A Cautionary Note on Pembrolizumab use in Patients with Ascending Aortic Aneurysms.

Case description: We describe a case of a patient treated with pembrolizumab (an immune checkpoint inhibitor) for metastatic scalp melanoma. He had a previous history of colorectal cancer, prostatic cancer and chronic polymyalgia rheumatica. The patient was known to have a stable ascending aortic aneurysm of 4.5 cm. However, he developed a rapid expansion of the ascending aortic aneurysm with the size crossing the threshold for surgery. The patient was referred to the cardiothoracic surgery service for intervention and he subsequently underwent surgery. The patient was electively admitted one week later for resection of aortic aneurysm, aortoplasty and external graft fixation. Pathologically, gross evidence of dissection was not identified; however, the histological analysis of the media showed laminar medial necrosis, multifocal in nature, with occasional clusters of histiocytic cells appreciated at their edge reminiscent of that seen in an inflammatory aortitis (granulomatous/giant cell type). Discussion: Immune checkpoint inhibitor-induced aortitis is becoming increasingly evident, and its presentation can vary. It has been discovered incidentally on surveillance imaging with the use of nivolumab. In other cases, patients have been symptomatic to severely symptomatic. Atezolizumab with carboplatin and etoposide has been reported to cause abdominal aortitis which was responsive to corticosteroids and subsequent discontinuation of atezolizumab. Pembrolizumab has been linked to a case of transverse aortic arch aortitis. In our case, the inflammatory aortitis due to pembrolizumab was the cause of the rapid expansion of the ascending aortic aneurysm. Conclusion: Patients with known aortic aneurysms should undergo careful surveillance when commencing immune-checkpoint inhibitor therapy. LEARNING POINTS: Immune checkpoint inhibitors are being increasingly used in the treatment of metastatic malignancy. However, they are a relatively new group of medications, and the side effect profile of each is yet to be fully recognised. Aortitis has occurred with several different immune checkpoint inhibitors.Patients with known aortic aneurysms should undergo careful surveillance when commencing immune checkpoint inhibitors.All interventional therapeutic options should be considered early in these patients on the development of aneurysmal expansion.

An incidental finding of large cell calcifying Sertoli cell tumor in an orchidectomy specimen for a separate adenomatoid tumor.

Introduction: Large cell calcifying Sertoli cell tumors are exceedingly rare. They are most commonly benign, but risks for malignancy include older age, larger size of tumor, and solitary tumors. To the author's knowledge, this is the first case reported of an incidental large cell calcifying Sertoli cell tumor when an orchidectomy was performed for a separate lesion. Case presentation: A 31-year-old male presented with a painless testicular lump. Ultrasound demonstrated an exophytic lesion in the superolateral aspect and calcifications were noted inferomedially and inferolaterally in the right testis. On histology from radical orchidectomy, the superolateral lesion was found to be an adenomatoid tumor, and the calcifications inferiorly represented a large cell calcifying Sertoli cell tumor. The background showed foci of germ cell neoplasia in situ but no evidence of invasive malignancy. Conclusion: Calcifications on ultrasound in isolation may represent large cell calcifying Sertoli Cell tumors.

Severe Aortic Valvular Incompetence From IgG4-Related Disease: An Unusual Entity.

IgG4-related disease (IgG4-RD) is a new clinical entity characterized by lymphoplasmacytic lesions rich in IgG4-positive plasma cells. Myocardial involvement is extremely rare and not a typical cardiovascular manifestation of IgG4-RD. We report a rare case of IgG4-RD-associated myocardial mass causing severe aortic incompetence, successfully treated with surgery and corticosteroids. (Level of Difficulty: Intermediate.).

Aberrant protein expression of Appl1, Sortilin and Syndecan-1 during the biological progression of prostate cancer.

Diagnosis and assessment of patients with prostate cancer is dependent on accurate interpretation and grading of histopathology. However, morphology does not necessarily reflect the complex biological changes occurring in prostate cancer disease progression, and current biomarkers have demonstrated limited clinical utility in patient assessment. This study aimed to develop biomarkers that accurately define prostate cancer biology by distinguishing specific pathological features that enable reliable interpretation of pathology for accurate Gleason grading of patients. Online gene expression databases were interrogated and a pathogenic pathway for prostate cancer was identified. The protein expression of key genes in the pathway, including adaptor protein containing a pleckstrin homology (PH) domain, phosphotyrosine-binding (PTB) domain, and leucine zipper motif 1 (Appl1), Sortilin and Syndecan-1, was examined by immunohistochemistry (IHC) in a pilot study of 29 patients with prostate cancer, using monoclonal antibodies designed against unique epitopes. Appl1, Sortilin, and Syndecan-1 expression was first assessed in a tissue microarray cohort of 112 patient samples, demonstrating that the monoclonal antibodies clearly illustrate gland morphologies. To determine the impact of a novel IHC-assisted interpretation (the utility of Appl1, Sortilin, and Syndecan-1 labelling as a panel) of Gleason grading, versus standard haematoxylin and eosin (H&E) Gleason grade assignment, a radical prostatectomy sample cohort comprising 114 patients was assessed. In comparison to H&E, the utility of the biomarker panel reduced subjectivity in interpretation of prostate cancer tissue morphology and improved the reliability of pathology assessment, resulting in Gleason grade redistribution for 41% of patient samples. Importantly, for equivocal IHC-assisted labelling and H&E staining results, the cancer morphology interpretation could be more accurately applied upon re-review of the H&E tissue sections. This study addresses a key issue in the field of prostate cancer pathology by presenting a novel combination of three biomarkers and has the potential to transform clinical pathology practice by standardising the interpretation of the tissue morphology.

Sarcoma and the 100,000 Genomes Project: our experience and changes to practice.

The largest whole genome sequencing (WGS) endeavour involving cancer and rare diseases was initiated in the UK in 2015 and ran for 5 years. Despite its rarity, sarcoma ranked third overall among the number of patients' samples sent for sequencing. Herein, we recount the lessons learned by a specialist sarcoma centre that recruited close to 1000 patients to the project, so that we and others may learn from our experience. WGS data was generated from 597 patients, but samples from the remaining approximately 400 patients were not sequenced. This was largely accounted for by unsuitability due to extensive necrosis, secondary to neoadjuvant radiotherapy or chemotherapy, or being placed in formalin. The number of informative genomes produced was reduced further by a PCR amplification step. We showed that this loss of genomic data could be mitigated by sequencing whole genomes from needle core biopsies. Storage of resection specimens at 4 °C for up to 96 h overcame the challenge of freezing tissue out of hours including weekends. Removing access to formalin increased compliance to these storage arrangements. With over 70 different sarcoma subtypes described, WGS was a useful tool for refining diagnoses and identifying novel alterations. Genomes from 350 of the cohort of 597 patients were analysed in this study. Overall, diagnoses were modified for 3% of patients following review of the WGS findings. Continued refinement of the variant-calling bioinformatic pipelines is required as not all alterations were identified when validated against histology and standard of care diagnostic tests. Further research is necessary to evaluate the impact of germline mutations in patients with sarcoma, and sarcomas with evidence of hypermutation. Despite 50% of the WGS exhibiting domain 1 alterations, the number of patients with sarcoma who were eligible for clinical trials remains small, highlighting the need to revaluate clinical trial design.