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Granulomatous interstitial nephritis (NIG) is a rare form of interstitial nephritis that can be related to acute or chronic clinical presentation. NIG is characterized by granulomas located to the renal interstitium and composed of either epithelioid histiocytes with giant cells and/or of foreign body reaction. The symptoms are unspecific and associate varying degrees of renal failure with abnormal urinanalysis. Extra-renal signs may point to systemic disease. Pathological examination from kidney percutaneous biopsy or surgical resection is required to assert NIG diagnosis and to guide the etiological research. The main causes of NIG are sarcoidosis, drug reactions, mycobacterial infections and crystalline nephropathies. Sarcoidosis is characterized by non-necrotic and well-formed giant cell epithelioid interstitial granulomas. Drug reactions have less well-defined granulomas with inconstant eosinophils. The presence of caseous necrosis within giant cell and epithelioid granulomas leads to infectious NIG diagnosis (tuberculosis and fungal infection). Identification of crystals within foreign body reaction can be improved by polarized light study. Xanthogranulomatous pyelonephritis and malakoplakia are rarer causes of NIG characterized by patches of histiocytes associated with inconstant giant cells. Differential diagnoses of NIG are represented by granulomatous reactions centered on glomeruli and vessels (vasculitis and emboli of cholesterol crystals). Less than 10% of NIG are idiopathic. The prognosis and the treatment vary according to the cause. The factors of poor renal prognosis are chronic irreversible tubulo-interstitial injury (tubular atrophy and interstitial fibrosis).

Introduction: High-grade lung neuroendocrine tumours with carcinoid morphology have been recently reported; they may represent the thoracic counterparts of grade 3 digestive neuroendocrine tumours. We aimed to study their genetic landscape including analysis of tumoral heterogeneity. Methods: Eleven patients with high-grade (>20% Ki-67 and/or >10 mitoses) lung neuroendocrine tumours with a carcinoid morphology were included. We analysed copy number variations, somatic mutations, and protein expression in 16 tumour samples (2 samples were available for 5 patients allowing us to study spatial and temporal heterogeneity). Results: Genomic patterns were heterogeneous ranging from “quiet” to tetraploid, heavily rearranged genomes. Oncogene mutations were rare and most genetic alterations targeted tumour suppressor genes. Chromosomes 11 (7/11), 3 (6/11), 13 (4/11), and 6–17 (3/11) were the most frequently lost. Altered tumour suppressor genes were common to both carcinoids and neuroendocrine carcinomas, involving different pathways including chromatin remodelling (KMT2A, ARID1A, SETD2, SMARCA2, BAP1, PBRM1, KAT6A), DNA repair (MEN1, POLQ, ATR, MLH1, ATM), cell cycle (RB1, TP53, CDKN2A), cell adhesion (LATS2, CTNNB1, GSK3B) and metabolism (VHL). Comparative spatial/temporal analyses confirmed that these tumours emerged from clones of lower aggressivity but revealed that they were genetically heterogeneous accumulating “neuroendocrine carcinoma-like” genetic alterations through progression such as TP53/RB1 alterations. Conclusion: These data confirm the importance of chromatin remodelling genes in pulmonary carcinoids and highlight the potential role of TP53 and RB1 to drive the transformation in more aggressive high-grade tumours.

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Introduction: Renal involvement is a severe manifestation of antineutrophil cytoplasmic antibody-associated vasculitis. Patients often progress to end-stage renal disease. The potential for renal recovery after the first flare has seldom been studied. Our objectives were to describe the evolution of the estimated glomerular filtration rate (eGFR) and identify factors associated with the change in the eGFR between diagnosis and the follow-up at 3 months (ΔeGFRM0–M3). Methods: This was a retrospective study over the period 2003–2018 of incident patients in the Nord-Pas-de-Calais (France). The primary outcome was the ΔeGFRM0–M3. Results: One hundred and seventy-seven patients were included. The eGFR at 3 months was significantly higher than at diagnosis (mean ± standard deviation, 40 ± 24 vs. 28 ± 26 mL/min/1.73 m2, p < 0.001), with a ΔeGFRM0–M3 of 12 ± 19 mL/min/1.73 m2. The eGFR at 12 months was higher than at 3 months (44 ± 13 vs. 40 ± 24 mL/min/1.73 m2, p = 0.003). The factors significantly associated with the ΔeGFRM0–M3 in multivariate analysis were the percentage of cellular crescents and neurological involvement. The mean increase in the eGFR was 2.90 ± 0.06 mL/min/1.73 m2 for every 10-point gain in the percentage of cellular crescents. Conclusions: Early renal recovery after the first flare of pauci-immune glomerulonephritis occurred mainly in the first 3 months of treatment. The percentage of cellular crescents was the main independent predictor of early renal recovery.

After infant deaths due to non-accidental head injury (NAHI) with subdural hematoma (SDH), the magistrates ask experts to date the traumatic event. To do so, the expert only has tools based on adult series of NAHI. We aimed to develop an SDH dating system applicable to infants aged under 3 years. We studied a retrospective multicenter collection of 235 infants who died between the ages of 0 and 36 months, diagnosed with SDH by forensic pathological examination and with known posttraumatic interval (PTI). Two pathologists assessed blindly and independently 12 histomorphological criteria relating to the clot and 14 relating to the dura mater in 73 victims (31 girls, 42 boys) whose median age was 3.8 months. Histopathological changes were significantly correlated with PTI for the appearance of red blood cells (RBCs) and the presence or absence of siderophages, and regarding the dura mater, the quantity of lymphocytes, macrophages, and siderophages; presence or absence of hematoidin deposits; collagen and fibroblast formation; neomembrane thickness; and presence or absence of neovascularization. Dating systems for SDH in adults are not applicable to infants. Notably, neomembrane of organized connective tissue is formed earlier in infants than in adults. Our dating system improves the precision and reliability of forensic pathological expert examination of NAHI, particularly for age estimation of SDH in infants. However, the expert can only define a time interval. Histopathology is indispensable to detect repetitive trauma.

Background and Aims Renal involvement is a severe manifestation of ANCA-associated vasculitis. Patients often progress to end-stage renal disease. The potential for renal recovery after a first flare has seldom been studied. Our objectives were to describe the evolution of the estimated glomerular filtration rate (eGFR) and identify factors associated with the change in eGFR between diagnosis and follow-up at 3 months (ΔeGFRM0–M3) in a cohort of patients with a first flare of pauci-immune glomerulonephritis. Methods This was a retrospective study over the period 2003–2018 of incident patients in the Nord-Pas-de-Calais (France). Patients were recruited if they had a first histologically-proven flare of pauci immune glomerulonephritis with at least 1 year of follow up. Kidney function was estimated with MDRD-equation and analysed at diagnosis, 3rd, 6th and 12th months. The primary outcome was ΔeGFRM0–M3. Factors evaluated were histological (Berden classification, interstitial fibrosis, percentage of crescents), clinical (extra-renal manifestations, sex, age) or biological (severity of acute kidney injury, dialysis, ANCA subtype). Results One hundred and seventy-seven patients were included. The eGFR at 3 months was significantly higher than at diagnosis (mean ± standard deviation, 40 ± 24 vs 28 ± 26 ml/min/1.73 m2, p < 0.001), with a ΔeGFRM0–M3 of 12 ± 19 ml/min/1.73 m2. The eGFR at 12 months was higher than at 3 months (44 ± 13 vs 40 ± 24 ml/min/1.73m2, p = 0.003). The factors significantly associated with ΔeGFRM0–M3 in univariate analysis were: sclerotic class according to Berden classification, percentage of interstitial fibrosis, percentage of cellular crescents, acute tubular necrosis, neurological involvement. The factors associated with ΔeGFRM0–M3 in multivariate analysis were the percentage of cellular crescents and neurological involvement. The mean increase in eGFR was 2.90 ± 0.06 ml/min/1.73m2 for every 10-point gain in the percentage of cellular crescents. ΔeGFRM0–M3 was not associated with the risks of end-stage renal disease or death in long-term follow-up. Conclusions Early renal recovery after a first flare of pauci-immune glomerulonephritis occurred mainly in the first three months of treatment. The percentage of cellular crescents was the main independent predictor of early renal recovery.

Context.— Distinguishing the different types of amyloid is clinically important because treatments and outcomes are different. Mass spectrometry is the new gold standard for amyloid typing, but it is costly and not widely available. Therefore, immunolabeling remains the first step in identifying the most common types of amyloidosis. In amyloid subtyping, direct immunofluorescence works well when applied to frozen sections, but immunohistochemistry on formalin-fixed, paraffin-embedded material often yields poor results, particularly for light chain amyloidosis. Recently, paraffin immunofluorescence has been described as a valuable salvage technique in renal pathology when frozen sections are not available but it has not been evaluated for extra-renal diseases. Objectives.— To evaluate the use of paraffin immunofluorescence for light-chain detection in extra-renal amyloidosis and other light-chain–associated diseases. Design.— First, we compared the staining intensity of both light chains between paraffin immunofluorescence and immunohistochemistry on a retrospective cohort of 28 cases of amyloidosis that have been previously typed. Then, we studied the role of paraffin immunofluorescence as an addition to our classical immunohistochemistry panel for amyloidosis typing. Results.— In the retrospective cohort, we found that paraffin immunofluorescence outperformed immunohistochemistry for light-chain detection. Then, in the prospective part of the study, we showed that the proportion of correctly classified cases increased from 50% to 71.9% with the adjunction of second-intention paraffin immunofluorescence to the immunohistochemistry procedure. Conclusions.— We therefore view paraffin immunofluorescence as a significant addition to the routine workflow for detection of light-chain–related diseases.

Granulomatous interstitial nephritis (NIG) is a rare form of interstitial nephritis that can be related to acute or chronic clinical presentation. NIG is characterized by granulomas located to the renal interstitium and composed of either epithelioid histiocytes with giant cells and/or of foreign body reaction. The symptoms are unspecific and associate varying degrees of renal failure with abnormal urinanalysis. Extra-renal signs may point to systemic disease. Pathological examination from kidney percutaneous biopsy or surgical resection is required to assert NIG diagnosis and to guide the etiological research. The main causes of NIG are sarcoidosis, drug reactions, mycobacterial infections and crystalline nephropathies. Sarcoidosis is characterized by non-necrotic and well-formed giant cell epithelioid interstitial granulomas. Drug reactions have less well-defined granulomas with inconstant eosinophils. The presence of caseous necrosis within giant cell and epithelioid granulomas leads to infectious NIG diagnosis (tuberculosis and fungal infection). Identification of crystals within foreign body reaction can be improved by polarized light study. Xanthogranulomatous pyelonephritis and malakoplakia are rarer causes of NIG characterized by patches of histiocytes associated with inconstant giant cells. Differential diagnoses of NIG are represented by granulomatous reactions centered on glomeruli and vessels (vasculitis and emboli of cholesterol crystals). Less than 10% of NIG are idiopathic. The prognosis and the treatment vary according to the cause. The factors of poor renal prognosis are chronic irreversible tubulo-interstitial injury (tubular atrophy and interstitial fibrosis).

The aims of this study were to determine whether tubulointerstitial damage in the form of interstitial fibrosis/tubular atrophy and total interstitial inflammation predicted progression to end stage renal disease (ESRD) and/or renal relapse (RR) in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). One hundred thirteen patients with AAV from six French centers with an index biopsy performed between 2003 and 2013 were included. Histological assessments using the AAV glomerular classification and the kidney allograft Banff classification were performed on pathological review. Biopsy tissues were also investigated by CD3, CD20, CD68, CD163, FOXP3 and RORγt immunohistochemical staining. Competing risks models were calculated. Of the 113 patients, 26 (23.0%) died during follow-up and 29 (25.6%) developed ESRD. Among the 94 patients who achieved remission by the end of induction therapy without developing ESRD, 26 (27.6%) experienced RR. The two independent prognostic factors for ESRD were the estimated glomerular filtration rate at presentation (HR 0.35; 95% CI 0.23-0.51; P 0.0001) and IF/TA 25% (HR 2.27; 95% CI 1.18-4.37; P = 0.014). When the distribution of interstitial immune cell phenotypes was included in a second multivariable model, the organization of lymphocytic infiltrates was also an independent predictor of ESRD (HR 2.86; 95% CI 1.35-6.1, P = 0.006). The independent risk factors for RR were a higher CD3/CD20 ratio (HR 1.39; 95% CI 1.05-1.85; P = 0.02) and the presence of RORγt positive cells (HR 2.70; 95% CI 1.11-6.54; P = 0.02). Our results highlight the prognostic value of initial histological evaluations in AAV. Measurements of tubulointerstitial damage and interstitial immune cell phenotype distributions should be considered to improve risk assessments for ESRD and RR.

Medical autopsies have been in considerable decline for several decades, in France and worldwide. We aimed to determine whether a medical autopsy still currently has a role to play in diagnosis, by analyzing its performance and diagnostic limitations. This dual-centre retrospective descriptive study included all medical autopsies performed in the university hospitals of Lille and Marseille, France, between January 2007 and December 2012. Autopsies of fetuses or stillborn infants, or those related to sudden infant deaths and research protocols were excluded. 412 medical autopsies were included. The male:female ratio was 1.5:1 and mean age was 27.3 years. Half of all autopsies were pediatric. Regarding anatomical region and/or injury mechanism, a clinical diagnosis was suggested in 52.2% of cases, an autopsy diagnosis in 55.6% and a microscopic diagnosis in 81.8%. There was very low agreement between the clinician’s suggested diagnosis and the final diagnosis, both for organ specific diseases and cause of death. Agreement was moderate between autopsy diagnoses and microscopic diagnoses for organ specific diseases and low for cause of death. From our findings we concluded that an autopsy associated with microscopic examination was still valuable in diagnosing cause of death. Microscopic examination was indispensable to determine certain causes of death.

Background Dating the traumatic event is usually done on subdural hematoma (SDH). After infant deaths due to Abusive head trauma (AHT) without SDH available, the magistrates still ask experts to date the traumatic event. To do so, the expert only has tools based on adult series of AHT. We aimed to develop a subarachnoid hemorrhage (SAH) and retinal hemorrhage (RH) dating system applicable to infants aged under 3 years. Methods and results We studied a retrospective multicenter collection of 235 infants who died between the ages of 0 and 36 months, diagnosed with SAH and/or RH by forensic pathological examination and with known posttraumatic interval (PTI). Two pathologists assessed blindly and independently 12 histomorphological features in 83 infants (35 girls, 48 boys) whose median age was 3.8 months. For SAH, histopathological changes were significantly correlated with PTI for the appearance of red blood cells, of fibrino-plaquetted organization, the quantity of lymphocytes and macrophages and the presence or absence of siderophages, collagen and fibroblast formation and presence or absence of neovascularization. For RH, histopathological changes were significantly correlated with PTI for the appearance of red blood cells, the presence or absence of siderophages and sclerosis of the retina. Conclusion Our HAS dating system improves the precision and reliability of forensic pathological expert examination of AHT, when SDH are not available, for age estimation in infants. The study of RH histomorphological changes does not allow for reliable dating.

The initial description of the keyhole defect was detailed as a peculiar gunshot entrance wound in the cranial vault due to firearm discharge in a tangential path. This injury may be described in two parts: a rounded section with inner table beveling and a triangular section with outer table beveling. We report a case of a gunshot skull wound "keyhole" shaped, appeared to have been made perpendicularly to the bone. Performing an experimental study on cranial bones with shots made perpendicularly to the skull approved this hypothesis, and bone injuries were then architecturally characterised using high-resolution micro computed tomography. The singular link between the tangential gunshot path and the keyhole pattern has been refuted several times, and some authors have hypothesised that there is an important role for concentric fractures that occur far away from the initial impact point of the bullet. Micro computed tomography analysis of the bone showed these keyhole defect features with a particular high description. Then, the whole pattern has a spider-web effect, and these concentric fractures could explain the keyhole pattern even in a perpendicular gunshot path.

We report the case of a 3-year-old child who died from the consequences of a cardio-respiratory arrest despite reanimation procedures. Echocardiography and magnetic resonance imaging (MRI) revealed a mass of the free wall of the left ventricle. Autopsy confirmed the existence of a solitary myocardial tumor, well-circumscribed, firm, with a whitish and trabeculated cut surface. Histologically, the tumor consisted of bundles of spindle-shaped and regular cells mingling with collagen and elastic fibers, insinuating themselves between myocytes in periphery. Calcifications were present. After immunohistochemistry, the cells were highlighted by anti-actin smooth muscle antibody; but they were not highlighted by anti-desmin, anti-β catenin and anti-Ki67 antibodies. The diagnosis of cardiac fibroma was made. The primary cardiac tumors of child are rare and usually benign. They are essentially represented by rhabdomyoma and fibroma. Cardiac fibroma mostly occurs during the first year of life. It can be revealed by cardiac insufficiency, arrhythmia, chest pain or sudden death.

We report the case of a 3-year-old child who died from the consequences of a cardio-respiratory arrest despite reanimation procedures. Echocardiography and magnetic resonance imaging (MRI) revealed a mass of the free wall of the left ventricle. Autopsy confirmed the existence of a solitary myocardial tumor, well-circumscribed, firm, with a whitish and trabeculated cut surface. Histologically, the tumor consisted of bundles of spindle-shaped and regular cells mingling with collagen and elastic fibers, insinuating themselves between myocytes in periphery. Calcifications were present. After immunohistochemistry, the cells were highlighted by anti-actin smooth muscle antibody; but they were not highlighted by anti-desmin, anti-β catenin and anti-Ki67 antibodies. The diagnosis of cardiac fibroma was made. The primary cardiac tumors of child are rare and usually benign. They are essentially represented by rhabdomyoma and fibroma. Cardiac fibroma mostly occurs during the first year of life. It can be revealed by cardiac insufficiency, arrhythmia, chest pain or sudden death.