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Single-cell technologies have revealed the complexity of the tumour immune microenvironment with unparalleled resolution1-9. Most clinical strategies rely on histopathological stratification of tumour subtypes, yet the spatial context of single-cell phenotypes within these stratified subgroups is poorly understood. Here we apply imaging mass cytometry to characterize the tumour and immunological landscape of samples from 416 patients with lung adenocarcinoma across five histological patterns. We resolve more than 1.6 million cells, enabling spatial analysis of immune lineages and activation states with distinct clinical correlates, including survival. Using deep learning, we can predict with high accuracy those patients who will progress after surgery using a single 1-mm2 tumour core, which could be informative for clinical management following surgical resection. Our dataset represents a valuable resource for the non-small cell lung cancer research community and exemplifies the utility of spatial resolution within single-cell analyses. This study also highlights how artificial intelligence can improve our understanding of microenvironmental features that underlie cancer progression and may influence future clinical practice.
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Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Análise de Célula Única , Microambiente Tumoral , Humanos , Adenocarcinoma de Pulmão/diagnóstico , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/cirurgia , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Pulmão/patologia , Pulmão/cirurgia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Microambiente Tumoral/imunologia , Progressão da Doença , Aprendizado Profundo , PrognósticoRESUMO
BACKGROUND: Management following endoscopic submucosal dissection (ESD) of pT1b esophageal adenocarcinoma (EAC) remains controversial. This study compared pathological and survival outcomes of patients after endoscopic resection (ER) of pT1b EAC followed by either en bloc esophagectomy or observation. METHODS: From 1/12 to 12/22, all patients with pT1b EAC treated with ER were identified from a prospectively maintained departmental database. ESD was curative (all of: Submucosal invasion < 500 µm; G1/2, LVI/PNI-; deep margin-) or non-curative (one or more of Submucosal invasion ≥ 500 µm; G3; LVI/PNI+; deep margin+). Patients were allocated to observation (OBS) or esophagectomy (SURG) based on patient factors/preference and pathological variables. RESULTS: 56/171 ERs met the inclusion criteria. ER was curative in 8/56 (14%) and non-curative in 48/56 (86%). OBS was undertaken after 8/27 (30%) curative and 19/27 (70%) non-curative resections. All 29 SURG patients had non-curative ERs and were younger, had lower Charlson comorbidity scores and had more deep margin + lesions than OBS patients. Post-esophagectomy, 15/29 (52%) had no residual disease within the surgical specimen while pT+N-/pT-N+/pT+N+ occurred in 5/3/6 (17%/10%/21%) patients. Of those with residual disease in the surgical specimen, 12/14 (86%) had deep margin + ERs; however, only ESD instead of EMR was independently associated with a lower risk of residual disease (OR 0.431, 95% CI - 0.016 to 1.234, p = 0.045). OBS and SURG patients had equivalent overall survival outcomes and recurrence was low in both groups even following non-curative ER. Follow-up was 28 months (0-102) and 30 months (0-97), respectively. CONCLUSION: In select patients, including some of those with a non-curative ESD resection of pT1B EAC, surveillance alone may be appropriate. Alternatives beyond traditional pathological features is needed to direct patient care more accurately.
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Adenocarcinoma , Ressecção Endoscópica de Mucosa , Neoplasias Esofágicas , Humanos , Esofagectomia , Neoplasias Esofágicas/cirurgia , Neoplasias Esofágicas/patologia , Adenocarcinoma/cirurgia , Adenocarcinoma/patologia , Estudos Retrospectivos , Resultado do Tratamento , Recidiva Local de Neoplasia/cirurgiaRESUMO
Congenital Langerhans cell histiocytosis (LCH) (formerly called Letterer-Siwe disease) is characterized by a clonal proliferation of Langerhans cells occurring in children at birth and manifests typically with multifocal cutaneous lesions, hepatosplenomegaly, lymphadenopathy, pulmonary lesions, and destructive osteolytic bone lesions. We present a case of LCH involving multiple systems high-risk organs (LCH MS-RO+), in a 32-week stillborn from a 20-year-old G2A1. The fetus was mildly hydropic and pale. Apart from maceration, the skin showed multiple targetoid lesions over the face, trunk, and limbs. There was hepatosplenomegaly and a pale brain. The placenta was large and bulky. Despite severe autolysis, histological examination showed disseminated histiocytes with multinucleated giant cells in the skin, lungs, thymus, mesenteric lymph nodes, spleen, and brain. By immunohistochemistry, the histiocytes were positive for S100, CD1a, and Langerin (CD207), confirming the diagnosis of LCH. There was extramedullary hematopoiesis in the spleen, brain, and placenta. Targeted next-generation sequencing performed on thymic DNA did not show the BRAF p.V600E variant but did show the MAP2K1 p.F53_Q58delinsL. Infants with LCH pose a diagnostic challenge due to their heterogeneous presentations. Our case is unusual in that the newborn presented with severe multiorgan involvement including brain and intrauterine death. LCH is still poorly understood requiring further genetic and molecular studies.
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Histiocitose de Células de Langerhans , Adulto , Criança , Feminino , Morte Fetal , Histiócitos , Histiocitose de Células de Langerhans/genética , Humanos , Imuno-Histoquímica , Recém-Nascido , Linfonodos/patologia , Adulto JovemRESUMO
Studies in pediatric high-grade astrocytomas (HGA) by our group and others have uncovered recurrent somatic mutations affecting highly conserved residues in histone 3 (H3) variants. One of these mutations leads to analogous p.Lys27Met (K27M) mutations in both H3.3 and H3.1 variants, is associated with rapid fatal outcome, and occurs specifically in HGA of the midline in children and young adults. This includes diffuse intrinsic pontine gliomas (80 %) and thalamic or spinal HGA (>90 %), which are surgically challenging locations with often limited tumor material available and critical need for specific histopathological markers. Here, we analyzed formalin-fixed paraffin-embedded tissues from 143 pediatric HGA and 297 other primary brain tumors or normal brain. Immunohistochemical staining for H3K27M was compared to tumor genotype, and also compared to H3 tri-methylated lysine 27 (H3K27me3) staining, previously shown to be drastically decreased in samples carrying this mutation. There was a 100 % concordance between genotype and immunohistochemical analysis of H3K27M in tumor samples. Mutant H3K27M was expressed in the majority of tumor cells, indicating limited intra-tumor heterogeneity for this specific mutation within the limits of our dataset. Both H3.1 and H3.3K27M mutants were recognized by this antibody while non-neoplastic elements, such as endothelial and vascular smooth muscle cells or lymphocytes, did not stain. H3K27me3 immunoreactivity was largely mutually exclusive with H3K27M positivity. These results demonstrate that mutant H3K27M can be specifically identified with high specificity and sensitivity using an H3K27M antibody and immunohistochemistry. Use of this antibody in the clinical setting will prove very useful for diagnosis, especially in the context of small biopsies in challenging midline tumors and will help orient care in the context of the extremely poor prognosis associated with this mutation.
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Astrocitoma/genética , Neoplasias Encefálicas/genética , Histonas/genética , Metionina/genética , Mutação/genética , Adolescente , Astrocitoma/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Criança , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Genótipo , Humanos , MasculinoRESUMO
BACKGROUND: Carcinosarcomas, a malignancy consisting of squamous cell carcinoma with sarcomatous features, are extremely rare and aggressive tumor of the vulva. Including this case, there are 17 cases reported in the literature. Risk factors for this entity are poorly understood. CASE REPORT: We describe the case of a rapidly growing primary vulvar carcinosarcoma developing in an 84-year-old woman. The patient had previously received pelvic radiation for a squamous carcinoma of the anal canal. The excised vulvar tumor showed a superficial squamous carcinomatous element, associated vulvar intraepithelial neoplasia, and a transition into deeper sarcomatous component. By immunohistochemistry, the carcinomatous component was positive for keratins and negative for vimentin and smooth muscle actin, whereas the sarcomatous component was negative for keratins and positive for vimentin and smooth muscle actin. The patient was treated with hemivulvectomy with sentinel lymph node dissection followed by limited postoperative chemotherapy. The FIGO stage of the vulvar cancer was stage IB (T1 N0 M0), but even with this low stage, the patient had recurrence 17 months after treatment and died of her disease 8 months later. We compared age and stage at presentation, treatment, disease-free survival, and overall survival of our case to other reported vulvar carcinosarcomas. CONCLUSIONS: Vulvar carcinosarcomas are poorly characterized aggressive tumors with poor outcome. This is the first case reported that points to previous radiation exposure as a possible etiologic agent for this lesion.
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Carcinossarcoma/diagnóstico , Carcinossarcoma/patologia , Radioterapia/efeitos adversos , Neoplasias Vulvares/diagnóstico , Neoplasias Vulvares/patologia , Idoso de 80 Anos ou mais , Feminino , Histocitoquímica , Humanos , Imuno-HistoquímicaRESUMO
Germline and somatic pathogenic variants (PVs) in DICER1 , encoding a miRNA biogenesis protein, are associated with a wide variety of highly specific pathologic entities. The lung tumors pleuropulmonary blastoma, pulmonary blastoma (PB), and well-differentiated fetal lung adenocarcinoma (WDFLAC) are all known to harbor DICER1 biallelic variants (loss of function and/or somatic hotspot missense mutations), and all share pathologic features reminiscent of the immature lung. However, the role of DICER1 PVs in non-small cell lung cancer (NSCLC) is relatively unknown. Here, we aimed to establish the spectrum of lung pathologies associated with DICER1 hotspot PVs and to compare the mutational landscape of DICER1 -mutated NSCLC with and without hotspots. We queried DNA sequencing data from 12,146 NSCLCs featuring somatic DICER1 variants. 235 (1.9%) cases harboring ≥ 1 DICER1 PV were found and 9/235 (3.8%) were DICER1 hotspot-positive cases. Histologic review of DICER1 hotspot-positive cases showed that all but one tumor were classified as within the histologic spectrum of PB/WDFLAC, whereas all the DICER1 non-hotspot double variants were classified as lung adenocarcinomas, not otherwise specified. Comparison between the mutational landscape of DICER1 hotspot-positive and hotspot-negative cases revealed a higher frequency of CTNNB1 mutations in the hotspot-positive cases (5/9 vs. 2/225; P <0.00001). We conclude that DICER1 somatic hotspots are not implicated in the most common forms of NSCLC but rather select for morphologic features of lung tumor types such as PB and WDFLAC. As a corollary, cases showing this tumor morphology should undergo testing for DICER1 variants, and if positive, genetic counseling should be considered.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , MicroRNAs , Blastoma Pulmonar , Humanos , Recém-Nascido , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Mutação , MicroRNAs/genética , Blastoma Pulmonar/genética , Ribonuclease III/genética , Mutação em Linhagem Germinativa , RNA Helicases DEAD-box/genéticaRESUMO
OBJECTIVE: Pulmonary blastoma is a rare, biphasic, adult-onset lung tumor. In this study, we investigate whether DICER1 pathogenic variants are a feature of pulmonary blastomas through in-depth analysis of the molecular events defining them. METHODS: We performed exome-wide sequencing and DNA methylation profiling of 8 pulmonary blastomas from 6 affected persons. RESULTS: We identified biallelic somatic DICER1 pathogenic variants in 7 of 8 cases. The remaining case had a solitary missense pathogenic variant in the RNase IIIb domain of DICER1. Six of 8 cases carried a CTNNB1 hotspot variant and 4 of 8 had a somatic pathogenic variant in TP53. Methylation analysis showed that the pulmonary blastomas clustered with other DICER1-mutated tumors and not with other more common types of lung cancer. CONCLUSION: We conclude somatic DICER1 pathogenic variants are the major driver of pulmonary blastoma and are likely to act in conjunction with CTNNB1 hotspot variants that are often present.
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BACKGROUND: Several regulatory agencies have approved the use of the neoadjuvant chemo-immunotherapy for resectable stage II and III of non-small cell lung cancer (NSCLC) and numerous trials investigating novel agents are underway. However, significant concerns exist around the feasibility and safety of offering curative surgery to patients treated within such pathways. The goal in this study was to evaluate the impact of a transition towards a large-scale neoadjuvant therapy program for NSCLC. METHODS: Medical charts of patients with clinical stage II and III NSCLC who underwent resection from January 2015 to December 2020 were reviewed. The primary outcome was perioperative complication rate between neoadjuvant-treated versus upfront surgery patients. Multivariable logistic regression estimated occurrence of postoperative complications and overall survival was assessed as an exploratory secondary outcome by Kaplan-Meier and Cox-regression analyses. RESULTS: Of the 428 patients included, 106 (24.8%) received neoadjuvant therapy and 322 (75.2%) upfront surgery. Frequency of minor and major postoperative complications was similar between groups (P = .22). Occurrence in postoperative complication was similar in both cohort (aOR = 1.31, 95% CI 0.73-2.34). Neoadjuvant therapy administration increased from 10% to 45% with a rise in targeted and immuno-therapies over time, accompanied by a reduced rate of preoperative radiation therapy use. 1-, 2-, and 5-year overall survival was higher in neoadjuvant therapy compared to upfront surgery patients (Log-Rank P = .017). CONCLUSIONS: No significant differences in perioperative outcomes and survival were observed in resectable NSCLC patients treated by neoadjuvant therapy versus upfront surgery. Transition to neoadjuvant therapy among resectable NSCLC patients is safe and feasible from a surgical perspective.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Terapia Neoadjuvante , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Terapia Neoadjuvante/métodos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Pneumonectomia , Estudos Retrospectivos , Taxa de Sobrevida , Complicações Pós-Operatórias/epidemiologia , Resultado do Tratamento , Estadiamento de Neoplasias , SeguimentosRESUMO
INTRODUCTION: The detection of prostate carcinoma relies on adequate sampling. We aimed to evaluate whether core length is a significant biopsy parameter in the detection of cancer, especially in the low risk cancer category group. MATERIALS AND METHODS: We retrospectively analyzed pathology reports of 197 patients (2196 biopsy cores) undergoing initial transrectal ultrasound guided biopsy. A multivariate analysis of age, total prostate-specific antigen (PSA) concentration, prostate gland volume, total number of cores and length of biopsy cores was performed. Secondary analyses included stratification by Gleason score. Single core analysis was done to calculate a workable cut off value for core length with optimal sensitivity and specificity in carcinoma detection. RESULTS: Mean age, PSA, prostate volume, and total number of cores were 66.9 years, 12.6 ng/mL, 47.2 cc and 11.1 cores, respectively. Whereas detection of cancer was significantly associated with advanced age (p < 0.01) and smaller prostate volumes (p < 0.001), PSA levels (p = 0.40) and number of cores (p = 0.20) were not significant predictive factors. Assessment of biopsy core lengths showed that cores harboring cancer (n = 307, average length 14.1 mm) were significantly longer than benign cores (n = 1889, average length = 13.2 mm) (p < 0.001). Core length analysis yielded 13 mm cores have an optimal sensitivity (42.8%) and specificity (76.5%) for detection of carcinoma (odds ratio: 2.43). Secondary analyses of Gleason score did not show any difference with respect to core length. CONCLUSION: This study suggests that core length is a biopsy parameter that affects detection of cancer and is an essential parameter for core biopsy quality.
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Biópsia com Agulha de Grande Calibre/métodos , Biópsia com Agulha de Grande Calibre/normas , Próstata/patologia , Neoplasias da Próstata/diagnóstico , Idoso , Humanos , Masculino , Análise Multivariada , Gradação de Tumores , Tamanho do Órgão , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Estudos Retrospectivos , Sensibilidade e EspecificidadeRESUMO
CONTEXT.: Changes in Paneth cell numbers can be associated with chronic inflammatory diseases of the gastrointestinal tract. So far, no consensus has been achieved on the number of Paneth cells and their relevance to celiac disease (CD). OBJECTIVES.: To compare crypt and Paneth cell granule areas between patients with CD and without CD (non-CD) using an artificial intelligence-based solution. DESIGN.: Hematoxylin-eosin-stained sections of duodenal biopsies from 349 patients at the McGill University Health Centre were analyzed. Of these, 185 had a history of CD and 164 were controls. Slides were digitized and NoCodeSeg, a code-free workflow using open-source software (QuPath, DeepMIB), was implemented to train deep learning models to segment crypts and Paneth cell granules. The total area of the entire analyzed tissue, epithelium, crypts, and Paneth cell granules was documented for all slides, and comparisons were performed. RESULTS.: A mean intersection-over-union score of 88.76% and 91.30% was achieved for crypt areas and Paneth cell granule segmentations, respectively. On normalization to total tissue area, the crypt to total tissue area in CD was increased and Paneth cell granule area to total tissue area decreased when compared to non-CD controls. CONCLUSIONS.: Crypt hyperplasia was confirmed in CD compared to non-CD controls. The area of Paneth cell granules, an indirect measure of Paneth cell function, decreased with increasing severity of CD. More importantly, our study analyzed complete hematoxylin-eosin slide sections using an efficient and easy to use coding-free artificial intelligence workflow.
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Introduction: Translocations of the ROS1 gene were found to drive tumorigenesis in 1% to 2% of lung adenocarcinoma. In clinical practice, ROS1 rearrangements are often screened by immunohistochemistry (IHC) before confirmation with either fluorescence in situ hybridization or molecular techniques. This screening test leads to a non-negligible number of cases that have equivocal or positive ROS1 IHC, without ROS1 translocation. Methods: In this study, we have analyzed retrospectively 1021 cases of nonsquamous NSCLC having both ROS1 IHC and molecular analysis using next-generation sequencing. Results: ROS1 IHC was negative in 938 cases (91.9%), equivocal in 65 cases (6.4%), and positive in 18 cases (1.7%). Among these 83 equivocal or positive cases, only two were ROS1 rearranged, leading to a low predictive positive value of the IHC test (2%). ROS1-positive IHC was correlated with an increased mRNA ROS1 transcripts. Moreover, we have found a mean statistically significant relationship between ROS1 expression and EGFR gene mutations, suggesting a crosstalk mechanism between these oncogenic driver molecules. Conclusion: This study demonstrates that ROS1 IHC represents true ROS1 mRNA expression, and raises the question of a potential benefit of combined targeted therapy in EGFR-mutated NSCLC.
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BACKGROUND: Somatic epidermal growth factor receptor (EGFR) pathogenic variants have been identified and are routinely tested in the molecular diagnosis of non-small cell lung cancer (NSCLC) as they represent a target for EGFR tyrosine kinase inhibitor (TKI) therapy. However, germline variants in EGFR are much less frequently reported. CASE PRESENTATION: Herein, we report the case of a 46-year-old woman diagnosed with lung adenocarcinoma who was found to harbor a rare germline missense variant in exon 21 of EGFR: NM_005228.5(EGFR):c.2527G>A (p.V843I). In the tumor, this variant (Cosmic ID COSV51767379) was accompanied by a secondary, known pathogenic EGFR variant in cis, also occurring in exon 21, c.2573T>G (p.L858R) (Cosmic ID 6224). Her mother was previously diagnosed with poorly differentiated lung carcinoma and her tumor was also found to harbour the p.V843I variant but no other pathogenic variants. Notably, the proband's sister, diagnosed with a lung carcinoma with sarcomatous features at age 44, did not carry this variant or any other somatic or germline EGFR variants. CONCLUSION: This is the second report of familial lung adenocarcinoma associated with the germline p.V843I variant, which remains classified as a variant of uncertain significance. The lack of segregation of this variant in the proband's affected sister illustrates the complexity with evaluating lung cancer predisposition factors. Currently, there is a paucity of data regarding the therapeutic outcomes of patients with tumors expressing this rare germline variant, therefore we propose an algorithm for the identification of at-risk individuals and families as the first step for their personalized management.
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Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Feminino , Humanos , Adulto , Pessoa de Meia-Idade , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Receptores ErbB/genética , Adenocarcinoma de Pulmão/tratamento farmacológico , Pulmão/patologia , MutaçãoRESUMO
INTRODUCTION: Whilst the American Joint Committee on Cancer 7th edition (AJCC7) classified pT4 non-small-cell lung cancers (NSCLC) as those with extra-pulmonary invasion, the revised 8th edition (AJCC8) included tumors > 7cm regardless of extra-pleural spread. We examined perioperative and long-term outcomes of classical T4 definitions with patients whose tumors were greater than 7cm without extra-pulmonary invasion. MATERIALS AND METHODS: A retrospective single center cohort study was performed. All consecutive patients with pT4 lesions between 2011 and 2018 were identified based on either the AJCC7 or AJCC8 classification. Clinicopathological variables were extracted and compared in a univariate manner. A multivariate Cox regression analysis was performed to assess factors associated with overall survival. RESULTS: Forty patients were allocated to AJCC7 and 118 to AJCC8. Patients in the former were more likely to have positive lymph nodes, synchronous metastasis, multifocal disease and lymphovascular invasion. AJCC7 patients were more likely to undergo pneumonectomy despite significantly more being treated with neoadjuvant therapy. Ninety-day mortality was higher in the AJCC7 group. There was no difference in long-term overall survival. On multivariate analysis male gender, squamous cell histology and increasing tumor size were associated with an increased risk of death. CONCLUSION: Although long-term outcomes were similar, the heterogenicity within the AJCC8 classification emphasizes the need to contextualize the perioperative outcomes for patients with pT4 NSCLC. These data are important for future iterations of the TNM classification in view of emerging neoadjuvant options for patients with cT4 operable NSCLC.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Masculino , Carcinoma Pulmonar de Células não Pequenas/patologia , Estadiamento de Neoplasias , Estudos Retrospectivos , Estudos de Coortes , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/cirurgia , PrognósticoRESUMO
The treatment paradigm for patients with stage II/III non-small-cell lung cancer (NSCLC) is rapidly evolving. We performed a modified Delphi process culminating at the Early-stage Lung cancer International eXpert Retreat (ELIXR23) meeting held in Montreal, Canada, in June 2023. Participants included medical and radiation oncologists, thoracic surgeons and pathologists from across Quebec. Statements relating to diagnosis and treatment paradigms in the preoperative, operative and postoperative time periods were generated and modified until all held a high level of consensus. These statements are aimed to help guide clinicians involved in the treatment of patients with stage II/III NSCLC.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Neoplasias Pulmonares/cirurgia , Consenso , Canadá , QuebequeRESUMO
BACKGROUND: Lung cancer is the leading cause of cancer death in both men and women. Quebec has the highest lung cancer mortality out of all provinces in Canada, believed to be caused by higher smoking rates. Molecular testing for lung cancer is standard of care due to the discovery of actionable driver mutations that can be targeted with tyrosine kinase inhibitors. To date, no detailed molecular testing characterization of Quebec patients with lung cancer using next generation sequencing (NGS) has been performed. MATERIALS AND METHODS: The aim of this study was to describe the genomic landscape of patients with lung cancer (n = 997) who underwent NGS molecular testing at a tertiary care center in Quebec and to correlate it with clinical and pathology variables. RESULTS: Compared to 10 other NGS studies found through a structured search strategy, our cohort had a higher prevalence of KRAS mutations (39.2%) compared to most geographical locations. Additionally, we observed a significant positive association between decreasing age and a higher proportion of KRAS G12C mutations. CONCLUSION: Overall, it remains important to assess institutional rates of actionable driver mutations to help guide governing bodies, fuel clinical trials and create benchmarks for expected rates as quality metrics.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Masculino , Humanos , Feminino , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/patologia , Quebeque/epidemiologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Atenção à Saúde , Sequenciamento de Nucleotídeos em Larga EscalaRESUMO
Recent publications have explored intranasal (i.n.) adenovirus-based (Ad) vaccines as an effective strategy for SARS-CoV-2 in pre-clinical models. However, the effects of prior immunizations and infections have yet to be considered. Here, we investigate the immunomodulatory effects of Mycobacterium bovis BCG pre-immunization followed by vaccination with an S-protein-expressing i.n. Ad, termed Ad(Spike). While i.n. Ad(Spike) retains some protective effect after 6 months, a single administration of BCG-Danish prior to Ad(Spike) potentiates its ability to control viral replication of the B.1.351 SARS-CoV-2 variant within the respiratory tract. Though BCG-Danish did not affect Ad(Spike)-generated humoral immunity, it promoted the generation of cytotoxic/Th1 responses over suppressive FoxP3+ TREG cells in the lungs of infected mice. Thus, this vaccination strategy may prove useful in limiting future pandemics by potentiating the long-term efficacy of mucosal vaccines within the context of the widely distributed BCG vaccine.
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Prognostic stratification of patients surgically resected with invasive pulmonary adenocarcinoma must be improved. Previous studies reported that complex glandular patterns (CGPs), cribriform and fused gland growth patterns, are associated with unfavorable prognosis. The goal of this study is to evaluate the prognostic value of CGPs in patients with resected stage I-IV lung adenocarcinoma. The presence of CGPs as a minor to predominant component was tested for association with overall survival (OS, n = 676) and relapse-free survival (RFS, n = 463) after surgery. CGPs were observed in 284 tumors (42.0%). Cribriform and fused gland were the predominant patterns in 35 and 37 cases, respectively. The presence of cribriform pattern was associated with worse RFS, but not OS. The fused gland pattern alone or grouped into CGPs with the cribriform pattern was not associated with OS and RFS. As a predominant pattern, cribriform was associated with the worse survival compared to the 5 recognized histologic patterns. Patients with fused gland-predominant tumors had 5-year survival that ranged between papillary- and micropapillary-predominant tumors. We conclude that cribriform-predominant, but not fused gland-predominant, is a subtype with poor prognosis similar to the solid and micropapillary subtypes. In contrast, the presence of a minor component of fused gland or CGPs (cribriform + fused gland) is not associated with survival. The cribriform pattern alone offers prognosis stratification improvement, but this effect is attenuated when combined into CGPs to define a subset of acinar-predominant tumors with poor prognosis. This argues against combining cribriform and fused gland into CGPs to summarize high-grade patterns.
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Adenocarcinoma de Pulmão , Adenocarcinoma , Neoplasias Pulmonares , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/cirurgia , Humanos , Neoplasias Pulmonares/patologia , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos RetrospectivosRESUMO
The transition towards digital pathology and an extensive selection of video conferencing platforms have helped provide continuity to education even during the COVID-19 pandemic. Innovative approaches for pathology education, will likely persist beyond the pandemic, as they have powerful didactic potential. While there is a wide selection of software for use as educational tools, an environment to access all resources with ease is clearly lacking. In this technical note, we highlight our customized educational applications built using a low-code approach. Our applications, developed with Microsoft Power Apps, serve both educational and examination purposes and are launched using Microsoft Teams. Building applications using a low-code approach has made our applications very specific to our use and enabled daily distanced education. Combined with existing features on Teams, such as file sharing, meeting scheduling, and messaging, the applications serve as a unique and customizable pathology educational platform.
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The immune contexture of pancreatic ductal adenocarcinoma (PDAC) is generally immunosuppressive. A role for immune checkpoint inhibitors (ICIs) in PDAC has only been demonstrated for the rare and hypermutated mismatch repair (MMR) deficient (MMR-d) subtype. Homologous recombination repair (HR) deficient (HR-d) PDAC is more prevalent and may encompass up to 20% of PDAC. Its genomic instability may promote a T-cell mediated anti-tumor response with therapeutic sensitivity to ICIs. To investigate the immunogenicity of HR-d PDAC, we used multiplex immunohistochemistry (IHC) to compare the density and spatial distribution of CD8+ cytotoxic T-cells, FOXP3+ regulatory T-cells (Tregs), and CD68+ tumor-associated macrophages (TAMs) in HR-d versus HR/MMR-intact PDAC. We also evaluated the IHC positivity of programmed death-ligand 1 (PD-L1) across the subgroups. 192 tumors were evaluated and classified as HR/MMR-intact (n=166), HR-d (n=25) or MMR-d (n=1) based on germline testing and tumor molecular hallmarks. Intra-tumoral CD8+ T-cell infiltration was higher in HR-d versus HR/MMR-intact PDAC (p<0.0001), while CD8+ T-cell densities in the peri-tumoral and stromal regions were similar in both groups. HR-d PDAC also displayed increased intra-tumoral FOXP3+ Tregs (p=0.049) and had a higher CD8+:FOXP3+ ratio (p=0.023). CD68+ TAM expression was similar in HR-d and HR/MMR-intact PDAC. Finally, 6 of the 25 HR-d cases showed a PD-L1 Combined Positive Score of >=1, whereas none of the HR/MMR-intact cases met this threshold (p<0.00001). These results provide immunohistochemical evidence for intra-tumoral CD8+ T-cell enrichment and PD-L1 positivity in HR-d PDAC, suggesting that HR-d PDAC may be amenable to ICI treatment strategies.
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INTRODUCTION: Primary carcinomas of the trachea are rare, with a reported annual incidence of one in a million. We present a case of a previously undescribed polypoid high-grade neuroendocrine carcinoma of the trachea. Resection of the carcinoma revealed only superficial invasion of the mucosa and without evidence of local or distant metastatic disease. Histologically, the tumor had high-grade features with necrosis and a high mitotic index. METHODS: Characterization of this rare neuroendocrine carcinoma of the trachea was performed by immunohistochemistry and whole-genome sequencing. RESULTS: Immunohistochemistry result was positive for neuroendocrine markers, p16 and an elevated Ki-67. Whole-genome sequencing of the lesion was performed and revealed a very unusual and very distinct mutational signature without relationship to other relevant neuroendocrine carcinomas. Neither known driver nor targetable mutations were found by whole-genome sequencing. Analysis of the sequence of numerous viral elements of human papillomavirus-18 suggests that the pathogenesis of the lesion is related to viral integration. The patient developed distal recurrence, which progressed to widespread pulmonary dissemination, presumably through aerogenous spread of disease. CONCLUSIONS: This is the first characterization of this type of tracheal tumor, including genomic findings, pathogenesis, and natural history.