Drug-induced renal disease is common and responsible for a variety of pathological effects on the kidney, many of which are potentially recoverable. The main types of renal injury predominantly involve the tubules and interstitium, leading to acute tubular injury and necrosis, or interstitial nephritis with inflammatory tubular injury. Aminoglycoside antibiotics, β-lactam antibiotics and non-steroidal anti-inflammatory agents are common offenders. Other types of renal injury are related to vascular damage and more rarely glomerular injury. Thrombotic microangiopathy is one of the most common types of acute vascular injury, whereas more chronic vascular changes leading to ischaemic fibrosis occur with long-term therapy with calcineurin inhibitors and analgesics. A knowledge of the drug history and possible nephrotoxic effects is crucial in renal biopsy interpretation for identifying drug-related renal disease.
This article is the second of two papers relating to the histopathological diagnosis of basaloid skin tumours and the uses of immunohistochemistry. The first paper focused on basal cell carcinoma and variants, and this paper will concentrate on tumours that may be confused with basal cell carcinoma. The basaloid tumours of the skin can be classified according to the general classification of skin tumours, including epidermal, appendageal (hair follicle and sweat gland derived) and others including cutaneous metastases. The areas of discussion concentrate on the distinction of basal cell carcinoma from basaloid squamous cell carcinoma, infiltrative basaloid tumours (desmoplastic trichoepithelioma, infiltrative basal cell carcinoma, microcystic adnexal carcinoma and eccrine epithelioma), follicular induction overlying dermatofibroma, basaloid proliferations in naevus sebaceus, trichoepithelioma, trichoblastoma, trichoepithelioma-like basal cell carcinoma, pilomatrical tumours and selected sweat gland tumours. The immunohistochemical stains that may be of use in differential diagnosis are discussed, including BerEP4, epithelial membrane antigen, CD10, bcl-2, Cam5.2, CK20, carcinoembryonic antigen and p53.
Gliomas are the commonest groups of tumours arising in the central nervous system (CNS) in both children and adults. Their incidence in both age groups appears to be increasing, for reasons that are poorly understood. The biological behaviour of gliomas varies from slow-growing well-demarcated tumours that are curable by excision to malignant invasive tumours that are uniformly fatal. Pathology has a major role to play in the management of patients with gliomas by providing a histological diagnosis and tumour grade, which are of major prognostic significance. Molecular genetic studies have found loss of genetic material in many gliomas, with progressive losses identified with increasing tumour grade. In oligodendrogliomas, loss of heterozygosity on chromosomes 1p and 19q is of therapeutic significance as a predictor of tumour response to chemotherapy. The forthcoming revision of the WHO classification of CNS tumours is expected to provide updated recommendations on glioma diagnosis and grading.
Basal cell carcinoma (BCC) is the prototypical basaloid tumour of the skin, but may show various patterns simulating other cutaneous tumours, particularly squamous cell carcinoma and trichoepithelioma (TE). Other challenges are presented by BCC with marked pleomorphism, glandular differentiation, neuroendocrine differentiation, clear cells and sarcomatoid change. Peripheral palisading and retraction (artefact) of the epithelium from the stroma are the most useful features to support a diagnosis of BCC, but can occasionally be seen in other benign and malignant cutaneous neoplasms and are inconspicuous or lacking in some cases of BCC. Increased ‘stromal’ mucin accompanying retraction and peripheral palisading is extremely suggestive of BCC and is rarely seen in other tumour types. Diffuse and strong BerEP4 staining and absence of epithelial membrane antigen staining is characteristic of BCC, and is an immunophenotype rarely encountered in other tumours except for TE. CD10 staining of the basaloid epithelium, in the absence of significant stromal staining, may support a diagnosis of TE-like BCC rather than TE in more organized variants.
There is a clinico-pathological continuum of infection-driven sepsis syndromes, the most severe being septic shock with multi-organ failure. The organ dysfunctions are due to inflammatory cytokines from remote sources (the site of infection) and constitute the systemic inflammatory response syndrome (SIRS). The common causes are Gram-positive and Gram-negative infections; the common infection sites are (in descending frequency) lung, blood stream, intra-abdominal disease, urological sepsis and surgical wounds; the commonest organ dysfunctions are systemic shock, kidney, lung, and heart. The differential diagnosis of severe sepsis includes disseminated malignancy, atherosclerosis, and haemophagocytic syndrome. New treatments for severe sepsis are being trialled to raise the poor survival rates in intensive care. The role of the autopsy is to describe carefully the organ lesions, provide microbiological evidence of infection, and to correlate these with the clinical features and therapeutic variables.
Antenatal magnetic resonance imaging (MRI) has become a widely available technique for examining the fetus during its normal development and in a variety of diseases, prompting the question of whether it should supplant the traditional incisional route to diagnosis. We review and compare the applications and limitations of both MRI and classical neuropathology, illustrated with selected cases. We conclude that fetal MRI should be regarded as neither threat nor irrelevance, but complimentary to neuropathological practice. For many conditions, combined information from the two investigations can support a diagnosis that would be tentative with either alone.
Advances in our understanding of glomerulonephritis (GN) have come from both clinical and research studies. New animal models of human GN, human and mouse genetic studies, and molecular and immunological tools have helped to identify new inflammatory mediators and regulatory molecules, resulting in a better understanding of the pathogenesis of human GN and novel therapeutic strategies. In this article, we review recent advances in Goodpasture's disease, antineutrophil cytoplasmic antibody-associated GN, membranous glomerulopathy, membranoproliferative GN and a new classification of lupus nephritis.
Liver transplantation has been increasingly used over the past four decades as an effective treatment for end-stage liver disease. Although the demand exceeds the supply of cadaveric organs, the donor pool has expanded with the increasing use of split-liver grafts, non-heart-beating donor livers and living-related donors. Histopathologists play a role in the pre-transplant and post-transplant period; their input is crucial in both identifying and monitoring post-transplant complications. The degree of acute cellular rejection is best assessed histologically, and biopsy interpretation informs changes to the immunosuppressive regimen. Chronic rejection is characterised by progressive ductopenia; a number of lesions have been identified that predict the likelihood of progression to chronic rejection. Other post-transplant complications readily assessed on liver core biopsies include vascular and biliary complications, infectious, recurrent and de novo disease. De novo hepatitis with ‘autoimmune’ features is described as is idiopathic chronic hepatitis, but the relationship of these lesions to alloimmune pathways remains uncertain. Although liver transplantation is generally performed in specialist centres, an increasing number of histopathologists working in non-specialist units are being exposed to post-transplant biopsies and need to be aware of the spectrum of changes that can occur.
A 61-year-old man underwent liver transplantation for alcoholic cirrhosis. The initial postoperative period was uneventful. During the second week he developed worsening liver biochemistry: aspartate transaminase (AST) 139 U/l (normal 5–43), alkaline phosphatase (ALP) 2048 U/l (normal 70–330), bilirubin 172mmol/l (normal 1–22). A liver biopsy was taken on day 15. Fig. 1(a,b) shows representative changes in portal tracts. Fig. 1(c,d) illustrates changes occurring in zone 3 of the liver parenchyma.
After a properly conducted autopsy, a small proportion of cases will not reveal a cause of death. This is probably of the order of 2–5%. However, before the death is recorded as unascertained, it is important that appropriate ancillary investigations have been conducted. These tests include toxicology, microbiology and genetic testing where appropriate. The history and scene examination findings must be known, and the possibility of a hidden homicide reasonably excluded. However, even with a full and thorough investigation, some natural disease processes such as cardiac conduction abnormalities and sudden death in epilepsy will result in a negative autopsy. If investigated properly, a cause of death may still be identified for decomposed bodies.
There are up to 500 epilepsy-related deaths annually in the UK, many of which are unwitnessed. Likely mechanisms for sudden and unexpected death in epilepsy (SUDEP) are cerebrogenic cardiac arrhythmias, or central respiratory depression occurring during the peri-ictal period. Pathologists should be informed of the circumstances of the death, severity of seizures, seizure control and the certainty of the clinical diagnosis of epilepsy; this allows accurate clinicopathological correlation. SUDEP autopsies include neuropathological assessment, histological examination of other organs and toxicology, and require the elimination of other causes of sudden death. Macroscopic (non-fatal) abnormalities described in SUDEP include evidence of previous cerebral injury, hippocampal sclerosis and cerebellar atrophy. Histological examination may reveal neuronal loss and gliosis consistent with seizure-related brain injury. Hippocampal sclerosis shows subfield-specific patterns of neuronal loss, granule cell dispersion and mossy fibre sprouting. Rarely, acute neuronal injury is seen as evidence of a more recent cerebral event. This article discusses the pathological findings and possible mechanisms in SUDEP, and future directions for pathology-based research.
A positive blood culture or culture of cerebrospinal fluid (CSF) obtained postmortem could be due to a genuine positive, to agonal spread, to postmortem translocation or to contamination. A review of published evidence indicates that, if specimens are taken with care, the majority is sterile. Mixed growth occurs in less than 10% and is mainly due to contamination. Postmortem translocation is rarely a problem if the body is refrigerated promptly after death. Agonal change is less common than often assumed. A single isolate of a potential pathogen in perinatal cases and in adult practice is likely to be a genuine positive (PPV>50%); in sudden unexpected death in infancy (SUDI), however, a single isolate should be regarded as only a possible cause of death (PPV<50%) in the absence of corroboration. If bacterial invasion causes or contributes to rapid death, there might not be time for the histological changes of inflammation to develop and more subtle signs should be sought; including cell counts and protein estimations of CSF. Sampling upper-airways secretions shortly after death and before refrigeration provides useful information if infection is suspected. The results can be compared with community controls in epidemiological studies. In the future, genomic and proteomic techniques need to be added to standard methods to determine the role of bacteria in sudden death. The key message is that if specimens are taken with care, and interpreted with care, then useful information can be obtained.
BRAF pV600E mutation is the most common oncogenic event and the most specific mutation for papillary thyroid carcinoma (PTC). Many studies over the last decade have shown a direct relationship between BRAF mutation and aggressive tumour characteristics, resulting in poor prognosis. However, several recent studies have suggested that BRAF mutation is not associated with poor prognosis of PTC. The present study was designed to evaluate the association between BRAF mutation with clinicopathological factors and tumour recurrence.In this retrospective study, BRAF mutation status was examined by direct sequencing on paraffin-embedded tumour specimens from 46 patients undergoing surgery for PTC in our institution from 1985 to 2000. The relationship between BRAF mutation and gender, advanced age, extrathyroid extension, multifocal tumour, cervical lymph node metastasis, tumour size and advanced pT stage of PTC and its predictive role for the risk of tumour recurrence were investigated with a median follow-up of 10.1 (± 6.5) years.BRAF mutation was detected in 20 of the 46 patients (43.5%) included in the study. No statistically significant correlation was demonstrated between the presence of BRAF mutation and the various clinicopathological factors studied. No significant difference in tumour recurrence rate or radioiodine sensitivity was observed between the two subgroups: mutant BRAF and wild-type BRAF.Although BRAF mutation appears to play a role in local tumour progression, it is not a risk factor for poor prognosis or tumour recurrence in PTC.
Gastrointestinal polyps are common lesions that usually present singly or in small numbers. Although the term ‘multiple colorectal polyposis’ was originally applied to patients carrying at least 100 large intestinal adenomas, it has subsequently become broadened to include patients carrying multiple polyps regardless of their nature. Most of the non-adenomatous polyposis syndromes are hereditary. They can be classified according to the dominant type of polyp, their distribution in the gastrointestinal tract and their potential for the development of gastrointestinal cancers. This review summarises their main clinical, genetic and histopathological features.
‘Pseudomyxoma peritonei’ (PMP) is the clinical term traditionally applied to the debilitating syndrome of grossly apparent gelatinous ascites associated with peritoneal deposits of mucinous tumours. For many years, PMP was mainly attributed to mucinous neoplasms arising in the ovary. However, in recent decades, it has become clear that most of this syndrome is related to discontinuous spread from the appendix. Despite the uniformly malignant clinical presentation noted among all histological grades of fully developed PMP, the pathological nomenclature advocated by some authors has continued to include non-malignant terms (reminiscent of the ovarian tumours classified as borderline) for those frequent cases with very-well-differentiated histology. This article will review the clinical and pathological features of PMP in the context of the literature, and maintain that, regardless of how well differentiated they are, all cases of PMP are examples of mucinous carcinoma. Grading as either low- or high-grade carcinoma is indicated for prognostication. This article will also discuss the terminology for mucinous appendiceal neoplasms removed from patients who have not yet developed PMP.
Alcohol is a substance that impacts the social, psychological, medical, economic and religious spheres of our existence. It is part of every society. Alcohol in moderation can be beneficial. Alcohol abuse mediates its effects both on the developing and the developed brain, directly or indirectly, and has acute and chronic complications. Damage to the developing brain can result from alcohol consumption in pregnancy. Misuse of alcohol in adults can affect both the central and the peripheral nervous system. Direct effects arise due to the toxic and intoxicating effects of alcohol. Nutritional deficiencies are thought to mediate most of the indirect effects of alcohol, as patients with alcohol dependence tend to eat less and derive most of their caloric intake from the alcoholic beverages they consume. Alcohol-related disease places a burden on our health-care systems. In this review, we examine the pathological effects of alcohol on the nervous system.
A neoplastic proliferation of peripheral nerve sheath cells (Schwann cells, fibroblasts and perineurial cells) and ganglion cells in the colorectum may give rise to the mucosal or submucosal polyps. Depending upon the predominant cell types, these neurogenic polyps can be classified as schwannomas, granular cell tumours, neurofibromas, perineuriomas, mixed nerve sheath tumours, ganglioneuromas or paragangliomas. Morphologically, the neoplastic cells repeat or mimic the corresponding nerve sheath cells or neurons in terms of growth pattern, histology and immunoreactivity. They are uncommon, but the polyps can occur in any age group, although the vast majority of patients are adults. The polyps can be either solitary (most peripheral nerve sheath tumours) or multiple, especially if associated with systemic diseases (i.e. syndromes involving the peripheral nerve tissue). They are usually incidental findings or may be accompanied by gastrointestinal symptoms. Almost all colorectal neurogenic polyps are benign, and they rarely undergo malignant transformation unless they are part of a syndromatic manifestation. However, these polyps may cause a diagnostic problem during screening for colorectal cancer. An accurate diagnosis of these entities will help clinicians to make appropriate management decisions.
Demyelination is characterised by destruction of normal myelin and can be either primary or secondary. Multiple sclerosis is the most common primary demyelinating disease. The disease commonly affects females with a mean age of onset of about 30 years. It is characterised clinically by relapses and remissions of neurological disturbance. The aetiology is multifactorial with gender, genetic and environmental factors contributing to disease susceptibility. The diagnosis remains clinical and confirmation is by histological examination of tissue obtained from multiple sites within the nervous system. Grossly, the brain shows numerous plaques scattered throughout the white and grey matter. The basic lesion on histology is the 'demyelinated plaque' with preserved axons set in a gliotic matrix. However, various other lesion types and patterns of demyelination are also identified histologically. Current research is investigating the role of stem cells and oligodendrocyte progenitors, and their potential in the repair of surviving axons.
The family of small round-cell tumours (SRCTs) represents a heterogeneous group of malignancies featuring a primitive, undifferentiated round-cell morphology. SRCTs mostly occur in children, adolescents and young adults, and tend to involve the skeletal system or soft tissue. They constitute approximately 20% of solid tumours in children and, because of their significant morphological overlap, have become a paradigm for an integrated approach to diagnosis. The combination of both immunophenotypic and genetic analysis with classic morphology has proved useful not only on diagnostic grounds, but also in the context of prognostication. This review will focus on SRCTs primarily involving soft tissues and includes the Ewing's family of tumours, also known as Ewing's sarcoma/primitive neuroectodermal tumour, alveolar rhabdomyosarcoma, desmoplastic SRCT, poorly differentiated round-cell synovial sarcoma and mesenchymal chondrosarcoma.
