World Health Organization (WHO) 2022 Classification Update: Radiologic and Pathologic Features of Papillary Renal Cell Carcinomas.

RATIONALE AND OBJECTIVES: To describe imaging and pathology features of newly defined papillary renal cell carcinoma (pRCC) based on the WHO 2022 update. MATERIALS AND METHODS: This retrospective study included 87 patients with 93 pathologically proven papillary renal cell carcinomas who underwent pre-treatment renal mass protocol CT or MRI. Baseline and post-treatment follow-up imaging was evaluated by two radiologists systematically based on established lexicon. RESULTS: At pathology, 63 (68%) were grade 1-2, 29 (31%) were grade 3-4, and 1 (%) was unreported. At surgical pathology, 84 (90%) were localized (≤pT2b), 5 (5%) were pT3a, and none were ≥pT3b; 4 (4%) had unknown pT stage (core biopsies). 33 (35%) had necrosis and 39 (41%) had hemorrhage. None had sarcomatoid or rhabdoid differentiation. At imaging, 73 (83%) were solid and 16 (17%) were cystic. Of 16 cystic masses, four were Bosniak class IIF (three were heterogeneously T1 hyperintense) and 12 were class IV. All were well-circumscribed. 92 (99%) were hypovascular. Median follow-up for 74 patients was 30 months (IQR 12-56). One untreated patient had non-regional nodal metastasis at presentation, and one patient had metastasis to lymph nodes and bones after surgery, but the patient had unresected renal masses elsewhere without pathology. Otherwise, no recurrence or metastases were detected. CONCLUSION: Most pRCCs present as a hypovascular, circumscribed, solid renal mass. A few pRCCs present as the newly defined Bosniak class IIF subtype. Our results can form the basis of a non-invasive, likelihood score to identify this relatively indolent pathology in the era of virtual biopsy and active surveillance.

Risk of malignancy in T1-hyperintense Bosniak version 2019 class II and IIF cystic renal masses.

BACKGROUND: Bosniak classification version 2019 includes cystic masses in class II and IIF based partly on their hyperintense appearance at T1-weighted MRI. The prevalence of malignancy in non-enhancing heterogeneously T1-hyperintense masses is unknown, nor whether the pattern of T1 hyperintensity affects malignancy likelihood. PURPOSE: To determine the malignancy proportion among six patterns of T1 hyperintensity within non-enhancing cystic renal masses. METHODS: This retrospective, single-institution study included 72 Bosniak class II and IIF, non-enhancing, T1-hyperintense cystic renal masses. Diagnosis was confirmed by histopathology or by follow-up imaging demonstrating 5-year size and morphologic stability, decreased in size by ≥ 30%, resolution, or Bosniak down-classification. Six patterns of T1 hyperintensity were pre-defined: homogeneous (pattern A), fluid-fluid level (pattern B), peripherally markedly T1-hyperintense (pattern C), containing a T1-hyperintense non-enhancing nodule (pattern D), peripherally T1-hypointense (pattern E), and heterogeneously T1-hyperintense without a distinct pattern (pattern F). Three readers independently assigned each mass to a pattern. Individual and mean malignancy proportion were determined. Mann-Whitney test and Fischer's exact test compared the likelihood of malignancy between patterns. Inter-reader agreement was analyzed with Gwet's agreement coefficient (AC). RESULTS: Among 72 masses, the mean number of masses assigned was 11 (15%) to pattern A, 21 (29%) to pattern B, 6 (8%) to pattern C, 7 (10%) to pattern D, 5 (7%) to pattern E, and 22 (31%) to pattern F. Five of 72 masses (7%) were malignant; none was assigned pattern A, B, or D. Mean malignancy proportion was 5% (0/9, 1/6, and 0/4) for pattern C, 13% (0/4, 1/3, and 1/7) for pattern E, and 18% (5/20, 3/21, and 4/25) for pattern F. Malignant masses were more likely assigned to pattern E or F (p = 0.003-0.039). Inter-reader agreement was substantial (Gwet's AC: 0.68). CONCLUSION: Bosniak version 2019 class IIF masses that are non-enhancing and heterogeneously T1-hyperintense with a fluid-fluid level are likely benign. Those that are non-enhancing and heterogeneously T1-hyperintense without a distinct pattern have a malignancy proportion up to 25% (5/20).

Does Milan affect management? A retrospective analysis of resection rate and time to surgery among Milan categories.

INTRODUCTION: The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) is an established system with reproducible risk of malignancies (ROM) for salivary gland fine needle aspiration (SGFNA). No studies have reviewed the relationship between Milan categories and the resection rate (RR) and time to resection (TTR). METHODS: We searched our database (January 1, 2011 to January 4, 2021) for non-lymphoma SGFNAs and assigned appropriate MSRSGC categories. RR and TTR were calculated and compared for each category. A literature search was performed; RRs and TTRs were compared. RESULTS: Seven hundred and eighty SGFNAs were identified, 333 with follow-up. RR was highest in suspicious for malignancy (SUS, V; 70.6%, n = 12/17), followed by the salivary gland neoplasm of uncertain malignant potential (SUMP, IVb; 69.6%, n = 80/115) and malignant (M, VI; 55.6%, n = 75/135). Among M, primary tumors had a higher RR (65.1%, n = 41/63) than metastases (47.2%, n = 34/72, p = .36). In literature review, SUS had the highest RR (69.3%, n = 233/336) followed by M (61.6%, n = 821/1332) and SUMP (60.2%, n = 632/1050). TTR was shorter in SUS (mean = 32.3 days, median = 25 days). Within the benign neoplasms (BN, IVa), Pleomorphic adenomas (PAs) had a higher RR than Warthin tumors (WTs) (66.3% vs. 37.2%, p < .00001), and a shorter TTR (median = 63 days vs. 90 days). CONCLUSIONS: Tumors classified as SUS had higher RR and at shorter intervals than those classified as SUMP. PAs have higher RRs and more expedient surgery than WTs. Cases classified as M are less likely to undergo follow-up than SUS, perhaps due to a lower RR for metastases.

Nondiagnostic salivary gland FNAs are associated with decreased risk of malignancy compared with "all-comer" patients: Analysis of the Milan System for Reporting Salivary Gland Cytopathology with a focus on Milan I: Nondiagnostic.

BACKGROUND: The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) reports a 25% rate of malignancy (ROM) for the Milan I: Nondiagnostic (ND) category. We clarify the ROM of ND salivary gland fine-needle aspirations (SGFNAs) based on our institutional experience and review of the literature. METHODS: Overall risk of malignancy (OROM) and that for those with surgical/flow cytometric follow-up (FROM) for each category and "all-comers" were calculated for Emory SGFNAs from January 2010 through March 2021. From a literature review of 50 articles using MSRSGC, distribution of diagnoses, rates of follow-up, FROM, and OROM by category were calculated. FROMs and OROMs between ND FNAs and all-comers were compared. Milan I rate was compared with the ratio of Milan I OROM to all-comer OROM. RESULTS: Of 819 SGFNAs at Emory, 12.8% (n = 105/819) were ND. Thirty-two had known follow-up, with 12 (37.5%) being malignant. Nonmucinous cyst contents accounted for 26.7% of ND SGFNAs (n = 28/105); all 7 with surgical follow-up were benign. Of 50 MSRSGC studies, 18.2% (n = 2384/13,129) of SGFNAs were classified as ND, 26.6% (n = 635/2384) with known follow-up. Total FROM and OROM for ND FNAs (15.7% and 4.1%, respectively) were significantly lower than those for all-comers (24.9% and 11.4%, respectively) (p < .001). There was no relationship between rate of ND SGFNA and ND ROM. CONCLUSIONS: The ND category is associated with a lower ROM than that of all-comer SGFNA patients. The "true" ROM for ND SGFNAs is likely best estimated by the 4.1% OROM. SGFNAs showing nonmucinous cyst contents have a particularly low ROM. Rate of ND SGFNAs does not influence ND ROM.

TDP-43 neurotoxicity and protein aggregation modulated by heat shock factor and insulin/IGF-1 signaling.

TAR DNA-binding protein 43 (TDP-43) plays a key role in the neurodegenerative diseases including amyotrophic lateral sclerosis and frontotemporal lobar degeneration. The nature of the TDP-43-mediated neurotoxicity associated with these diseases is not yet understood. Here, we have established transgenic Caenorhabditis elegans models that express human TDP-43 variants in the nervous system, including the full-length wild-type (WT) and mutant proteins and a pathologic C-terminal fragment. The C. elegans models developed severe locomotor defects associated with the aggregation of TDP-43 in neurons. In comparison to parallel Cu/Zn superoxide dismutase worm models, transgenic full-length TDP-43, including the WT protein, was highly neurotoxic. In addition, TDP-43 demonstrated an unusually high tendency to aggregate, a property intrinsic to the WT protein. The C-terminal 25 kDa fragment of TDP-43 was unstable but remarkably aggregation-prone. Distinct disulfide-linked TDP-43 dimers and oligomers were detected. In C. elegans, the neurotoxicity and the protein aggregation of TDP-43 were regulated by environmental temperature and heat shock transcriptional factor 1, indicating that a deficiency in protein quality control is a risk factor for TDP-43 proteinopathy. Furthermore, the neurotoxicity and the protein aggregation of TDP-43 can be significantly attenuated by a deficiency in the insulin/insulin-like growth factor 1 (IGF-1) signaling in C. elegans and mammalian cells. These results suggest that protein misfolding underlies the aging-dependent neurodegeneration associated with TDP-43 and that the insulin/IGF-1 signaling may be a target for therapies.