Homologous recombination pathway gene variants identified by tumor-only sequencing assays in lung carcinoma patients.

Background: The homologous recombination (HR) repair pathway plays a key role in double-stranded DNA break repair, and germline HR pathway gene variants are associated with increased risk of several cancers, including breast and ovarian cancer. HR deficiency is also a therapeutically targetable phenotype.

Methods: Somatic (tumour-only) sequencing was performed on 1,109 cases of lung tumors, and the pathological data were reviewed to filter for lung primary carcinomas.

Getting Your Laboratory on Track With Neurotrophic Receptor Tyrosine Kinase.

Context.—: Neurotrophic receptor tyrosine kinase (NTRK) fusion testing has both diagnostic and therapeutic implications for patient care. With 2 tumor-agnostic US Food and Drug Administration-approved tropomyosin receptor kinase (TRK) inhibitors, testing is increasingly used for therapeutic decision making.

Proceedings From the ASCO/College of American Pathologists Immune Checkpoint Inhibitor Predictive Biomarker Summit.

Purpose: Immune checkpoint inhibition (ICI) therapy represents one of the great advances in the field of oncology, highlighted by the Nobel Prize in 2018. Multiple predictive biomarkers for ICI benefit have been proposed. These include assessment of programmed death ligand-1 expression by immunohistochemistry, and determination of mutational genotype (microsatellite instability or mismatch repair deficiency or tumor mutational burden) as a reflection of neoantigen expression.

CNViz: An R/Shiny Application for Interactive Copy Number Variant Visualization in Cancer.

Copy number variants (CNVs) comprise a class of mutation which includes deletion, duplication, or amplification events that range in size from smaller than a single-gene or exon, to the size of a full chromosome. These changes can affect gene expression levels and are thus implicated in disease, including cancer. Although a variety of tools and methodologies exist to detect CNVs using data from massively parallel sequencing (also referred to as next-generation sequencing), it can be difficult to appreciate the copy number profile in a list format or as a static image.

TERT gene rearrangement in chordomas and comparison to other TERT-rearranged solid tumors.

Chordomas are rare, slow-growing neoplasms thought to arise from the foetal notochord remnant. A limited number of studies that examined the mutational profiles in chordomas identified potential driver mutations, including duplication in the TBXT gene (encoding brachyury), mutations in the PI3K/AKT signaling pathway, and loss of the CDKN2A gene. Most chordomas remain without clear driver mutations, and no fusion genes have been identified thus far.

A Curriculum for Genomic Education of Molecular Genetic Pathology Fellows: A Report of the Association for Molecular Pathology Training and Education Committee.

Molecular genetic pathology (MGP) is a subspecialty of pathology and medical genetics and genomics. Genomic testing, which is defined as that which generates large data sets and interrogates large segments of the genome in a single assay, is increasingly recognized as essential for optimal patient care through precision medicine. The most common genomic testing technologies in clinical laboratories are next-generation sequencing and microarray.

Bayesian approach to interpreting somatic cancer sequencing data: a case in point.

Cancer lineage/tissue-of-origin assignment in cancers of unknown primary remains a challenge even when aided by massively parallel sequencing. The stakes are high for patients as many contemporary therapeutic strategies are disease-specific, and the biological differences can influence the patients' responses. Herein, we provide an example of how Bayesian analysis can be used to merge data from clinical history, histology, immunohistochemistry (IHC) and cancer DNA sequencing to assist in tissue-of-origin assignment.

Long Non-coding RNAs in Pulmonary Neuroendocrine Neoplasms.

Pulmonary neuroendocrine neoplasms (NENs) are classified into low-grade neuroendocrine tumors and high-grade neuroendocrine carcinomas (NECs). There are significant differences in therapeutic strategies of the different NEN subtypes, and therefore, precise classification of pulmonary NENs is critical. However, challenges in pulmonary NEN classification include overlap of diagnostic histological features among the subtypes and reduced or negative expression of neuroendocrine markers in poorly differentiated pulmonary NECs.

Impact of and Co-Mutations on Outcomes After First-Line Systemic Therapy Among Patients With -Mutated Advanced Non-Small-Cell Lung Cancer.

Purpose: The gene encodes a serine/threonine protein kinase that regulates cell polarity and functions as a tumor suppressor. Patients with non-small-cell lung cancer (NSCLC) and mutations often have other co-mutations. We evaluated the impact of and co-mutations on outcomes after first-line systemic therapy for patients with metastatic or recurrent NSCLC that harbors mutations.

Validation of a Next-Generation Sequencing Assay Targeting RNA for the Multiplexed Detection of Fusion Transcripts and Oncogenic Isoforms.

Context.—: Next-generation sequencing is a high-throughput method for detecting genetic abnormalities and providing prognostic and therapeutic information for patients with cancer. Oncogenic fusion transcripts are among the various classifications of genetic abnormalities present in tumors and are typically detected clinically with fluorescence in situ hybridization (FISH).

Cyclin D1 expression and novel mutational findings in Rosai-Dorfman disease.

Rosai-Dorfman disease (RDD) is an enigmatic histiocytic disorder classically diagnosed by a distinctive combination of pathological features: emperipolesis, or migration of intact haematological cells through the voluminous cytoplasm of lesional histiocytes, and expression of S100 by these histiocytes. The pathogenesis has long been elusive until the recent detection of recurrent and mutually exclusive mutations in several oncogenes in the mitogen-activated protein kinase (MAPK) pathway. Based on these findings, we investigated a cohort of 21 RDD patients and found that the lesional histiocytes in 86% (18/21) of patients exhibited strong and diffuse nuclear Cyclin D1 expression, which not only may provide a diagnostic marker for this sometimes pathologically challenging disease, but also probably reflects constitutive MAPK pathway activation because we additionally identified phosphorylated-ERK expression in 90% (19/21) of cases.

Histologic, immunohistochemical, and molecular features of pituicytomas and atypical pituicytomas.

Pituicytoma is a rare, poorly characterized tumor of the sellar region that is thought to be derived from neurohypophyseal pituicytes. Resection of pituicytomas is often associated with significant morbidity including diabetes insipidus and panhypopituitarism. Most of the literature on this tumor exists as small case series or case reports.

Thyroid-Like Follicular Carcinoma of the Kidney With Extensive Sarcomatoid Differentiation: A Case Report and Review of the Literature.

Thyroid-like follicular carcinoma of the kidney (TLFCK) is an extremely rare primary renal malignancy that typically has an indolent course and good prognosis. Histologically, this tumor mimics follicular carcinoma of the thyroid; however, typical thyroid markers are negative. There are fewer than 40 cases reported in the literature, and thus, the prognosis and course of disease is not well understood.

Development and Validation of Molecular Assays for Limited Tissue Samples.

As the value of molecular testing of cancer specimens increases, the number of tests imposed on tumor specimens also increases, often in tension with the amount of tumor material available. To develop and validate molecular assays for limited specimens, there are specific concerns that must be addressed, including DNA quality, quantity, and abundance; the number of targets/ability to multiplex; and the analytical sensitivity and specificity of the assay itself. Ultimately, weighing these considerations during assay validation in the overall context of clinical utility and laboratory workflow is critical for delivering the highest level of personalized care to patients.

Validation of a next-generation sequencing oncology panel optimized for low input DNA.

One caveat of next-generation sequencing (NGS)-based clinical oncology testing is the high amount of input DNA required. We sought to develop a focused NGS panel that could capture hotspot regions in relevant genes requiring 0.5-10 ng input DNA.

Expression of Insulinoma-Associated Protein 1 (INSM1) and Orthopedia Homeobox (OTP) in Tumors with Neuroendocrine Differentiation at Rare Sites.

Insulinoma-associated protein 1 (INSM1) and orthopedia homeobox (OTP) are transcription factors that play a critical role in neuroendocrine (NE) and neuroepithelial cell development. INSM1 has been identified in multiple tumors of NE or neuroepithelial origin, whereas OTP expression has been mainly studied in NE tumors of pulmonary origin. Expression of OTP appears to correlate with poorer prognosis in pulmonary carcinoids; however, its expression patterns in other NE/neuroepithelial tumors need further investigation.

SETD2 mutations in primary central nervous system tumors.

Mutations in SETD2 are found in many tumors, including central nervous system (CNS) tumors. Previous work has shown these mutations occur specifically in high grade gliomas of the cerebral hemispheres in pediatric and young adult patients. We investigated SETD2 mutations in a cohort of approximately 640 CNS tumors via next generation sequencing; 23 mutations were detected across 19 primary CNS tumors.

Genomic heterogeneity of ALK fusion breakpoints in non-small-cell lung cancer.

In lung adenocarcinoma, canonical EML4-ALK inversion results in a fusion protein with a constitutively active ALK kinase domain. Evidence of ALK rearrangement occurs in a minority (2-7%) of lung adenocarcinoma, and only ~60% of these patients will respond to targeted ALK inhibition by drugs such as crizotinib and ceritinib. Clinically, targeted anti-ALK therapy is often initiated based on evidence of an ALK genomic rearrangement detected by fluorescence in situ hybridization (FISH) of interphase cells in formalin-fixed, paraffin-embedded tissue sections.

Insulinoma-associated 1: A novel nuclear marker in Merkel cell carcinoma (cutaneous neuroendocrine carcinoma).

Merkel cell carcinoma (MCC) is a rare, clinically aggressive, cutaneous neuroendocrine (NE) neoplasm. As a tumor with small, round, blue cells, the histologic differential diagnosis for MCC can include melanoma, metastatic small cell carcinoma (SCC), nodular hematopoietic tumors, basal cell carcinoma (BCC), atypical variants of squamous carcinoma and the uncommon occurrence of primary cutaneous Ewing sarcoma. In cases with atypical histology or without the classic immunophenotype, the diagnosis can be challenging.

The Evolving Role of Companion Diagnostics for Breast Cancer in an Era of Next-Generation Omics.

A companion diagnostic is a test for a specific biomarker-approved by the United States Food and Drug Administration-qualifying a patient to receive a specific, associated therapy. As interest has grown in precision medicine over the past decade, the principle of companion diagnostics has gained increasing purchase among laboratory professionals, clinicians, regulators, and even patients. The evolution of the biomarkers used to stratify and treat breast cancer illustrates the history of companion diagnostics and provides a lens through which to examine potential challenges.

INSM1: A Novel Immunohistochemical and Molecular Marker for Neuroendocrine and Neuroepithelial Neoplasms.

Objectives: Neuroendocrine neoplasms (NENs) are heterogeneous neoplasms, which are sometimes malignant, although predicting metastasis is difficult. INSM1 is a transcription factor expressed transiently in embryonic neuroendocrine (NE) tissue, thought to coordinate termination of cell division with differentiation of NE and neuroepithelial cells. In adult tissues, INSM1 has been identified in multiple tumors of NE or neuroepithelial origin but has not been thoroughly investigated as a potential neoplastic marker.

Pleuroparenchymal fibroelastosis: a pattern of chronic lung injury.

Pleuroparenchymal fibroelastosis (PPFE) is a rare condition currently described as an upper lobe subpleural and interstitial proliferation of predominantly elastic fibers. The etiology is unknown, and no specific diagnostic criteria have been reported. Here we report 5 cases of PPFE, 1 man and 4 women, 3 of them diagnosed at the time autopsy, 1 diagnosed in an explanted lung, and 1 diagnosed on a surgical wedge biopsy.