Variability in endometrial carcinoma pathology practice: opportunities for improvement with molecular classification.

We assessed the landscape of diagnostic pathology practice and how molecular classification could potentially impact management of patients with endometrial cancer by collecting patient samples, clinicopathologic data, and patient outcomes from EC patients diagnosed in 2016 at 10 Canadian tertiary cancer centers and 19 community hospitals. ProMisE molecular subtype (POLEmut, MMRd, p53abn, No Specific Molecular Profile (NSMP)) was assigned retrospectively. 1357 patients were fully evaluable including 85 POLEmut (6.3%), 380 MMRd (28.0%), 643 NSMP (47.4%), and 249 p53abn ECs (18.3%). Immunohistochemistry (IHC) for MMR proteins was undertaken at the time of primary diagnosis in 2016 in only 42% of the cohort (570/1357; range 3.5-95.4%/center). p53 IHC had only been performed in 21.1% of the cohort (286/1357; range 10.1-41.9%/center). Thus, based on the retrospective molecular subtype assignment, 54.7% (208/380) of MMRd EC had not been tested with MMR IHC (or MSI) and 48.2% (120/249) of p53abn ECs were not tested with p53 IHC in 2016. Molecular subtype diversity within histotypes was profound; most serous carcinomas were p53abn (91.4%), but only 129/249 (51.8%) p53abn EC were serous. Low-grade (Gr1-2) endometrioid carcinomas were mostly NSMP (589/954, 61.7%) but included all molecular subtypes, including p53abn (19/954, 2.0%). Molecular subtype was significantly associated with clinical outcomes (p < 0.001) even in patients with stage I disease (OS p = 0.006, DSS p < 0.001, PFS p < 0.001). Assessment of national pathologic practice in 2016 shows highly variable use of MMR and p53 IHC and demonstrates significant opportunities to improve and standardize biomarker reporting. Inconsistent, non-reflexive IHC resulted in missed opportunities for Hereditary Cancer Program referral and Lynch Syndrome diagnosis, and missed potential therapeutic implications (e.g., chemotherapy in p53abn EC, immune blockade for MMRd EC). Routine integration of molecular subtyping into practice can improve the consistency of EC pathology assessment and classification.

Clinicopathologic predictors of renal outcomes in light chain cast nephropathy: a multicenter retrospective study.

Light chain cast nephropathy (LCCN) in multiple myeloma often leads to severe and poorly reversible acute kidney injury. Severe renal impairment influences the allocation of chemotherapy and its tolerability; it also affects patient survival. Whether renal biopsy findings add to the clinical assessment in predicting renal and patient outcomes in LCCN is uncertain. We retrospectively reviewed clinical presentation, chemotherapy regimens, hematologic response, and renal and patient outcomes in 178 patients with biopsy-proven LCCN from 10 centers in Europe and North America. A detailed pathology review, including assessment of the extent of cast formation, was performed to study correlations with initial presentation and outcomes. Patients presented with a mean estimated glomerular filtration rate (eGFR) of 13 ± 11 mL/min/1.73 m2, and 82% had stage 3 acute kidney injury. The mean number of casts was 3.2/mm2 in the cortex. Tubulointerstitial lesions were frequent: acute tubular injury (94%), tubulitis (82%), tubular rupture (62%), giant cell reaction (60%), and cortical and medullary inflammation (95% and 75%, respectively). Medullary inflammation, giant cell reaction, and the extent of cast formation correlated with eGFR value at LCCN diagnosis. During a median follow-up of 22 months, mean eGFR increased to 43 ± 30 mL/min/1.73 m2. Age, ß2-microglobulin, best hematologic response, number of cortical casts per square millimeter, and degree of interstitial fibrosis/tubular atrophy (IFTA) were independently associated with a higher eGFR during follow-up. This eGFR value correlated with overall survival, independently of the hematologic response. This study shows that extent of cast formation and IFTA in LCCN predicts the quality of renal response, which, in turn, is associated with overall survival.

Variation in practice in endometrial cancer and potential for improved care and equity through molecular classification.

OBJECTIVES: We measured the variation in practice across all aspects of endometrial cancer (EC) management and assessed the potential impact of implementation of molecular classification. METHODS: Centers from across Canada provided representative tumor samples and clinical data, including preoperative workup, operative management, hereditary cancer program (HCP) referrals, adjuvant therapy, surveillance and outcomes, for all EC patients diagnosed in 2016. Tumors were classified into the four ProMisE molecular subtypes. RESULTS: A total of 1336 fully evaluable EC patients were identified from 10 tertiary cancer centers (TC; n = 1022) and 19 community centers (CC; n = 314). Variation of surgical practice across TCs was profound (14-100%) for lymphadenectomy (LND) (mean 57% Gr1/2, 82% Gr3) and omental sampling (20% Gr1/2, 79% Gr3). Preoperative CT scans were inconsistently obtained (mean 32% Gr1/2, 51% Gr3) and use of adjuvant chemo or chemoRT in high risk EC ranged from 0-55% and 64-100%, respectively. Molecular subtyping was performed retrospectively and identified 6% POLEmut, 28% MMRd, 48% NSMP and 18% p53abn ECs, and was significantly associated with survival. Within patients retrospectively diagnosed with MMRd EC only 22% had been referred to HCP. Of patients with p53abn EC, LND and omental sampling was not performed in 21% and 23% respectively, and 41% received no chemotherapy. Comparison of management in 2016 with current 2020 ESGO/ESTRO/ESP guidelines identified at least 26 and 95 patients that would have been directed to less or more adjuvant therapy, respectively (10% of cohort). CONCLUSION: Molecular classification has the potential to mitigate the profound variation in practice demonstrated in current EC care, enabling reproducible risk assessment, guiding treatment and reducing health care disparities.

Renal comorbidities in collapsing variant focal segmental glomerulosclerosis: more than a coincidence?

BACKGROUND: Collapsing focal segmental glomerulosclerosis (FSGS) has various underlying etiologies and often leads to renal failure. The impact of biopsy-proven renal comorbidities in promoting collapsing glomerulopathy (CG) has not been systematically evaluated in large comparative studies. Those data are reported here. METHODS: Biopsies with the initial diagnosis of CG in native (n = 321) or transplant kidneys (n = 30) were identified in the University of North Carolina nephropathology database (1 January 2011 to 1 January 2016). Two cohorts were defined: 'sole' CG without and 'accompanied' CG with significant morphologic renal comorbidities. Tip-variant FSGS (T-FSGS) and time-matched biopsies served as control cohorts for comparative analyses. RESULTS: CG was significantly more common in native (4.4%) and transplant biopsies (4.1%) compared with T-FSGS (0.7 and <0.1%, respectively, difference versus CG P < 0.01). 'Associated' disease was significantly more common in CG (native: 151/321; 47.0%, transplant: 21/30; 70%, P < 0.05) versus T-FSGS (native: 14/51; 27.5%, transplant: exceptional; all differences versus CG P < 0.05). In native biopsies with 'accompanied' CG but not in control groups, stenosing vasculopathies including thrombotic microangiopathies were significantly more prevalent (P < 0.01). In transplants, the high incidence of 'accompanied' CG was linked to de novo diseases, mainly rejection and vascular injury. In native kidneys, membranous glomerulopathies were prevalent in 'accompanied' T-FSGS (36%) and CG (14%) (difference versus time-matched controls P < 0.01 and P < 0.05, respectively); they were uncommon in transplants. CONCLUSIONS: CG but not T-FSGS shows a high rate of comorbidities, with prominent vasculopathies presumably driving 'ischemic' CG-specific glomerular injury and also the disease course. These findings facilitate future studies into therapy, prognosis and reversibility of 'accompanied' CG.

Endometrial Biopsy in Low-Risk Women: Are We Over-Investigating?

The appropriate age at which to perform endometrial biopsy for abnormal uterine bleeding (AUB) is controversial. This study aimed to determine the prevalence of malignant and premalignant pathologies in women aged 41-49 years with AUB and without risk factors for endometrial cancer. Records of women who had undergone a biopsy at the gynaecology clinic of the Centre hospitalier de l'Université de Montréal between 2014 and 2018 were reviewed. Of the 209 women included in the study, 2 had atypical hyperplasia, which resolved without treatment, and 3 had hyperplasia without atypia. The remaining women had benign results, showing that the prevalence of malignant and premalignant endometrial pathologies is low in this subgroup of patients.

Distinct Histologic, Immunohistochemical and Clinical Features Associated With Serous Endometrial Intraepithelial Carcinoma Involving Polyps.

The origin of serous endometrial intraepithelial carcinoma (SEIC) is debated, due to its premalignant and independently malignant nature. It often arises next to endometrial serous carcinoma (ESC), with a propensity for polypoid growth. We aimed to better characterize this discrepancy by analyzing the clinical, histologic, and immunohistochemical features of polypoid carcinoma associated with SEIC (P-SEIC), and compared them with usual endometrial serous carcinoma without SEIC (UESC). Consecutive patients with P-SEIC were recruited and compared with UESC controls from our institutional research center. Clinical, histologic, and immunohistochemical (IHC, ER, PR, P53, Napsin-A, WT1, P16) were analyzed. BRCA testing results and familial history were also extracted from clinical databases. Welch T test, Pearson χ, and Fisher exact test were performed in SPSS version 23. A total of 37 P-SEIC and 25 UESC were the basis of a case-control study. P-SEIC was associated with more bilateral ovarian involvement (P=0.026), yet showed lower rates of myometrial invasion (P=0.002). P-SEIC showed a statistically different IHC profile: p53+, p16+, ER+, PR+, and WT-1+, and high rates of Napsin-A, while UESC was p53+, p16+, WT-1-, Napsin-A-, with lower rates of ER and PR. We also identified 2 patients who received prophylactic salpingo-oophorectomy for BRCA mutations and who subsequently developed P-SEIC with its unique IHC pattern. Our results suggest different underlying expression profiles and possibly diverging molecular signatures between both P-SEIC and UESC. If confirmed in further molecular studies, it could lead to a distinct molecular subclass.

C4d-expressing glomerulopathy and proteinuria post transplantation of a too-big-for-size mismatched kidney allograft: An unusual case with good outcome
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A 5-year-old severely growth-retarded child with tubulointerstitial, oliguric end-stage renal disease received an adult-size kidney transplant. Three years post grafting under standard triple immunosuppression (mycophenolate mofetil, tacrolimus, and prednisone) de novo nephrotic range proteinuria without the nephrotic syndrome developed. Graft function was normal (serum creatinine: 0.2 - 0.3 mg/dL), there were no donor-specific HLA antibodies (DSA), and the urine sediment was inactive. Two biopsies collected 3 and 4 years post-transplantation showed severe glomerular capillary wall remodeling and associated pseudolinear C4d staining as morphologic correlates for the proteinuria. Changes resembled those seen in so-called "size-mismatch transplant glomerulopathies". There was no evidence of a glomerulonephritis, acute or chronic rejection including transplant glomerulopathy, interstitial fibrosis, peritubular capillary C4d deposits, or multilamination of peritubular capillary basement membranes. The glomerular changes were not detected in the implantation zero-hour biopsy or the recipient's native renal biopsy. At the end of follow-up 64 months post transplantation, proteinuria persisted at subnephrotic levels in the setting of stable graft function and undetectable DSAs. This unique case adds to the list of causes of nonrejection-associated post-transplant proteinuria. It demonstrates for the first time that a too-large-for-body-size mismatched graft is associated with a presumably sheer stress-induced C4d expressing glomerulopathy, severe proteinuria, and favorable outcome.
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A Prospective Study on Complement Activation Distinguishes Focal Segmental Glomerulosclerosis from Minimal Change Disease.

Introduction: Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are related podocytopathies with distinct kidney outcomes. Surprisingly, elevated urinary activation fragments have been found in FSGS despite little complement deposition on immunofluorescence (IF) staining. Whether complement activation distinguishes FSGS from MCD, participating in the development of segmental lesions, remains unknown. Methods: We performed an observational study in patients with MCD and FSGS, and proteinuria ≥1 g/g of creatinine. We included both primary and secondary or unknown causes. We compared urinary fragments of terminal pathway activation, sC5b9, and C5a expressed as creatinine ratios, between MCD and FSGS. Results: Patients with FSGS (n = 41) had a serum albumin of 31±10 g/l and proteinuria of 5.1 (2.6-9.1) g/g at sampling, whereas those with MCD (n = 15) had a lower serum albumin (22 ± 9 g/l; P = 0.002), and a proteinuria of 3.8 (1.9-7.7) g/g (P = 0.40). Urinary sC5b9 and C5a were 8.7 (1.7-52.3) and 1.26 (0.45-1.84) µg/mmol of creatinine, respectively in patients with FSGS; compared to 0.8 (0.0-1.5) and 0.06 (0.01-0.15) µg/mmol of creatinine in MCD (P < 0.001), respectively. We found no association between urinary complement fragments and age, estimated glomerular filtration rate (eGFR), or chronic kidney lesions. When analyzing samples with proteinuria ≥ 3 g/g, the c-statistics for urinary sC5b9 and C5a were 0.96 and 1.00, respectively, in differentiating FSGS from MCD. Conclusion: We found no urinary complement activation fragments in MCD, in comparison to FSGS, despite similar levels of proteinuria. This suggests a role for complement activation in the pathogenesis of FSGS and provides an additional tool for distinguishing these 2 entities.

Gastric-type adenocarcinoma of the endocervix: Potentially overcoming resistant behavior with surgery.

Objective: Gastric-type adenocarcinoma of the endocervix (GAS) is a rare form of human papillomavirus-independent cervical cancer commonly described as an insidious disease bearing a poor prognosis. Based on scarce data, uncertainty persists pertaining to its oncologic management. Method: All cases of well-differentiated GAS treated at our institution from 2010 to 2021 were reviewed. Clinical characteristics, diagnostic tests results and oncologic outcomes were recorded and analyzed. Kaplan-Meier curves and log rank test were performed to compare survival curves between patients with tumors confined to the cervix (group 1: up to stage IB3) versus locally advanced or metastatic (group 2: stages II to IV). Results: Cervical cytologies and biopsies yielded low detection rates (38 and 42% respectively) leading to 87% of patients with locally advanced or metastatic disease at diagnosis. Median overall survival (OS) was 40.0 ± 15.9 months with a clear dichotomy in survival when comparing patients with disease confined to the cervix to those with higher stages (respectively 59.0 vs 12.0 months, p = 0.047). None of the 5 patients initially managed with concurrent chemoradiotherapy (CCRT) responded to treatment but fortunately 3 of the latter achieved remission after surgery. Conclusion: Well-differentiated GAS did not show favorable response to chemotherapy and radiation. Surgical resection seems to be a cornerstone in the management of this disease, as all patients who achieved remission were treated with surgery, either upfront or after suboptimal response to CCRT. We suggest considering aggressive upfront surgery when feasible. If CCRT is selected to avoid upfront exenterative procedures, rapid evaluation of tumor response is recommended.

Acute Tubulointerstitial Nephritis in a Patient on Anti-Programmed Death-Ligand 1 Triggered by COVID-19: A Case Report.

RATIONALE: Immune checkpoint inhibitors are monoclonal antibodies used in the treatment of various types of cancers. The downside of using such molecules is the potential risk of developing immune-related adverse events. Factors that trigger these autoimmune side effects are yet to be elucidated. Although any organ can potentially be affected, kidney involvement is usually rare. In this case report, we describe the first known instance of a patient being treated with an inhibitor of programmed death-ligand 1 (anti-PD-L1, a checkpoint inhibitor) who develops acute tubulointerstitial nephritis after contracting the severe acute respiratory syndrome coronavirus 2. PRESENTING CONCERNS OF THE PATIENT: A 62-year-old patient, on immunotherapy treatment for stage 4 squamous cell carcinoma, presents to the emergency department with symptoms of lower respiratory tract infection. Severe acute kidney injury is discovered with electrolyte imbalances requiring urgent dialysis initiation. Further testing reveals that the patient has contracted the severe acute respiratory syndrome coronavirus 2. DIAGNOSIS: A kidney biopsy was performed and was compatible with acute tubulointerstitial nephritis. INTERVENTIONS: The patient was treated with high dose corticosteroid therapy followed by progressive tapering. OUTCOMES: Rapid and sustained normalization of kidney function was achieved after completion of the steroid course. NOVEL FINDINGS: We hypothesize that the viral infection along with checkpoint inhibitor use has created a proinflammatory environment which led to a loss of self-tolerance to renal parenchyma. Viruses may play a more important role in the pathogenesis of autoimmunity in this patient population than was previously thought.

Surgical management of intravascular leiomyomatosis.

Intravascular leiomyomatosis is a rare entity defined by benign smooth uterine muscle cells that typically originate from the uterus with the potential to spread into veins possibly up to the heart. The diagnosis for patients presenting with cardiac symptoms may be difficult and imaging often interpreted as thrombus or atrial myxoma.

Peritoneal Keratin Granulomatosis Is a Clinical and Radiological Mimicker of Endometrial Adenocarcinoma With Peritoneal Involvement.

Peritoneal keratin granulomatosis is a rare tumor-like lesion caused by deposition of tumor-produced keratin. It may be associated with endometrial or ovarian endometrioid adenocarcinoma, atypical polypoid adenomyoma of the endometrium, or ruptured mature teratomas of the ovary. We present 2 cases of peritoneal keratin granulomatosis associated with FIGO (International Federation of Gynecology and Obstetrics) stage 1 endometrial adenocarcinoma. This entity can mimic advanced-stage disease clinically and radiologically, as it did in those cases, and constitutes a diagnostic pitfall that pathologists and surgeons must be aware.

Pelvic Aggressive Angiomyxoma: Major Challenges in Diagnosis and Treatment.

Aggressive pelvic angiomyxoma is a very rare mesenchymal tumor that is usually diagnosed in premenopausal female patients. The current mainly reported treatment is wide surgical excision. Other treatment options, such as radiotherapy and hormonal therapy, have been suggested as potential alternatives. A 61-year-old postmenopausal female patient presented with hematuria that led to the identification of a perirectal mass on abdominopelvic imaging. A 46-year-old female patient presented with a perineal mass of unknown etiology. Despite extensive investigations, the diagnosis could not be confirmed before surgical resection in both patients. Surgical excisions were performed and revealed the presence of an aggressive angiomyxoma with positive estrogen and progesterone tumoral receptors in both cases. Radiological and clinical recurrence was noted in one patient. Tumor regression was noted in this patient after treatment with a luteinizing hormone-releasing hormone (LHRH) agonist with long-term remission. The diagnosis of a perirectal aggressive angiomyxoma is an exceedingly rare event. Preoperative biopsy and pathological diagnosis are challenging and often yields poor results. Its slow growth and expression of hormonal receptors make noninvasive therapeutic strategies, such as radiotherapy, gonadotropin-releasing hormone agonists, or even watchful waiting, valid options in selected patients. Due to the lack of reported cases, the best treatment has yet to be elucidated.

Estimating the Change in Renal Function During the First Year of Therapy in ANCA-Associated Vasculitis.

INTRODUCTION: Studies in antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) consistently show that the months following diagnosis have the greatest impact on the long-term renal function. Yet, it remains uncertain how much early gain should be expected with treatment. We sought to determine the factors associated with the change in glomerular filtration rate (GFR) throughout the first year. METHODS: We retrospectively reviewed patients from 3 university hospitals who received treatments. We assessed the proportions of glomeruli with crescents, with global sclerosis, the AAV glomerulonephritis classification, the severity of chronic vascular and tubulo-interstitial disease, and the presence of acute tubular injury (ATI). We used repeated-measures analyses of variance (ANOVAs) to determine factors associated with the change in GFR throughout the first year. RESULTS: There were 162 individuals with AAV identified, 96 with a valid renal biopsy and 82 with at least 12 months of follow-up. The initial GFR of 30 ± 25 ml/min per 1.73 m2 rose by 15 ± 20 during the first year. The severity of pathology findings, myeloperoxidase positivity, and those with kidney- and lung-limited disease presented with a lower GFR. Younger patients with a lower initial GFR and the presence of ATI correlated with a greater increase in GFR by 12 months. A higher proportion of crescents did not predict the change in GFR, contrary to global glomerulosclerosis, where each 10% increase added a loss of 2.7 ± 1.3 ml/min per 1.73 m2 per year (P = 0.03). These factors remained independent of each other. CONCLUSION: Multiple factors influence renal recovery during the first year of therapy. Estimating the change in GFR early on will help identify and reassess outliers.

Total knee arthroplasty in hemophilic arthropathy.

UNLABELLED: Chronic arthropathy causes major functional disability in patients with severe hemophilia. OBJECTIVE: To evaluate the results of total knee arthroplasty (TKA) and its impact on both quality of life and clotting factor use in patients with severe hemophilia. PATIENTS AND METHODS: We evaluated 17 TKAs in 12 patients. The TKAs were performed between 1986 and 1996, and follow-up was 8-132 months (mean, 54 months). Mean age at arthroplasty was 39 years (22-51 years). Quality of life was evaluated using the Short Form 36 (SF-36). RESULTS: Results were good or excellent in 94% of patients. The improvement was greatest for pain. Recurrent hemarthrosis in six patients and development of an anticoagulant in two patients were the only postoperative complications. Clotting factor use did not decrease significantly after surgery. SF-36 scores showed an increase in physical activity responsible for an improvement in quality-of-life indicators. However, this improvement in functional capabilities seemed to wane over time as a result of arthropathy in other joints and of intercurrent diseases. CONCLUSION: TKA for hemophilic arthropathy provides good results that translate into quality-of-life gains.