Kaposi sarcoma‐associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV8), is a recent addition to the list of human viruses that are directly associated with lymphoproliferative disorders. KSHV was first shown to be involved in multicentric Castleman disease and primary effusion lymphoma (PEL). Subsequently, the virus was identified in solid lymphomas, often of extranodal sites, with morphological and immunophenotypic characteristics similar to those of PEL, and in other lymphoproliferative disorders with heterogeneous clinicopathological presentations. The recent advances in our understanding of the histology, immunophenotype and pathogenesis of these KSHV‐associated lymphoproliferative disorders are reviewed.
Non‐alcoholic fatty liver disease (NAFLD) is the most common hepatic disorder in western countries, and its incidence is increasing. This review outlines the significant health burden posed by NAFLD and discusses what is presently known about its pathogenesis, including the roles of the metabolic syndrome, obesity, insulin resistance, hepatic steatosis, reactive oxygen species, inflammatory cytokines and adipocytokines. The way in which NAFLD is clinically diagnosed is described, and areas of uncertainty surrounding its investigation are identified, before discussing the relative merits of the limited treatment options available and looking ahead to potential therapeutic strategies for the future.
Lobular neoplasia is a relatively uncommon lesion, which is frequently diagnosed in biopsy specimens taken for other reasons. Although the histological features of this lesion are well known, its biological significance as a “risk indicator” or “breast cancer precursor” has been a matter of debate. This review provides an update on recent clinicopathological and molecular data on lobular neoplasia and how these have changed the way these lesions are perceived and, most importantly, managed. Furthermore, the current recommendations for the management of lobular neoplasia diagnosed on core needle biopsies proposed in the National Health Service Breast Cancer Screening guidelines are discussed.
lobular carcinoma in situ; atypical lobular hyperplasia; E‐cadherin; pleomorphic lobular carcinoma; β‐catenin
Long term ulcerative colitis (UC) increases the risk of colorectal cancer (CRC). DNA aneuploidy is a common feature of both dysplastic and non‐dysplastic colonic epithelia from patients with longstanding UC, and is regarded as an early sign of possible malignant transformation. The spindle proteins Aurora A, BUB1B and Mad2 have been implicated as contributors to aneuploidy and carcinogenesis.
To investigate the role of these spindle proteins in relation to DNA aneuploidy and during the progressive morphological changes in ulcerative colitis associated colorectal cancer (UCCRC).
Tissue microarrays were made from 31 colectomy specimens from patients with longstanding UC. Expression of Aurora A, BUB1B and Mad2 was investigated by immunohistochemistry and their relation to ploidy status, mucosal morphology and Ki67 levels was explored.
Expression of Aurora A and BUB1B was significantly associated with the progressive morphological changes of UCCRC. In the progression from non‐dysplastic to dysplastic mucosa, Aurora A expression decreased while BUB1B expression increased. There was an increasing incidence of aneuploidy with progression towards cancer; expression of all spindle proteins was associated with the level of Ki67 but not with aneuploidy.
Due to the significant differences in Aurora A and BUB1B expression in dysplastic compared non‐dysplastic mucosa, these proteins may serve as putative biological markers for the progressive morphological changes in UC associated carcinogenesis. The close relationship to Ki67 levels reflect that spindle proteins are expressed in tissues with a high proliferative rate; a role for these proteins in the development of aneuploidy was not found.
Hepatitis C virus (HCV) is well known for its aetiological role in chronic non‐A, non‐B viral hepatitis, liver cirrhosis and hepatocellular carcinoma; in addition, the virus has also been implicated in a number of extra‐hepatic “autoimmune” disease manifestations. A causative association between HCV and non‐Hodgkin lymphoma (NHL) was postulated relatively recently and has been the subject of intense investigation, as well as some debate. On the strength of epidemiological data, emerging biological investigations and clinical observations, HCV appears to be involved in the pathogenesis of at least a proportion of patients with NHL. Morphologically, HCV‐associated lymphomas represent a variety of histological subtypes including marginal zone lymphoma (splenic, nodal and extranodal), small lymphocytic lymphoma/chronic lymphocytic leukaemia, lymphoplasmacytic lymphoma and diffuse large B‐cell lymphoma. Remarkably, some HCV‐associated NHL appears to be highly responsive to antiviral therapy, providing some clinical evidence for this relationship, as well as the prospect for novel therapeutic intervention.
Epstein–Barr virus (EBV) is a herpesvirus associated with approximately 1% of tumours worldwide. EBV is the epitome of B lymphotropic viruses, but the spectrum of tumours it is associated with extends to T lymphocyte and NK cell malignancies, various types of carcinomas and smooth muscle tumours. Ubiquitous EBV infection in humans implies that most individuals carry EBV‐infected cells. Therefore, mere detection of the virus in individuals with a tumour is not sufficient for establishing a causal relationship between both events, but instead requires unequivocal detection of viral nucleic acids or viral proteins in the tumour cells. Recent controversies about EBV infection in several carcinomas mainly resulted from such technical issues. The gold standard remains in situ EBER detection, but detection of EBNA1 would be an interesting alternative. EBV detection can be helpful for diagnostic, prognostic and therapeutic purposes. The rate of EBV association with entities such as NK/T cell tumours of the nasal type is so high that absence of detection of the virus in such a lesion should cast doubt of the accuracy of the diagnosis. Similarly, diagnosis of EBV‐associated follicular pseudo‐tumour obviously requires detection of the virus. EBV‐positive common gastric adenocarcinomas seem to have a better prognosis than their EBV‐negative counterparts and identification of the virus in B cell lymphoproliferations in immunocompromised individuals will guide therapeutic options. In conclusion, EBV‐associated tumours are common enough to be relevant for the pathologist in everyday practice, but there is a need to facilitate detection of the virus (eg EBNA1 antibody).
An update on current practice
breast cancer; core needle biopsy; diagnosis; pathology
The term “columnar cell lesions” encompasses a spectrum of processes, characterised by variably dilated acini, lined by one to several layers of tightly packed, columnar‐shaped epithelial cells. These lesions have received renewed attention in the literature due to their high prevalence in biopsy specimens taken for assessment of mammographically detected microcalcification. In addition, increasing interest has been directed at the sub‐set of columnar cell lesions with varying degrees of cytological atypia. Recent observational and molecular genetic studies have provided strong circumstantial evidence to suggest that at least some of these lesions may represent the earliest morphologically identifiable, non‐obligate precursor of low grade breast carcinomas. However, the risk of both local recurrence and progression to invasive cancer appears to be exceedingly low. This review provides an update on recent clinicopathological and molecular data on columnar cell lesions and how these have changed our perception of, and the classification system for, these lesions. In addition, guidelines for the management of patients with columnar cell lesions diagnosed in core needle biopsy specimens are provided.
Although the morphology of the pathognomonic Reed–Sternberg cells of Hodgkin lymphoma (HL) was described over a century ago, it was not until recently that their origin from B lymphocytes was recognised. The demonstration that a proportion of cases of HL harbour the Epstein–Barr virus (EBV) and that its genome is monoclonal in these tumours suggests that the virus contributes to the development of HL in some cases. This review summarises current knowledge of the pathogenesis of HL with particular emphasis on the association with EBV.
Burkitt lymphoma (BL) is an aggressive B‐cell malignancy with endemic, sporadic and immunodeficiency‐associated variants. It has been known for many years that the fundamental transforming event in BL is the translocation of the MYC gene, and the events that bring about this translocation and those that allow cells to survive with the constitutive expression of MYC have been the subject of intense investigation. Epstein–Barr virus (EBV) infection, malaria, immunodeficiency and spontaneous, somatic mutation can all contribute to the origin and maintenance of this cancer and their mechanisms are the subject of this review.
Apocrine metaplasia is a very common finding in the female breast after the age of 25. It is so common that many people regard it as a normal component of the breast. This, however, is only really the case in apocrine sweat glands of the axilla and in the peri‐areolar apocrine glands. The apocrine cell does, however, contribute to a number of different breast lesions, some of which are very taxing diagnostically; apocrine variants of both in‐situ and invasive cancer are encountered. This review considers the common apocrine metaplastic lesions seen in fibrocystic change as well as apocrine adenoma, apocrine change within sclerosing adenosis, atypical apocrine lesions and apocrine malignancies.
apocrine; metaplasia; breast; atypical; adenosis; apocrine carcinoma
Adult T‐cell leukaemia/lymphoma (ATLL) is a mature T‐cell neoplasm of post‐thymic lymphocytes aetiologically linked to the human T‐cell lymphotropic virus, HTLV‐I, and with a distinct geographical distribution. The disease manifests with leukaemia in greater than two thirds of patients, while the remaining patients have a lymphomatous form. According to the disease manifestations, various forms which differ in clinical course and prognosis have been recognised: acute, chronic, smouldering and lymphoma. Organomegaly, skin involvement, circulating atypical lymphocytes (“flower” cells) with a CD4+ CD25+ phenotype and hypercalcaemia are the most common disease features. The diagnosis should be based on a constellation of clinical features and laboratory investigations. The latter comprise: lymphocyte morphology, immunophenotype, histology of the tissues affected in the pure lymphoma forms and serology or DNA analysis for HTLV‐I. The differential diagnosis of ATLL includes other mature T‐cell neoplasms such as T‐cell prolymphocytic leukaemia (T‐PLL), Sézary syndrome (SS), peripheral T‐cell lymphomas and occasionally healthy carriers of the virus or Hodgkin disease. The clinical course is aggressive with a median survival of less than 12 months in the acute and lymphoma forms. Despite major advances in understanding the pathogenesis of the disease, management of these patients remains a challenge for clinicians as they do not respond or achieve only transient responses to therapies used in high‐grade lymphomas. The use of antiretroviral agents such as zidovudine in combination with interferon‐alpha, with or without concomitant chemotherapy, has shown activity in this disease with improvement in survival and response rate. Consolidation with high dose therapy and autologous or allogeneic stem‐cell transplantation should be considered in young patients.
Needle core biopsy (NCB), as part of triple assessment for preoperative evaluation and diagnosis of breast cancer, is now considered as an established, highly accurate method for diagnosing breast cancer that has replaced either fine needle aspiration cytology or excisional biopsy as the initial diagnostic biopsy procedures in many institutions. In addition to its primary role in establishing an accurate histological diagnosis, NCB can potentially provide important additional pathological prognostic information which may be of direct clinical value in certain situations, such as patients being considered for preoperative (neoadjuvant) therapy. With this background in mind we briefly review the current role of NCB in breast cancer diagnosis and then concentrate this review on the usefulness and issues relating to use of this technique in providing accurate, reliable and clinically relevant preoperative prognostic and predictive information in patients with breast cancer.
This study aims to review histological and immunohistochemical features that are useful in the diagnosis of metastases to the breast. Histological features were compared between non‐haematological metastases to the breast and 100 consecutive core biopsy specimens of primary invasive carcinomas of the breast. 18 non‐haematological metastases to the breast were diagnosed over a 10‐year period (0.3% of malignant mammary tumours). Elastosis and carcinoma in situ were seen only in primary mammary cancers. Two‐thirds of tumours had features raising the possibility of metastasis, such as clear cell carcinoma suggestive of renal origin and small cell carcinoma suggestive of pulmonary origin. The features observed in haematological metastases are also described. Immunohistochemical panels to distinguish mammary carcinoma (oestrogen receptor, gross cystic fluid protein‐15) from common metastases to the breast, including carcinoma of the lung (thyroid transcription factor‐1), malignant melanoma (S100, HMB45, melan‐A) and ovarian serous papillary carcinoma (Wilms' tumour 1), are discussed. The pathologist has a key role in considering the diagnosis of metastasis to the breast if the histological features are unusual for a primary mammary tumour. The clinical history is vital in some cases. Immunohistochemistry plays a useful supplementary role.
Human T‐cell lymphotropic virus‐I (HTLV‐I) is the cause of adult T‐cell leukaemia/lymphoma. Various viral proteins, especially, but not exclusively, Tax have been implicated in oncogenesis, mostly through in vitro studies. Tax transactivates a large and apparently ever expanding list of human genes through transcriptional factors. Elucidating not only the pathways but also the timing of action of HTLV proteins is important for understanding the pathogenesis and development of new treatments.
“Basal” breast cancers are dominating the breast research literature at present and pathologists are under increasing pressure to evaluate for such a phenotype by their surgical and oncological colleagues. There is also much confusion about how to assess cancers, which immunohistochemical markers to use, what meaning and benefit this provides, and what the surgeons and oncologists will do with the information. Much remains to be done to answer all these questions but here we try to shed light on some of the issues and suggest what is still to come.
The incidence of lymphoma in patients with HIV infection greatly exceeds that of the general population. The increased risk for lymphoma appears related to multiple factors, including the transforming properties of the retrovirus itself, the immunosuppression and cytokine dysregulation that results from the disease, and, most importantly, opportunistic infections with other lymphotrophic herpes viruses such as Epstein–Barr virus and human herpesvirus 8. Histologically lymphomas fall into three groups: (1) those also occurring in immunocompetent patients; (2) those occurring more specifically in HIV‐positive patients; and (3) those also occurring in patients with other forms of immunosuppression. Aggressive lymphomas account for the vast majority cases. They frequently present with advanced stage, bulky disease with high tumour burden and, typically, involve extranodal sites. Clinical outcome appears to be worse than in similar aggressive lymphomas in the general population. However, following the introduction of highly active antiretroviral therapy, the risk for developing lymphoma in the context of HIV infection has decreased and the clinical outcome has improved.