 12p (i12p) or gain of 12p material as a common and characteristic molecular alteration. Type III GCT originate from distorted postpubertal germ cells (e.g. spermatogonia) in adult patients and have changes on chromosome 9 with amplification of the DMRT1 gene. Type I GCT encompass prepubertal-type teratomas and yolk-sac tumours (YST). Type II GCT include seminoma, embryonal carcinoma, choriocarcinoma, postpubertal-type teratoma and postpubertal-type YST. Types I and II GCT both show similar morphology, but are separated from each other by the detection of a GCNIS and an i12p in type II GCT. For type II GCT it is especially important to detect non-seminomatous elements, as these tumours have a worse biological behaviour and need a different treatment to seminomas. In contrast to types I and II GCT, type III tumours are equivalent to spermatocytic tumours and usually occur in elderly men, with few exceptions in young adults. The development of types I and II GCT seems to depend not upon driver mutations, but rather on changes in the epigenetic landscape. Furthermore, different pluripotency associated factors (e.g. OCT3/4, SOX2, SOX17) play a crucial role in GCT development and can be used as immunohistochemical markers allowing to distinguish the different subtypes from each other in morphologically challenging tissue specimens. Especially in metastatic sites, a morphological and immunohistochemical diagnostic algorithm is important to detect small subpopulations of each non-seminomatous GCT subtype, which are associated with a poorer prognosis and need a different treatment. Furthermore, primary extragonadal GCT of the retroperitoneum or mediastinum develop from misguided germ cells during embryonic development, and might be challenging to detect in small tissue biopsies due to their rarity at corresponding sites. This review article summarises the pathobiological and developmental aspects of the three different types of testicular GCT that can be helpful in the histopathological examination of tumour specimens by pathologists.

Extracranial metastasis from a frontal embryonal tumor to the parotid: Cytomorphologic features of a rare occurrence.

Embryonal tumors of the central nervous system (CNS) are rare and aggressive malignancies accounting for less than 1% of all central nervous system tumors. The occurrence of metastasis to extracranial sites, especially the parotid region, is highly uncommon. We present a rare case of metastatic frontal embryonal tumor (ET) in the parotid region. A 9-year-old boy presented with a progressively enlarging left parotid mass. Past history revealed that he was a known case of a frontal lobe embryonal tumor. Fine-needle aspiration cytology (FNAC) combined with immunocytochemistry from the parotid revealed a metastatic embryonal tumor. This case report highlights the importance of considering metastatic tumors in evaluating parotid masses, even in pediatric patients, and emphasizes the diagnostic potential of FNAC in diagnosing such rare and unusual tumors for prompt and appropriate patient management.

The Effect of Socioeconomic Status and Race/Ethnicity on the Risk of Presenting With Advanced Stage at Diagnosis in Embryonal Tumors.

We evaluated whether socioeconomic status (SES), race/ethnicity, and their interaction were associated with the presentation of advanced stage at diagnosis in embryonal tumors. Children 0 to 19 years of age diagnosed with embryonal tumors between 2006 and 2018 were identified from the US Surveillance, Epidemiology, and End Results program database specialized with Census Tract SES/Rurality. SES quintile was derived from a composite index for census tracts. We performed logistic regression to estimate odds ratios (ORs) and 95% confidence intervals by SES and race/ethnicity, adjusting for sex, age, and diagnosis year. Overall, no significant associations were found between either SES or race/ethnicity and the risk of presenting with advanced stage at diagnosis, although patterns of risk reductions were observed in atypical teratoid/rhabdoid tumors and embryonal rhabdomyosarcoma with increasing SES. In the stratified analysis, decreased odds of presenting with advanced-stage embryonal rhabdomyosarcoma were observed for Hispanics with higher SES (OR: 0.24, 95% Confidence Interval: 0.08-0.75) compared with Hispanics with lower SES. Future studies incorporating individual-level SES, cancer-specific staging information, and potential demographic, clinical, epidemiological, and genetic risk factors are warranted to confirm our findings.

Diagnostic and therapeutic challenges with germ cell tumours associated with transverse testicular ectopia and persistent Müllerian duct syndrome.

Transverse testicular ectopia (TTE) is an infrequent ectopic testis where both testes descend via the same inguinal canal, located in the same hemiscrotum, and augments the risk of developing testicular tumours. Type II TTE is accompanied by persistent Müllerian duct syndrome, where the Müllerian structures persist for various reasons. Here, we present a case of an adult in his early 30s, who presented with a right testicular swelling and was diagnosed as type II TTE and testicular mixed germ cell tumour after surgery. We could find only 13 similar cases of TTE and testicular tumours in the literature. Our case highlights the importance of clinical acumen with detailed history, meticulous clinical examination, radiological investigations and a detailed pathological examination while dealing with such sporadic presentations.

Micro-RNA-371a-3p in Germ Cell Testicular Tumors on Diagnosis: A Prospective Case-Control Study in Turkish Population.

PURPOSE: We aimed to evaluate the diagnostic sensitivity and specificity of the miRNA-371a-3p for the primary diagnosis of germ cell tumors (GCT) and to investigate its relationship with pathological factors and clinical stage in the Turkish population. MATERIALS AND METHODS: In this prospective study, a total of 60 patients with GCTs, and 40 healthy male controls were examined for serum levels of miRNA-371a-3p before orchiectomy and again two weeks after surgery. The miRNA-371a-3p, alpha-fetoprotein (AFP), and beta-human chorionic gonadotropin (bHCG) levels in the preoperative and postoperative periods were compared at different clinical stages. Receiver operating characteristics curve analyses were performed to determine the sensitivity and specificity of miRNA-371a-3p. Clinical and pathological factors such as clinical stage (CS), tumor size, histology, rete testis invasion, and lymphovascular invasion, potentially impacting miRNA-371a-3p expression levels (relative quantity, RQ), were evaluated statistically. RESULTS: The sensitivity of miR-371a-3p in GCT patients was 98.3%, and the specificity was 95% (AUC = 0.997 [95%Cl:0.99-1], p < .001). miR-371a-3p expression was not detected in two patients with teratoma. The median miR-371a-3p RQ was 489 times in GCT and 2.2 times in the Control group (p < .001). In the postoperative period, there was a significant decrease in AFP and bHCG levels in all CS-1 (p = .01) and 30% of the other CS (p = .3). Throughout this time there was a decrease of 19 times at the miR-371a-3p RQ in CS-1(p < .001) and 1.6 times in the other CS (p < .001). The miR-371a-3p RQs were correlated with tumor size and CS. CONCLUSION: The miR-371a-3p seems to have higher diagnostic accuracy than classical serum tumor markers in GCT.

Current outstanding challenges in germ cell tumors.

PURPOSE OF REVIEW: Despite the remarkable advances in the treatment of germ cell tumors (GCT), several challenges remain. This review aims to highlight some of these challenges and provide guidance on how to navigate through them. RECENT FINDINGS: Patients with International Germ Cell Cancer Collaborative Group poor risk disease have worse prognosis and investigating novel therapeutic interventions are warranted in this population. Patients with brain metastases require a multidisciplinary approach by a group of clinicians experienced in the management of germ cell tumors. Patients with platinum refractory disease have poor prognosis and development of novel treatment options is urgently needed. Conventional tumor markers including alpha fetoprotein and human chorionic gonadotropin remain standard. Development of novel biomarkers to detect minimal residual disease or teratoma is needed. SUMMARY: Management of patients with GCT requires a multidisciplinary approach. Patients should preferably be evaluated at tertiary care centers with expertise in the management of this disease.

Mediastinal Germ-cell Tumors Relapse in a Male With Klinefelter Syndrome. Is Longer Surveillance Needed?

Germ cell tumors (GCTs) are a heterogeneous group of pediatric cancers. In up to one-third of male patients, a primary mediastinal location is associated with the presence of Klinefelter syndrome (KS). We describe a case of mediastinal GCT in a patient, with unacknowledged KS, that presented a relapse 7 years from diagnosis, that is, 2 years after the end of the follow-up program usually recommended for patients with GCT. There are no recommendations for screening for KS in patients with mediastinal GCT and there are no specific guidelines for surveillance of GCT in KS patients. Our experience suggests that KS should be suspected in patients with mediastinal GCT, and a longer follow-up plan should be implemented when GCT occurs in patients with KS.

New insights on testicular cancer prevalence with novel diagnostic biomarkers and therapeutic approaches.

BACKGROUND: Testicular cancer (TC), comprising merely 1% of male neoplasms, holds the distinction of being the most commonly encountered neoplasm among young males. RECENT FINDINGS: Most cases of testicular neoplasms can be classified into two main groups, namely germ cell tumors representing approximately 95% of the cases, and sex cord-stromal tumors accounting for about 5% of the cases. Moreover, its prevalence is on the rise across the globe. TC is a neoplastic condition characterized by a favorable prognosis. The advent of cisplatin-based chemotherapeutic agents in the latter part of the 1970s has led to a significant enhancement in the 5-year survival rate, which presently surpasses 95%. Given that TC is commonly detected before reaching the age of 40, it can be anticipated that these individuals will enjoy an additional 40-50 years of life following successful treatment. The potential causes of TC are multifactorial and related to different pathologies. Accurate identification is imperative to guarantee the utmost efficacious and suitable therapy. To a certain degree, this can be accomplished through the utilization of blood examinations for neoplastic indicators; nonetheless, an unequivocal diagnosis necessitates an evaluation of the histological composition of a specimen via a pathologist. CONCLUSION: TC is multifactorial and has various pathologies, therefore this review aimed to revise the prenatal and postnatal causes as well as novel diagnostic biomarkers and the therapeutic strategies of TC.

Clinical characteristics and predictive factors of delayed diagnosis in patients with sellar germ cell tumors.

PURPOSE: To investigate the clinical characteristics and predictive factors associated with delayed diagnosis in patients with sellar germ cell tumors (GCTs), aiming for early diagnosis. METHODS: A total of 345 patients with sellar GCTs were retrospectively collected. Patients were classified into a delayed diagnosis group (> 6 months from onset to diagnosis) and a non-delayed diagnosis group (≤ 6 months). We compared general characteristics, clinical symptoms, diagnostic methods, treatment strategies, tumor prognosis, and pituitary function between the two groups. Predictive factors for delayed diagnosis were explored using multivariate logistic regression analysis. RESULTS: 225 patients (65.2%) experienced delayed diagnosis. Although there was no association between delayed diagnosis and survival rates or tumor recurrence rates, the delayed diagnosis group had a higher incidence of central diabetes insipidus, central adrenal insufficiency, central hypothyroidism, central hypogonadism, and growth hormone deficiency. Moreover, polyuria/polydipsia (OR 5.46; 95% CI 2.33-12.81), slow growth (OR 5.86; 95% CI 2.61-13.14), amenorrhea (OR 6.82; 95% CI 2.68-17.37), and germinoma (OR 4.99; 95% CI 1.08-3.61) were associated with a higher risk of delayed diagnosis, while older age of onset (OR 0.88; 95% CI 0.84-0.94) and nausea/vomiting (OR 0.31; 95% CI 0.15-0.63) contributed to earlier diagnosis. CONCLUSION: In patients with sellar GCTs, delayed diagnosis is common and linked to increased pituitary dysfunction. The initial symptoms of slow growth, polyuria/polydipsia, and amenorrhea, as well as germinoma with negative tumor markers, predict the possibility of a delayed diagnosis. Early diagnosis is crucial to minimize the impact of sellar GCTs on pituitary function.

Burnt out testicular tumor - A case report.

ABSTRACT: Spontaneous regression of testicular tumors known as burnt-out tumor of testis is a rare entity and is seen in about 5% of testicular germ cell tumors. It is described as a spontaneously, completely, or partially regressed testicular tumor with or without metastasis in the absence of any treatment. This entity is now included in the 2016 classification of testicular tumors. This is probably only the second case presented in India. High degree of awareness of this entity by the pathologist, clinician, and radiologist is necessary for proper management and survival of the patient.

MicroRNAs in Testicular Germ Cell Tumors: The Teratoma Challenge.

Testicular germ cell tumors (TGCTs) are relatively common in young men, making accurate diagnosis and prognosis assessment essential. MicroRNAs (miRNAs), including microRNA-371a-3p (miR-371a-3p), have shown promise as biomarkers for TGCTs. This review discusses the recent advancements in the use of miRNA biomarkers in TGCTs, with a focus on the challenges surrounding the noninvasive detection of teratomas. Circulating miR-371a-3p, which is expressed in undifferentiated TGCTs but not in teratomas, is a promising biomarker for TGCTs. Its detection in serum, plasma, and, potentially, cystic fluid could be useful for TGCT diagnosis, surveillance, and monitoring of therapeutic response. Other miRNAs, such as miR-375-3p and miR-375-5p, have been investigated to differentiate between TGCT subtypes (teratoma, necrosis/fibrosis, and viable tumors), which can aid in treatment decisions. However, a reliable marker for teratoma has yet to be identified. The clinical applications of miRNA biomarkers could spare patients from unnecessary surgeries and allow for more personalized therapeutic approaches. Particularly in patients with residual masses larger than 1 cm following chemotherapy, it is critical to differentiate between viable tumors, teratomas, and necrosis/fibrosis. Teratomas, which mimic somatic tissues, present a challenge in differentiation and require a comprehensive diagnostic approach. The combination of miR-371 and miR-375 shows potential in enhancing diagnostic precision, aiding in distinguishing between teratomas, viable tumors, and necrosis. The implementation of miRNA biomarkers in TGCT care could improve patient outcomes, reduce overtreatment, and facilitate personalized therapeutic strategies. However, a reliable marker for teratoma is still lacking. Future research should focus on the clinical validation and standardization of these biomarkers to fully realize their potential.