Biliary tract cancers: French national clinical practice guidelines for diagnosis, treatments and follow-up (TNCD, SNFGE, FFCD, UNICANCER, GERCOR, SFCD, SFED, AFEF, SFRO, SFP, SFR, ACABi, ACHBPT).

INTRODUCTION: This document is a summary of the French intergroup guidelines of the management of biliary tract cancers (BTC) (intrahepatic, perihilar and distal cholangiocarcinomas, and gallbladder carcinomas) published in September 2023, available on the website of the French Society of Gastroenterology (SNFGE) (www.tncd.org). METHODS: This collaborative work was conducted under the auspices of French medical and surgical societies involved in the management of BTC. Recommendations were graded in three categories (A, B and C) according to the level of scientific evidence until August 2023. RESULTS: BTC diagnosis and staging is mainly based on enhanced computed tomography, magnetic resonance imaging and (endoscopic) ultrasound-guided biopsy. Treatment strategy depends on BTC subtype and disease stage. Surgery followed by adjuvant capecitabine is recommended for localised disease. No neoadjuvant treatment is validated to date. Cisplatin-gemcitabine chemotherapy combined to the anti-PD-L1 inhibitor durvalumab is the first-line standard of care for advanced disease. Early systematic tumour molecular profiling is recommended to screen for actionable alterations (IDH1 mutations, FGFR2 rearrangements, HER2 amplification, BRAFV600E mutation, MSI/dMMR status, etc.) and guide subsequent lines of treatment. In the absence of actionable alterations, FOLFOX chemotherapy is the only second-line standard-of-care. No third-line chemotherapy standard is validated to date. CONCLUSION: These guidelines are intended to provide a personalised therapeutic strategy for daily clinical practice. Each individual BTC case should be discussed by a multidisciplinary team.

MRI and rectal endoscopy sonography performance to diagnose the digestive depth infiltration of pelvic endometriosis.

INTRODUCTION: The main objective of this study was to evaluate the performances of MRI and rectal endoscopy sonography (RES) in predicting the depth of bowel wall infiltration by deep infiltrating endometriosis (DIE). MATERIAL AND METHOD: We conducted a single center retrospective study from April 2014 to March 2020 including all patients who had undergone digestive tract resection (discoid or segmental) for DIE removal and who had benefited from full preoperative imaging workup based on both pelvic MRI and RES. RESULTS: Fifty two patients were enrolled in the study. Median age was 35.8 years (26.1-44.5 years). Indications for surgery mainly comprised chronic pelvic pain (94.2%) and infertility (36.5%). Overall, pathological examination showed digestive involvement in 92.3% of patients, while transmural infiltration was found in 38.4% of cases. In contrast, both MRI and RES suspected transmural involvement in 42 patients (80.8%). Corresponding sensitivity and specificity were 0.95 [95% CI (0.751-0.999)] and 0.28 [95% CI (0.137-0.467)], respectively. Our results revealed agreement between MRI and RES in 85% of cases with a kappa at 0.5 [95% CI (0.207-0.803), moderate agreement]. Subgroup analysis in patients with transmural MRI lesions showed a sensitivity of 0.95 [95% CI (0.740-0.999)] and a specificity of 0.13 [95% CI (0.028-0.336)]. CONCLUSION: Our study suggests that performing a second-line examination is not useful if there is no transmural impairment in MRI or RES. Nevertheless, the combination of these two preoperative examinations seems to be essential for the evaluation of the depth of digestive involvement of endometriosis to guide surgical management as effectively as possible. The constitution and training of multidisciplinary expert groups must be developed to be able to offer optimal patient management.

CINSARC signature outperforms gold-standard TNM staging and consensus molecular subtypes for clinical outcome in stage II-III colorectal carcinoma.

The outcome of stage II-III colorectal cancer (CRC) is highly variable and therapeutic choice is currently based on TNM staging with a few additional biomarkers. However, studies show that some stage III patients have a better prognosis than some stage II patients. A promising consensus molecular (CMS) classification with prognostic relevance has been developed, but it is not used in daily practice. Our team developed CINSARC, a 67-gene expression prognostic signature, whose prognostic value has been demonstrated in many cancer types. It is applicable to formalin-fixed, paraffin-embedded (FFPE) blocks using NanoString® technology. We investigated whether it could predict outcome in stage II-III CRC. We established the CINSARC classification on the TCGA retrospective cohort comprising 297 stage II-III CRC patients using RNA sequencing and on a second independent cohort comprising 169 cases using NanoString® technology. We compared its recurrence-free and overall survival prognostic value with TNM staging and CMS classification. In the TCGA cohort, we showed that CINSARC significantly splits the population of stage II-III CRC into two groups with different progression-free interval (P = 1.68 × 10-2; HR = 1.87 [1.11-3.16]) and overall survival (P = 3.73 × 10-3; HR = 2.45 [1.31-4.59]) and is a strong prognostic factor in multivariate analysis, outperforming TNM staging and CMS classification. We validated these results in the second cohort by applying CINSARC on FFPE samples with Nanostring® technology. CINSARC is a ready-to-use tool with a robust independent prognostic value in stage II-III CRC.

An unusual phenotype occurs in 15% of mismatch repair-deficient tumors and is associated with non-colorectal cancers and genetic syndromes.

Immunohistochemistry (IHC) and/or MSI-PCR (microsatellite instability-polymerase chain reaction) tests are performed routinely to detect mismatch repair deficiency (MMR-D). Classical MMR-D tumors present a loss of MLH1/PMS2 or MSH2/MSH6 with MSI-High. Other profiles of MMR-D tumors have been described but have been rarely studied. In this study, we established a classification of unusual MMR-D tumors and determined their frequency and clinical impact. All MMR-D tumors identified between 2007 and 2017 were selected. Any profile besides the classical MMR-D phenotype was defined as unusual. For patients with unusual MMR-D tumors, IHC, and PCR data were reviewed, the tumor mutation burden (TMB) was evaluated and clinical and genetic features were collected. Of the 4948 cases of MMR testing, 3800 had both the available IHC and MSI-PCR results and 585 of these had MMR-D. After reviewing the IHC and PCR, 21% of the cases initially identified as unusual MMR-D were reclassified, which resulted in a final identification of 89 unusual MMR-D tumors (15%). Unusual MMR-D tumors were more often associated with non-CRC than classical MMR-D tumors. Unusual MMR-D tumors were classified into four sub-groups: i) isolated loss of PMS2 or MSH6, ii) classical loss of MLH1/PMS2 or MSH2/MSH6 without MSI, iii) four MMR proteins retained with MSI and, iv) complex loss of MMR proteins, with clinical characteristics for each sub-group. TMB-high or -intermediate was shown in 96% of the cancers studied (24/25), which confirmed MMR deficiency. Genetic syndromes were identified in 44.9% (40/89) and 21.4% (106/496) of patients with unusual and classical MMR-D tumors, respectively (P < 0.001). Five patients treated with an immune checkpoint inhibitor (ICI) had a prolonged clinical benefit. Our classification of unusual MMR-D phenotype helps to identify MMR deficiency. Unusual MMR-D phenotype occurs in 15% of MMR-D tumors. A high frequency of genetic syndromes was noted in these patients who could benefit from ICI.

Feasibility of comprehensive genotyping specimens from radial endobronchial ultrasonography and electromagnetic navigation bronchoscopy.

INTRODUCTION: Mini-invasive bronchoscopic techniques (such as radial endobronchial ultrasonography (rEBUS) and electromagnetic navigation (EMN)) have been developed to reach the peripheral lung but result in small samples. The feasibility of an adequate molecular testing from these specimens has been very little studied. METHODS: We retrospectively reviewed EMN and rEBUS procedures performed in patients diagnosed with lung cancer in our institution in 2017 and 2018. We analysed the sensitivity for rEBUS and EMN and each sampling method, and the feasibility of a comprehensive molecular testing. RESULTS: In total, 317 rEBUS and 14 EMN were performed. Median sizes of tumours were 16 and 32 mm for EMN and rEBUS, respectively. Overall sensitivity for rEBUS and EMN was 84.3%. Cytology was found to be complementary with biopsies, with 13.3% of cancer diagnosed on cytology while biopsies were negative. Complication rate was 2.4% (pneumothorax 1.5%, mild haemoptysis 0.9%). Genotyping (immunohistochemistry for ROS1 and ALK followed by fluorescence in situ hybridisation if positive and hybrid capture next-generation sequencing covering 48 genes), when ordered (n=188), was feasible in 69.1% (EGFR 17.7%, KRAS 31.7%, BRAF 4.8%, ALK 1.2%, MET 3.1%, HER2 0.8%). PD-L1 (programmed death-ligand 1) expression, when ordered (n=232), could be analysed in 94% of cases. Overall, 56.9% (33 out of 58) of patients for whom genotyping was not feasible underwent a second sampling (12 pretreatment, 21 at progression), allowing for the detection of six actionable genotypes (five EGFR, one MET). CONCLUSION: rEBUS and EMN are sensitive and safe procedures that result in limited samples, often not suitable for genotyping, highlighting the importance of integrating liquid biopsy in routine testing.

Bronchoscopic Treatment of Endobronchial Inflammatory Myofibroblastic Tumors.

Endobronchial localizations of inflammatory myofibroblastic tumors are very unusual. We report the multimodal, bronchoscopic management of 3 cases, offering durable local control in all cases (including 2 patients who were definitively cured). Although surgery is usually considered the gold standard, therapeutic bronchoscopy should probably be considered as a frontline option for proximal lesions with limited base (< 10 mm2) because of uncommon metastatic spread and delayed local recurrence. Of note, 1 of our cases is a rare airway case after allograft hematopoietic stem cell transplant.

Tumor Cells Hijack Macrophage-Produced Complement C1q to Promote Tumor Growth.

Clear-cell renal cell carcinoma (ccRCC) possesses an unmet medical need, particularly at the metastatic stage, when surgery is ineffective. Complement is a key factor in tissue inflammation, favoring cancer progression through the production of complement component 5a (C5a). However, the activation pathways that generate C5a in tumors remain obscure. By data mining, we identified ccRCC as a cancer type expressing concomitantly high expression of the components that are part of the classical complement pathway. To understand how the complement cascade is activated in ccRCC and impacts patients' clinical outcome, primary tumors from three patient cohorts (n = 106, 154, and 43), ccRCC cell lines, and tumor models in complement-deficient mice were used. High densities of cells producing classical complement pathway components C1q and C4 and the presence of C4 activation fragment deposits in primary tumors correlated with poor prognosis. The in situ orchestrated production of C1q by tumor-associated macrophages (TAM) and C1r, C1s, C4, and C3 by tumor cells associated with IgG deposits, led to C1 complex assembly, and complement activation. Accordingly, mice deficient in C1q, C4, or C3 displayed decreased tumor growth. However, the ccRCC tumors infiltrated with high densities of C1q-producing TAMs exhibited an immunosuppressed microenvironment, characterized by high expression of immune checkpoints (i.e., PD-1, Lag-3, PD-L1, and PD-L2). Our data have identified the classical complement pathway as a key inflammatory mechanism activated by the cooperation between tumor cells and TAMs, favoring cancer progression, and highlight potential therapeutic targets to restore an efficient immune reaction to cancer.

Pancreatic cancer: French clinical practice guidelines for diagnosis, treatment and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, ACHBT, AFC).

BACKGROUND: This document is a summary of the French intergroup guidelines regarding the management of pancreatic adenocarcinoma (PA), updated in July 2018. DESIGN: This collaborative work was produced under the auspices of all French medical and surgical societies involved in the management of PA. It is based on the previous guidelines, recent literature review and expert opinions. Recommendations were graded in three categories, according to the level of evidence. RESULTS: Over the last seven years, significant changes in PA management have been implemented in clinical practice. Imaging/staging: diffusion magnetic resonance imaging is useful before surgery to rule out small liver metastases. SURGERY: centralization of pancreatic surgery in expert centers is associated with a decreased postoperative mortality. Adjuvant chemotherapy: modified FOLFIRINOX in fit patients, or gemcitabine, or 5-FU, or gemcitabine plus capecitabine, to be discussed on a case-by-case basis. Locally advanced PA: no survival benefit of chemoradiotherapy. Metastatic PA: FOLFIRINOX and gemcitabine plus nab-paclitaxel combination are first-line standards in fit patients; second-line with 5FU/nal-IRI or 5FU/oxaliplatin combination after first-line gemcitabine. CONCLUSION: Guidelines for management of PA are continuously evolving and need to be regularly updated. This constant progress is made possible through clinical and translational research. However, as each individual case is particular, they cannot substitute to multidisciplinary tumor board discussion.

Gastric cancer: French intergroup clinical practice guidelines for diagnosis, treatments and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO).

INTRODUCTION: This document is a summary of the French Intergroup guidelines regarding the management of gastric cancer published in October 2016, available on the website of the French Society of Gastroenterology (SNFGE) (www.tncd.org), updated in October 2017. METHODS: This collaborative work was realized under the auspices of several French medical societies involved in management of gastric cancer. Recommendations are graded in three categories (A-C), according to the amount of evidence found in the literature until July 2017. RESULTS: There are several known risk factors for gastric cancer, including Helicobacter pylori and genetic predispositions, both requiring a specific screening for patients and their relatives. The diagnosis and staging evaluation are essentially based on gastroscopy plus biopsies and computed tomography scan. The endoscopic ultrasonography can be used for superficial tumors in case of discussion for endoscopic resection (T1N0). For local disease (N+ and/or T > T1), the strategic therapy is based on surgery associated with perioperative chemotherapy. In the absence of preoperative treatment (for any raison), the postoperative chemoradiotherapy (or chemotherapy) should be discussed for patients with stage II or III tumor. For metastatic disease, the treatment is based on "palliative" chemotherapy consisting in a doublet or triplet regimens depending of age, performance status and HER2 tumor status. For patients with limited metastatic disease, surgical resection could be discussed in multidisciplinary meeting in case of stable disease after chemotherapy. CONCLUSION: These guidelines in gastric cancer are done to help decision for daily clinical practice. These recommendations are permanently being reviewed. Each individual case must be discussed within a multidisciplinary team.

One year of experience using the Paris System for Reporting Urinary Cytology.

BACKGROUND: The Paris System for Reporting Urinary Cytology (TPS) was published in November 2015. It focuses on the diagnosis of high-grade urothelial carcinoma (HGUC) and provides criteria with which to define the category of atypical urothelial cells (AUC). The objective of the current study was to compare two 1-year consecutive periods before and after use of TPS. METHODS: A total of 1634 and 1814 urine cytology cases, respectively, were analyzed before and after use of TPS. Histological diagnosis within 6 months was available for 330 and 299 cases, respectively. RESULTS: After use of TPS, the authors reported significantly fewer low-grade urothelial neoplasms (0.94% vs 1.84%; P<.05) and more cases that were suspicious for HGUC (2.09% vs 0.73%; P<.01) compared with before use of TPS. For the AUC category, there was no significant change in frequency noted for before versus after TPS (6.12% vs 5.18%), whereas the rate of detection of HGUC on histology significantly increased after TPS when compared with before TPS (49.02% vs 28.17%; P<.02). For the HGUC category, neither the frequency (4.69% vs 4.47%) nor the risk of malignancy (89.39% vs 91.04% with HGUC on histology) were found to be significantly different when comparing before and after use of TPS. CONCLUSIONS: In the authors' practice, TPS helped to better characterize the categories of AUC, low-grade urothelial neoplasm, and suspicious for HGUC, which were associated with a higher risk of HGUC compared with the authors' previous classification. Cancer Cytopathol 2018;126:430-6. © 2018 American Cancer Society.

A new subtype of high-grade mandibular osteosarcoma with RASAL1/MDM2 amplification.

In contrast to long bone osteosarcoma, mandibular osteosarcoma is highly heterogeneous and morphologically overlaps with benign tumors, obscuring diagnosis and treatment selection. Molecular characterization is difficult due to the paucity of available specimens of this rare disease. We aimed to characterize the spectrum of mandibular osteosarcoma using immunohistochemistry and molecular techniques (quantitative polymerase chain reaction and sequencing) and compare them with benign fibro-osseous lesions. Forty-nine paraffin-embedded mandible osteosarcoma tissue samples were collected retrospectively and compared with 10 fibrous dysplasia and 15 ossifying fibroma cases. These were analyzed for molecular markers thought to differ between the different diseases and subtypes: MDM2 (murine double-minute type 2) overexpression, GNAS (guanine nucleotide-binding protein/α subunit) mutations, and amplification of MDM2 and/or RASAL1 (RAS protein activator like 1). Five fibroblastic high-grade osteosarcoma subtypes showed MDM2 amplification, including 2 with a microscopic appearance of high-grade osteosarcoma with part low-grade osteosarcoma (differentiated/dedifferentiated osteosarcoma) and MDM2 overexpression. The other 3 contained a coamplification of MDM2 and RASAL1, a signature also described for juvenile ossifying fibroma, with no overexpression of MDM2. These were of the giant cell-rich high-grade osteosarcoma, with areas mimicking juvenile ossifying fibroma (ossifying fibroma-like osteosarcoma). Our results show that some diagnosed high-grade osteosarcomas are differentiated/dedifferentiated osteosarcomas and harbor an overexpression and amplification of MDM2. In addition, juvenile ossifying fibromas can potentially evolve into giant cell-rich high-grade osteosarcomas and are characterized by a RASAL1 amplification (osteosarcoma with juvenile ossifying fibroma-like genotype). Thus, the presence of a RASAL1 amplification in ossifying fibroma may indicate a requirement for closer follow-up and more aggressive management.

Chromosomal rearrangements involving the NTRK1 gene in colorectal carcinoma.

Chromosomal rearrangements of the NTRK1 gene, which encodes the high affinity nerve growth factor receptor (tropomyosin related kinase, TRKA), have been observed in several epithelial cancers, such as colon cancer, papillary thyroid carcinoma or non small cell lung cancer. The various NTRK1 fusions described so far lead to constitutive activation of TRKA kinase activity and are oncogenic. We further investigated here the existence and the frequency of NTRK1 gene rearrangements in colorectal cancer. Using immunohistochemistry and quantitative reverse transcriptase PCR, we analyzed a series of human colorectal cancers. We identified two TRKA positive cases over 408, with NTRK1 chromosomal rearrangements. One of these rearrangements is a TPM3-NTRK1 fusion already observed in colon cancer, while the second one is a TPR-NTRK1 fusion never described in this type of cancer. These findings further confirm that translocations in the NTRK1 gene are recurring events in colorectal cancer, although occurring at a low frequency (around 0.5%).

A comparative immunohistochemistry study of diagnostic tools in salivary gland tumors: usefulness of mammaglobin, gross cystic disease fluid protein 15, and p63 cytoplasmic staining for the diagnosis of mammary analog secretory carcinoma?

BACKGROUND: Mammary analog secretory carcinoma (MASC) of the salivary gland has been recently described according to morphological, immunohistochemical, and molecular (ETV6-NTRK3 translocation) similarities with the mammary secretory carcinoma. The most important differential diagnostic considerations of MASC are low-grade adenocarcinoma not otherwise specified (NOS), cystadenocarcinoma, and acinic cell carcinoma (AciCC). These tumors may share an overlapping morphology with MASC, and additional immunohistochemical studies are required to reinforce the diagnosis. Mammaglobin, GCDFP-15, and p63 staining have been reported in MASC. Our study was designed to check the specificity of these antibodies in MASC compared to other frequent tumors of salivary glands. METHODS: A series of 62 salivary gland tumors [10 MASCs, 5 adenocarcinomas NOS and 2 cystadenocarcinomas with MASC features and without ETV6 rearrangement, one low-grade cribriform cystadenocarcinoma (LGCCC), 9 AciCCs, 10 MECs, 10 adenoid cystic carcinomas (AdeCCs), 5 polymorphous low-grade adenocarcinomas (PLGAs), and 10 pleomorphic adenomas (PAs)] was analyzed by immunohistochemistry with mammaglobin, GCDFP-15, and p63 antibodies. RESULTS: Positivity for mammaglobin was observed in all MASCs, cystadenocarcinomas, LGCCC, and PLGAs, in some adenocarcinomas NOS, PAs, and MECs, rarely in AciCCs and never in AdeCCs. Positivity for GCDFP-15 was observed in most of the tumor types except in AdeCCs. Interestingly, cytoplasmic positivity for p63 was observed in most of MASCs and PLGAs while rarely in adenocarcinomas NOS and PAs, and never in the other tumor types. CONCLUSION: Our study revealed the usefulness of mammaglobin and p63 cytoplasmic staining to define which tumors are worth to be screened for ETV6 rearrangement.