Opposing post-translational modifications regulate Cep76 function to suppress centriole amplification.

Centrioles are critical for many cellular processes including cell division and cilia assembly. The number of centrioles within a cell is under strict control, and deregulation of centriole copy number is a hallmark of cancer. The molecular mechanisms that halt centriole amplification have not been fully elucidated. Here, we found that centrosomal protein of 76 kDa (Cep76), previously shown to restrain centriole amplification, interacts with cyclin-dependent kinase 2 (CDK2) and is a bona fide substrate of this kinase. Cep76 is preferentially phosphorylated by cyclin A/CDK2 at a single site S83, and this event is crucial to suppress centriole amplification in S phase. A novel Cep76 mutation S83C identified in a cancer patient fails to prevent centriole amplification. Mechanistically, Cep76 phosphorylation inhibits activation of polo-like kinase 1 (Plk1), thereby blocking premature centriole disengagement and subsequent amplification. Cep76 can also be acetylated, and enforced acetylation at K279 dampens the protein's ability to inhibit amplification and precludes S83 phosphorylation. Acetylation of Cep76 normally occurs in G2 phase and correlates with loss of protein function. Our data suggest that temporal changes in post-translational modifications of Cep76 during the cell cycle regulate its capacity to suppress centriole amplification, and its deregulation may contribute to malignancy.

Mitochondrial respiratory chain deficiency in Caenorhabditis elegans results in developmental arrest and increased life span.

The growth and development of Caenorhabditis elegans are energy-dependent and rely on the mitochondrial respiratory chain (MRC) as the major source of ATP. The MRC is composed of approximately 70 nuclear and 12 mitochondrial gene products. Complexes I and V are multisubunit proteins of the MRC. The nuo-1 gene encodes the NADH- and FMN-binding subunit of complex I, the NADH-ubiquinone oxidoreductase. The atp-2 gene encodes the active-site subunit of complex V, the ATP synthase. The nuo-1(ua1) and atp-2(ua2) mutations are both lethal. They result in developmental arrest at the third larval stage (L3), arrest of gonad development at the second larval stage (L2), and impaired mobility, pharyngeal pumping, and defecation. Surprisingly, the nuo-1 and atp-2 mutations significantly lengthen the life spans of the arrested animals. When MRC biogenesis is blocked by chloramphenicol or doxycycline (inhibitors of mitochondrial translation), a quantitative and homogeneous developmental arrest as L3 larvae also results. The common phenotype induced by the mutations and drugs suggests that the L3-to-L4 transition may involve an energy-sensing developmental checkpoint. Since approximately 200 gene products are needed for MRC assembly and mtDNA replication, transcription, and translation, we predict that L3 arrest will be characteristic of mutations in these genes.

Nonnasal lymphoma expressing the natural killer cell marker CD56: a clinicopathologic study of 49 cases of an uncommon aggressive neoplasm.

Expression of the natural killer (NK) cell antigen CD56 is uncommon among lymphomas, and those that do are almost exclusively of non-B-cell lineage and show a predilection for the nasal and nasopharyngeal region. This study analyzes 49 cases of nonnasal CD56+ lymphomas, the largest series to date, to characterize the clinicopathologic spectrum of these rare neoplasms. All patients were Chinese. Four categories could be delineated. (1) Nasal-type NK/T cell lymphoma (n = 34) patients were adults 21 to 76 years of age (median, 50 years), including 25 men and 9 women. They presented with extranodal disease, usually in multiple sites. The commonest sites of involvement were skin, upper aerodigestive tract, testis, soft tissue, gastrointestinal tract, and spleen. Only 7 cases (21%) apparently had stage I disease. The neoplastic cells were often pleomorphic, with irregular nuclei and granular chromatin, and angiocentric growth was common. The characteristic immunophenotype was CD2+ CD3/Leu4- CD3epsilon+ CD56+, and 32 cases (94%) harbored Epstein-Barr virus (EBV). Follow-up information was available in 29 cases: 24 died at a median of 3.5 months; 3 were alive with relapse at 5 months to 2.5 years; and 2 were alive and well at 3 and 5 years, respectively. (2) Aggressive NK cell leukemia/lymphoma (n = 5) patients presented with hepatomegaly and blood/marrow involvement, sometimes accompanied by splenomegaly or lymphadenopathy. The neoplastic cells often had round nuclei and azurophilic granules in the pale cytoplasm. All cases exhibited an immunophenotype of CD2+ CD3/Leu4- CD56+ CD16- CD57- and all were EBV+. All of these patients died within 6 weeks. (3) In blastoid NK cell lymphoma (n = 2), the lymphoma cells resembled those of lymphoblastic or myeloid leukemia. One case studied for CD2 was negative and both cases were EBV-. One patient was alive with disease at 10 months and one was a recent case. (4) Other specific lymphoma types with CD56 expression (n = 8) included one case each of hepatosplenic gammadelta T-cell lymphoma and S100 protein+ T-cell lymphoproliferative disease and two cases each of T-chronic lymphocytic/prolymphocytic leukemia, lymphoblastic lymphoma, and true histiocytic lymphoma. All of these cases were EBV-. Six patients died at a median of 6.5 months. Nonnasal CD56+ lymphomas are heterogeneous, but all pursue a highly aggressive clinical course. The nasal-type NK/T-cell lymphoma and aggressive NK cell leukemia/lymphoma show distinctive clinicopathologic features and a very strong association with EBV. Blastoid NK cell lymphoma appears to be a different entity and shows no association with EBV.

Lipoadenoma of the parotid gland with probable striated duct differentiation.

We report an example of lipoadenoma of the parotid gland, a previously undescribed tumor of the salivary gland. It is a well-circumscribed tumor comprising an intimate admixture of mature fat cells and branching narrow tubules. The tubules were elongated and had small or absent lumina, resulting in a remarkable Sertoliform pattern. They were lined by columnar cells, which were supported by a basal cell layer. The latter cells lacked evidence of myoepithelial differentiation but were best highlighted by immunostaining for high molecular-weight cytokeratin (34 beta E12). Comparison with the normal salivary gland components showed the greatest homology of the neoplastic tubules with the striated duct, which normally has an incomplete basal cell layer. The latter phenomenon is under-recognized, with some current textbooks still describing the presence of a single cell type only in the striated duct of the salivary gland.

T- and T/natural killer-cell lymphomas of the salivary gland: a clinicopathologic, immunohistochemical and molecular study of six cases.

Primary salivary gland lymphomas are almost always of B lineage, with most being represented by low grade B-cell lymphoma of mucosa-associated lymphoid tissue. This study characterizes the rare non-B-cell lymphomas of the salivary gland based on an analysis of six cases. All patients were men, with a mean age of 53.5 years. They presented with submandibular or parotid mass, which on histological examination showed extensive interstitial infiltration by small, medium-sized, or large lymphoid cells. There was prominent invasion and expansion of the ducts and acini in five cases. Angioinvasion was evident in two cases. Three cases were of T lineage and were CD56 negative; one of these cases expressed CD30. Three cases showed an immunophenotype of CD2+ CD3(f)- CD3(p)+ CD56+, consistent with T/natural killer (NK) cell lymphoma. In situ hybridization for Epstein-Barr virus (EBV)-encoded early nuclear RNA (EBER) showed positive reaction exclusively in the three CD56+ cases. Clonal T-cell populations were shown in two CD56-negative cases by polymerase chain reaction on paraffin sections using primers for the T-cell-receptor (TCR) gamma-chain gene, but not in the other four cases (the three CD56+ cases and one CD56- case). Four patients (two CD56+ and two CD56-) died within 3 years, and two were disease free at 4 and 1.5 years, respectively. This study shows that salivary gland T- or T/NK-cell lymphomas cannot be reliably distinguished from B-cell lymphomas on morphological grounds alone, because both can show prominent lymphoepithelial lesions. It appears that T/NK-cell lymphomas, which are often extranodal in localization and strongly associated with Epstein-Barr virus (EBV), show a predilection to involve the salivary glands as well.

Cytokeratin 20 immunoreactivity distinguishes Merkel cell (primary cutaneous neuroendocrine) carcinomas and salivary gland small cell carcinomas from small cell carcinomas of various sites.

Cytokeratin 20 (CK20) is a low-molecular-weight cytokeratin (CK) that shows restricted expression in the gastrointestinal epithelium, urothelium, and Merkel cell. Recent studies have suggested that since Merkel cell (primary cutaneous neuroendocrine) carcinomas are consistently CK20-positive, this feature may help to distinguish it from pulmonary small cell carcinomas. However, only limited numbers of these tumors have been studied, and the pattern of CK20 expression in other small cell carcinomas has not been established. Therefore, we studied CK20 expression in small cell carcinomas from a wide variety of sites. Immunohistochemical study was performed on paraffin sections using CK20 antibody, coupled with antigen retrieval by pressure cooking in citrate buffer. The cases included 34 Merkel cell carcinomas and 89 small cell carcinomas from various sites (pulmonary, 37; gastrointestinal tract, nine; pharynx and tongue, two; sinonasal tract, three; salivary gland, five; larynx, nine; breast, two; thymus, three; uterine cervix and corpus, 12, prostate, three; urinary bladder, two; kidney, one; pancreas, one). In addition, all cases were immunostained with pan-CK (MNF-116) and low-molecular-weight CK (CAM5.2) antibodies to ascertain their epithelial nature. With the exception of one case, all Merkel cell carcinomas were CK20-positive; and 30 of the 33 cases showed a punctate pattern. Almost 100% of tumor cells were positive, except for two cases that showed staining of 10% and 30% of tumor cells, respectively. Among the other small cell carcinomas, only five cases were CK20-positive, including one of 37 pulmonary (40% cells positive in punctate pattern), one of 11 cervical (10% cells positive), and three of five salivary gland (100% cells positive). We conclude that CK20-positivity in a small cell carcinoma of uncertain origin strongly predicts a diagnosis of Merkel cell carcinoma, especially if the majority of tumor cells are positive. A negative CK20 reaction can practically rule out Merkel cell carcinoma, provided that an effective antigen retrieval technique is used and appropriate staining is obtained with other cytokeratin antibodies. The frequent CK20 positivity observed in salivary gland small cell carcinomas in this series suggests that at least some of them may be more closely related biologically to Merkel cell carcinoma than to pulmonary-type small cell carcinoma. This may explain why they are far less clinically aggressive than other small cell carcinomas.

Endocrine ductal carcinoma in situ (E-DCIS) of the breast: a form of low-grade DCIS with distinctive clinicopathologic and biologic characteristics.

Endocrine ductal carcinoma in situ (E-DCIS), first characterized by Cross et al. in 1985, is an uncommon entity, and there is little information on its pathobiologic features and natural history in the literature. This report describes the largest series of 34 cases: 14 cases were pure in situ (group A), and 20 were accompanied by an invasive component (group B). All except three patients were over the age of 60 years, with the mean being 69.5 years for group A and 72.6 years for group B. Except for six patients in group A who had nipple discharge, all had a breast mass. On follow-up, one of five group A patients developed local recurrence 5 years after mastectomy, and two of seven group B patients developed another invasive primary in the contralateral breast. Histologically, E-DCIS showed expansile intraductal growths forming solid sheets and festoons traversed by delicate fibrovascular septa. Accumulation of basophilic mucin might be found within the growth and the fibrovascular septa. There were variable degrees of stromal sclerosis. In some cases, the solid intraductal cellular proliferations were focally punctuated by microglandular spaces and rosettes. Comedo necrosis was absent. Intraductal papillomas were found in the immediate vicinity of the tumors in 18 cases and invariably showed pagetoid involvement by E-DCIS. Pagetoid spread into the adjacent ducts and ductules was also a common feature (17 cases). The tumor cells were polygonal, oval, or spindly, often with eccentrically placed, bland-looking, ovoid nuclei and abundant eosinophilic granular cytoplasm. Intracellular mucin was commonly demonstrable. Immunostaining for myoepithelium using muscle-specific actin antibody confirmed the in situ nature of the E-DCIS component. The majority of tumor cells showed strong staining with the neuroendocrine markers chromogranin, synaptophysin, and neuron-specific enolase (monoclonal). Immunostaining also dramatically highlighted the pagetoid spread into the papillomas and ductules by outlining the tumor cells between the negatively stained residual ductal epithelium and myoepithelium. All cases were immunoreactive for estrogen and progesterone receptor, but not p53 and c-erbB2. The Ki-67 index was < 5%. Ultrastructural studies on four cases showed many dense-core neurosecretory granules and larger mucigen granules. In group B cases, the invasive component, which comprised 5-95% of the tumor, included colloid carcinoma, 12; "carcinoid" tumor, 3; mixed "carcinoid"/colloid carcinoma, 4; and small cell neuroendocrine carcinoma, 1. Neuroendocrine markers were also consistently demonstrable in the invasive component. In conclusion, E-DCIS is predominantly a disease of older women that is frequently accompanied by papillomas in the vicinity and may present as nipple discharge (an uncommon presentation in the usual forms of DCIS). It can mimic epitheliosis histologically, but the pagetoid spread is a helpful clue to its neoplastic nature. The bland nuclear morphology, lack of necrosis, and biologic marker profile suggest that E-DCIS is a form of low-grade DCIS despite its solid growth pattern. The invasive carcinomas associated with E-DCIS are also neuroendocrine programmed rather than the usual types of ductal carcinomas, suggesting that E-DCIS represents a biologically distinctive category of DCIS.

Aggressive T/natural killer cell lymphoma presenting as testicular tumor.

BACKGROUND: Nonnasal CD56+ T/natural killer (NK) cell lymphomas with morphologic and immunogenetic features similar to those of the distinctive nasal T/NK cell lymphoma are uncommon and have been characterized only recently. They show predominantly extranodal presentation, high stage disease, a highly aggressive course, strong association with Epstein-Barr virus (EBV), and lack of T cell receptor gene rearrangement. Only one previously reported case had a testicular presentation, although the testis is not uncommonly involved during the course of disease in both nasal and nonnasal T/NK cell lymphomas. METHODS: Three patients with T/NK cell lymphoma who presented initially with a testicular mass are reported. RESULTS: The three patients underwent orchidectomy for testicular tumor. Histologically, the testes showed diffuse dense infiltration of medium-sized or large lymphoma cells. Antiocentric growth and necrosis were prominent in two cases. The lymphoma had the following immunophenotype: CD2+ CD3 epsilon+ CD56+ compatible with T/NK cell lymphoma; two lacked staining with Leu4 (CD3), and one had weak staining. With immunohistochemical preparations, it was noted that the rete testis stained consistently for CD56, and the Leydig cells and Sertoli cells showed patchy staining. The neoplastic cells harbored EBV, as demonstrated by in-situ hybridization. Additional sites of disease were detected at the time of the diagnosis in one patient (nose) or appeared soon afterwards in all three patients (skin or gastrointestinal tract). All three patients died within 5 months. CONCLUSIONS: This study confirms that testicular CD56+ T/NK cell lymphoma tends to disseminate early, pursues an aggressive course, and is strongly associated with EBV. CD56 recognizes the neural cell adhesion molecule (NCAM), which exhibits homophilic binding properties. The expression of CD56 in the normal testicular constituents can perhaps explain the tendency for T/NK cell lymphoma to localize in this organ.

Utility of a paraffin section-reactive CD56 antibody (123C3) for characterization and diagnosis of lymphomas.

Although expression of CD56 (neural cell adhesion molecule, a natural killer cell marker) is uncommon among lymphomas, this feature has defined a distinctive and important category of lymphoma: the putative natural killer (NK) cell lymphoma, which shows a predilection for the upper aerodigestive tract, skin, skeletal muscle, and other extranodal sites and pursues an aggressive clinical course. Thus far, CD56 expression can be reliably analyzed only on fresh or frozen tissues. In this study, we evaluated the sensitivity and specificity of a CD56 antibody, 123C3, when applied on routine formalin-fixed, paraffin-embedded tissues for analysis of lymphomas, by comparing the staining results with those obtained on frozen tissues using the CD56 antibody NKH1. The 123C3 antibody worked on paraffin sections only with prior antigen retrieval using a pressure cooker or a microwave oven. Among 32 CD56+ T/NK cell lymphomas and one CD56+ B-lymphoblastic lymphoma, the neoplastic cells showed crisp membrane staining with 123C3 in all cases. None of the 24 CD56- T-cell lymphomas and 50 CD56-B-cell lymphomas stained with 123C3. In normal or reactive lymphoid tissues from a variety of sites, there were few small lymphocytes (< 0.1%) that showed cell membrane staining with 123C3, although occasional plasma cells might show cytoplasmic staining. We conclude that with suitable antigen retrieval procedures, 123C3 can be reliably applied on routine paraffin sections for detection of CD56 expression in lymphomas. Furthermore, this antibody can be used to support a diagnosis of lymphoma or to detect residual disease for cases of CD56+ T/NK cell lymphoma in which the neoplastic lymphoid cells are small and show minimal atypia, especially in small biopsies.

Discordant CD3 expression in lymphomas when studied on frozen and paraffin sections.

The results of CD3 staining in the T or putative natural killer (NK) cell lymphomas of nasal and extranasal sites as reported in the literature have been confusing, with some studies reporting a low rate of CD3 positivity and others a high frequency of CD3 staining. The former studies were performed on fresh or frozen tissues, whereas the latter were performed on paraffin sections using a polyclonal antiserum (poly-CD3). Although previous studies have suggested a high concordance rate of CD3 staining between fresh/frozen tissues and paraffin sections, many CD3- cases have not been studied, and the more reliable antigen retrieval techniques have not been applied. In this study, we addressed the question of discordant CD3 expression by comparing the results of CD3 staining in lymphomas as studied on frozen sections and as studied on paraffin sections (with antigen retrieval effected by pressure cooking). This series was biased toward inclusion of a high percentage of cases of putative NK cell lymphomas, which are prevalent among Asians and usually show a CD2+ CD3(Leu4)- CD56+ immunophenotype. Among 35 cases of CD3(Leu4)- T- and T/NK-cell lymphomas, 30 (86%) showed staining with poly-CD3 on paraffin sections. All 15 CD3(Leu4)+ T-cell lymphomas showed positive staining with poly-CD3 on paraffin sections. None of 60 B-cell lymphomas were stained by poly-CD3, confirming no loss of specificity of staining with this antiserum despite use of an effective antigen-retrieval technique. The discordance rate of CD3 staining in T- and T/NK-cell lymphomas in this series was 60%, and this phenomenon was most commonly observed in the CD56+ T/NK-cell lymphomas: CD3(Leu4)- in frozen sections but poly-CD3+ in paraffin sections. Therefore, to avoid confusion, we propose designating the results based on fresh/frozen tissues CD3(f) and those based on poly-CD3 application on paraffin sections CD3(p) in future reporting of CD3 immunophenotype.

The MIC2 antibody 013. Practical application for the study of thymic epithelial tumors.

The lymphocytes that accompany thymomas express an immature T-cell phenotype, as usually demonstrated by CD1 or TdT immunoreactivity. Even when thymomas metastasize or occur in ectopic sites, the infiltrating T lymphocytes show this unique immature phenotype, contrasting with thymic and nonthymic carcinomas, in which the infiltrating T lymphocytes typically show a mature phenotype (CD1 and TdT negative). Therefore, the presence of an immature T-cell population in an epithelial tumor strongly supports a diagnosis of thymoma. The availability of an antibody that consistently marks immature T-cells in routine paraffin sections would be of great help in the study of thymic tumors. In this report, we describe the use of MIC2 antibody (013), which has been widely used for the diagnosis of Ewing's sarcomas and peripheral primitive neuroectodermal tumors because it intensely stains thymocytes. Immunohistochemical staining was performed on paraffin sections of normal/hyperplastic thymus (18 cases), thymoma (62 cases), thymic carcinoma (nine cases), tumors showing borderline features between thymoma and thymic carcinoma (three cases), and ectopic hamartomatous thymoma (two cases). T-cell and B-cell antibodies were also applied to aid in the interpretation. In the normal thymus, almost all lymphocytes in the cortex stained with 013, whereas fewer than 5% of those in the medulla were 013 positive. In thymomas, including the three ectopic thymomas and the single case of metastatic thymoma, most lymphocytes were 013 positive, except the spindle-cell foci (medullary thymoma or medullary component of mixed thymoma), in which the percentage of 013-positive lymphocytes was lower (5-30%). Within the pale foci of "medullary differentiation" and the perivascular spaces of lymphocyte-rich thymomas, few lymphocytes showed 013 positivity, indicating that the T lymphocytes in these areas were more mature. None of the thymic carcinomas harbored 013-positive lymphocytes. Among the three cases of borderline thymoma/thymic carcinoma, only one harbored 013-positive lymphocytes. The 013-positive lymphocytes were not seen in the ectopic hamartomatous thymomas. In normal lymph nodes and nonthymic carcinomas studied as controls, there were no or at most small numbers of isolated 013-positive lymphocytes. We conclude that interpreted in the proper context, MIC2 antibody can serve as a useful marker of immature T-cells and thus help in the confirmation of a diagnosis of thymoma in small biopsy specimens, ectopic thymoma, or metastatic thymoma; in the distinction between invasive thymoma and thymic carcinoma; and in the classification of thymomas.

Primary lymphoepithelioma-like carcinoma of the lung. A clinicopathologic study of 11 cases.

BACKGROUND: Lymphoepithelioma-like carcinoma (LELC), best known to occur in the nasopharynx, can arise in a variety of sites, such as the salivary gland, thymus, lung, stomach, and skin. Primary LELC of the lung is very rare, with only limited information in the literature. METHODS: The clinicopathologic features of 11 patients with pulmonary LELC collected from two regional hospitals in Hong Kong are described. RESULTS: The patients, all Chinese, were aged 38 to 73 years (median, 54 years), with equal sex incidence. Two of the 8 patients were smokers. Four presented with coin lesions incidentally discovered on chest X-ray, five with cough and blood-stained sputum, and two with pleural effusion. The tumor formed a discrete (9 patients) or an ill-defined (1 patient) nodule in the lung, or, rarely, showed extensive bilateral pulmonary involvement (1 patient). The major bronchi were not involved except in 1 patient. Three patients had lymph node metastasis at presentation; two of them had bone metastasis, one at presentation and one after 9 months. The tumors had pushing margins, and grew in the form of anastomosing islands and sheets, comprising syncytial-appearing large cells with vesicular nuclei and prominent nucleoli. They were infiltrated by an appreciable number of small lymphocytes and plasma cells. Intratumoral amyloid globules were found in one tumor. In five patients, the tumor showed intraepithelial growth within the small bronchi; this could represent either the in-situ phase of the tumor or pagetoid spread into the bronchial epithelium. The neoplastic cells of all patients harbored Epstein-Barr virus (EBV) as demonstrated by in situ hybridization for EBV-encoded small nuclear RNAs. All eight Asian patients with pulmonary LELC previously reported in the literature similarly have been EBV-positive, whereas the four reported Caucasian patients all have been EBV-negative. CONCLUSION: Lymphoepithelioma-like carcinoma of lung occurring in Asians is an EBV-associated neoplasm; it also appears to occur at a higher frequency in Asians than Caucasians. It usually presents as a solitary subpleural nodule, and there is no strong association with cigarette smoking. Most patients have early stage disease at presentation. From the limited available data, the behavior of LELC of lung is highly variable, ranging from apparent curability by excision (particularly for localized disease) to highly aggressive, extensive disease at presentation.

Detection of Epstein-Barr virus in Hodgkin's disease occurring in an Oriental population.

Like Burkitt's lymphoma, the strength of association of Epstein-Barr virus (EBV) with Hodgkin's disease occurring in different populations and clinical settings is highly variable, being 30% to 50% in Western countries, nearly 100% in Third World countries like Peru and Honduras, and nearly 100% in patients seropositive for human immunodeficiency virus. Data on the Oriental populations are very limited. Therefore, the current study was performed on the Chinese population of Hong Kong, where the incidence of Hodgkin's disease is low and EBV seroconversion occurs early in life. Twenty-three consecutive samples of Hodgkin's disease collected from 18 male and five female patients over a 12-year period were studied. The first age peak occurred in the second decade of life, and the second peak in the seventh decade. Using the sensitive and specific EBV-encoded RNAs (EBERs) in situ localization technique, positive labeling of the Reed-Sternberg cells and their variants was detected in five of five samples (100%) of mixed cellularity, nine of 16 samples (56%) of nodular sclerosing, one of one sample (100%) of lymphocyte depleted, and none of one sample (0%) of nodular lymphocyte predominant Hodgkin's disease. Further analysis of the data by age group yielded the following results: four of five (80%) for age younger than 15 years, three of nine (33%) for age 15 to 49, and eight of nine (89%) for age 50 or higher, confirming the reported strong association of EBV with Hodgkin's disease at the extremes of life. The overall positivity rate was 65%, which was intermediate between that reported in the Western populations and that in the Third World countries. These findings can be explained by the epidemiological pattern of Hodgkin's disease in Hong Kong, in which the first age peak is left-shifted to a younger age compared with that of Western populations (but not as early as that observed in Third World countries), moving the peak toward an age bracket in which Hodgkin's disease shows stronger association with EBV.

A study of the association of Epstein-Barr virus with Burkitt's lymphoma occurring in a Chinese population.

There is a strong association (approximately 95%) of endemic Burkitt's lymphoma with Epstein-Barr virus (EBV), whereas the association is weak for the sporadic form occurring in Western countries (approximately 15%). In the Middle East, North Africa and South America, 60-80% of Burkitt's lymphomas harbour EBV. These epidemiological differences suggest that either the endemicity of EBV or socio-economic conditions, or both, may influence the pathogenetic role of EBV in Burkitt's lymphoma. Since only meagre data are available on Asians, this study was performed to address this issue by studying cases from Hong Kong, where EBV seroconversion occurs in the first few years of life but the socio-economic conditions approach those of Western countries. In situ hybridization for EBV encoded RNAs (EBERs) was performed on paraffin sections of 18 cases of Burkitt's lymphoma. Labelling of the neoplastic cells was detected in five cases (27.7%). In contrast, among 54 cases of B-cell lymphomas of various subtypes studied for comparison, signals for EBER were detected in only one case each of T-cell-rich large B-cell lymphoma, anaplastic large cell lymphoma and Reed-Sternberg-like cells occurring in B-cell chronic lymphocytic leukaemia/small lymphocytic lymphoma. The strong labelling with oligo-dT probe (which hybridized with the polyadenylated ends of mRNA) in all cases suggested that the negative results were genuine and not due to poor preservation of RNA in the tissues. Thus, among B-cell neoplasms occurring in Chinese, Burkitt's lymphoma shows a statistically stronger association (P < 0.01) with EBV than with other types of B-cell lymphoma.(ABSTRACT TRUNCATED AT 250 WORDS)

Endocrine malignancies that may mimic benign lesions.

A variety of malignant tumors that occur in endocrine organs may mimic benign lesions histologically. In this article, a number of such tumors are selected for discussion, including several variants of papillary thyroid carcinoma (encapsulated follicular, diffuse sclerosing, diffuse follicular, macrofollicular, cystic, and stroma-rich), paucicellular anaplastic thyroid carcinoma, primary thyroid low grade B-cell lymphoma of mucosa-associated lymphoid tissue type, adrenocortical carcinoma, and parathyroid carcinoma. Emphasis is placed on the histological clues that are helpful for recognizing the malignant nature of these lesions.