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Atreye MajumdarSambit K. MohantyObjective This article identifies and evaluates the frequency of mutations in the BCR-ABL1 kinase domain (KD) of chronic myeloid leukemia (CML) patients who showed suboptimal response to their current tyrosine kinase inhibitor (TKI) regime and assesses their clinical value in further treatment decisions. Materials and Methods Peripheral and/or bone marrow were collected from 791 CML patients. Ribonucleic acid was extracted, reverse transcribed, and Sanger sequencing method was utilized to detect single-nucleotide variants (SNVs) in BCR-ABL1 KD. Results Thirty-eight different SNVs were identified in 29.8% ( n = 236/791) patients. T315I, E255K, and M244V were among the most frequent mutations detected. In addition, one patient harbored a novel L298P mutation. A subset of patients from the abovementioned harbored compound mutations (13.3%, n = 33/236). Follow-up data was available in 28 patients that demonstrated the efficacy of TKIs in correlation with mutation analysis and BCR-ABL1 quantitation. Molecular response was attained in 50% patients following an appropriate TKI shift. A dismal survival rate of 40% was observed in T315I-harboring patients on follow-up. Conclusion This study shows the incidence and pattern of mutations in one of the largest sets of Indian CML patients. In addition, our findings strengthen the prognostic value of KD mutation analysis among strategies to overcome TKI resistance.
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BACKGROUND AND OBJECTIVE: TP53 loss-of-function (TP53LOF) mutations might be a driver of poor prognosis and chemoresistance in both human papillomavirus (HPV)-independent (HPV-) and HPV-associated (HPV+) penile squamous cell carcinoma (PSCC). Here, we aim to describe transcriptomic differences in the PSCC microenvironment stratified by TP53LOF and HPV status. METHODS: We used single-cell RNA sequencing (scRNA-seq) and T-cell receptor sequencing to obtain a comprehensive atlas of the cellular architecture of PSCC. TP53LOF and HPV status were determined by targeted next-generation sequencing and sequencing HPV-DNA reads. Six HPV+ TP53 wild type (WT), six HPV- TP53WT, and four TP53LOF PSCC samples and six controls were included. Immunohistochemistry and hematoxylin-eosin confirmed the morphological context of the observed signatures. Prognostic differences between patient groups were validated in 541 PSCC patients using Kaplan-Meier survival estimates. KEY FINDINGS AND LIMITATIONS: Patients with aberrant p53 staining fare much worse than patients with either HPV- or HPV+ tumors and WT p53 expression. Using scRNA-seq, we revealed 65 cell subtypes within 83 682 cells. TP53LOF tumors exhibit a partial epithelial-to-mesenchymal transition, immune-excluded, angiogenic, and morphologically invasive environment, underlying their aggressive phenotype. HPV- TP53WT tumors show stemness and immune exhaustion. HPV+ TP53WT tumors mirror normal epithelial maturation with upregulation of antibody-drug-conjugate targets and activation of innate immunity. Inherent to the scRNA-seq analysis, low sample size is a limitation and validation of signatures in large PSCC cohorts is needed. CONCLUSIONS AND CLINICAL IMPLICATIONS: This first scRNA-seq atlas offers unprecedented in-depth insights into PSCC biology underlying prognostic differences based on TP53 and HPV status. Our findings provide clues for testing novel biomarker-driven therapies in PSCC. PATIENT SUMMARY: Here, we analyzed tissues of penile cancer at the level of individual cells, which helps us understand why patients who harbor a deactivating mutation in the TP53 gene do much worse than patients lacking such a mutation. Such an analysis may help us tailor future therapies based on TP53 gene mutations and human papillomavirus status of these tumors.
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Mutación , Infecciones por Papillomavirus , Neoplasias del Pene , Fenotipo , Análisis de la Célula Individual , Proteína p53 Supresora de Tumor , Humanos , Masculino , Neoplasias del Pene/genética , Neoplasias del Pene/virología , Neoplasias del Pene/patología , Proteína p53 Supresora de Tumor/genética , Infecciones por Papillomavirus/genética , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/virología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/virología , Carcinoma de Células Escamosas/patología , Medicina de Precisión , Persona de Mediana Edad , Papillomaviridae/genética , Pronóstico , Microambiente Tumoral/genética , Anciano , Virus del Papiloma HumanoRESUMEN
ABSTRACT: Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasm that is genetically characterized by the presence of the Philadelphia (Ph) chromosome. Variant Ph translocation has been observed in 5% to 10% of the CML cases. In the previous studies, many different types of variant Ph translocations have been observed involving chromosomes 1p36, 3p21, 5q13, 6p21, 9q22, 11q13, 12p13, 17p13, and 10p15. According to the published literature, only two cases with the complex translocations involving long arm of chromosome 16 at band q24 have been reported. We report two female patients with complex translocation (three-way) involving chromosomes 9, 22, and 16 at breakpoint q24 and both patients responded well to Imatinib. The present study included 469 patients of clinically diagnosed CML patients who were referred for cytogenetic analysis to our laboratory. Cytogenetic analysis was performed by GTG banding, and the karyotype was designated according to the International System for Human Cytogenetic Nomenclature. Fluorescence in situ hybridization (FISH) analysis was performed for complex and variant BCR-ABL cases. Of total 469 cases, 248 patients showed classical Ph chromosome [t(9;22)(q34;q11.2)], 198 cases were normal, and 23 patients had variant and complex Ph chromosome translocation. Two patients showed three-way translocation involving long arm of chromosomes 9, 22, and 16 at band 9q34, 22q11.2, and 16q24. In this report, patients with variant Ph translocation did not have a significantly different outcome as compared to the classical translocation. Both cases responded well to Imatinib.
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Cromosomas Humanos Par 9 , Leucemia Mielógena Crónica BCR-ABL Positiva , Cromosoma Filadelfia , Translocación Genética , Humanos , Antineoplásicos/uso terapéutico , Cromosomas Humanos Par 16/genética , Cromosomas Humanos Par 22/genética , Cromosomas Humanos Par 9/genética , Mesilato de Imatinib/uso terapéutico , Hibridación Fluorescente in Situ , Cariotipificación , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnósticoRESUMEN
Accurate diagnosis of neuroblastoma may be challenging, especially with limited or inadequate specimen and at the metastatic sites due to overlapping imaging, histopathologic, and immunohistochemical (immunohistochemistry [IHC]; infidelity among various lineage-associated transcription factors eg FLI1, transducin-like enhancer 1, etc) features. GATA3 and ISL1 have recently been described as markers of neuroblastic differentiation. This study aims at determining the diagnostic utility of GATA3 and ISL1 in differentiating neuroblastoma from other pediatric malignant small round blue cell tumors.We evaluated GATA3 and ISL1 expression in 74 pediatric small round blue cell tumors that included 23 NMYC-amplified neuroblastomas, 11 EWSR1-rearranged round cell sarcomas, 7 SYT::SSX1-rearranged synovial sarcomas, 5 embryonal rhabdomyosarcomas, 10 Wilms tumors (nephroblastomas), 7 lymphoblastic lymphoma, 7 medulloblastoma, and 4 desmoplastic small round cell tumor.All 23 neuroblastomas (moderate to strong staining in >50% of the tumor cells), 5â T-lymphoblastic lymphomas (moderate to strong staining in 40%-90% of the tumor cells), and 2 desmoplastic small round cell tumors (weak to moderate staining in 20%-30% of the tumor cells) expressed GATA3, while other tumors were negative. ISL1 immunoreactivity was observed in 22 (96%) neuroblastomas (strong staining in in >50% of the tumor cells, n = 17; moderate to strong staining in 26%-50% of the tumor cells, n = 5), 3 embryonal rhabdomyosarcoma (moderate to strong staining in 30%-85% of the tumor cells), 1 synovial sarcoma (weak staining in 20% of the tumor cells), and 7 medulloblastoma (strong staining in 60%-90% of the tumor cells). Other tumors were negative. Overall, GATA3 showed 86% specificity, 100% sensitivity, and 90% accuracy for neuroblastoma, with a positive predictive value (PPV) and negative predictive value (NPV) of 77% and 100%, respectively. ISLI showed 72% specificity, 96% sensitivity, and 81% accuracy for neuroblastoma, with a PPV and NPV of 67% and 97%, respectively. After the exclusion of T-lymphoblastic lymphoma and desmoplastic small round cell tumors, GATA3 had 100% specificity, sensitivity, accuracy, and PPV and NPV for neuroblastoma. Similarly, in pediatric small round blue cell tumors, ISL1 had 100% specificity, sensitivity, accuracy, PPV, and NPV for neuroblastoma, after embryonal rhabdomyosarcoma, synovial sarcoma, and medulloblastoma were excluded. CONCLUSIONS: GATA3 and ISL1 may be valuable in the diagnostic work-up of neuroblastoma and may reliably be used to support the neuroblastic lineage of pediatric small round blue cell tumors. Furthermore, dual positivity helps in challenging scenarios, when there is equivocal imaging, overlapping IHC features, limited specimen, and the lack of facility for a molecular work up.
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Neoplasias Cerebelosas , Neoplasias Renales , Meduloblastoma , Neuroblastoma , Leucemia-Linfoma Linfoblástico de Células Precursoras , Rabdomiosarcoma Embrionario , Sarcoma Sinovial , Tumor de Wilms , Humanos , Niño , Sarcoma Sinovial/diagnóstico , Sarcoma Sinovial/genética , Neuroblastoma/diagnóstico , Tumor de Wilms/diagnóstico , Neoplasias Renales/diagnóstico , Neoplasias Renales/genética , Biomarcadores de Tumor , Diagnóstico Diferencial , Factor de Transcripción GATA3RESUMEN
Background. Whole slide imaging (WSI) represents a paradigm shift in pathology, serving as a necessary first step for a wide array of digital tools to enter the field. It utilizes virtual microscopy wherein glass slides are converted into digital slides and are viewed by pathologists by automated image analysis. Its impact on pathology workflow, reproducibility, dissemination of educational material, expansion of service to underprivileged areas, and institutional collaboration exemplifies a significant innovative movement. The recent US Food and Drug Administration approval to WSI for its use in primary surgical pathology diagnosis has opened opportunities for wider application of this technology in routine practice. Main Text. The ongoing technological advances in digital scanners, image visualization methods, and the integration of artificial intelligence-derived algorithms with these systems provide avenues to exploit its applications. Its benefits are innumerable such as ease of access through the internet, avoidance of physical storage space, and no risk of deterioration of staining quality or breakage of slides to name a few. Although the benefits of WSI to pathology practices are many, the complexities of implementation remain an obstacle to widespread adoption. Some barriers including the high cost, technical glitches, and most importantly professional hesitation to adopt a new technology have hindered its use in routine pathology. Conclusions. In this review, we summarize the technical aspects of WSI, its applications in diagnostic pathology, training, and research along with future perspectives. It also highlights improved understanding of the current challenges to implementation, as well as the benefits and successes of the technology. WSI provides a golden opportunity for pathologists to guide its evolution, standardization, and implementation to better acquaint them with the key aspects of this technology and its judicial use. Also, implementation of routine digital pathology is an extra step requiring resources which (currently) does not usually result increased efficiency or payment.
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Inteligencia Artificial , Patología Quirúrgica , Humanos , Reproducibilidad de los Resultados , Procesamiento de Imagen Asistido por Computador/métodos , Microscopía/métodos , Patología Quirúrgica/métodosRESUMEN
Background. Spindle cell/sclerosing rhabdomyosarcoma is a rare neoplasm and has an aggressive clinical course. Because of its rarity, we performed a multi-institutional collaboration to comprehend the overarching clinical, histopathological, and immunohistochemical characteristics of a cohort of spindle cell/sclerosing rhabdomyosarcoma. Materials and Methods. Forty-five patients with spindle cell/sclerosing rhabdomyosarcoma were identified. Demographics, clinical, histopathological, and immunohistochemistry data were reviewed and recorded. Results. The patients' age ranged from 1 to 85 years with a male to female ratio of 1.2:1. There were 15 children/adolescents and 30 adults. Eighteen (40%) tumors were located in the head and neck region. Twenty-four (53%) tumors displayed a bimorphic cellular arrangement with hypercellular areas having short, long, and sweeping fascicular and herringbone pattern, and hypocellular areas with stromal sclerosis and associated hyalinized and/or chondromyxoid matrix. Histomorphological differentials considered were leiomyosarcoma, malignant peripheral nerve sheath tumor, fibrosarcoma, nodular fasciitis, liposarcoma, synovial sarcoma, sarcomatoid carcinoma, solitary fibrous tumor, dermatofibrosarcoma protuberans, and schwannoma. Six tumors exhibited marked stromal sclerosis. The myogenic nature was confirmed by immunohistochemistry. Positivity for at least one skeletal muscle-associated marker (MyoD1 and/or myogenin) was observed. Conclusion. Spindle cell/sclerosing rhabdomyosarcoma diagnosis can be challenging as a number of malignant spindle cell neoplasm mimic this entity. Thus a correct diagnosis requires immunohistochemical work up with a broad panel of antibodies. In view of rarity of this neoplasm, further studies on a large cohort of patients with clinical follow-up data are needed for a better understanding of this tumor.
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Neurofibrosarcoma , Rabdomiosarcoma , Adulto , Niño , Adolescente , Humanos , Masculino , Femenino , Lactante , Preescolar , Adulto Joven , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Inmunohistoquímica , Esclerosis/patología , Rabdomiosarcoma/diagnóstico , Rabdomiosarcoma/patología , Músculo Esquelético/patología , Biomarcadores de TumorRESUMEN
OBJECTIVES: Penile squamous cell carcinomas (PCs) are rare malignancies with a dismal prognosis in a metastatic setting; therefore, novel immunotherapeutic modalities are an unmet need. One such modality is the immune checkpoint molecule programmed cell death ligand 1 (PD-L1). We sought to analyze PD-L1 expression and its correlation with various clinicopathologic parameters in a contemporary cohort of 134 patients with PC. METHODS: A cohort of 134 patients with PC was studied for PD-L1 immunohistochemistry. The PD-L1 expression was evaluated using a combined proportion score with a cutoff of 1 or higher to define positivity. The results were correlated with various clinicopathologic parameters. RESULTS: Overall, 77 (57%) patients had positive PD-L1 expression. Significantly high PD-L1 expression was observed in high-grade tumors (P = .006). We found that 37% of human papillomavirus (HPV)-associated subtypes and 73% of other histotype tumors expressed PD-L1, while 63% of HPV-associated tumors and 27% of other histotype tumors did not (odds ratio, 1.35; P = .002 when compared for HPV-associated groups vs all others). Similarly, PD-L1-positive tumors had a 3.61-times higher chance of being node positive than PD-L1-negative tumors (P = .0009). In addition, PD-L1 high-positive tumors had a 5-times higher chance of being p16ink4a negative than PD-L1 low-positive tumors (P = .004). The PD-L1-positive tumors had a lower overall survival and cancer-specific survival than PD-L1-negative tumors. CONCLUSIONS: Overall, PD-L1 expression is associated with high-grade and metastatic tumors. Lower PD-L1 expression is observed more frequently in HPV-associated (warty or basaloid) subtypes than in other, predominantly HPV-independent types. As a result, PD-L1 positivity, including higher expression, portends lower overall and cancer-specific survival. These data provide a rational for further investigating PD-L1-based immunotherapeutics in PC.
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Carcinoma de Células Escamosas , Infecciones por Papillomavirus , Neoplasias del Pene , Masculino , Humanos , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/metabolismo , Antígeno B7-H1/metabolismo , Ligandos , Pronóstico , Carcinoma de Células Escamosas/patología , Neoplasias del Pene/patología , Apoptosis , Biomarcadores de Tumor/metabolismoRESUMEN
AIMS: Pathology education is a core component of medical training, and its literature is critical for refining educational modalities. We performed a cross-sectional bibliometric analysis to explore publications on pathology education, focusing on new medical education technologies. METHODS: The analysis identified 64 pathology journals and 53 keywords. Relevant articles were collected using a web application, PaperScraper, developed to accelerate literature search. Citation data were collected from multiple sources. Descriptive statistics, with time period analysis, were performed using Microsoft Excel and visualised with Flourish Studio. Two article groups were further investigated with a bibliometric software, VOSViewer, to establish co-authorship and keyword relationships. RESULTS: 8946 citations were retrieved from 905 selected articles. Most articles were published in the last decade (447, 49.4%). The top journals were Archives of Pathology & Laboratory Medicine (184), Human Pathology (122) and the American Journal of Clinical Pathology (117). The highest number of citations was found for Human Pathology (2120), followed by Archives of Pathology & Laboratory Medicine (2098) and American Journal of Clinical Pathology (1142). Authors with different backgrounds had the greatest number of articles and citations. 12 co-authorship, 3 keyword and 8 co-citation clusters were found for the social media/online resources group, 8 co-authorship, 4 keyword and 7 co-citation clusters for the digital pathology/virtual microscopy/mobile technologies group. CONCLUSIONS: The analysis revealed a significant increase in publications over time. The emergence of digital teaching and learning resources played a major role in this growth. Overall, these findings underscore the transformative potential of technology in pathology education.
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Bibliometría , Humanos , Estados Unidos , Estudios TransversalesRESUMEN
BACKGROUND: The understanding of molecular mechanisms involved in non-small cell lung carcinoma (NSCLC) has revolutionized significantly in the recent years. These have helped to develop personalized management strategies by identifying specific molecular alterations such as mutations in EGFR, ROS1, BRAF, ERBB2, MET, ALK, and KRAS genes. These mutations are targetable ensuring a better clinical outcome. Next-generation sequencing (NGS) methodology is the recommended technique for the identification of driver mutations in the five hot-spot genes (EGFR, ALK, ROS1, MET, and BRAF) involved in the NSCLC. NGS has numerous advantages including multiplexing, tissue conservation, identification of rare and novel variants, and reduced cost over the sequential single gene testing. Herein, we sought to demonstrate the mutational profile in NSCLC and their clinicopathologic correlation in a contemporary cohort of Indian NSCLC patients. Additionally, we studied the correlation of oncogenic driver mutations with PD-L1 status in these patients. MATERIALS AND METHODS: Five fifty-two stage IV NSCLC patients (adenocarcinoma=490; squamous cell carcinoma=51; adenosquamous carcinoma=5; large cell carcinoma=2; sarcomatoid carcinoma=3; spindle cell carcinoma=1) underwent broad molecular profiling by a custom-made, targeted DNA- and RNA-based five hot-spot genes lung cancer panel (EGFR, ALK, ROS1, BRAF, and MET), compatible with the NGS Ion S5 system. The mutations were correlated with the clinicopathologic characteristics. Additionally, PD-L1 expression status, available on 252 tumors, was correlated with the oncogenic drivers. RESULTS: Validation of the 5 gene panel yielded the following results: a) specificity of 99.74%; b) sensitivity of 100% for single nucleotide variants (SNVs) (>5% variant allele frequency, VAF), indels (>10% VAF) and fusions; c) 100% intra- and inter-run reproducibility; d) 88% inter-laboratory agreement. Validated panel was then used to analyze clinical samples. Sixty percentage tumors harbored either one (54.71%) or multiple (3.26%) mutations. EGFR and BRAF V600E mutations, ALK and ROS1 rearrangements, and MET exon 14 skipping mutation were observed in 38.41% (n = 212) and 2.72% (n = 15) patients, 12.14% (n = 67) and 3.62% (n = 20) patients, and 1.09% (n = 6) patients, respectively. EGFR exon 19 deletion accounted for 52.83% of all mutations, followed by L858R (35.85%), T790M (5.19%), exon 20 insertions (6.6%), and other rare mutations (G719X, L861Q, S768I) (9.91%). Concurrent EGFR with ALK, EGFR with ROS1, EGFR with MET, and EGFR with BRAF were observed in 10, 4, 1, and 3 patients, respectively. PD-L1 was expressed in 134 patients (53.2%). Exon 19 deletion was more prevalent in PD-L1 negative tumors whereas exon 21 substitution (L858R) was seen more in PD-L1 positive tumors. CONCLUSIONS: This is one of the largest cohorts of NSCLC for comprehensive targeted mutational profiling and correlation with the PD-L1 expression. The mutations are more prevalent in non-smoker females for all genes, except ALK (non-smoker males). MET and BRAF mutations are more common in elderly population whereas EGFR mutations, and ALK and ROS1 genes rearrangements are more prevalent in younger population. The most common histopathologic subtype/feature associated with various mutations was as follows: acinar with EGFR, solid with ALK, macronucleoli with ROS1, signet ring with MET, and micropapillary with BRAF.
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Carcinoma de Pulmón de Células no Pequeñas , Carcinoma , Neoplasias Pulmonares , Masculino , Femenino , Humanos , Anciano , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Proteínas Proto-Oncogénicas B-raf/genética , Antígeno B7-H1/genética , Reproducibilidad de los Resultados , Mutación , Proteínas Proto-Oncogénicas/genética , Inhibidores de Proteínas QuinasasRESUMEN
Papillary cystadenoma (PC) of the salivary gland is an uncommon benign epithelial neoplasm that shows predominantly multicystic growth pattern with intraluminal papillary proliferation and areas of oncocytic differentiation. We report a case of papillary cystadenoma of the parotid gland in a 44-years-old female. The patient presented with painful nodular swelling in the right parotid region for two months. Ultrasonography revealed a well marginated oval lesion with altered signal intensity involving the superficial lobe. The excision specimen showed a neoplasm with multicystic spaces having papillary projections lined by benign low-grade epithelium and supported by fibrovascular cores. No significant cytological atypia or mitosis was observed. The cells were immunoreactive for Keratin, Keratin 7, and were negative for Keratin 20, AR, HeR2/neu, TTF1, CDX2, and GATA3. p63 and Keratin 5/6 highlighted the myoepithelial cell layer lining the cystic spaces as well as the papillary projections. The Ki-67 proliferation index was 6%. The patient is on close clinical and imaging follow-up for the last 1year and 8 months without any evidence of disease recurrence or metastasis. Rarity of the lesion and distinct histomorphology warrants appropriate knowledge and discussion of the subject.
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Cistoadenoma Papilar , Cistoadenoma , Humanos , Femenino , Adulto , Cistoadenoma Papilar/patología , Recurrencia Local de Neoplasia/patología , Glándula Parótida/patología , Células Oxífilas/patología , Epitelio/patología , Cistoadenoma/patologíaRESUMEN
Solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm known to occur at various soft tissue and visceral locations. Kidney is a rarely reported site for these tumors. Most of the SFTs described in the kidney exhibit a classical CD34-positive patternless spindle cell histology. Focal round cell morphology is seldom reported. Herein, we describe a 48-year-old male patient with renal SFT. This tumor had pure round cell morphology with a CD34-/STAT6+ immunophenotype. Fluorescent in situ hybridization and a multiplexed sequencing assay performed on an Illumina® HiSeq 4000 platform revealed NAB2 and STAT6 gene rearrangement. Renal tumors with round cell morphology are diagnostically challenging and SFT is not often considered in the differential diagnosis of a round cell tumor of the kidney. Moreover, a CD34-negative profile can be rather confounding while diagnosing such lesions. In such scenarios, a strong nuclear STAT6 immunostaining is extremely helpful in clinching the diagnosis. SFT should always be considered in the differential diagnosis of round cell tumors of the kidney due to significant diagnostic and therapeutic implications.
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Bladder cancer (BC) is characterized by significant histopathologic and molecular heterogeneity. The discovery of molecular pathways and knowledge of cellular mechanisms have grown exponentially and may allow for better disease classification, prognostication, and development of novel and more efficacious noninvasive detection and surveillance strategies, as well as selection of therapeutic targets, which can be used in BC, particularly in a neoadjuvant or adjuvant setting. This article outlines recent advances in the molecular pathology of BC with a better understanding and deeper focus on the development and deployment of promising biomarkers and therapeutic avenues that may soon make a transition into the domain of precision medicine and clinical management for patients with BC.
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Until very recently, surgery, chemotherapy, and radiation therapy have been the mainstay of treatment in non-small cell carcinomas (NSCLCs). However, recent advances in molecular immunology have unveiled some of the complexity of the mechanisms regulating cellular immune responses and led to the successful targeting of immune checkpoints in attempts to enhance antitumor T-cell responses. Immune checkpoint molecules such as cytotoxic T-lymphocyte associated protein-4, programmed cell death protein-1, and programmed death ligand (PD-L) 1 have been shown to play central roles in evading cancer immunity. Thus, these molecules have been targeted by inhibitors for the management of cancers forming the basis of immunotherapy. Advanced NSCLC has been the paradigm for the benefits of immunotherapy in any cancer. Treatment decisions are made based on the expression of PD-L1 on the tumor cells and the presence or absence of driver mutations. Patients with high PD-L1 expression (≥50%) and no driver mutations are treated with single-agent immunotherapy whereas, for all other patients with a lower level of PD-L1 expression, a combination of chemotherapy and immunotherapy is preferred. Thus, PD-L1 blockers are the only immunotherapeutic agents approved in advanced NSCLC without any oncogenic driver mutations. PD-L1 immunohistochemistry, however, may not be the best biomarker in view of its dynamic nature in time and space, and the benefits may be seen regardless of PD -L1 expression. Each immunotherapy molecule is prescribed based on the levels of PD-L1 expression as assessed by a Food and Drug Administration-approved companion diagnostic assay. Other biomarkers that have been studied include tumor mutational burden, the T-effector signature, tumor-infiltrating lymphocytes, radiomic assays, inflammation index, presence or absence of immune-related adverse events and specific driver mutations, and gut as well as local microbiome. At the current time, none of these biomarkers are routinely used in the clinical decision-making process for immunotherapy in NSCLC. However, in individual cases, they can be useful adjuncts to conventional therapy. This review describes our current understanding of the role of biomarkers as predictors of response to immune checkpoint molecules. To begin with a brief on cancer immunology in general and in NSCLC, in particular, is discussed. In the end, recent advancements in laboratory techniques for refining biomarker assays are described.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/terapia , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/genética , Antígeno B7-H1 , Proteínas de Punto de Control Inmunitario/uso terapéutico , Patólogos , Biomarcadores de Tumor/metabolismoRESUMEN
Primary renal synovial sarcoma is a rare aggressive mesenchymal neoplasm of the kidney that accounts for less than 1% of renal sarcomas. Herein, we describe the clinicopathologic and molecular findings of 14 renal synovial sarcoma patients in one of the largest case series to date and to our knowledge, the only renal synovial sarcoma series to use novel SS18-SSX IHC. Clinicopathologic, IHC, molecular, management, and follow-up data were reviewed and analyzed. Macroscopically, the tumors had either homogeneous, tan-white, and solid (n = 10), variegated and solid (n = 3), or variegated and solid-cystic (n = 1) cut surfaces. Spindle cell (n = 10), round cell (n = 3), and round to epithelioid morphologies (n = 1) were observed. SS18-SSX IHC was positive in all 14 tumors (diffuse, n = 10; multifocal, n = 2; focal, n = 2). All the tumors harbored SS18::SSX1/2 gene rearrangement. Metastases to the liver, brain, and lung (n = 1); liver and bone (n = 1); liver and diaphragm (n = 1) were identified. Adjuvant chemotherapy was administered in 11/12 patients. Follow-up was available for 10 patients (time period range: 5 to 24 months). Four patients died of disease, and six patients are alive with no recurrence or metastasis. As SS18-SSX IHC showed an excellent concordance with the FISH results, this may reliably be used in the IHC panel of spindle/round cell sarcomas of the kidney and as a molecular surrogate for renal synovial sarcoma, particularly in a resource-limited setting. Also, the tumors with focal SS18-SSX expression had lower break apart signals in the FISH assay (19% and 23% in two tumors with focal SS18-SSX IHC positivity).
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Sarcoma Sinovial , Humanos , Sarcoma Sinovial/diagnóstico , Sarcoma Sinovial/genética , Proteínas de Fusión Oncogénica/genética , Pulmón/patologíaRESUMEN
Background. Neuroendocrine differentiation in the prostate gland ranges from clinically insignificant neuroendocrine differentiation detected with markers in an otherwise conventional prostatic adenocarcinoma to a lethal high-grade small/large cell neuroendocrine carcinoma. The concept of neuroendocrine differentiation in prostatic adenocarcinoma has gained considerable importance due to its prognostic and therapeutic ramifications and pathologists play a pivotal role in its recognition. However, its awareness, reporting, and resource utilization practice patterns among pathologists are largely unknown. Methods. Representative examples of different spectrums of neuroendocrine differentiation along with a detailed questionnaire were shared among 39 urologic pathologists using the survey monkey software. Participants were specifically questioned about the use and awareness of the 2016 WHO classification of neuroendocrine tumors of the prostate, understanding of the clinical significance of each entity, and use of different immunohistochemical (IHC) markers. De-identified respondent data were analyzed. Results. A vast majority (90%) of the participants utilize IHC markers to confirm the diagnosis of small cell neuroendocrine carcinoma. A majority (87%) of the respondents were in agreement regarding the utilization of type of IHC markers for small cell neuroendocrine carcinoma for which 85% of the pathologists agreed that determination of the site of origin of a high-grade neuroendocrine carcinoma is not critical, as these are treated similarly. In the setting of mixed carcinomas, 62% of respondents indicated that they provide quantification and grading of the acinar component. There were varied responses regarding the prognostic implication of focal neuroendocrine cells in an otherwise conventional acinar adenocarcinoma and for Paneth cell-like differentiation. The classification of large cell neuroendocrine carcinoma was highly varied, with only 38% agreement in the illustrated case. Finally, despite the recommendation not to perform neuroendocrine markers in the absence of morphologic evidence of neuroendocrine differentiation, 62% would routinely utilize IHC in the work-up of a Gleason score 5 + 5 = 10 acinar adenocarcinoma and its differentiation from high-grade neuroendocrine carcinoma. Conclusion. There is a disparity in the practice utilization patterns among the urologic pathologists with regard to diagnosing high-grade neuroendocrine carcinoma and in understanding the clinical significance of focal neuroendocrine cells in an otherwise conventional acinar adenocarcinoma and Paneth cell-like neuroendocrine differentiation. There seems to have a trend towards overutilization of IHC to determine neuroendocrine differentiation in the absence of neuroendocrine features on morphology. The survey results suggest a need for further refinement and development of standardized guidelines for the classification and reporting of neuroendocrine differentiation in the prostate gland.
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Carcinoma de Células Acinares , Carcinoma de Células Grandes , Carcinoma Neuroendocrino , Carcinoma de Células Pequeñas , Tumores Neuroendocrinos , Neoplasias de la Próstata , Masculino , Humanos , Próstata/patología , Tumores Neuroendocrinos/diagnóstico , Tumores Neuroendocrinos/patología , Patólogos , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/patología , Carcinoma Neuroendocrino/patología , Carcinoma de Células Pequeñas/patología , Carcinoma de Células Acinares/patología , Carcinoma de Células Grandes/patología , Encuestas y CuestionariosRESUMEN
Meningeal Rosai-Dorfman disease, a type of sporadic Rosai-Dorfman disease, is a rare occurrence. A few cases are reported in the English literature with an adequate immunohistochemical workup. This entity clinically and radiologically mimics either a meningeal or a parenchymal neoplasm with meningeal extension, warranting a thorough histopathologic evaluation. A broad histologic differential necessitates a detailed immunohistochemical characterization to render a correct diagnosis that has significant therapeutic and prognostic implications. Herein, we report a case of isolated meningeal Rosai-Dorfman disease in a 50-years-old human immunodeficiency virus-positive male patient with an emphasis on the histopathology, immunoprofile, and differential diagnoses.
Asunto(s)
Histiocitosis Sinusal , Masculino , Humanos , Persona de Mediana Edad , Histiocitosis Sinusal/diagnóstico , Histiocitosis Sinusal/patología , Meninges/patología , Diagnóstico DiferencialRESUMEN
Low-grade oncocytic tumour (LOT) of the kidney has recently emerged as a potential novel tumour type. Despite similarity to oncocytoma or eosinophilic chromophobe renal cell carcinoma, it shows diffuse keratin 7 immunohistochemistry (IHC) and negative KIT (CD117), which differs from both. We aimed to identify the molecular characteristics of these tumours. Seventeen tumours (one male, 16 female, nine previously published) fitting the original description of this entity (solid eosinophilic cell morphology, often with areas of tumour cells loosely stretched in oedematous stroma, and the above IHC features) were analysed with a next-generation sequencing panel of 324 cancer-associated genes from formalin-fixed, paraffin-embedded tissue. All tumours harboured at least one alteration in either TSC1 (n = 7, 41%), TSC2 (n = 2, 12%), MTOR (n = 5, 29%) or PIK3CA (n = 4, 24%). Four tumours harboured a second alteration, including two NF2, one each in conjunction with MTOR and TSC2 alterations, one PTEN with TSC1 alteration and one tumour with both MTOR and TSC1 alterations. No other renal cancer-related or recurring gene alterations were identified. In addition to the previously described IHC findings, 16 of 16 were positive for GATA3. Eleven patients with follow-up had no metastases or recurrent tumours. Recurrent tuberous sclerosis/MTOR pathway gene alterations in LOT support its consideration as a distinct morphological, immunohistochemical and genetic entity. PIK3CA is another pathway member that may be altered in these tumours. Further study will be necessary to determine whether tumour behaviour or syndromic associations differ from those of oncocytoma and chromophobe carcinoma, warranting different clinical consideration.
Asunto(s)
Adenoma Oxifílico , Carcinoma de Células Renales , Neoplasias Renales , Humanos , Masculino , Femenino , Recurrencia Local de Neoplasia , Carcinoma de Células Renales/genética , Neoplasias Renales/genética , Mutación , Adenoma Oxifílico/genética , Riñón , Serina-Treonina Quinasas TOR/genética , Factor de Transcripción GATA3/genética , Fosfatidilinositol 3-Quinasa Clase I/genéticaRESUMEN
The fifth edition of the World Health Organization (WHO) classification of urinary and male genital organ tumors has been recently published in 2022. The application of molecular profiling has made a substantial impact on the classification of urologic tumors. The new WHO classification introduces a group of molecularly well-defined renal tumor subtypes. The significant changes include addition of a category of "other oncocytic tumors" with oncocytoma/chromophobe renal cell carcinoma (chRCC)-like features, elimination of the subcategorization of type 1/2 papillary RCC, and inclusion of eosinophilic solid and cystic RCC as an independent tumor entity. The WHO/ISUP grading now has been recommended for all RCCs. Major nomenclature changes include replacement of histologic "variants" by "subtypes," "clear cell papillary renal cell carcinoma" to "clear cell renal cell tumor," "TCEB1-mutated RCC" to "ELOC-mutated RCC," "hereditary leiomyomatosis and renal cell carcinoma" to "fumarate hydratase-deficient RCC," "RCC-Unclassified" to "RCC-NOS," "primitive neuroectodermal tumor" to "embryonic neuroectodermal tumor," "testicular carcinoid" to "testicular neuroendocrine tumor," and "basal cell carcinoma of the prostate" to "adenoid-cystic (basal-cell) carcinoma of the prostate." Metastatic, hematolymphoid, mesenchymal, melanocytic, soft tissue, and neuroendocrine tumors are collectively discussed in separate chapters. It has been suggested that the morphological classification of urothelial cancer be replaced with a new molecular taxonomic classification system.
Asunto(s)
Carcinoma Basocelular , Carcinoma de Células Renales , Neoplasias Renales , Tumores Neuroendocrinos , Neoplasias Cutáneas , Humanos , Masculino , Carcinoma de Células Renales/patología , Neoplasias Renales/patología , Genitales Masculinos/patología , Organización Mundial de la Salud , Neoplasias Cutáneas/patologíaRESUMEN
Solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm known to occur at various soft tissue and visceral locations. Kidney is one of the rare locations for these tumors with around 64 cases being available in the literature. Most of the renal SFTs are tan-white, solid, firm, unencapsulated, and lobulated masses. A predominantly cystic renal SFT has never been reported in the literature. Herein we describe a case of multicystic renal SFT in a 44-year-old male with the characteristic CD34 + /STAT6 + immunophenotype. A careful gross and microscopic examination is warranted while dealing with cystic spindle cell neoplasms of the kidney and SFT should always be considered in the differential diagnosis. STAT6 immunohistochemistry is quite specific for the diagnosis. Moreso, a detailed immunopanel is necessary to exclude other spindle cell neoplasms of the kidney because of significant therapeutic and prognostic implications.
Asunto(s)
Neoplasias Renales , Tumores Fibrosos Solitarios , Masculino , Humanos , Adulto , Biomarcadores de Tumor , Tumores Fibrosos Solitarios/diagnóstico , Tumores Fibrosos Solitarios/cirugía , Tumores Fibrosos Solitarios/genética , Riñón/patología , Neoplasias Renales/patología , Pronóstico , Factor de Transcripción STAT6/genéticaRESUMEN
As machine learning (ML) solutions for genitourinary pathology image analysis are fostered by a progressively digitized laboratory landscape, these integrable modalities usher in a revolution in histopathological diagnosis. As technology advances, limitations stymying clinical artificial intelligence (AI) will not be extinguished without thorough validation and interrogation of ML tools by pathologists and regulatory bodies alike. ML solutions deployed in clinical settings for applications in prostate pathology yield promising results. Recent breakthroughs in clinical artificial intelligence for genitourinary pathology demonstrate unprecedented generalizability, heralding prospects for a future in which AI-driven assistive solutions may be seen as laboratory faculty, rather than novelty.