The amyloid state of protein organization is typically associated with debilitating human neuropathies and is seldom observed in physiology. Here, we uncover a systemic program that leverages the ...amyloidogenic propensity of proteins to regulate cell adaptation to stressors. On stimulus, cells assemble the amyloid bodies (A-bodies), nuclear foci containing heterogeneous proteins with amyloid-like biophysical properties. A discrete peptidic sequence, termed the amyloid-converting motif (ACM), is capable of targeting proteins to the A-bodies by interacting with ribosomal intergenic noncoding RNA (rIGSRNA). The pathological β-amyloid peptide, involved in Alzheimer's disease, displays ACM-like activity and undergoes stimuli-mediated amyloidogenesis in vivo. Upon signal termination, elements of the heat-shock chaperone pathway disaggregate the A-bodies. Physiological amyloidogenesis enables cells to store large quantities of proteins and enter a dormant state in response to stressors. We suggest that cells have evolved a post-translational pathway that rapidly and reversibly converts native-fold proteins to an amyloid-like solid phase.
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•Nuclear amyloid bodies (A-bodies) form from systemic protein amyloidogenesis•An amyloid-converting motif and ribosomal intergenic lncRNA mediate amyloidogenesis•The heat-shock chaperone pathway disaggregates A-bodies•Upon stimuli, cells activate physiological amyloidogenesis to enter a dormant state
Audas et al. find that to adapt to stressors, heterogeneous proteins convert to an amyloid-like state and form subnuclear amyloid bodies (A-bodies), which requires a specific protein motif and ribosomal intergenic lncRNA. Upon stimuli termination, Hsp chaperones disaggregate A-bodies. This pathway regulates reversible amyloidogenesis of the Alzheimer’s disease-associated pathological β-amyloid peptide.
* Context.--Nephrogenic adenoma (NA) is a common urinary tract lesion typically associated with urothelial disruption, leading to implantation of shed renal tubular cells. NA may demonstrate a ...spectrum of architectural and cytologic features mimicking urothelial carcinoma (UC), adenocarcinoma (including clear cell adenocarcinoma and prostatic adenocarcinoma), and invasion. However, admixed UC and NA has not been described. Objective.--To describe cases where the NA was intimately intermixed with UC, potentially mimicking variant differentiation or invasion. Design.--In 3 health care systems we identified specimens of NA and UC intimately intermixed with each other to the extent that they could mimic a spectrum of one lesion. We assessed patterns of NA and clinical implications of misdiagnosing NA as glandular differentiation of UC. Results.--There were 4 women and 29 men (median age, 72 years; range, 31-89 years). Twenty-four patients had transurethral resections, 3 had biopsies, and 6 had major resections. Fourteen had noninvasive high-grade papillary UC, 6 had carcinoma in situ, and 11 had invasive high-grade UC. In 2 patients, NA developed in a papillary urothelial neoplasm with extensive denudation. Three patients had fibromyxoid NA infiltrated by invasive UC. Classical NA (n = 30) had tubulopapillary (n = 18), pure tubular (n = 7), or pure papillary architecture (n = 5). In 1 lesion, NA was present in muscularis propria, and 2 lesions involved adventitia. NA could have been misdiagnosed as invasion in 17 of 22 (77%) noninvasive tumors or higher stage in 19 of 33 (58%). Conclusions.--NA can be intermingled with highgrade UC, expanding the spectrum of entities that must be considered in the differential diagnosis, as it may mimic glandular or tubular differentiation, invasion, and a higher stage of disease. Misinterpretation of NA in such a setting may incorrectly convey a more aggressive biological potential of cancer to clinicians. doi: 10.5858/arpa.2021-0620-OA
To evaluate the presence and analyze the pathological changes within the testes of patients who died or recovered from severe acute respiratory syndrome coronavirus 2 (COVID-19) complications.
Testis ...tissue was collected from autopsies of COVID-19 positive (n=6) and negative men (n=3). Formalin-fixed paraffin-embedded tissues were stained with hematoxylin and eosin (H&E) and subjected to immunofluorescence for angiotensin-converting enzyme 2 (ACE-2) expression. Fluorescent-labeled tissue slides were imaged on a quantitative pathology scope with various zoom levels allowing for qualitative and quantitative interpretation. Tissue from four COVID-19 positive autopsy cases and a live seroconverted patient was imaged with transmission electron microscopy (TEM).
H&E histomorphology showed three of the six COVID-19 biopsies had normal spermatogenesis while the remaining three had impaired spermatogenesis. TEM showed the COVID-19 virus in testis tissue of one COVID-19 positive autopsy case and the live biopsy, H&E stain on the same autopsy case demonstrated interstitial macrophage and leukocyte infiltration. Immunofluorescent stained slides from six COVID-19 positive men demonstrated a direct association between increased quantitative ACE-2 levels and impairment of spermatogenesis.
The novel COVID-19 has an affinity for ACE-2 receptors. Since ACE-2 receptor expression is high in the testes, we hypothesized that COVID-19 is prevalent in testes tissue of infected patients. This study suggests the male reproductive tract, specifically the testes, may be targets of COVID-19 infection. We found an inverse association between ACE-2 receptor levels and spermatogenesis, suggesting a possible mechanism of how COVID-19 can cause infertility.
Since 1966, when Donald Gleason, MD, first proposed grading prostate cancer based on its histologic architecture, there have been numerous changes in clinical and pathologic practices relating to ...prostate cancer. Patterns 1 and 2, comprising more than 30% of cases in the original publications by Gleason, are no longer reported on biopsy and are rarely diagnosed on radical prostatectomy. Many of these cases may even have been mimickers of prostate cancer that were described later with the use of contemporary immunohistochemistry. The original Gleason system predated many newly described variants of prostate cancer and our current concept of intraductal carcinoma. Gleason also did not describe how to report prostate cancer on biopsy with multiple cores of cancer or on radical prostatectomy with separate tumor nodules. To address these issues, the International Society of Urological Pathology first made revisions to the grading system in 2005, and subsequently in 2014. Additionally, a new grading system composed of Grade Groups 1 to 5 that was first developed in 2013 at the Johns Hopkins Hospital and subsequently validated in a large multi-institutional and multimodal study was presented at the 2014 International Society of Urological Pathology meeting and accepted both by participating pathologists as well as urologists, oncologists, and radiation therapists. In the present study, we describe updates to the grading of prostate cancer along with the new grading system.
Eosinophilic renal neoplasms include a spectrum of solid and papillary tumors ranging from indolent benign oncocytoma to highly aggressive malignancies. Recognition of the correct nature of the ...tumor, especially in biopsy specimens, is paramount for patient management.
To review the diagnostic approach to eosinophilic renal neoplasms with light microscopy and ancillary techniques.
Review of the published literature and personal experience.
The following tumors are in the differential diagnosis of oncocytic renal cell neoplasm: oncocytoma, chromophobe renal cell carcinoma (RCC), hybrid tumor, tubulocystic carcinoma, papillary RCC, clear cell RCC with predominant eosinophilic cell morphology, follicular thyroid-like RCC, hereditary leiomyomatosis-associated RCC, acquired cystic disease-associated RCC, rhabdoid RCC, microphthalmia transcription factor translocation RCC, epithelioid angiomyolipoma, and unclassified RCC. In low-grade nonpapillary eosinophilic neoplasms, distinction between oncocytoma and low-grade RCC mostly rests on histomorphology; however, cytokeratin 7 immunostain may be helpful. In high-grade nonpapillary lesions, there is more of a role for ancillary techniques, including immunohistochemistry for cytokeratin 7, CA9, CD10, racemase, HMB45, and Melan-A. In papillary eosinophilic neoplasms, it is important to distinguish sporadic type 2 papillary RCC from microphthalmia transcription factor translocation and hereditary leiomyomatosis-associated RCC. Histologic and cytologic features along with immunohistochemistry and fluorescence in situ hybridization tests for TFE3 (Xp11.2) and TFEB t(6;11) are reliable confirmatory tests. Eosinophilic epithelial neoplasms with architecture, cytology, and/or immunoprofile not qualifying for either of the established types of RCC should be classified as unclassified eosinophilic RCC and arbitrarily assigned a grade (low or high).
A small cell-like change in prostate has been described in high-grade prostatic intraepithelial neoplasia (PIN), intraductal prostatic adenocarcinoma, and invasive prostate cancer. It occurs when ...these processes have a cribriform architecture. To date, small cell-like change has not been described in benign glands. Herein, I describe such a change in cribriform central zone histology from a radical prostatectomy with a spatially remote treatment naïve Grade Group 3 prostate cancer. The cancer did not have cribriform morphology or intraductal prostatic adenocarcinoma. The small cell-like change was positive for racemase in PIN-4 cocktail and no nuclei were highlighted by Ki-67. This is the first report of a small cell-like change in benign prostate tissue. Although rare, such finding in cribriform architecture of central zone histology can potentially be misinterpreted as a neoplastic process.
In 2019, the Genitourinary Pathology Society (GUPS) and International Society of Urological Pathology (ISUP) held their own consensus conferences on prostate cancer grading and reporting, with ...separately published manuscripts. The majority of GUPS and ISUP grading recommendations are compatible, but for some issues there is a lack of concordance or recommendations between the societies. As a result, both in practice and in research, these differences may manifest in difficulties when comparing pathology reports or data.
A pilot study to describe histopathological features of penile tissue of patients who recovered from symptomatic COVID-19 infection and subsequently developed severe erectile dysfunction (ED).
Penile ...tissue was collected from patients undergoing surgery for penile prosthesis for severe ED. Specimens were obtained from two men with a history of COVID-19 infection and two men with no history of infection. Specimens were imaged with TEM and H&E staining. RT-PCR was performed from corpus cavernosum biopsies. The tissues collected were analyzed for endothelial Nitric Oxide Synthase (eNOS, a marker of endothelial function) and COVID-19 spike-protein expression. Endothelial progenitor cell (EPC) function was assessed from blood samples collected from COVID-19 (+) and COVID-19 (-) men.
TEM showed extracellular viral particles ~100 nm in diameter with peplomers (spikes) near penile vascular endothelial cells of the COVID-19 (+) patients and absence of viral particles in controls. PCR showed presence of viral RNA in COVID-19 (+) specimens. eNOS expression in the corpus cavernosum of COVID-19 (+) men was decreased compared to COVID-19 (-) men. Mean EPC levels from the COVID-19 (+) patients were substantially lower compared to mean EPCs from men with severe ED and no history of COVID-19.
Our study is the first to demonstrate the presence of the COVID-19 virus in the penis long after the initial infection in humans. Our results also suggest that widespread endothelial cell dysfunction from COVID-19 infection can contribute to ED. Future studies will evaluate novel molecular mechanisms of how COVID-19 infection leads to ED.
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