Well-defined Disease Entities Research Articles

Genomics Driving Diagnosis and Treatment of Inborn Errors of Immunity With Cancer Predisposition

Inborn errors of immunity (IEI) are genetically and clinically heterogeneous disorders that, in addition to infection susceptibility and immune dysregulation, can have an enhanced cancer predisposition. The increasing availability of upfront next-generation sequencing diagnostics in immunology and oncology have uncovered substantial overlap of germline and somatic genetic conditions that can result in immunodeficiency and cancer. However, broad application of unbiased genetics in these neighboring disciplines still needs to be deployed, and joined therapeutic strategies guided by germline and somatic genetic risk factors are lacking. We illustrate the current difficulties encountered in clinical practice, summarize the historical development of pathophysiological concepts of cancer predisposition, and review select genetic, molecular, and cellular mechanisms of well-defined and illustrative disease entities such as DNA repair defects, combined immunodeficiencies with Epstein-Barr virus susceptibility, autoimmune lymphoproliferative syndromes, regulatory T-cell disorders, and defects in cell intrinsic immunity. We review genetic variants that, when present in the germline, cause IEI with cancer predisposition but, when arising as somatic variants, behave as oncogenes and cause specific cancer entities. We finally give examples of small molecular compounds that are developed and studied to target genetically defined cancers but might also proof useful to treat IEI.

EORTC Classification for Primary Cutaneous Lymphomas: A Proposal From the Cutaneous Lymphoma Study Group of the European Organization for Research and Treatment of Cancer

AbstractPrimary cutaneous lymphomas represent a heterogeneous group of T- and B-cell lymphomas that show considerable variation in histology, phenotype, and prognosis. Recently, the European Organization for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Project Group has reached consensus on a new classification for this group of diseases. The EORTC classification for primary cutaneous lymphomas is based on a combination of clinical, histologic, and immunophenotypic criteria, and thus contains well-defined disease entities rather than histologic subgroups. In addition, this new classification contains a number of provisional entities, which may display characteristic histologic features, but are not yet well defined clinically. These provisional entities account for less than 5% of all primary cutaneous lymphomas. In this report the basic principles of this new classification, as well as the characteristic features of the different disease entities, are described. In addition, survival data of 626 patients with primary cutaneous lymphomas derived from the registry of the Dutch Cutaneous Lymphoma Working Group, illustrating the clinical validity of this new classification, are presented.

Diagnosing Alzheimer’s disease in Kraepelin’s clinic, 1909–1912

Existing accounts of the early history of Alzheimer’s disease have focused on Alois Alzheimer’s (1864–1915) publications of two ‘peculiar cases’ of middle-aged patients who showed symptoms associated with senile dementia, and Emil Kraepelin’s (1856–1926) discussion of these and a few other cases under the newly introduced name of ‘Alzheimer’s disease’ in his Textbook of Psychiatry. This article questions the underpinnings of these accounts that rely mainly on publications and describe ‘presenility’ as a defining characteristic of the disease. Drawing on archival research in the Munich psychiatric clinic, in which Alzheimer and Kraepelin practised, this article looks at the use of the category as a diagnostic label in practice. It argues that the first cases only got their exemplary status as key referents of Alzheimer’s disease in later readings of the original publications. In the 1900s, the published cases rather functioned as material to think about the limits of the category of senile dementia. The examination of paper technologies in the Munich psychiatric clinic reveals that the use of the clinical diagnosis of Alzheimer’s disease was not limited to patients of a certain age and did not exclude ‘senile’ cases. Moreover, the archival records reflect that many diagnoses of Alzheimer’s disease were noted in the medical records as suspicions rather than conclusions. Against this background, the article argues that in theory and practice, Alzheimer’s disease was not treated as a well-defined disease entity in the Munich clinic, but as an exploratory category for the clinical and histopathological investigation of varieties of organic brain diseases.

Adhesive capsulitis of the hip.

Adhesive capsulitis of the hip (ACH) is not a well-defined disease entity. We evaluated the change in the clinical features of patients whose chief complaint was inability to sit cross-legged on the floor. All patients had painful limitation in hip joint motion. Based on the diagnosis of ACH, active stretching exercise (ASE) was recommended. In February 2013 and June 2014, a total of 44 patients (50 hips), who visited outpatient clinic in 2011, were evaluated by telephone interviews. Recovery of hip motion was analyzed according to compliance with ASE and abnormalities found on plane radiographs and magnetic resonance (MR) images. There were 27 women and 17 men with mean age of 51.7 years. In the first telephone interview, 40 patients (45 hips) reported improvement in hip motion but 4 patients (5 hips) reported absolutely no improvement. Compliance with ASE did not affect recovery of motion ( p = 0.225). On plain radiographs, 10 patients (22.7%) had abnormal finding in both hips. Those abnormal findings were not correlated with symptom and did not show adverse effect on motion recovery. Sixteen patients took MR images outside, and abnormal findings such as round ligament or labral tear were observed in nine patients. Those abnormal findings neither correlated with the symptom nor affected motion recovery adversely. In the second telephone interview, nine hips of further improvement and two hips of recurrence were identified. Most cases showed improvement in the range of motion with or without ASE. Surgical treatments including arthroscopy seemed to be unnecessary for these patients.

Absceso y tuberculosis pulmonar

Si la tuberculosis pulmonar es conocida desde los tiempos más remotos y el absceso del pulmón es considerado, desde el siglo XIX, como una entidad patológica perfectamente definida, es evidente que la asociación absceso y tuberculosis pulmonar no tiene su verdadera expresión de estudio, sino en los últimos años.

Emerging trends in acquired neonatal intestinal disease: is it time to abandon Bell's criteria?

In the last decade, it has become increasingly clear that necrotizing enterocolitis (NEC) is neither a uniform nor a well-defined disease entity. There are many factors that are forcing this unwelcome realization upon the neonatal and pediatric surgery communities. In the course of this manuscript we will review the history and the physical findings of the disparate etiologies of acquired neonatal intestinal diseases (ANIDs), some which do lead to the common final pathology of NEC and some which do not. New guidelines for distinguishing between ANIDs will also be suggested.

Central vestibular disorders

Dizziness or vertigo is an erroneous perception of selfmotion or object-motion as well as an unpleasant distortion of static gravitational orientation. It is caused by a mismatch between the vestibular, visual, and somatosensory systems. Thanks to their functional overlap, the three systems are able to compensate, in part, for each other's deficiencies. Thus, vertigo is not a well-defined disease entity, but rather a multisensory syndrome that results when there is a pathological dysfunction of any of the stabilizing sensory systems (e.g., central vestibular disorders, peripheral vestibular diseases with asymmetric input into the vestibular nuclei). This article provides an overview of the most important and frequent forms of central vestibular vertigo syndromes, including basilar/vestibular migraine, which are characterized by ocular motor, postural, and perceptual signs. In a simple clinical classification they can be separated according to the three major planes of action of the vestibulo-ocular reflex: yaw, roll, and pitch. A tonic imbalance in yaw is characterized by horizontal nystagmus, lateropulsion of the eyes, past-pointing, rotational and lateral body falls, and lateral deviation of the perceived straight-ahead. A tonic imbalance in roll is defined by torsional nystagmus, skew deviation, ocular torsion, tilts of head, body, and the perceived vertical. Finally, a tonic imbalance in pitch can be characterized by some forms of upbeat or downbeat nystagmus, fore-aft tilts and falls, and vertical deviation of the perceived straight ahead. The thus defined syndromes allow for a precise topographic diagnosis as regards their level and side.

Adjacent Segment Disease in the Cervical Spine: Review of Current Knowledge

Cervical disc disease is a common, well-defined disease entity responsible for axial neck pain, radiculopathy and, rarely, myelopathy. Often, the standard of care for those patients refractory to medical management is anterior cervical discectomy and fusion. The success of this operation is well documented. One of the purported long-term complications of this procedure is adjacent segment disease (ASD), also known as transitional syndrome. The mechanism of and, indeed, even the casual relationship between spine fusion and ASD is actively debated. Despite this debate, surgical procedures have been developed to ameliorate or avoid this complication. These motion-preserving procedures are postulated to curb ASD to the extent that this problem is related to a change in biomechanics of the fused cervical spine. They would not be expected to alter the natural history of the aging cervical disc. Therefore, the purpose of this article is to review our current understanding of adjacent segment disease in the cervical spine as it relates to the natural history of spondylosis, fusion, and motion-preserving procedures.

A journey of hope: lessons learned from studies on rare diseases and orphan drugs

Rare diseases are frequently life-threatening or chronically debilitating and the impact on the quality of life of affected patients and their family members is thus significant. However, drug development for these conditions has been limited by a lack of understanding of the underlying mechanisms of disease and the relative unavailability of subjects for clinical trials, as well as the prohibitive cost of investing in a novel pharmaceutical agent with poor market potential. Nevertheless, the introduction of Orphan Drug legislations has provided important incentives for the development of orphan drugs (i.e. drugs that have been abandoned or 'orphaned' by major drug companies). Moreover, recent studies on rare diseases, including inherited immunodeficiencies and metabolic disorders, have served not only to alleviate the plight of patients with rare diseases, but also yielded valuable information on biological processes of relevance for other, more common conditions. These lessons, along with the crucial importance of cooperation between academic institutions, pharmaceutical companies, patient advocacy groups and society in the elucidation of rare diseases, are highlighted in the present review.

Dizziness.

The article gives an overview of the most frequent forms of vertigo, that are of peripheral-labyrinthine, central-vestibular, psychogenic, or physiologic origin. Dizziness or vertigo is a result of a mismatch between 3 sensory systems: the vestibular, the visual, and the somatosensory systems. These systems are mutually interactive and redundant in that orientation and balance are guided by simultaneous reafferent cues. The functional ranges of the systems overlap, thus permitting them to compensate in part for each other's deficiencies. Vertigo is not a well-defined disease entity, but rather a multisensory syndrome induced either by stimulation of the intact sensorimotor system by motion (eg, physiologic vertigo as in motion sickness or height vertigo), or by pathologic dysfunction of any of the stabilizing sensory systems (eg, peripheral vestibular as in vestibular neuritis, or central vestibular as in vertebro-basilar ischemia). The core region in vestibular vertigo syndromes is the vestibulo-ocular reflex, a 3-neuron arc that mediates the information of the semicircular canals and otoliths via the vestibular nerve and vestibular nucleus to the ocular motor nuclei (VI, IV, III) and the supranuclear integration centers in the ponto-mesencephalic brain stem. Clinical phenomena characteristic for physiological and pathologic vertigo syndromes include postural, perceptual, oculomotor, and vegetative syndromes, which manifest with ataxia, nystagmus, vertigo, and nausea. Thus, the clinical testing must include examinations of postural, perceptual, oculomotor, and vegetative dysfunctions.

Cutaneous lymphomas other than mycosis fungoides in Singapore: a clinicopathological analysis using recent classification systems

Cutaneous lymphomas other than mycosis fungoides (MF) are a heterogeneous group with wide variations in clinical presentation, biological behaviour and prognosis. New classification systems have been designed or proposed in recent years, with well-defined disease entities and emphasis on the importance of site. This study aims to analyse a series of non-MF lymphomas in an institution-based dermatological setting in Singapore, based on the European Organization for Research and Treatment of Cancer (EORTC) classification and the World Health Organization (WHO) classification. A secondary objective is to highlight the clinical utility of both classification systems. Forty cases diagnosed over a 12-year period were examined by immunohistochemistry with antibodies targeting CD3, CD4, CD5, CD8, CD20, CD30, CD43, CD45RO, CD56 and CD68 in paraffin-embedded specimens. The immunohistological diagnosis was correlated with the clinical presentation and staging investigations for the final diagnosis and the course of disease recorded. Non-MF T-cell lymphomas presenting in the skin comprised 31 cases (78%) and were 3(1/2) times more common than B-cell lymphomas, which comprised nine cases (22%). The common subtypes were lymphomatoid papulosis, CD30+ large cell cutaneous T-cell lymphoma and subcutaneous panniculitis-like T-cell lymphoma. The commonly ascribed B-cell pattern with infiltrates in the mid and deep dermis and perivascular spaces was seen in 60% of T-cell lymphomas. Overall, there were equal numbers of primary cutaneous T-cell lymphomas and those due to concurrent or secondary cutaneous lymphoma. Five of six cases of subcutaneous panniculitis-like T-cell lymphoma had concurrent cutaneous and systemic involvement and their median survival was 7 months. The predominance of cutaneous T-cell lymphomas in this case series closely matched that reported from east Asia; cutaneous B-cell lymphomas are much less common than in Europe. The EORTC classification, which is designed only for primary cutaneous lymphomas, should be used in conjunction with the WHO classification because of the high prevalence of cutaneous lymphomas as the secondary site of disease from systemic lymphoma. In addition, subcutaneous panniculitis-like T-cell lymphoma is a primary cutaneous lymphoma where systemic involvement is common at initial presentation. We propose full immunophenotyping and complete clinical evaluation with staging investigations for all patients presenting with cutaneous lymphomas other than MF.

Helping to understand studies examining genetic susceptibility to sepsis

Helping to understand studies examining genetic susceptibility to sepsis

Classification of cell lineage and anatomical site, and prognosis of extranodal T-cell lymphoma -- natural killer cell, cytotoxic T lymphocyte, and non-NK/CTL types.

Due to their minority among the non-Hodgkin lymphomas, classification of extranodal T-cell lymphomas, including those of the natural killer (NK) cell type, has long been controversial and unclear, and the clinical outcome is not well clarified. Recently, new well-defined disease entities have been described based on tumor cell biology combined with anatomical site, clinical features, Epstein-Barr virus (EBV) status, and cell lineage as determined by immunophenotype and genotype. Cytological features are usually not specific, and there are no morphologic correlates with the classification of extranodal T/NK-cell lymphomas. From a human T-cell lymphotropic virus type 1 (HTLV-1) endemic area in Japan, we report here the analysis of 144 cases of extranodal T-cell lymphoma, from which fresh tissues were available. As the clinicopathological features were known, we simply reclassified the cases according to cell lineage and anatomical site. The extranodal T-cell lymphomas were classified into three types on the basis of cell lineage: (1) natural killer cell (NK) type [sCD3-, CD56+, T-cell receptor gene (TCR) germline], (2) cytotoxic T lymphocyte (CTL) type [sCD3+, TIA-1+, TCR rearranged, CD8+/-, CD4-/+], and (3) non-NK/CTL type [sCD3+, TIA-1-, TCR rearranged, CD4+/-, CD8-/+]. In addition to cell lineage, the anatomical site and clinical features were added for subclassification. NK type tumors (35 cases) included the lymphoblastic type, nasal/nasal-type NK lymphoma, and NK leukemia. The CTL type (46 cases) included anaplastic large cell lymphoma (ALCL), cutaneous type, intestinal, gamma delta T-cell type, and an unspecified type. The non-NK/CTL type (63 cases) included adult T-cell leukemia/lymphoma (ATLL), mycosis fungoides (MF), and an unspecified type. With the exception of ATLL and MF, most extranodal T-cell lymphomas had a cytotoxic phenotype of NK type or CTL type and were often associated with EBV infection. MF and the unspecified type within the non-NK/CTL tumors, with the exception of ATLL, had a favorable prognosis. However, NK and CTL types, with the exception of ALCL, were associated with a poor prognosis. Our results indicate that anatomical site and cell lineage are useful predictors of clinical outcomes of extranodal T-cell lymphomas.

Nasal CD56 positive small round cell tumors

CD56-positive nasal and nasal-type natural killer (NK)/T-cell lymphoma is now a well-defined disease entity. Rare cases of blastic NK-cell lymphoma positive for CD56 have been recently reported. However, CD56 expression is also identified in several types of non-hematopoietic small round cell tumors in which lymphoma is included as a differential consideration. Here, we present nine cases of CD56+ small round cell tumors of histological origin unrelated to nasal NK/T-cell lymphoma. Eight of the nine cases presented as solid tumors of the sinonasal region. Clinical, histological, ultrastructural, and immunohistochemical examination and gene analysis for T-cell receptor (TcR) and immunoglobulin heavy chain (IgH) genes and in situ hybridization (ISH) for Epstein-Barr virus (EBV) were performed. Two cases presented with features consistent with blastic NK-cell lymphoma or lymphoblastic lymphoma of NK-cell phenotype. These cases showed features of lymphoblastic lymphoma, phenotypes of sCD3-, cCD3+, CD45+, CD56+, TdT+, and human leukocyte antigen (HLA)-DR+, germline of IgH and TcR genes, and EBV negative reactivity. One case had myeloid/NK-precursor acute leukemia/lymphoma with a phenotype of CD13+, CD33+, CD34+, CD56+, and MPO-. Three cases were neurogenic, including one case of olfactory neuroblastoma and two of primitive neuroectodermal tumors (PNET). It was difficult to differentiate CD56+ PNET from blastic NK-cell lymphoma, especially when only paraffin-embedded sections were available. Myogenic markers, such as HHF35, alpha-sarcomeric actin, and desmin, were positive in three cases of rhabdomyosarcomas. Our findings suggest that as CD56 is used more routinely as a marker in immunohistochemical staining, the differential diagnosis of extranodal lymphohematological malignancies and small round cell tumors will become more complicated.

Rationale of a new classification for the group of primary cutaneous lymphomas.

In the last decade many studies showed that primary cutaneous lymphomas have another clinical behavior and prognosis, and therefore require a different therapeutic approach, as compared with their primary nodal equivalents. Because, until recently, classification systems for non-Hodgkin's lymphomas were purely based on histologic criteria, and did not recognize the special character of these lymphomas, primary cutaneous lymphomas were not uncommonly diagnosed incorrectly and/or treated inappropriately with unnecessarily aggressive therapies. For that reason the Cutaneous Lymphoma Group of the European Organization for Research and Treatment of Cancer (EORTC) proposed a separate classification for the group of primary cutaneous lymphomas. This EORTC classification is consistently based on a combination of clinical, histologic, immunophenotypical and genetic criteria, and includes well-defined and recognizable disease entities. It contains a limited number of cutaneous T-cell lymphomas and cutaneous B-cell lymphomas, which together constitute more than 95% of all primary cutaneous lymphomas. Herein, the rationale and the basic principles of the EORTC classification are presented, and the relationship between the EORTC classification and other recent classification systems, such as the Revised European-American Classification for Lymphoid Neoplasms (REAL classification) and the proposed World Health Organization classification, are discussed.

EORTC Classification for primary cutaneous lymphomas: A comparison with the R.E.A.L. Classification and the proposed WHO Classification

Primary cutaneous lymphomas differ significantly from their nodal equivalents in clinical behaviour and prognosis, and often require a different therapeutic approach. Since currently used classification systems for non-Hodgkin lymphomas do not or insufficiently recognize the special character of these lymphomas, primary cutaneous lymphomas are not uncommonly diagnosed incorrectly, and/or treated inappropriately with unnecessarily aggressive therapies. For that reason the Cutaneous Lymphoma Group of the European Organization for Research and Treatment of Cancer (EORTC) has recently proposed a separate classification for the group of primary cutaneous lymphomas. The EORTC Classification is consistently based on a combination of clinical, histological, immunophenotypical and genetic criteria, and includes well-defined and recognizable disease entities. It contains a limited number of cutaneous T-cell lymphomas and cutaneous B-cell lymphomas, which comprise more than 95% of all primary cutaneous lymphomas. The clinical significance of this classification has been validated by long-term follow-up data of more than 800 patients with a primary cutaneous lymphoma. The basic principles of the EORTC Classification will be presented, and current controversies between the EORTC Classification on the one hand, and the R.E.A.L. Classification and the proposed WHO Classification on the other will be discussed.

Serum antibodies to Balamuthia mandrillaris, a free-living amoeba recently demonstrated to cause granulomatous amoebic encephalitis.

Free-living amoebae cause three well-defined disease entities: a rapidly fatal primary meningoencephalitis, a chronic granulomatous amoebic encephalitis (GAE), and a chronic amoebic keratitis. GAE occurs in immunocompromised persons. Recently, another type of free-living amoeba, Balamuthia mandrillaris, has been shown to cause GAE. The finding that this amoeba has caused infection in some healthy children has raised the possibility that humans may lack immunity to B. mandrillaris. Human serum was examined for the presence of surface antibodies specific for this amoeba by immunofluorescence. Sera from adults contained titers of 1/64-1/256 of anti-B. mandrillaris antibodies (IgM and IgG classes), which did not cross-react with other amoebae. Cord blood contained very low antibody levels, but levels similar to those in adults were seen in serum of 1- to 5-year-old children.

Free‐living amoebae: pathogenicity and immunity

Free-living amoebae causes three well-defined disease entities: (i) primary amoebic meningoencephalitis, caused by Naegleria fowleri, (ii) granulomatous amoebic encephalitis and (iii) chronic amoebic keratitis, caused by species of Acanthamoeba. Both Naegleria infections and chronic amoebic keratitis occur in healthy individuals while granulomatous amoebic encephalitis is often associated with patients with acquired immunodeficiencies. The different pathogenic behaviour of these organisms is associated with differences in life cycle, amoeboidal locomotion, enzyme composition (such as phospholipase A), and cytotoxins, as well as natural host immunity. Immunity against these amoebae (whether acquired or natural) involves a combination of complement, antibody and cell-mediated immunity. Evidence suggests that the major mechanisms of immunity against these amoebae is activation of phagocytic cells, especially neutrophils, by lymphokines and opsonization of the amoebae by antibody which promote an antibody dependent cellular destruction of the organism.

The honeycomb stomach: coalesced gastric angiodysplasia

Vascular ectasias of the gastrointestinal tract were considered rare before the 1960s but since then have been frequently identified as a cause of gastrointestinal hemorrhage. l-G They are more commonly encountered in the cecum but can occur anywhere in the stomach or small intestine. Awareness of their existence increases the chances of endoscopic recognition. We report a case of giant angiodysplasia of the antrum with an interesting and unusual endoscopic appearance characterized by many angiodysplastic lesions that appeared to have coalesced, forming a giant red lesion resembling a honeycomb. Diffuse gastric antral vascular ectasia has emerged as a distinct, well-defined disease entity with distinctive endoscopic patterns.

Desquamative Interstitial Pneumonia-Like Reaction Accompanying Pulmonary Lesions

Six patients with specific pulmonary diseases had pulmonary tissue surgically resected for diagnostic purposes. All six cases were characterized by space-occupying lesions surrounded by a peculiar reaction of the pulmonary parenchyma indistinguishable from desquamative interstitial pneumonia. If small biopsies from these areas had been taken, a diagnosis of desquamative interstitial pneumonia would have been made, and the underlying process would have gone undetected. These cases corroborate even further the concept that desquamative interstitial pneumonia is a pattern of pulmonary reaction, rather than a well-defined disease entity. Furthermore, it seems advisable to make the dianosis of desquamative interstitial pneumonia only when other conditions have been carefully ruled out by thorough clinical and pathologic investigations.