Fu DJ, Miller AD, Southard TL
… +3 more, Flesken-Nikitin A, Ellenson LH, Nikitin AY
Annu Rev Pathol
· 2018 Jan · PMID 29059010
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Rapid advances in stem cell biology and regenerative medicine have opened new opportunities for better understanding disease pathogenesis and the development of new diagnostic, prognostic, and treatment approaches. Many...Rapid advances in stem cell biology and regenerative medicine have opened new opportunities for better understanding disease pathogenesis and the development of new diagnostic, prognostic, and treatment approaches. Many stem cell niches are well defined anatomically, thereby allowing their routine pathological evaluation during disease initiation and progression. Evaluation of the consequences of genetic manipulations in stem cells and investigation of the roles of stem cells in regenerative medicine and pathogenesis of various diseases such as cancer require significant expertise in pathology for accurate interpretation of novel findings. Therefore, there is an urgent need for developing stem cell pathology as a discipline to facilitate stem cell research and regenerative medicine. This review provides examples of anatomically defined niches suitable for evaluation by diagnostic pathologists, describes neoplastic lesions associated with them, and discusses further directions of stem cell pathology.
Annu Rev Pathol
· 2018 Jan · PMID 28934563
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Hemophagocytic lymphohistiocytosis is a life-threatening disorder characterized by unbridled activation of cytotoxic T lymphocytes, natural killer (NK) cells, and macrophages resulting in hypercytokinemia and immune-medi...Hemophagocytic lymphohistiocytosis is a life-threatening disorder characterized by unbridled activation of cytotoxic T lymphocytes, natural killer (NK) cells, and macrophages resulting in hypercytokinemia and immune-mediated injury of multiple organ systems. It is seen in both children and adults and is recognized as primary (driven by underlying genetic mutations that abolish critical proteins required for normal function of cytotoxic T cells and NK cells) or secondary (resulting from a malignant, infectious, or autoimmune stimulus without an identifiable underlying genetic trigger). Clinical and laboratory manifestations include fever, splenomegaly, neurologic dysfunction, coagulopathy, liver dysfunction, cytopenias, hypertriglyceridemia, hyperferritinemia, hemophagocytosis, and diminished NK cell activity. It is treated with immune suppressants, etoposide, and allogeneic hematopoietic stem cell transplantation; more than 50% of children who undergo transplant survive, but adults have quite poor outcomes even with aggressive management. Newer agents directed at subduing the uncontrolled immune response in a targeted fashion offer promise in this highly morbid disease.
Annu Rev Pathol
· 2017 Jan · PMID 28135565
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Neurofibromatosis type 1 (NF1) is a common neurogenetic disorder in which affected children and adults are predisposed to the development of benign and malignant nervous system tumors. Caused by a germline mutation in th...Neurofibromatosis type 1 (NF1) is a common neurogenetic disorder in which affected children and adults are predisposed to the development of benign and malignant nervous system tumors. Caused by a germline mutation in the NF1 tumor suppressor gene, individuals with NF1 are prone to optic gliomas, malignant gliomas, neurofibromas, and malignant peripheral nerve sheath tumors, as well as behavioral, cognitive, motor, bone, cardiac, and pigmentary abnormalities. Although NF1 is a classic monogenic syndrome, the clinical features of the disorder and their impact on patient morbidity are variable, even within individuals who bear the same germline NF1 gene mutation. As such, NF1 affords unique opportunities to define the factors that contribute to disease heterogeneity and to develop therapies personalized to a given individual (precision medicine). This review highlights the clinical features of NF1 and the use of genetically engineered mouse models to define the molecular and cellular pathogenesis of NF1-associated nervous system tumors.
Annu Rev Pathol
· 2017 Jan · PMID 28135564
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Astrocytes undergo important phenotypic changes in many neurological disorders, including strokes, trauma, inflammatory diseases, infectious diseases, and neurodegenerative diseases. We have been studying the astrocytes...Astrocytes undergo important phenotypic changes in many neurological disorders, including strokes, trauma, inflammatory diseases, infectious diseases, and neurodegenerative diseases. We have been studying the astrocytes of Alexander disease (AxD), which is caused by heterozygous mutations in the GFAP gene, which is the gene that encodes the major astrocyte intermediate filament protein. AxD is a primary astrocyte disease because GFAP expression is specific to astrocytes in the central nervous system (CNS). The accumulation of extremely large amounts of GFAP causes many molecular changes in astrocytes, including proteasome inhibition, stress kinase activation, mechanistic target of rapamycin (mTOR) activation, loss of glutamate and potassium buffering capacity, loss of astrocyte coupling, and changes in cell morphology. Many of these changes appear to be common to astrocyte reactions in other neurological disorders. Using AxD to illuminate common mechanisms, we discuss the molecular pathology of AxD astrocytes and compare that to astrocyte pathology in other disorders.
Annu Rev Pathol
· 2017 Jan · PMID 28135563
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Systemic mastocytosis is a clonal disorder of mast cells that may variably present with characteristic skin lesions, episodes of mast cell mediator release, and disturbances of hematopoiesis. No curative therapy presentl...Systemic mastocytosis is a clonal disorder of mast cells that may variably present with characteristic skin lesions, episodes of mast cell mediator release, and disturbances of hematopoiesis. No curative therapy presently exists. Conventional management has relied on agents that antagonize mediators released by mast cells, inhibit mediator secretion, or modulate mast cell proliferation. Recent advances in the molecular understanding of the pathophysiology of systemic mastocytosis have provided new therapeutic considerations, including new and novel tyrosine kinase inhibitors.
Thiele JA, Bethel K, Králíčková M
… +1 more, Kuhn P
Annu Rev Pathol
· 2017 Jan · PMID 28135562
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Evaluation of circulating tumor cells (CTCs) has demonstrated clinical validity as a prognostic tool based on enumeration, but since the introduction of this tool to the clinic in 2004, further clinical utility and wides...Evaluation of circulating tumor cells (CTCs) has demonstrated clinical validity as a prognostic tool based on enumeration, but since the introduction of this tool to the clinic in 2004, further clinical utility and widespread adoption have been limited. However, immense efforts have been undertaken to further the understanding of the mechanisms behind the biology and kinetics of these rare cells, and progress continues toward better applicability in the clinic. This review describes recent advances within the field, with a particular focus on understanding the biological significance of CTCs, and summarizes emerging methods for identifying, isolating, and interrogating the cells that may provide technical advantages allowing for the discovery of more specific clinical applications. Included is an atlas of high-definition images of CTCs from various cancer types, including uncommon CTCs captured only by broadly inclusive nonenrichment techniques.
Annu Rev Pathol
· 2017 Jan · PMID 28135561
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Focal cortical dysplasias (FCDs) are malformations of cortical development (MCDs) that are highly associated with medication-resistant epilepsy and are the most common cause of neocortical epilepsy in children. FCDs are...Focal cortical dysplasias (FCDs) are malformations of cortical development (MCDs) that are highly associated with medication-resistant epilepsy and are the most common cause of neocortical epilepsy in children. FCDs are a heterogeneous group of developmental disorders caused by germline or somatic mutations that occur in genes regulating the PI3K/Akt/mTOR pathway-a key pathway in neuronal growth and migration. Accordingly, FCDs are characterized by abnormal cortical lamination, cell morphology (e.g., cytomegaly), and cellular polarity. In some FCD subtypes, balloon cells express proteins typically seen in neuroglial progenitor cells. Because recurrent intractable seizures are a common feature of FCDs, epileptogenic electrophysiological properties are also observed in addition to local inflammation. Here, we will summarize the current literature regarding FCDs, addressing the current classification system, histopathology, molecular genetics, electrophysiology, and transcriptome and cell signaling changes.
Annu Rev Pathol
· 2017 Jan · PMID 28135560
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Hydatidiform moles are intriguing pathologic entities representing abnormal placental villous tissue with unique genetic profiles and a wide spectrum of morphologic features, which makes accurate diagnosis challenging. O...Hydatidiform moles are intriguing pathologic entities representing abnormal placental villous tissue with unique genetic profiles and a wide spectrum of morphologic features, which makes accurate diagnosis challenging. Overrepresentation of the paternal genome in sporadic hydatidiform moles (purely androgenetic in complete hydatidiform moles and diandric triploid in partial hydatidiform moles) is a fundamental genetic event leading to global alteration of imprinting gene expression in the molar trophoblast. Rare familial biparental hydatidiform moles (due to NLRP7 or KHDC3L mutations) share such global imprinting alterations, implying a common end point of pathogenesis. Despite being the cornerstone of diagnosis, routine morphologic assessment of hydatidiform moles continues to suffer from interobserver diagnostic variability, emphasizing the need for new diagnostic modalities. Analyses of p57 expression by immunohistochemistry and polymerase chain reaction-based DNA genotyping have emerged as powerful diagnostic methods for accurate classification of hydatidiform moles. Algorithmic approaches combining histology and these ancillary techniques provide the best diagnostic practice currently available.
Annu Rev Pathol
· 2017 Jan · PMID 28068483
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Fungi are ubiquitous in our environment, and a healthy immune system is essential to maintain adequate protection from fungal infections. When this protection breaks down, superficial and invasive fungal infections cause...Fungi are ubiquitous in our environment, and a healthy immune system is essential to maintain adequate protection from fungal infections. When this protection breaks down, superficial and invasive fungal infections cause diseases that range from irritating to life-threatening. Millions of people worldwide develop invasive infections during their lives, and mortality for these infections often exceeds 50%. Nevertheless, we are normally colonized with many of the same disease-causing fungi (e.g., on the skin or in the gut). Recent research is dramatically expanding our understanding of the mechanisms by which our immune systems interact with these organisms in health and disease. In this review, we discuss what is currently known about where and how the immune system interacts with common fungi.
Annu Rev Pathol
· 2017 Jan · PMID 28068482
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Next-generation sequencing has substantially enhanced our understanding of the genetics of primary brain tumors by uncovering several novel driver genetic alterations. How many of these genetic modifications contribute t...Next-generation sequencing has substantially enhanced our understanding of the genetics of primary brain tumors by uncovering several novel driver genetic alterations. How many of these genetic modifications contribute to the pathogenesis of brain tumors is not well understood. An exciting paradigm emerging in cancer biology is that oncogenes actively reprogram cellular metabolism to enable tumors to survive and proliferate. We discuss how some of these genetic alterations in brain tumors rewire metabolism. Furthermore, metabolic alterations directly impact epigenetics well beyond classical mechanisms of tumor pathogenesis. Metabolic reprogramming in brain tumors is also influenced by the tumor microenvironment contributing to drug resistance and tumor recurrence. Altered cancer metabolism can be leveraged to noninvasively image brain tumors, which facilitates improved diagnosis and the evaluation of treatment effectiveness. Many of these aspects of altered metabolism provide novel therapeutic opportunities to effectively treat primary brain tumors.
Annu Rev Pathol
· 2017 Jan · PMID 27959637
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Chronic rhinosinusitis (CRS) is a troublesome, chronic inflammatory disease that affects over 10% of the adult population, causing decreased quality of life, lost productivity, and lost time at work and leading to more t...Chronic rhinosinusitis (CRS) is a troublesome, chronic inflammatory disease that affects over 10% of the adult population, causing decreased quality of life, lost productivity, and lost time at work and leading to more than a million surgical interventions annually worldwide. The nose, paranasal sinuses, and associated lymphoid tissues play important roles in homeostasis and immunity, and CRS significantly impairs these normal functions. Pathogenic mechanisms of CRS have recently become the focus of intense investigations worldwide, and significant progress has been made. The two main forms of CRS that have been long recognized, with and without nasal polyps, are each now known to be heterogeneous, based on underlying mechanism, geographical location, and race. Loss of the immune barrier, including increased permeability of mucosal epithelium and reduced production of important antimicrobial substances and responses, is a common feature of many forms of CRS. One form of CRS with polyps found worldwide is driven by the cytokines IL-5 and IL-13 coming from Th2 cells, type 2 innate lymphoid cells, and probably mast cells. Type 2 cytokines activate inflammatory cells that are implicated in the pathogenic mechanism, including mast cells, basophils, and eosinophils. New classes of biological drugs that block the production or action of these cytokines are making important inroads toward new treatment paradigms in polypoid CRS.
Annu Rev Pathol
· 2017 Jan · PMID 27959636
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Amyloidoses are a spectrum of disorders caused by abnormal folding and extracellular deposition of proteins. The deposits lead to tissue damage and organ dysfunction, particularly in the heart, kidneys, and nerves. There...Amyloidoses are a spectrum of disorders caused by abnormal folding and extracellular deposition of proteins. The deposits lead to tissue damage and organ dysfunction, particularly in the heart, kidneys, and nerves. There are at least 30 different proteins that can cause amyloidosis. The clinical management depends entirely on the type of protein deposited, and thus on the underlying pathogenesis, and often requires high-risk therapeutic intervention. Application of mass spectrometry-based proteomic technologies for analysis of amyloid plaques has transformed the way amyloidosis is diagnosed and classified. Proteomic assays have been extensively used for clinical management of patients with amyloidosis, providing unprecedented diagnostic and biological information. They have shed light on the pathogenesis of different amyloid types and have led to identification of numerous new amyloid types, including ALECT2 amyloidosis, which is now recognized as one of the most common causes of systemic amyloidosis in North America.
Annu Rev Pathol
· 2017 Jan · PMID 27959635
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Notch receptors influence cellular behavior by participating in a seemingly simple signaling pathway, but outcomes produced by Notch signaling are remarkably varied depending on signal dose and cell context. Here, after...Notch receptors influence cellular behavior by participating in a seemingly simple signaling pathway, but outcomes produced by Notch signaling are remarkably varied depending on signal dose and cell context. Here, after briefly reviewing new insights into physiologic mechanisms of Notch signaling in healthy tissues and defects in Notch signaling that contribute to congenital disorders and viral infection, we discuss the varied roles of Notch in cancer, focusing on cell autonomous activities that may be either oncogenic or tumor suppressive.
Annu Rev Pathol
· 2017 Jan · PMID 27959634
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Established infectious agents continue to be a major cause of human morbidity and mortality worldwide. However, the causative agent remains unknown for a wide range of diseases; many of these are suspected to be attribut...Established infectious agents continue to be a major cause of human morbidity and mortality worldwide. However, the causative agent remains unknown for a wide range of diseases; many of these are suspected to be attributable to yet undiscovered microorganisms. The advent of unbiased high-throughput sequencing and bioinformatics has enabled rapid identification and molecular characterization of known and novel infectious agents in human disease. An exciting era of microbe discovery, now under way, holds great promise for the improvement of global health via the development of antimicrobial therapies, vaccination strategies, targeted public health measures, and probiotic-based preventions and therapies. Here, we review the history of pathogen discovery, discuss improvements and clinical applications for the detection of microbially associated diseases, and explore the challenges and strategies for establishing causation in human disease.
Annu Rev Pathol
· 2017 Jan · PMID 27959633
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Engineered T cells are currently in clinical trials to treat patients with cancer, solid organ transplants, and autoimmune diseases. However, the field is still in its infancy. The design, and manufacturing, of T cell th...Engineered T cells are currently in clinical trials to treat patients with cancer, solid organ transplants, and autoimmune diseases. However, the field is still in its infancy. The design, and manufacturing, of T cell therapies is not standardized and is performed mostly in academic settings by competing groups. Reliable methods to define dose and pharmacokinetics of T cell therapies need to be developed. As of mid-2016, there are no US Food and Drug Administration (FDA)-approved T cell therapeutics on the market, and FDA regulations are only slowly adapting to the new technologies. Further development of engineered T cell therapies requires advances in immunology, synthetic biology, manufacturing processes, and government regulation. In this review, we outline some of these challenges and discuss the contributions that pathologists can make to this emerging field.
Annu Rev Pathol
· 2017 Jan · PMID 27959632
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Liver cancer is the second leading cause of cancer mortality worldwide, causing more than 700,000 deaths annually. Because of the wide landscape of genomic alterations and limited therapeutic success of targeting tumor c...Liver cancer is the second leading cause of cancer mortality worldwide, causing more than 700,000 deaths annually. Because of the wide landscape of genomic alterations and limited therapeutic success of targeting tumor cells, a recent focus has been on better understanding and possibly targeting the microenvironment in which liver tumors develop. A unique feature of liver cancer is its close association with liver fibrosis. More than 80% of hepatocellular carcinomas (HCCs) develop in fibrotic or cirrhotic livers, suggesting an important role of liver fibrosis in the premalignant environment (PME) of the liver. Cholangiocarcinoma (CCA), in contrast, is characterized by a strong desmoplasia that typically occurs in response to the tumor, suggesting a key role of cancer-associated fibroblasts (CAFs) and fibrosis in its tumor microenvironment (TME). Here, we discuss the functional contributions of myofibroblasts, CAFs, and fibrosis to the development of HCC and CCA in the hepatic PME and TME, focusing on myofibroblast- and extracellular matrix-associated growth factors, fibrosis-associated immunosuppressive pathways, as well as mechanosensitive signaling cascades that are activated by increased tissue stiffness. Better understanding of the role of myofibroblasts in HCC and CCA development and progression may provide the basis to target these cells for tumor prevention or therapy.
Annu Rev Pathol
· 2017 Jan · PMID 27959631
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This review reflects the trajectory of my career in hematopathology, and my personal reflections on scientific advances in the field. During the course of more than 40 years, the approach to classification of hematologic...This review reflects the trajectory of my career in hematopathology, and my personal reflections on scientific advances in the field. During the course of more than 40 years, the approach to classification of hematological malignancies has evolved from descriptive approaches, based on either cytological or clinical features, to a modern approach, which incorporates cutting-edge technologies. My philosophy has focused on defining individual diseases, an approach that can best lead to an understanding of molecular pathogenesis. To quote Carolus Linnaeus ( 1 , p. 19), the father of taxonomy, "The first step in wisdom is to know the things themselves; this notion consists in having a true idea of the objects; objects are distinguished and known by classifying them methodically and giving them appropriate names. Therefore, classification and name-giving will be the foundation of our science."
Annu Rev Pathol
· 2017 Jan · PMID 27959630
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Necroptosis is a form of regulated cell death that critically depends on receptor-interacting serine-threonine kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL) and generally manifests with morphological featu...Necroptosis is a form of regulated cell death that critically depends on receptor-interacting serine-threonine kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL) and generally manifests with morphological features of necrosis. The molecular mechanisms that underlie distinct instances of necroptosis have just begun to emerge. Nonetheless, it has already been shown that necroptosis contributes to cellular demise in various pathophysiological conditions, including viral infection, acute kidney injury, and cardiac ischemia/reperfusion. Moreover, human tumors appear to obtain an advantage from the downregulation of key components of the molecular machinery for necroptosis. Although such an advantage may stem from an increased resistance to adverse microenvironmental conditions, accumulating evidence indicates that necroptosis-deficient cancer cells are poorly immunogenic and hence escape natural and therapy-elicited immunosurveillance. Here, we discuss the molecular mechanisms and relevance to disease of necroptosis.
Annu Rev Pathol
· 2017 Jan · PMID 27959629
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The vertebrate complement system consists of sequentially interacting proteins that provide for a rapid and powerful host defense. Nearly 60 proteins comprise three activation pathways (classical, alternative, and lectin...The vertebrate complement system consists of sequentially interacting proteins that provide for a rapid and powerful host defense. Nearly 60 proteins comprise three activation pathways (classical, alternative, and lectin) and a terminal cytolytic pathway common to all. Attesting to its potency, nearly half of the system's components are engaged in its regulation. An emerging theme over the past decade is that variations in these inhibitors predispose to two scourges of modern humans. One, occurring most often in childhood, is a rare but deadly thrombomicroangiopathy called atypical hemolytic uremic syndrome. The other, age-related macular degeneration, is the most common form of blindness in the elderly. Their seemingly unrelated clinical presentations and pathologies share the common theme of overactivity of the complement system's alternative pathway. This review summarizes insights gained from contemporary genetics for understanding how dysregulation of this powerful innate immune system leads to these human diseases.
Annu Rev Pathol
· 2017 Jan · PMID 27959628
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Melanoma is a complex and genomically diverse malignancy, and new genes and signaling pathways involved in pathogenesis continue to be discovered. Mechanistic insights into gene and immune regulation in melanoma have led...Melanoma is a complex and genomically diverse malignancy, and new genes and signaling pathways involved in pathogenesis continue to be discovered. Mechanistic insights into gene and immune regulation in melanoma have led to the development of numerous successful and innovative pharmacologic agents over recent years. Multiple targeted therapies and immunotherapies have already entered the clinic, becoming new standards of care and transforming the prognosis for many patients with malignant melanoma. In this review, we provide an overview of the current understanding of signaling and immune regulation in melanoma and implications for responses to treatment, organized in the framework of hallmark characteristics in cancer.