Mesenchymal-like Tumor Cells and Myofibroblastic Cancer-Associated Fibroblasts Are Associated with Progression and Immunotherapy Response of Clear Cell Renal Cell Carcinoma.

Immune checkpoint inhibitors (ICI) represent the cornerstone for the treatment of patients with metastatic clear cell renal cell carcinoma (ccRCC). Despite a favorable response for a subset of patients, others experience primary progressive disease, highlighting the need to precisely understand the plasticity of cancer cells and their cross-talk with the microenvironment to better predict therapeutic response and personalize treatment. Single-cell RNA sequencing of ccRCC at different disease stages and normal adjacent tissue (NAT) from patients identified 46 cell populations, including 5 tumor subpopulations, characterized by distinct transcriptional signatures representing an epithelial-to-mesenchymal transition gradient and a novel inflamed state. Deconvolution of the tumor and microenvironment signatures in public data sets and data from the BIONIKK clinical trial (NCT02960906) revealed a strong correlation between mesenchymal-like ccRCC cells and myofibroblastic cancer-associated fibroblasts (myCAF), which are both enriched in metastases and correlate with poor patient survival. Spatial transcriptomics and multiplex immune staining uncovered the spatial proximity of mesenchymal-like ccRCC cells and myCAFs at the tumor-NAT interface. Moreover, enrichment in myCAFs was associated with primary resistance to ICI therapy in the BIONIKK clinical trial. These data highlight the epithelial-mesenchymal plasticity of ccRCC cancer cells and their relationship with myCAFs, a critical component of the microenvironment associated with poor outcome and ICI resistance. SIGNIFICANCE: Single-cell and spatial transcriptomics reveal the proximity of mesenchymal tumor cells to myofibroblastic cancer-associated fibroblasts and their association with disease outcome and immune checkpoint inhibitor response in clear cell renal cell carcinoma.

Preferentially expressed Antigen in MElanoma immunohistochemistry as an adjunct for evaluating ambiguous melanocytic proliferation.

The histopathological assessment of diagnostically ambiguous melanocytic proliferation remains one of the biggest challenges in the dermatopathology field. Preferentially expressed Antigen in MElanoma (PRAME) immunostaining has been shown highly specific for distinguishing unequivocal malignant melanocytic proliferation from benign ones. Knowledge on its utility for evaluating ambiguous melanocytic neoplasms remains limited. We retrieved in our institutional database all cases of diagnostically ambiguous melanocytic neoplasms from January 2016 to January 2021. Each case was subclassified into "favor benign" or "favor malignant" neoplasm using all collected data. Immunohistochemical expression of PRAME was assessed and correlated with the final subclassification. Using a previously proposed scoring system, diffuse immunopositivity (>75% of tumor cells) was considered positive. Furthermore, for ambiguous melanocytic proliferation occurring on a pre-existing nevus, the staining was considered positive if more than 75% of the morphologically atypical neoplastic cells were labeled, excluding morphologically unambiguous benign nevocytes. Fifty-five cases of ambiguous melanocytic proliferation were examined. Thirty-one cases were finally subclassified as "favor malignant" neoplasms and 24 as "favor benign" neoplasms. Thirty-one tumors showed immunopositivity for PRAME, representing, respectively, 8.3% and 93.5% of "favor benign" and "favor malignant" neoplasms. The specificity and sensitivity of PRAME immunohistochemistry for benign/malignant distinction were, respectively, 91.7% and 93.5%.PRAME IHC shows high sensitivity and specificity for distinguishing malignant challenging melanocytic proliferations from benign ones and could be used as an everyday tool. However, PRAME immunoreactivity should be interpreted cautiously, knowing that rare benign melanocytic neoplasms could show diffuse positivity.

[Histopathological diagnosis of an intoxication]. / Une intoxication de diagnostic histologique.

Ethylene glycol poisoning is relatively rare, with around a hundred cases reported each year in France. Its diagnosis is often challenging and delayed because of a several hours' free interval between ingestion of the toxic and the onset of the first symptoms. Ethylene glycol is a colorless and odorless liquid primarily found in automotive coolants, whose toxicity is linked to its hepatic metabolites. Histologically, ethylene glycol poisoning is characterized by abundant tissular deposits of calcium oxalate crystals. Under polarized light, these crystals appear birefringent and iridescent. Their microscopic appearance and their distribution are pathognomonic of oxalosis. Due to its frequent misleading presentation, the diagnosis of ethylene glycol poisoning is sometimes only made after an autopsy. Hereafter, we report the case of a 59-year-old man diagnosed with ethylene glycol intoxication after a post-mortem histopathological examination of organs.

Prognostic significance of residual lymphovascular invasion after resection of locally advanced and borderline resectable pancreatic adenocarcinomas treated by neoadjuvant chemotherapy.

BACKGROUND: The current study aimed to identify histological prognostic factors after resection of locally advanced (LA) and borderline (BL) pancreatic adenocarcinomas treated by neoadjuvant chemotherapy (NC). METHODS: A retrospective review was performed of patients with LA and BL adenocarcinomas operated after NC between January 2010 and April 2018. Prognostic factors for survival were assessed by multivariate Cox analysis. RESULTS: Of the 84 patients, 29 had BL and 55 had LA pancreatic adenocarcinomas. Seventy-five patients underwent synchronous venous resection and 57 underwent arterial resection. The median overall survival from surgery was 21.10 months (BL 23-LA 21) (95% CI: 14.8-30.3) with 1-, 3-, and 5-year overall survival rates of 73%, 32%, and 20%, respectively. Multivariate analysis identified lymphovascular invasion (LVI) as an independent prognostic factor for overall survival (HR: 2.32, 95% CI: 1.28-4.22; p = 0.004). Patients without LVI (n = 37) had superior median overall and 5-year survival rates (31.0 months [40 from diagnosis]; 39%) compared to patients with LVI (n = 47; 14.4 months [22 from diagnosis]; 7%). The absence of residual LVI was associated with major pathologic response rates (p < 0.05). CONCLUSION: The persistence of LVI at pathology after resection of LA and BL treated by neoadjuvant chemotherapy predicts poor response and limited long-term survival.

Cutaneous manifestations in patients with coronavirus disease 2019: clinical and histological findings.

The clinical spectrum of coronavirus disease 2019 is getting wider with the exponential increase of patients worldwide. Initially described with flu-like symptoms, variable cutaneous manifestations have been reported, with only few histopathological descriptions. Detection of the virus in cutaneous samples has been assessed in very few cases until now, and the causative role of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has not been proven for every type of cutaneous manifestations yet. We aimed to describe histological features of cutaneous eruptions occurring concomitantly to SARS-CoV-2 infection and assess by immunochemistry and in situ hybridization using RNAscope validation techniques the presence of the virus in skin lesions. We retrieved all skin biopsies received in the departments of pathology and dermatopathology, University Hospital of Strasbourg, performed in hospitalized SARS-CoV-2-infected patients presenting concomitant cutaneous manifestations since March 2020. In situ hybridization and immunostaining using a polyclonal SARS nucleocapsid protein antibody were performed on each sample. Skin biopsies from six patients presenting morbilliform eruption concomitant to SARS-CoV-2 infection were available for evaluation. All six samples showed varying degrees of spongiosis, perivascular inflammatory infiltrates of the dermis, and, for some of them, discrete interface dermatitis. In situ hybridization and immunohistochemistry were negative in all cutaneous samples. Morbilliform rash concomitant to SARS-CoV-2 infection is characterized by mild and unspecific histopathological features with no detectable viral RNA and protein and appears then not to be directly caused by the virus. Even if, at least for a few cases, the differential diagnosis with drug hypersensitivity reaction can be difficult, these cutaneous eruptions seem to rather correspond to paraviral rashes.

A Nonsmoker Man in His 40s With a Diagnosis of Genetic-Related Idiopathic Pulmonary Fibrosis (Surfactant-Protein C Gene Mutation).

A nonsmoker man in his 40s underwent bilateral lung transplantation with a referral diagnosis of genetic-related idiopathic pulmonary fibrosis (IPF). The patient had no medical history in childhood and early adulthood, nor was there a family history of IPF. His nonsmoker father presented with lung cancer at 59 years of age. The patient was a professional brass instrument player; he had started playing at 9 years of age, and he was recently playing 3 to 4 h per day. He had a 7-year clinical history of chronic cough and shortness of breath. Bilateral fine crackles were present at clinical examination. There was no digital clubbing. Data had been collected since 2015: no clinical or immunologic signs of connective tissue disease were evident, including autoantibodies for myositis or anti-synthetase syndrome. Chest radiograph showed diffuse interstitial lung disease. Results of pulmonary function tests yielded a restrictive pattern with decreased FVC and decreased total lung capacity (69% and 47% of predicted, respectively). The FEV1/FVC ratio was 86%, and carbon monoxide transfer coefficient was 36% of predicted. BAL cellular analysis consisted of macrophages (66%), lymphocytes (19%; CD4+/CD8+ ratio, 0.16), neutrophils (10%), and eosinophils (5%).