Abstract BACKGROUND Pineoblastoma is an aggressive, rare tumor of the pineal gland. Due to rarity of pineoblastoma, no large-scale prospective clinical trial data is available to guide clinical practice. Patients often receive treatment based on approaches to other high-grade embryonal central nervous system (CNS) tumors such as medulloblastoma. Multimodality treatment typically consists of maximal surgical resection followed by radiation therapy and chemotherapy. Despite treatment, recurrence is common and five-year survival rate is 60-70%. Pineoblastoma can disseminate through the leptomeninges, which is associated with poor survival. No therapy is known to confer a survival benefit in the setting of leptomeningeal disease (LMD) related to pineoblastoma. MATERIAL AND METHODS We report radiographic response and longer than expected survival for a patient with LMD related to pineoblastoma treated with single-agent temozolomide chemotherapy. RESULTS A 22-year-old male with a history of pineoblastoma presented with periodic headaches and leptomeningeal enhancement on surveillance imaging. 5 years prior to presentation (age 17), he was initially diagnosed with pineoblastoma after gross total resection followed by treatment with proton craniospinal radiation and adjuvant carboplatin/vincristine chemotherapy. Surveillance craniospinal MRIs identified diffuse leptomeningeal enhancement involving the posterior fossa and diffusely throughout the spine and lumbosacral nerve roots. While cerebrospinal fluid (CSF) cytology was negative for tumor cells on three separate occasions, CSF cell-free DNA (cfDNA) analysis isolated tumor DNA. He was started on temozolomide chemotherapy with near complete resolution of leptomeningeal enhancement on MRI after 2 cycles and complete resolution after 6 cycles. Treatment was well-tolerated with grade 1 fatigue as the only toxicity. Patient remains alive 20 months after initial diagnosis of LMD with resolution of headaches and durable radiographic response. CONCLUSION This case highlights utility of CSF cfDNA as a companion tool for diagnosis of LMD. Durable clinical and radiographic response achieved suggests temozolomide can be considered as a salvage treatment option for recurrent pineoblastoma with LMD.

Although patients benefit from immune checkpoint inhibition (ICI) therapy in a broad variety of tumors, resistance may arise from immune suppressive tumor microenvironments (TME), which is particularly true of hepatocellular carcinoma (HCC). Since oncolytic viruses (OV) can generate a highly immune-infiltrated, inflammatory TME, OVs could potentially restore ICI responsiveness via recruitment, priming, and activation of anti-tumor T cells. Here we find that on the contrary, an oncolytic vesicular stomatitis virus, expressing interferon-ß (VSV-IFNß), antagonizes the effect of anti-PD-L1 therapy in a partially anti-PD-L1-responsive model of HCC. Cytometry by Time of Flight shows that VSV-IFNß expands dominant anti-viral effector CD8 T cells with concomitant relative disappearance of anti-tumor T cell populations, which are the target of anti-PD-L1. However, by expressing a range of HCC tumor antigens within VSV, combination OV and anti-PD-L1 therapeutic benefit could be restored. Our data provide a cautionary message for the use of highly immunogenic viruses as tumor-specific immune-therapeutics by showing that dominant anti-viral T cell responses can inhibit sub-dominant anti-tumor T cell responses. However, through encoding tumor antigens within the virus, oncolytic virotherapy can generate anti-tumor T cell populations upon which immune checkpoint blockade can effectively work.

Glioblastoma (GBM) is the most prevalent malignant tumor of the central nervous system. The prognosis of GBM is grim, with a median overall survival of 14.6 months and only 6.9% of patients surviving 5 years after the initial diagnosis. Despite poor outcomes, standard therapy of surgical resection, radiotherapy, chemotherapy, and tumor-treating fields has remained largely unchanged. The introduction of immune checkpoint inhibitors (ICI) has been a paradigm shift in oncology, with efficacy across a broad spectrum of cancer types. Nonetheless, investigations of ICIs in both newly diagnosed and recurrent GBM have thus far been disappointing. This lack of clinical benefit has been largely attributed to the highly immunosuppressive nature of GBM. However, immunotherapy still holds promise for the treatment of GBM, with combinatorial strategies offering hope for potentially overcoming these current limitations. In this review, we discuss the outcomes of clinical trials employing ICIs in patients with GBM. Afterward, we review ICI combination strategies and how these combinations may overcome the immunosuppressive microenvironment of GBM in the context of preclinical/clinical evidence and ongoing clinical trials.

Background: Extracranial metastases occur in <2% of cases of glioblastoma (GBM). When metastases do occur, bone is the most common destination. Herein, we review clinical characteristics of GBM patients with osseous metastases and evaluate both potential risk factors and prognostic significance. Methods: Using an institutional database, we identified and retrospectively analyzed 6 patients with both GBM and osseous metastases. We collected data on patient demographics, tumor genetics, clinical courses, and outcomes. Given the rarity of metastatic GBM, we conducted historical comparisons using previously published literature. Results: Five patients with osseous metastases (83%) were male, with a median age of 46 years at GBM diagnosis (range: 20-84). All patients had IDH-wildtype, MGMT promoter unmethylated GBM and 5 (83%) had alterations in TP53. All patients underwent surgical resection for GBM followed by radiation with concurrent and adjuvant temozolomide. Four patients (67%) received bevacizumab prior to bone metastasis diagnosis. Bone metastases were discovered at a median of 12.2 months (range: 5.3-35.2) after GBM diagnosis and 4.8 months after starting bevacizumab (range: 3.5-13.2). Three patients (50%) received immunotherapy. After osseous metastasis diagnosis, the median survival was 25 days (range: 13-225). Conclusion: In our cohort, most patients were male and young at the time of GBM diagnosis. All patients had IDH-wildtype, MGMT promoter unmethylated GBM, and most had alterations in TP53, which may be important for osseous metastasis. Most patients received bevacizumab, which has been associated with earlier metastasis. Osseous metastases of GBM occur and portend a dismal prognosis in an already aggressive malignancy.

Purpose of Review This review aims to discuss recent research regarding the biomolecules explored in liquid biopsies and their potential clinical uses for adult-type diffuse gliomas. Recent Findings Evaluation of tumor biomolecules via cerebrospinal fluid (CSF) is an emerging technology in neuro-oncology. Studies to date have already identified various circulating tumor DNA, extracellular vesicle, micro-messenger RNA and protein biomarkers of interest. These biomarkers show potential to assist in multiple avenues of central nervous system (CNS) tumor evaluation, including tumor differentiation and diagnosis, treatment selection, response assessment, detection of tumor progression, and prognosis. In addition, CSF liquid biopsies have the potential to better characterize tumor heterogeneity compared to conventional tissue collection and CNS imaging. Summary Current imaging modalities are not sufficient to establish a definitive glioma diagnosis and repeated tissue sampling via conventional biopsy is risky, therefore, there is a great need to improve non-invasive and minimally invasive sampling methods. CSF liquid biopsies represent a promising, minimally invasive adjunct to current approaches which can provide diagnostic and prognostic information as well as aid in response assessment.

Leptomeningeal disease (LMD) remains a challenging condition with a dismal prognosis. In this case study, we report partial response of LMD in a patient with metastatic large cell neuroendocrine carcinoma following treatment with proton craniospinal irradiation (CSI), bevacizumab, and pembrolizumab. Two years after the initial diagnosis, he presented with LMD. He underwent proton CSI with bevacizumab followed by combination therapy with pembrolizumab and bevacizumab. He had a partial disease response with progression-free survival after LMD diagnosis of 4.6 months. He unfortunately developed pembrolizumab induced hypophysitis, after which he experienced rapid neurologic clinical progression. Overall, this novel combination led to a durable partial response which warrants prospective evaluation.

Background Neurofibromatosis type 2 (NF2)-related schwannomatosis is an autosomal dominant tumor-predisposition syndrome characterized by bilateral vestibular schwannomas (VS). In patients with VS associated with NF2, vascular endothelial growth factor A inhibitor, bevacizumab, is a systemic treatment option. The aim of this study is to retrospectively evaluate NF2 patient responses to bevacizumab on VS growth and symptom progression.Methods This is a retrospective analysis of patients seen at the Mayo Clinic Rochester Multidisciplinary NF2 Clinic.Results Out of 76 patients with NF2 evaluated between 2020 and 2022, we identified 19 that received treatment with bevacizumab. Thirteen of these patients discontinued bevacizumab after median treatment duration of 12.2 months. The remaining 6 patients are currently receiving bevacizumab treatment for a median duration of 9.4 months as of March, 2023. Fifteen patients had evaluable brain MRI data, which demonstrated partial responses in 5 patients, stable disease in 8, and progression in 2. Within 6 months of bevacizumab discontinuation, 5 patients had rebound growth of their VS greater than 20% from their previous tumor volume, while 3 did not. Three patients with rebound growth went on to have surgery or irradiation for VS management.Conclusions Our single-institution experience confirms prior studies that bevacizumab can control progression of VS and symptoms associated with VS growth. However, we note that there is the potential for rapid VS growth following bevacizumab discontinuation, for which we propose heightened surveillance imaging and symptom monitoring for at least 6 months upon stopping anti-VEGF therapy.

Despite decades of research and numerous clinical trials, the prognosis of patients diagnosed with glioblastoma (GBM) remains dire with median observed survival at 8 months. There is a critical need for novel treatments for GBM, which is the most common malignant primary brain tumor. Major advances in cancer therapeutics such as immune checkpoint inhibitors and chimeric antigen receptor (CAR) T-cell therapy have not yet led to improved outcomes for GBM. Conventional therapy of surgery followed by chemoradiation with or without tumor treating fields remains the standard of care. One of the many approaches to GBM therapy currently being explored is viral therapies. These typically work by selectively lysing target neoplastic cells, called oncolysis, or by the targeted delivery of a therapeutic transgene via a viral vector. In this review, we discuss the underlying mechanisms of action and describe both recent and current human clinical trials using these viruses with an emphasis on promising viral therapeutics that may ultimately break the field's current stagnant paradigm.

Abstract BACKGROUND Although glioblastoma (GBM) is the most common malignant primary brain tumor in adults, extracranial metastasis is rare, occurring in <2% of cases. This rarity has been attributed to the blood brain barrier, immunologic factors, lack of traditional lymphatics in the brain, and the poor prognosis of GBM, limiting its opportunity to metastasize. When GBM does metastasize, bone is the most common destination. GBM may spread hematogenously to bone, especially to vertebral bodies via the surrounding venous plexus. In this single-institution study, we review the clinical characteristics of GBM patients with osseous metastases and evaluate potential risk factors and prognostic significance. MATERIAL AND METHODS Using an institutional database, we identified and retrospectively analyzed 6 GBM patients with osseous metastases and studied their demographics, tumor genetics, clinical courses, and outcomes. RESULTS Five of 6 (83%) GBM patients with osseous metastases were male, with a median age of 46 years at GBM diagnosis (range: 20-84). All patients had IDH wild type and MGMT unmethylated GBM with mutations in TP53. Two patients (33%) were initially diagnosed with gliosarcoma. All patients were treated with surgical resection followed by radiation with concurrent and adjuvant temozolomide. Five patients (83%) received bevacizumab for vasogenic edema (n=4) or intracranial tumor progression (n=1) prior to bone metastasis diagnosis. Bone metastases were diagnosed a median of 12.2 months (range: 5.3-35.2) after GBM diagnosis and 4.8 months after starting bevacizumab (range: 3.5-13.2). Two patients (33%) received immune checkpoint inhibitor therapy and two patients (33%) received tumor-treating fields prior to bone metastasis discovery. Bone metastases were symptomatic in 2 patients, presenting with back pain (n=1) and leg weakness and urinary incontinence (n=1). Three patients (50%) had concurrent metastases to other organs. Osseous metastases were biopsy-confirmed in 3 (50%) cases, while the other 3 patients had no known alternative malignancy to explain their bone metastases. After osseous metastasis discovery, the median survival was 27 days (range: 13-225). CONCLUSION Most of our GBM patients with osseous metastases were male and most, but not all, were young at GBM diagnosis. Tumor genetics common to all patients included IDH wild type, MGMT unmethylated status, and TP53 mutation, which may be important for osseous metastasis. Most patients received bevacizumab, which may be associated with earlier metastasis. While rare, metastatic GBM should be within the differential for GBM patients with bone pain or progressive neurologic symptoms, as osseous metastases portend a dismal prognosis in an already aggressive malignancy.

Belzutifan is a selective inhibitor of hypoxia-inducible factor 2 alpha (HIF-2a) that has emerged as a targeted therapy option for Von Hippel–Lindau (VHL) syndrome-associated tumors with recent FDA approval. There is limited real-world evidence regarding safety and efficacy in CNS hemangioblastoma. Our objective was to report on our clinical experience with belzutifan in adult patients with VHL-associated CNS hemangioblastoma. We retrospectively reviewed our institutional experience of belzutifan in adult patients (> 18 years of age at time of therapy) with VHL and craniospinal CNS hemangioblastomas not amenable to surgical resection. The period for study review was October 2021 to March 2023. 4 patients (all female) with a median age of 36 years at time of belzutifan initiation were included. Median duration of therapy at last follow-up was 11 months (6–17 months). All patients had radiographic response to therapy after a median of 3 months (2–5 months), with maximal response to therapy after a median of 8 months (3–17 months). Therapy was well tolerated, with the most common adverse effect being anemia. No patients had treatment pauses or dose adjustments due to belzutifan-related toxicity. No patients experienced hypoxia. We showed that belzutifan is safe and well-tolerated with strong disease response for CNS hemangioblastoma in adults with VHL, supporting continued use of belzutifan in this patient population. Future studies should assess duration of treatment, effects of cessation after long-term use, and markers of therapeutic response.

Glioblastoma (GBM) is the most common malignant primary brain tumor and confers a dismal prognosis. With only two FDA-approved therapeutics showing modest survival gains since 2005, there is a great need for the development of other disease-targeted therapies. Due, in part, to the profound immunosuppressive microenvironment seen in GBMs, there has been a broad interest in immunotherapy. In both GBMs and other cancers, therapeutic vaccines have generally yielded limited efficacy, despite their theoretical basis. However, recent results from the DCVax-L trial provide some promise for vaccine therapy in GBMs. There is also the potential that future combination therapies with vaccines and adjuvant immunomodulating agents may greatly enhance antitumor immune responses. Clinicians must remain open to novel therapeutic strategies, such as vaccinations, and carefully await the results of ongoing and future trials. In this review of GBM management, the promise and challenges of immunotherapy with a focus on therapeutic vaccinations are discussed. Additionally, adjuvant therapies, logistical considerations, and future directions are discussed.

In multiple models of oncolytic virotherapy, it is common to see an early anti-tumor response followed by recurrence. We have previously shown that frontline treatment with oncolytic VSV-IFN-β induces APOBEC proteins, promoting the selection of specific mutations that allow tumor escape. Of these mutations in B16 melanoma escape (ESC) cells, a C-T point mutation in the cold shock domain-containing E1 (CSDE1) gene was present at the highest frequency, which could be used to ambush ESC cells by vaccination with the mutant CSDE1 expressed within the virus. Here, we show that the evolution of viral ESC tumor cells harboring the escape-promoting CSDE1C-T mutation can also be exploited by a virological ambush. By sequential delivery of two oncolytic VSVs in vivo, tumors which would otherwise escape VSV-IFN-β oncolytic virotherapy could be cured. This also facilitated the priming of anti-tumor T cell responses, which could be further exploited using immune checkpoint blockade with the CD200 activation receptor ligand (CD200AR-L) peptide. Our findings here are significant in that they offer the possibility to develop oncolytic viruses as highly specific, escape-targeting viro-immunotherapeutic agents to be used in conjunction with recurrence of tumors following multiple different types of frontline cancer therapies.

Abstract BACKGROUND Neurofibromatosis type 2-related schwannomatosis (NF2) is an autosomal dominant tumor-predisposition syndrome characterized by bilateral vestibular schwannomas (VS) as well as other nervous system tumors. Management decisions for NF2-related VS are typically predicated on tumor size, associated symptoms, patient age, and comorbidities. Observation, surgical resection, and stereotactic radiosurgery can be viable options. In patients with VS associated with NF2, vascular endothelial growth factor A (VEGF-A) inhibitor, bevacizumab, is a systemic treatment option. In this single institution study, we review our clinical experience in patients with NF2 who received bevacizumab for VS and evaluate the effect of bevacizumab treatment on VS growth and symptom progression. MATERIAL AND METHODS This is a retrospective analysis of patients seen at the Mayo Clinic Rochester Multidisciplinary NF2 Clinic. Three-dimensional volumetric data for VS were measured using manual segmentation with Visage PACS software under the direct supervision of a board-certified neuroradiologist. RESULTS Out of 76 patients with NF2 evaluated in the past 3 years, we identified 19 that received treatment with bevacizumab. Median age of NF2 diagnosis was 19 years (range 0.5-61) with a median NF2 phenotype severity score of 2 (range 1-3). Thirteen of these patients have discontinued bevacizumab, accounting for a median duration of 12.2 months (range 3.3-88 months) of bevacizumab treatment. Bevacizumab was discontinued due to hypertension (n=5), proteinuria and renal dysfunction (n=3), tumor progression (n=2), fatigue or other intolerance (n=2), or non-compliance (n=1). The remaining 6 patients are currently receiving bevacizumab treatment for a median duration of 9.4 months as of March 2023 (range 3.7-48.3 months). Fifteen patients had brain MRI data available to evaluate VS change during bevacizumab treatment, with partial response observed in 5 patients, stable disease in 8, and progression in 2. Ten of the 13 patients who stopped bevacizumab had MRI data to evaluate VS change following treatment termination. Within 6 months of bevacizumab discontinuation, 6 patients had rebound growth of their VS between 21-95% from their previous tumor volume, while 4 did not. Three patients with rebound growth went on to have surgery or irradiation for VS management. CONCLUSION Our single institution experience confirms that bevacizumab can slow progression of VS and symptoms associated with VS growth. However, we note that there is the potential for rapid VS growth following bevacizumab discontinuation, for which we propose heightened surveillance imaging and symptom monitoring for at least 6 months upon stopping anti-VEGF therapy.

A 65-year-old woman presented with nausea, headache, and visual changes. MRI of the brain identified dural-based lesions involving the right cerebellum, right tentorium, and left anterior falx believed to be consistent with meningiomas (Figure, A–C). Owing to unclear association between imaging findings and clinical symptoms, surveillance was recommended. Follow-up was inadvertently delayed. Repeat imaging at 7 months revealed enlarging tentorial lesion, treated with gamma knife radiosurgery (GKRS) (Figure, D). Further growth prompted resection of the cerebellar lesion. Tumor cells were positive for STAT6 on immunohistochemistry, establishing solitary fibrous tumor (SFT) as the diagnosis. PET-CT identified fluorodeoxyglucose-avid hepatic lesion, with biopsy confirming STAT6, CD34, and synaptophysin-positive metastatic SFT (Figure, E–F). After additional GKRS, systemic therapy with sunitinib was started. SFTs are mesenchymal neoplasms predominantly affecting young adults that should be included in the differential of durally based lesions.1 Given propensity for extracranial metastasis, systemic imaging should be obtained on establishing tissue diagnosis.2

A 62-year-old woman presented to an outside emergency department with a 24-hour history of vomiting-associated chest pain. She described a nonradiating retrosternal ache with dyspnea and diaphoresis after multiple episodes of nonbilious and severe vomiting. Recent history was notable for amoxicillin/clavulanic acid–treated colitis. After failure to improve, she was diagnosed as having Clostridium difficile and completed 10 days of treatment with vancomycin. Two weeks prior to presentation, fidaxomicin was initiated because of persistent symptoms and ongoing stool positivity.

A 28-year-old man with no significant medical history presented to his primary care provider with 4 months of progressive left-testicular enlargement. His symptoms were not associated with pain, dysuria, fever, weight loss, or recent trauma. He was sexually active only with his wife. He endorsed using condoms for contraception and denied unsafe sexual practices. On presentation, the patient was a young, healthy-appearing man with vital signs within normal limits. Physical examination revealed a normal penis without ulceration or urethral discharge. The left testicle was grossly enlarged, compared with the right, measuring approximately 6 cm in length with an irregular shape. The right testicle was within normal limits, measuring 4 cm in length. There was no erythema of the scrotum, and both testicles were nontender to palpation. There was neither herniation noted through the inguinal rings nor palpable lymphadenopathy. Prostate examination revealed a firm, appropriately sized prostate without irregular nodularity. The results of the remainder of the physical examination were within normal limits.1.What is the next best step in managing this patient?a.Prescribe a course of antibiotics and follow up in 1 week.b.Computed tomography of the abdomen and pelvisc.Testicular biopsyd.Scrotal ultrasound with Dopplere.Radical orchiectomy Although epididymitis or epididymo-orchitis are common causes for testicular swelling, the predominant presenting symptoms include pain and other clinical signs of infection such as fever, rigors, and dysuria.1Trojian T.H. Lishnak T.S. Heiman D. Epididymitis and orchitis: an overview.Am Fam Physician. 2009; 79: 583-587PubMed Google Scholar Further, the 4-month time course is inconsistent with acute infection. Testicular cancer must be within the differential for any patient who presents with a testicular mass.2Stephenson A. Eggener S.E. Bass E.B. et al.Diagnosis and treatment of early stage testicular cancer: AUA guideline.J Urol. 2019; 202: 272-281Crossref PubMed Scopus (47) Google Scholar It is the most common cancer of young men, and its incidence has been increasing over time.3Cheng L. Albers P. Berney D.M. et al.Testicular cancer.Nat Rev Dis Primers. 2018; 4: 29Crossref PubMed Scopus (61) Google Scholar Further, treatment results in cure in greater than 90% of patients, indicating that significant harm could be done by delaying the diagnosis and treatment. Although infection is a possibility, testicular cancer must be evaluated for before empiric antibacterial treatment. Computed tomography (CT) of the abdomen and pelvis is clinically useful in the management of testicular cancer, but use here is premature.4Gilligan T. Lin D.W. Aggarwal R. et al.NCCN Clinical Practice Guidelines in Oncology: Testicular Cancer (Version 3.2020, May 12, 2020).https://www.nccn.org/professionals/physician_gls/pdf/testicular_blocks.pdfGoogle Scholar Computed tomography should be used after diagnosis to characterize the cancer stage, and it would be inappropriate to expose the patient to this level of radiation before, when less potentially harmful and expensive options are available. Testicular biopsy is never warranted in a patient with suspected testicular cancer as the insult may lead to tumor seeding and higher rates of local recurrence.2Stephenson A. Eggener S.E. Bass E.B. et al.Diagnosis and treatment of early stage testicular cancer: AUA guideline.J Urol. 2019; 202: 272-281Crossref PubMed Scopus (47) Google Scholar,4Gilligan T. Lin D.W. Aggarwal R. et al.NCCN Clinical Practice Guidelines in Oncology: Testicular Cancer (Version 3.2020, May 12, 2020).https://www.nccn.org/professionals/physician_gls/pdf/testicular_blocks.pdfGoogle Scholar Further, it is premature to collect tissue before imaging the mass. Scrotal ultrasound is the next best step in evaluation of a solid testicular mass in this patient.4Gilligan T. Lin D.W. Aggarwal R. et al.NCCN Clinical Practice Guidelines in Oncology: Testicular Cancer (Version 3.2020, May 12, 2020).https://www.nccn.org/professionals/physician_gls/pdf/testicular_blocks.pdfGoogle Scholar At this time, serum tumor markers should also be collected: specifically, alpha-fetoprotein (AFP), beta-human chorionic gonadotropin (β-HCG), and lactate dehydrogenase (LDH). Ultrasound is a low-cost, low-risk procedure that has a high likelihood of ruling in or out testicular cancer by differentiating it from more benign conditions such as hydroceles or cysts.2Stephenson A. Eggener S.E. Bass E.B. et al.Diagnosis and treatment of early stage testicular cancer: AUA guideline.J Urol. 2019; 202: 272-281Crossref PubMed Scopus (47) Google Scholar,4Gilligan T. Lin D.W. Aggarwal R. et al.NCCN Clinical Practice Guidelines in Oncology: Testicular Cancer (Version 3.2020, May 12, 2020).https://www.nccn.org/professionals/physician_gls/pdf/testicular_blocks.pdfGoogle Scholar Treatment of testicular cancer usually involves orchiectomy of the involved testicle, but surgery is not warranted at this stage of the work-up.4Gilligan T. Lin D.W. Aggarwal R. et al.NCCN Clinical Practice Guidelines in Oncology: Testicular Cancer (Version 3.2020, May 12, 2020).https://www.nccn.org/professionals/physician_gls/pdf/testicular_blocks.pdfGoogle Scholar The differential for testicular masses is broad, including hydrocele, varicocele, spermatocele, hematomas, and herniation. Radical orchiectomy is not a benign procedure and, as such, should be reserved for lesions that have high likelihood of malignancy. This should be determined by ultrasound, which has a high likelihood of differentiating testicular cancer from benign lesions. Scrotal ultrasound with Doppler revealed a normally sized right testicle, measuring 4.3 x 3.1 x 2.5 cm and 7.4 mL in volume, with homogeneous echogenicity and appropriate arterial flow. The left testicle measured 6.1 x 2.7 x 3.9 cm with a volume of 50.5 mL, with conglomerate of solid heterogeneous masses with internal vascularity. Laboratory evaluation revealed the following (reference ranges provided parenthetically): hemoglobin 15.0 g/dL (13.2 to 16.6 g/dL); platelets 192 x 109/L (135 to 317 x 109/L); leukocytes 5.9 x 109/L (3.4 to 9.6 x 109/L); sodium 142 mmol/L (135 to 145 mmol/L); potassium 5.0 mmol/L (3.6 to 5.2 mmol/L); chloride 103 mmol/L (98 to 107 mmol/L); bicarbonate 27 mmol/L (22 to 29 mmol/L); blood urea nitrogen 17 mg/dL (8 to 24 mg/dL); creatinine 1.09 mg/dL (0.74 to 1.35 mg/dL); AFP 2.8 ng/mL (<6.0 ng/mL); β-HCG <0.6 IU/L (<1.4 IU/L); LDH 538 U/L (122 to 222 U/L). He subsequently had sperm cryopreservation and underwent an uncomplicated left radical orchiectomy for suspected testicular cancer. Gross specimen included a left testicle of 91 grams and 6.4 x 4.8 x 4.1 cm with an attached 14.9-cm spermatic cord. A multilobar, tan, fleshy, and necrotic mass, involving the entirety of the testicular parenchyma, was noted; margins were negative.2.Which one of the following is most likely to be found on pathology evaluation following radical orchiectomy?a.Sex-cord stromal tumorb.Benign massc.Germ-cell tumord.Testicular lymphomae.Secondary testicular tumor Sex-cord stromal tumors are a type of nongerm cell tumor (NGCT). All NGCTs originate from nongerminal testicular cells, such as Leydig, Sertoli, granulosa, or theca cells. Nongerm cell tumors make up only approximately 5% of testicular tumors, making this diagnosis unlikely.5Dilworth J.P. Farrow G.M. Oesterling J.E. Non-germ cell tumors of testis.Urology. 1991; 37: 399-417Abstract Full Text PDF PubMed Scopus (91) Google Scholar Benign masses are also possible causes of testicular masses; however, they do not typically arise from the gonad itself but rather the paratesticular tissue.6Amin M.B. Selected other problematic testicular and paratesticular lesions: rete testis neoplasms and pseudotumors, mesothelial lesions and secondary tumors.Mod Pathol. 2005; 18: S131-S145Crossref PubMed Scopus (115) Google Scholar In general, benign lesions rarely involve the testicular parenchyma. This makes a finding of benign mass much less likely, as our patient does have testicular parenchyma involvement. Further, although benign masses present similarly to malignant lesions with testicular enlargement, gonadal tissue is more likely to become hyperplasic, and malignancy is much more common than benign growths.6Amin M.B. Selected other problematic testicular and paratesticular lesions: rete testis neoplasms and pseudotumors, mesothelial lesions and secondary tumors.Mod Pathol. 2005; 18: S131-S145Crossref PubMed Scopus (115) Google Scholar The other classification of testicular tumors besides NGCTs is testicular tumors arising from germ cells, or germ-cell tumors (GCTs); these are by far the most common cause of testicular masses concerning for malignancy, excluding easily imaged findings such as hydroceles and varicoceles.4Gilligan T. Lin D.W. Aggarwal R. et al.NCCN Clinical Practice Guidelines in Oncology: Testicular Cancer (Version 3.2020, May 12, 2020).https://www.nccn.org/professionals/physician_gls/pdf/testicular_blocks.pdfGoogle Scholar They make up 95% of testicular neoplasms and include a diverse number of distinct subtypes that can be isolated or present in a heterogeneous population containing 2 or more distinct morphologies. Germ-cell tumors are further differentiated into either seminomas, nonseminomas, or a mix between the two. The most common of these is a seminoma, composed of cells that originate in germinal epithelium of the seminiferous tubules, which is found in approximately 50% of the time and is present in 1 of 5 heterogeneous GCT tumors.3Cheng L. Albers P. Berney D.M. et al.Testicular cancer.Nat Rev Dis Primers. 2018; 4: 29Crossref PubMed Scopus (61) Google Scholar Nonseminomas originate from pluripotent germinal cells and include embryonal carcinomas, yolk-sac tumors, choriocarcinoma, and teratomas. Other potential etiologies of a malignant testicular mass include testicular lymphoma, which also most commonly presents with painless unilateral testicular enlargement. However, this is predominantly a disease of the elderly and rarely presents in patients younger than 60 years of age. Further, it accounts for less than 5% of testicular malignancies, making this diagnosis unlikely.5Dilworth J.P. Farrow G.M. Oesterling J.E. Non-germ cell tumors of testis.Urology. 1991; 37: 399-417Abstract Full Text PDF PubMed Scopus (91) Google Scholar Any tissue in the body can become a host for secondary metastases. However, metastases to the testicles are extremely rare and are most commonly found incidentally on autopsy in much older patients.7Hanash K.A. Metastatic tumors to the testicles.Prog Clin Biol Res. 1985; 203: 61-67PubMed Google Scholar It would be less likely in a patient with benign examination results and normal laboratory work-up results. The tumor pathology returned positive for seminoma with tumor extension limited to the left testis. Postorchiectomy tumor-marker work-up revealed AFP 2.4 ng/mL (<6.0 ng/mL); β-HCG <0.6 IU/L (<1.4 IU/L); and LDH 254 U/L (122 to 222 U/L).3.In addition to repeat serum tumor markers, which one of the following is the most appropriate next step in management for this patient?a.Full-body positron emission tomography (PET) scanb.Chest x-ray, CT scan of abdomen and pelvisc.Brain magnetic resonance imaging (MRI), CT scan of chest, abdomen, and pelvisd.Chest x-ray, technetium 99-m skeletal scintigraphye.No further imaging is necessary. Positron emission tomography scans should not be used in the initial evaluation of testicular cancer.4Gilligan T. Lin D.W. Aggarwal R. et al.NCCN Clinical Practice Guidelines in Oncology: Testicular Cancer (Version 3.2020, May 12, 2020).https://www.nccn.org/professionals/physician_gls/pdf/testicular_blocks.pdfGoogle Scholar The suggested imaging for testicular cancer staging is a CT abdomen and pelvis scan with contrast material, in addition to chest imaging, either by chest x-ray or CT. When deciding between chest x-ray or CT, chest x-ray is preferred for stage 1 seminoma, whereas, in nonseminomas, CT of the chest may be prioritized.2Stephenson A. Eggener S.E. Bass E.B. et al.Diagnosis and treatment of early stage testicular cancer: AUA guideline.J Urol. 2019; 202: 272-281Crossref PubMed Scopus (47) Google Scholar Brain imaging is not warranted for testicular cancer staging.2Stephenson A. Eggener S.E. Bass E.B. et al.Diagnosis and treatment of early stage testicular cancer: AUA guideline.J Urol. 2019; 202: 272-281Crossref PubMed Scopus (47) Google Scholar Although testicular cancer does metastasize, it commonly does so to the lymph nodes.3Cheng L. Albers P. Berney D.M. et al.Testicular cancer.Nat Rev Dis Primers. 2018; 4: 29Crossref PubMed Scopus (61) Google Scholar Only very rarely does testicular cancer spread to the brain and generally only in patients with already high disease burden.4Gilligan T. Lin D.W. Aggarwal R. et al.NCCN Clinical Practice Guidelines in Oncology: Testicular Cancer (Version 3.2020, May 12, 2020).https://www.nccn.org/professionals/physician_gls/pdf/testicular_blocks.pdfGoogle Scholar Likewise, bone scan or technetium 99-m skeletal scintigraphy is not indicated in initial staging of testicular cancer. It is generally used when metastases are suspected in the bone following clinical suspicion, such as focal bone pain. Further imaging is always warranted in staging testicular cancer following orchiectomy.2Stephenson A. Eggener S.E. Bass E.B. et al.Diagnosis and treatment of early stage testicular cancer: AUA guideline.J Urol. 2019; 202: 272-281Crossref PubMed Scopus (47) Google Scholar,4Gilligan T. Lin D.W. Aggarwal R. et al.NCCN Clinical Practice Guidelines in Oncology: Testicular Cancer (Version 3.2020, May 12, 2020).https://www.nccn.org/professionals/physician_gls/pdf/testicular_blocks.pdfGoogle Scholar Although the specific pathology of this testicular cancer is limited to the left testes, this does not definitively rule out extratesticular disease. In this patient, CT of the abdomen and pelvis following left inguinal orchiectomy revealed neither lymphadenopathy nor metastases. Chest x-ray also revealed no thoracic lymphadenopathy or metastatic processes. As such, the patient was determined to have stage 1 disease. Treatment options were discussed with the patient, which included adjuvant chemotherapy, radiation, or surveillance. The patient elected to proceed with surveillance.4.Which one of the following is true regarding this patient’s need for surveillance?a.Imaging surveillance is not required.b.Routine serum tumor markersc.Routine CT of the abdomend.Routine CT of the chest, abdomen, and pelvis and serum tumor makerse.Routine PET scan This patient has an excellent prognosis with stage I disease; however, there is a significant risk of relapse within the first 5 years. Although risk of mortality is low, approximately 15% to 18% of patients with stage 1 seminoma will relapse.3Cheng L. Albers P. Berney D.M. et al.Testicular cancer.Nat Rev Dis Primers. 2018; 4: 29Crossref PubMed Scopus (61) Google Scholar Therefore, surveillance is a key requirement following curative testicular cancer therapy despite the stage of the disease. Tumor markers are also integral portions of testicular cancer surveillance, although tumor markers are generally elevated in nonseminomas. Our patient did not have an elevated AFP or β-HCG before treatment, which is typical of pure seminomas.3Cheng L. Albers P. Berney D.M. et al.Testicular cancer.Nat Rev Dis Primers. 2018; 4: 29Crossref PubMed Scopus (61) Google Scholar If AFP had been elevated, the patient would, by definition, not have a seminoma but rather a mixed or nonseminoma such as choriocarcinoma or a yolk-sac tumor.3Cheng L. Albers P. Berney D.M. et al.Testicular cancer.Nat Rev Dis Primers. 2018; 4: 29Crossref PubMed Scopus (61) Google Scholar National Comprehensive Cancer Network (NCCN) guidelines specify that patients like ours, with stage IA pure seminoma, do not require serum tumor markers; however, many institutions recommend that they be collected, regardless. The surveillance modality of choice is CT of the abdomen. Specific recommendations for stage 1 seminoma include history, physical examination, and cross-sectional imaging of the abdomen, with or without the pelvis, every 4 to 6 months for the first 2 years, followed by 6 to 12 months for the next 3 to 5 years.4Gilligan T. Lin D.W. Aggarwal R. et al.NCCN Clinical Practice Guidelines in Oncology: Testicular Cancer (Version 3.2020, May 12, 2020).https://www.nccn.org/professionals/physician_gls/pdf/testicular_blocks.pdfGoogle Scholar Chest imaging is done purely based on clinical indication. Additional imaging after 5 years is not generally recommended, as most relapse occurs within the first 2 years of curative treatment and less than 1% of GCTs relapse after 5 years. If new disease is noted in a patient with GCT 5 years after treatment, it is important to consider new primary disease from the remaining testicle, as there is a lifetime 2% risk of contralateral GCT among patients with previous GCT.2Stephenson A. Eggener S.E. Bass E.B. et al.Diagnosis and treatment of early stage testicular cancer: AUA guideline.J Urol. 2019; 202: 272-281Crossref PubMed Scopus (47) Google Scholar Positron emission tomography is not routinely recommended for surveillance of GCT relapse. Surveillance imaging was started at 3 and 6 months. During the second CT scan at 6 months, the patient was found to have a newly enlarged retroperitoneal lymph node, 3.5 cm in length, which was concerning for relapse. He was treated with chemotherapy, and following 3 cycles of treatment with bleomycin, etoposide, and cisplatin, a repeat CT scan of his chest, abdomen, and pelvis revealed no residual disease. Serum tumor markers were collected and were within normal limits.5.Which one of the following is true regarding long term health effects in this patient?a.He has no increased risk of developing cardiovascular disease.b.He has no increased risk of developing metabolic syndrome.c.The patient is unlikely to be able to achieve paternity.d.He has a higher risk of developing hypogonadism.e.His likelihood of developing a second malignancy is similar to that of the general population. Cardiovascular disease is a significant risk factor that requires monitoring in long-term survivors of testicular cancer, and survivors of testicular cancer have significantly increased risk of myocardial infarction compared with the population.8van den Belt-Dusebout A.W. Nuver J. de Wit R. et al.Long-term risk of cardiovascular disease in 5-year survivors of testicular cancer.J Clin Oncol. 2006; 24: 467-475Crossref PubMed Scopus (254) Google Scholar Risk is particularly elevated in patients with nonseminomas and those who received mediastinal radiation or combination cisplatin-containing chemotherapy. Likewise, patients with testicular cancer also have elevated risks of metabolic syndrome.9Wethal T. Kjekshus J. Røislien J. et al.Treatment-related differences in cardiovascular risk factors in long-term survivors of testicular cancer.J Cancer Surviv. 2007; 1: 8-16Crossref PubMed Scopus (45) Google Scholar Elevated risk is seen predominantly in patients treated with chemotherapy or radiotherapy and in patients with persistent hypogonadism. This is thought to be due to increased short- and long-term endothelial dysfunction caused by chemotherapy as well as the endothelial damage caused by ionizing radiation. Although preservation of fertility should be offered to all patients with testicular cancer before initiating treatment, the likelihood that the patient will be able to achieve paternity without assistance is good.10Jacobs L.A. Vaughn D.J. Hypogonadism and infertility in testicular cancer survivors.J Natl Compr Canc Netw. 2012; 10: 558-563Crossref PubMed Scopus (19) Google Scholar Spermatogenesis recovers to 50% and 80% at 2 and 5 years, respectively. At 15 years following treatment, there is a 85% rate of paternity. Despite the likely recovery of spermatogenesis, the patient has increased risk of hypogonadism compared with the general population.11Nord C. Bjøro T. Ellingsen D. et al.Gonadal hormones in long-term survivors 10 years after treatment for unilateral testicular cancer.Eur Urol. 2003; 44: 322-328Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar The age-adjusted risk of hypogonadism is almost 4-fold higher in survivors of testicular cancer and increases further with intensity of treatment, including those patients who received cisplatin-based chemotherapy. Finally, survivors of testicular cancer have elevated risks of developing secondary malignancies.12Fung C. Fossa S.D. Beard C.J. Travis L.B. Second malignant neoplasms in testicular cancer survivors.J Natl Compr Canc Netw. 2012; 10: 545-556Crossref PubMed Scopus (25) Google Scholar The largest risk is seen in patients who received combination chemoradiation, with the next largest risk seen with radiation monotherapy, then chemotherapy alone. Relative risk for secondary malignancy is approximately twice that compared with the general population. Particularly at-risk sites include the stomach, pancreas, and connective tissue. Overall, the patient should have regular physical examinations with monitoring of weight and blood pressure. Hormonal function should be assessed regularly, with particular attention paid to signs of hypogonadism. Secondary malignancy should remain within the differential diagnosis for new patient complaints, and physical examinations should include evaluation of lymph nodes and the contralateral testicle. This patient currently has regular-follow ups with both an oncologist and primary care physician. Testicular cancer is the most common solid malignancy in young men and accounts for approximately 1% of cancers in men overall, with peak incidence between ages 14 and 44.3Cheng L. Albers P. Berney D.M. et al.Testicular cancer.Nat Rev Dis Primers. 2018; 4: 29Crossref PubMed Scopus (61) Google Scholar Although specific etiologies are not well understood, there are several known risks factors for the development of testicular cancer, the most significant of which are family history and previous cryptorchidism. The risk of testicular cancer is greatly magnified in patients with male first-degree relatives who were previously diagnosed with testicular cancer, and a personal history of cryptorchidism increases risk by 5-fold.2Stephenson A. Eggener S.E. Bass E.B. et al.Diagnosis and treatment of early stage testicular cancer: AUA guideline.J Urol. 2019; 202: 272-281Crossref PubMed Scopus (47) Google Scholar,3Cheng L. Albers P. Berney D.M. et al.Testicular cancer.Nat Rev Dis Primers. 2018; 4: 29Crossref PubMed Scopus (61) Google Scholar The most common presentation of testicular cancer is a unilateral, painless, and firm testicular mass that is generally found incidentally. They can be associated with pain in a minority of patients, with as many as a one-third presenting with generalized aching pain. Acute pain is less common and only seen in approximately 10% of newly presenting patients. Metastasis is also not common at first presentation, but clinical signs that should be evaluated for anorexia, weight loss, new cough or dyspnea, lymphadenopathy, bone pain, and lower-extremity swelling.5Dilworth J.P. Farrow G.M. Oesterling J.E. Non-germ cell tumors of testis.Urology. 1991; 37: 399-417Abstract Full Text PDF PubMed Scopus (91) Google Scholar Any male patient who presents with a new solid mass in the testes should be considered to have testicular cancer until it is proven otherwise. The prognosis of almost all testicular tumors is excellent with prompt care, and most patients will achieve cure with simple orchiectomy. Scrotal ultrasound with Doppler is the imaging modality of choice, as it can easily distinguish between intrinsic and extrinsic testicular lesions. Before orchiectomy, all men should be offered fertility preservation and sperm cryopreservation. Ideally, a baseline sperm count and banking should be performed before radiologic evaluation in men seeking preservation of fertility. The large majority of testicular cancers are GCTs and requires only orchiectomy of the affected testicle and close surveillance for 5 years. Advanced disease is found most commonly in the lymph nodes, followed by the lungs, which, if found, does not imply poor prognosis. Treatment for advanced disease is typically chemotherapy or radiation, and treatment remains curative in the majority of patients. Overall, 5-year rates of survival for testicular cancer exceed 90%.2Stephenson A. Eggener S.E. Bass E.B. et al.Diagnosis and treatment of early stage testicular cancer: AUA guideline.J Urol. 2019; 202: 272-281Crossref PubMed Scopus (47) Google Scholar,3Cheng L. Albers P. Berney D.M. et al.Testicular cancer.Nat Rev Dis Primers. 2018; 4: 29Crossref PubMed Scopus (61) Google Scholar For chemotherapy-resistant disease, there are currently several clinical trials evaluating the efficacy of immunotherapy, which may further improve survival rates in the future.3Cheng L. Albers P. Berney D.M. et al.Testicular cancer.Nat Rev Dis Primers. 2018; 4: 29Crossref PubMed Scopus (61) Google Scholar