bluuebunny/crossref_metadata_2025 huggingface dataset:
Apoptosis in nasopharyngeal carcinoma as related to histopathological characteristics and clinical stage
Authors: Harn H J , Hsieh H F , Ho L I , Yu C P , Chen J H , Chiu C C , Fan H C , Lee W H
Published: March 2003

Aims

We investigated the significance of apoptosis, using the terminal deoxynucleotidyl transferase mediated dUTP‐digoxigenin nick end‐labelling method, in nasopharyngeal carcinoma biopsy samples.

Methods and results

The apoptotic index (AI) in 50 nasopharyngeal carcinomas was compared with various histopathological features and clinical stage. Also, the AI was correlated with p53, bcl‐2 and Ki67 expression by immunohistochemistry. In histopathological studies, the AI was significantly higher in mixed cellular type (MC) than in keratizing squamous cell type (KS) and spindle cell type (SC) (P < 0.001) which worsens prognosis. In tumour stage analyses, AI was higher in early stage (stage 2 and 3) than in high stage (stage 4). In addition, there was a significant correlation between the AI and p53 expression (P < 0.001) but not with proliferative activity (P = 0.15). In NPC containing p53 protein positive tumour cells, there was a significantly higher apoptotic rate.

Conclusions

These findings indicate that apoptosis is related to type and stage of nasopharyngeal carcinoma. They also confirm the role of p53 in regulating tumour apoptosis.
Expression and subcellular localization of human AP endonuclease 1 (HAP1/Ref‐1) protein: a basis for its role in human disease
Authors: Kakolyris  , Kaklamanis  , Giatromanolaki  , Koukourakis  , Hickson  , Barzilay  , Turley  , Leek  , Kanavaros  , Georgoulias  , Gatter  , Harris
Published: March 2003

Aims: Human AP endonuclease 1 (HAP1) plays a major role in the repair of apurinic/apyrimidinic (AP) sites in cellular DNA by catalysing hydrolytic cleavage of the phosphodiester backbone 5′ to the site. HAP1 is also known to be a potent reduction–oxidation (redox) factor, regulating the binding activity of a number of transcription factors. The purpose of the present study was to examine the expression of HAP‐1 in a wide range of human tissues.

Methods and results

Using a recently developed specific rabbit polyclonal antibody, we performed immunohistochemistry on paraffin‐embedded tissue material. Nuclear staining was detected in crypt cells of the small and large intestine, epithelial cells of breast ducts, basal cells of the skin, alveolar cells of the lung, lymphocytes of the marginal zone of the spleen, in the surface epithelium and stromal cells of the ovary and the transitional epithelium of the bladder. Unexpectedly for a presumed nuclear protein, the staining pattern in some cell populations was mainly cytoplasmic (e.g. superficial cells of gastrointestinal tract, Langerhans cells, Leydig cells and spermatocytes, epithelium of the prostate glands), or both cytoplasmic and nuclear (e.g. epithelial cells of thymus, follicular thyroid cells, parietal cells of the stomach, glandular epithelial cells of the cervix, epithelial cells of exocrine pancreas).

Conclusion

This differential expression in a wide spectrum of cells is indicative of a potential multifunctional action of HAP1, not necessarily restricted to a role in the nucleus.
Cystic partially differentiated nephroblastoma in an adult: an immunohistochemical, lectin histochemical and ultrastructural study
Authors: Nagao T , Sugano I , Ishida Y , Tajima Y , Masai M , Nagakura K , Matsuzaki O , Kondo Y , Nagao K
Published: March 2003

Aims

Cystic partially differentiated nephroblastoma (CPDN) is an uncommon renal multicystic tumour, usually affecting early infants. To our knowledge, this report describes the first case of CPDN occurring in an adult.

Methods and results

A 45‐year‐old man was found incidentally to have a left renal cystic tumour, measuring 20 mm in diameter, at the lower pole far from the pelvis. The tumour was composed of multilocular cystic spaces of variable size and intervening septa without solid nodular areas. The cysts were lined by a single layer of flattened, hobnail, or columnar epithelium. The septa were made of mesenchymal cells, which were admixed with small numbers of loosely aggregated blastemal cells, occasional tubular structures in various stages of development, and a few glomeruloid structures. The tumour cells had no anaplasia, and mitoses were rare. Immunohistochemical and lectin histochemical studies revealed that the cyst lining epithelium and the tubular structures in the septa expressed predominantly the markers for distal tubules and collecting ducts. Ultrastructurally, the cyst lining cells closely resembled collecting duct cells while some tubular structures showed an immature nephrogenic morphology. The patient was alive and well without evidence of recurrence 11 months after surgery.

Conclusions

CPDN does occur in adults, as experienced in Wilms' tumour, though its incidence is extremely low. This study suggests that CPDN may show maturation intermediate between cystic nephroma and Wilms' tumour, even in adult cases.
p53 expression, p21 expression and the apoptotic index in endometrioid endometrial adenocarcinoma
Authors: Burton  , Stewart  , Heatley  , Royds  , Wells
Published: March 2003

Aims

Although several genetic abnormalities are known to occur in endometrial cancer, including tp53 gene mutation, the pathogenesis of this common malignancy remains poorly defined. We investigated the relationship between overexpression of p53 protein, p21 protein expression and apoptosis in endometrial carcinoma.

Methods and results

Sixteen cases of endometrial carcinoma in which polymerase chain reaction analysis had demonstrated the absence of a tp53 gene mutation were selected on the basis of p53 protein expression; p21 protein expression and the apoptotic index were then determined for each case. The proportion of cells in each case expressing p53 and p21 protein immunoreactivity was compared with the apoptotic index. Overall, no significant correlation was demonstrated between p53 and p21 immunoreactivity, or between either p53 or p21 and the apoptotic index.

Conclusions

Factors other than p53 are involved in the regulation of p21 expression and apoptosis in endometrioid endometrial adenocarcinomas without p53 mutations. Despite the small numbers used in this study, the data suggest a correlation between low levels of p53 immunoreactivity and apoptosis. We postulate that high levels of p53 immunoreactivity may be due to abnormal stabilization of the p53 protein. Follow‐up studies are needed with a larger data set.
Malignant myxoid endobronchial tumour: a report of two cases with a unique histological pattern
Authors: Nicholson  , Baandrup  , Florio  , Sheppard  , Fisher
Published: March 2003

Aims

To present two cases of malignant endobronchial myxoid tumours with a highly distinctive sarcomatoid pattern not previously described at this site, and discuss their histogenesis in relation to previously documented endobronchial neoplasms.

Methods and results

Both tumours presented in young adult females and were purely sarcomatoid with interweaving cords of small uniform, rounded or slightly elongated cells lying within a myxoid stroma. The stroma was alcian blue positive, but sensitive to hyaluronidase in both cases. The tumour cells contained a small volume of periodic acid–Schiff‐positive eosinophilic cytoplasm and stained positively for vimentin only, but there also was a prominent background population of CD68‐positive dendritic cells. Ultrastructural studies showed that the tumour cells contained an excess of rough endoplasmic reticulum, with some of the cisternae appearing dilated, and scalloping of the cell surfaces, although no intracisternal tubules were identified.

Conclusions

Although the histological pattern was most reminiscent of extraskeletal myxoid chondrosarcoma, the sensitivity of the stroma to pretreatment with hyaluronidase precluded the diagnosis. However, there were similarities with the sarcomatoid component of malignant salivary gland‐type mixed tumours of the lung and this tumour possibly represents a variant of a bronchial gland tumour. Despite this uncertainty over origin, this pattern should be recognized as part of the differential diagnosis of myxoid tumours in the lung, as an apparently indolent type of malignant endobronchial neoplasm.
Spindle cell tumours of the breast: practical approach to diagnosis
Authors: Al‐Nafussi A
Published: March 2003

Spindle cell tumours of the breast are uncommon and often present diagnostic challenges. The most important is the sarcomatoid/metaplastic carcinoma, which has monophasic and biphasic variants. Each of these groups presents special diagnostic difficulties. In the monophasic variant the mesenchymal component predominates and the epithelial element forms a minor component often detected only after immunohistochemical study. The spindle cell areas may be bland and therefore under‐diagnosed as nodular fasciitis or fibromatosis. Alternatively they may be highly malignant with a pattern that is misinterpreted as primary sarcoma of the breast. In the biphasic variant, the difficulty is in distinguishing between sarcomatoid carcinoma, myoepithelial carcinoma or malignant phyllodes tumour. Other spindle cell lesions of the breast include the various myofibroblastic tumours, the spindle cell variant of adenomyoepithelioma, the varied primary breast sarcomas, metastatic tumours with spindle cell morphology and, finally, the very rare follicular dendritic cell tumour. A simple practical approach to the diagnosis of spindle cell lesions is presented to help the general surgical pathologist to compile a differential diagnosis and to arrive at the correct conclusion
Phenotypes in canalicular adenoma of human minor salivary glands reflect the interplay of altered secretory product, absent neuro‐effector relationships and the diversity of the microenvironment
Authors: Triantafyllou  , Coulter  , Scott
Published: March 2003

Aims

Uncertainty about the factors influencing phenotypes in salivary canalicular adenoma prompted the present investigation.

Methods and results

Specimens of canalicular adenoma from 15 patients were examined with the use of histology, histochemistry for protein, mucosubstances and pigments, nerve staining and immunocytochemistry for cytoskeleton components. The tumours consisted largely of simple cells lining tubules that were occasionally cystic or branching and budding, and were set in loose, vascular and often haemorrhagic stroma. Other phenotypes recognized were mucous cells, apocrine‐like cells, pigmented cells, microliths and stromal macrophages, detected in 26.6%, 20%, 33.3%, 20% and 53.3% of the patients, respectively. Simple cells showed moderate levels of ‐SH groups and strong immunoreactivity for ‘simple’ epithelial phenotype cytokeratin. The simple cells lining cystic tubules showed additional immunoreactivity for ‘stratified’ epithelial phenotype cytokeratin, possibly an adaptation to mechanical pressure. Lumina showed variable levels of neutral and carboxylated glycoproteins, and chondroitin sulphate. Stroma showed high levels of chondroitin sulphate and hyaluronic acid. Mucous cells showed high levels of ‐SS‐ groups and nonsulphated glycoproteins. Apocrine‐like cells contained lipofuscin. Pigmented cells contained haemosiderin, possibly a consequence of localized iron overload. Microliths contained mucosubstances. Macrophages often contained lipofuscin. No nerves were found in relation to the tumours.

Conclusions

The results suggest that, contrary to popular belief, phenotypes in canalicular adenoma do not reflect histogenetic concepts but rather may derive from the interplay between an altered secretory product, consisting of glycosaminoglycan and an immature form of glycoprotein, the lack of neuro‐effector relationships and the different microenvironments throughout the tumour.
Mycobacterial cervical lymphadenitis: the histological features of non‐tuberculous mycobacterial infection
Authors: Kraus  , Benharroch  , Kaplan  , Sion‐Vardy  , Leiberman  , Dima  , Shoham  , Fliss
Published: March 2003

Aims

The distinction between nontuberculous mycobacterial (NTM) lymphadenitis and other causes of cervical lymphadenitis is critical, as different entities call for different treatments. Despite modern diagnostic techniques for NTM infections their prompt and accurate diagnosis is still difficult. We assessed the value of different histological features in diagnosing clinically suggestive NTM cervical lymphadenitis in cases of granulomatous cervical lymphadenitis.

Methods and results

A retrospective study of 30 patients with a clinical diagnosis of NTM cervical lymphadenitis was carried out. The patients were divided into three subgroups and several histological parameters were examined in each subgroup. A comparison was made with cases of proven tuberculous lymphadenitis. Four histological features (presence of microabscesses, ill‐defined granulomas, noncaseating granulomas and a small number of giant cells) were found with significant statistical difference when comparison was made between the NTM group and the tuberculosis group.

Conclusions

A rapid and accurate diagnostic procedure for NTM lymphadenitis is not yet available. Therefore, in the presence of a suggestive clinical picture for NTM lymphadenitis, we propose four histological features which support this diagnosis, thus allowing prompt therapeutic intervention.
Ber EP4 and epithelial membrane antigen aid distinction of basal cell, squamous cell and basosquamous carcinomas of the skin
Authors: Beer T W , Shepherd P , Theaker J M
Published: March 2003

Aims

: Seventy‐five skin tumours were studied to investigate the value of immunohistochemistry in differentiating basal cell, squamous cell and basosquamous carcinomas of the skin.

Methods and results

: Archived paraffin‐embedded tissue samples of basal cell carcinomas (n = 39), squamous cell carcinomas (n = 23) and basosquamous carcinomas (n = 13) were stained immunohistochemically using a panel of antibodies. All of the basal cell carcinomas stained positively for Ber EP4, in contrast to the group of squamous cell carcinomas, that showed no staining. Basosquamous carcinomas all showed at least some areas of Ber EP4 positivity. None of the basal cell carcinomas, but most of the squamous cell carcinomas (22 of 23) expressed epithelial membrane antigen (EMA). Only one of the basosquamous carcinomas expressed EMA positivity focally. CAM 5.2, carcinoembryonic antigen (CEA) and 34βE12 antibodies lacked specificity in relation to the different tumour types.

Conclusion

: Distinction of basal and squamous cell carcinomas of the skin can be readily achieved with routine immunohistochemistry using Ber EP4 and EMA. Identification of basosquamous carcinoma is also facilitated with this method.
Tamoxifen‐associated postmenopausal adenomyosis exhibits stromal fibrosis, glandular dilatation and epithelial metaplasias
Authors: McCluggage W G , Desai V , Manek S
Published: March 2003

Aims

Adenomyosis is relatively rare in postmenopausal women but recent reports have described its occurrence in this age group in patients taking tamoxifen. This study describes the pathology of nine cases of adenomyosis in postmenopausal women who were taking this medication.

Methods and results

The pathology of the nine tamoxifen‐associated cases was compared to five cases of postmenopausal adenomyosis not associated with tamoxifen. Morphological features present within adenomyosis more often in those taking tamoxifen were cystic dilatation of glands (which sometimes resulted in grossly visible intramural cystic lesions), fibrosis of the stroma and various epithelial metaplasias. The proliferative activity within the adenomyosis, as determined by MIB1 staining, was higher in the tamoxifen group.

Conclusions

The study supports an association between tamoxifen therapy and the presence of adenomyosis in postmenopausal women. The aforementioned morphological features are characteristic of polypoid and nonpolypoid surface endometrium associated with tamoxifen and their occurrence within the adenomyosis is likely to represent extension of the surface epithelial changes. Adenomyosis may be more common than is generally realized in women taking tamoxifen and may account for postmenopausal bleeding in these patients.
Hyperplastic polyps and DNA microsatellite unstable cancers of the colorectum
Authors: Jass J R , Young J , Leggett B A
Published: March 2003

Although the scientific and clinical rationale for classifying colorectal cancer according to mechanisms underlying genetic instability is well supported, little is known of the early morphogenesis of sporadic cancer showing high levels of DNA microsatellite instability (MSI‐H). Evidence is accumulating that the traditional adenoma–carcinoma sequence may not apply to sporadic MSI‐H colorectal cancer. The serrated pathway comprising hyperplastic polyps, mixed polyps and serrated adenomas may serve as the missing link. This review relates the recently described CpG island methylator phenotype (CIMP) to the serrated pathway. Two rate‐limiting genetic steps may underlie the neoplastic pathway associated with CIMP. A transmembrane receptor expressed by pericryptal myofibroblasts (HPP1) may be implicated in the transition from normal to hyperplasia whereas inactivation of hMLH1 is responsible for the conversion of hyperplasia to dysplasia through loss of DNA mismatch repair. These mechanisms fit with clinical observations relating to sporadic MSI‐H colorectal cancer, specifically proximal location, multiplicity, higher frequency among females and rapid evolution of early cancer.
Specific staining of human chorionic gonadotropin β in benign and malignant gastrointestinal tissues with monoclonal antibodies
Authors: Louhimo J , Nordling S , Alfthan H , Von Boguslawski K , Stenman U‐H , Haglund C
Published: March 2003

Specific staining of human chorionic gonadotropin β in benign and malignant gastrointestinal tissues with monoclonal antibodies

Aims: Human chorionic gonadotropin (hCG) β in serum is a promising tumour marker for gastrointestinal malignancies. Our aim was to investigate the expression of hCGβ by immunohistochemistry in various gastrointestinal cancers and benign tissues.

Methods and results: A monoclonal antibody (MAb) specific for free hCGβ was used to stain 107 tissue samples from various gastrointestinal malignancies and 36 benign or normal tissue samples. The specificity of the staining was verified and the results compared with those obtained with a widely used commercial polyclonal antibody (PAb) which reacts with both free hCGβ and intact hCG, as well as with luteinizing hormone β. With the MAb, we observed positive immunohistochemical staining in 24% of the malignant gastrointestinal tumours. Gastric (60%) and pancreatic (56%) carcinomas, as well as extrahepatic cholangiocarcinomas (36%), were positive most frequently. We also discovered immunoreactivity in half of the non‐malignant samples from pancreatic and biliary tissues. With the PAb, hCG immunoreactivity was evident more frequently in some cancers, but the staining was diffuse and occasionally polymorphonuclear leucocytes were strongly stained.

Conclusions: This study shows that our MAbs specific for hCGβ are well suited for immunohistochemistry. Our results confirm previous findings on gastrointestinal cancers and, furthermore, we demonstrate hCGβ tissue expression in pancreatic adenocarcinoma. The results support reports on hCGβ as a serum tumour marker for digestive tract diseases.
The spectrum of micronodular thymic epithelial tumours with lymphoid B‐cell hyperplasia
Authors: Tateyama H , Saito Y , Fujii Y , Okumura M , Nakamura K , Tada H , Yasumitsu T , Eimoto T
Published: March 2003

The spectrum of micronodular thymic epithelial tumours with lymphoid B‐cell hyperplasia

Aims: A rare type of thymoma, micronodular thymoma with lymphoid B‐cell hyperplasia, was recently reported by Suster and Moran. Thymic epithelial tumours with a similar pattern but with varied cytological features of the tumour cells are analysed.

Methods and results: A total of 11 cases of thymic epithelial tumours characterized by micronodular proliferation of tumour cells separated by abundant lymphoid stroma with prominent germinal centres were reviewed clinicopathologically and examined immunohistochemically. The presence of Epstein–Barr virus (EBV) genome was also examined by in‐situ hybridization. Based on the morphology of tumour epithelial cells, cases were subdivided into four groups: group 1 (two cases) having spindle epithelial cells; group 2 (two cases) showing an admixture of spindle and polygonal epithelial cells; group 3 (five cases) having polygonal epithelial cells, with mild to moderate cytological atypia in four cases, and group 4 (two cases) representing lymphoepithelioma‐like carcinoma. The degree of cytological atypia and the number of tumour cells positive for MIB‐1 and p53 gradually increased towards group 4. The abundant lymphoid stroma in all cases contained many CD20‐positive B‐cells and CD3 and CD45RO‐positive T‐cells. CD99‐positive immature T‐cells were present in all cases of groups 1 and 2 and in most cases of group 3, but not in both cases of group 4 tumours. IgG, IgM and IgD‐positive plasma cells and lymphocytes were also present in all cases, more prominent in those of groups 3 and 4. The EBV genome was detected in only a few lymphocytes in five cases.

Conclusions: The tumours in this series belong to a distinct category of thymic epithelial tumours and each of the above groups may constitute a spectrum in the continuum of cytological atypia. The aetiological relationship of EBV with these tumours could not be proved. The lymphoid B‐cell hyperplasia may result from a host immune response and may suggest a favourable clinical course of this type of tumour.
Lung carcinoma with rhabdoid cells: a clinicopathological study and survival analysis of 14 cases
Authors: Shimazaki H , Aida S , Sato M , Deguchi H , Ozeki Y , Tamai S
Published: March 2003

Lung carcinoma with rhabdoid cells: a clinicopathological study and survival analysis of 14 cases

Aims: We determined the clinicopathological features of primary lung carcinomas with rhabdoid cells by defining the immunophenotype of rhabdoid cells and analysing survival.

Methods and results: Rhabdoid cells are distinctive in having an eccentric nucleus and a large intracytoplasmic inclusion on routinely stained sections. Based on the number of rhabdoid cells, 45 cases of large cell carcinoma were divided into the following three types: lung tumour with a rhabdoid phenotype (LTRP) (n=4), lung carcinoma with a small number of rhabdoid cells (LCSR) (n=10), large cell carcinoma containing no rhabdoid cells (LCNR) (n=31). LTRP is composed of at least 10% rhabdoid cells. In LCSR the percentage of rhabdoid cells is less than 10%. LTRP and LCSR are associated with locally advanced disease. Immunohistochemical stains were positive for epithelial markers in all LTRP and eight LCSR, for neuroendocrine markers in one LTRP and three LCSR. The outcome is worse for patients with LTRP than LCSR or LCNR. LCSR shows a trend close to LCNR. Stage‐matched survival analysis, however, revealed no statistically significant difference among the histological subtypes.

Conclusions: Rhabdoid cells are heterogeneous except for epithelial markers and vimentin positivity. Less than 5% of rhabdoid cells has a negligible effect on prognosis.
Colorectal neoplasia in ulcerative colitis—recent advances
Authors: Wong N A C S , Harrison D J
Published: March 2003

Colorectal neoplasia in ulcerative colitis—recent advances

It is recognized that ulcerative colitis (UC) predisposes to the development of colorectal adenocarcinoma (CRC), and the molecular pathway for this process differs from that for sporadic CRCs. However, several important details regarding the risk factors for and the molecular changes underlying UC‐related colorectal carcinogenesis have only come to light lately. First, recent data suggest environmental factors related to long‐standing inflammation contribute more to this increased cancer risk than an inherited susceptibility. Second, molecular changes that may represent the first steps in the development of neoplasia are being increasingly identified in non‐dysplastic, colitic mucosa. Third, there is now good evidence suggesting that UC‐related CRC may develop along more than one molecular pathway. These emerging data will hopefully contribute to attempts to prevent the development of UC‐related CRC, e.g. through refining surveillance programmes. Details of the molecular heterogeneity of UC‐related dysplasia and CRC may also help develop reliable tools for diagnosing the former and for predicting the behaviour of the latter. Finally, there is increasing awareness of non‐epithelial colorectal malignancies which are associated with UC and may potentially increase in incidence with changes in the medical management of this inflammatory disease.
Expression of MMP‐2 is associated with progression and lymph node metastasis of gastric carcinoma
Authors: Mönig S P , Baldus S E , Hennecken J K , Spiecker D B , Grass G , Schneider P M , Thiele J , Dienes H P , Hölscher A H
Published: March 2003

Expression of MMP‐2 is associated with progression and lymph node metastasis of gastric carcinoma

Aims: One important step in tumour invasion is the penetration of the basement membrane. Matrix metalloproteinases (MMPs) play a key role in the migration of normal and malignant cells through the basement membrane. The aim of this study was to investigate correlations between matrix metalloproteinase 2 (MMP‐2) immunoreactivity and currently used classification systems and possible relationships between lymph node metastasis and MMP‐2 expression.

Methods and results: This prospective study analysed specimens obtained from 114 gastric cancer patients (mean age 64 years; range 33–86 years) who underwent gastrectomy with extended lymphadenectomy. All specimens were categorized according to UICC classification, WHO classification, tumour differentiation, Laurén classification, Ming classification and Goseki classification. Formalin‐fixed paraffin‐embedded tumour specimens were stained using an avidin–biotin complex peroxidase assay. MMP‐2 expression in the tumour epithelium was studied by immunohistochemistry with semiquantitative (score 0–3) evaluation. The MMP‐2 staining pattern was positive (score 1–3) in 93 (81.6%) specimens and negative (score 0) in 21 (18.4%) samples. No significant correlations were found between MMP‐2 expression and other variables such as age, tumour differentiation, WHO, Lauren, Goseki, and Ming classifications. In contrast, the intensity of MMP‐2 staining in tumour cells correlated significantly with depth of tumour infiltration (T‐stage), lymph node metastasis (N‐stage), distant metastasis (M‐stage), and UICC stage.

Conclusions: Expression of MMP‐2 is strongly associated with tumour progression and lymph node metastasis in gastric cancer. Therefore MMP‐2 staining may be clinically useful as predictor of tumour progression, especially for lymph node metastasis.
Histiocyte‐rich, T‐cell‐rich B‐cell lymphoma: a distinct diffuse large B‐cell lymphoma subtype showing characteristic morphologic and immunophenotypic features
Authors: Achten R , Verhoef G , Vanuytsel L , De Wolf‐Peeters C
Published: March 2003

Histiocyte‐rich, T‐cell‐rich B‐cell lymphoma: a distinct diffuse large B‐cell lymphoma subtype showing characteristic morphologic and immunophenotypic features

Aims: The clinicopathological features of histiocyte‐rich, T‐cell‐rich B‐cell lymphoma (HRTR‐BCL) were first recognized in 1992. In this study, 60 cases of HRTR‐BCL were analysed in order to provide a detailed morphological and immunophenotypical profile of the disorder.

Methods and results: HRTR‐BCL is easily distinguished from other B‐cell lymphomas rich in stromal T‐cells by (i) a diffuse or vaguely nodular growth pattern, (ii) the presence of a minority population of CD15−, CD20+ large neoplastic B‐cells, (iii) a prominent stromal component composed of both T‐cells and non‐epithelioid histiocytes, and (iv) the scarcity of small reactive B‐cells. These criteria also enable a reliable distinction from lymphocyte‐rich classical Hodgkin’s lymphoma (CHL), from lymphocyte‐predominant Hodgkin’s lymphoma (LPHL), paragranuloma type and from peripheral T‐cell lymphoma. Based on the morphology of the neoplastic cells and on their frequent bcl‐6 immunoreactivity, we speculate that HRTR‐BCL may be derived from a progenitor cell of germinal centre origin.

Conclusions: HRTR‐BCL presents characteristic clinical features, affecting predominantly middle‐aged men who present with advanced stage disease and are at high risk of treatment failure. Considering these distinctive clinicopathological features, recognizing HRTR‐BCL as a lymphoma entity may be justified.
Reduced HBME‐1 immunoreactivity of papillary thyroid carcinoma and papillary thyroid carcinoma‐related neoplastic lesions with Hürthle cell and/or apocrine‐like changes
Authors: Mai K T , Bokhary R , Yazdi H M , Thomas J , Commons A S
Published: March 2003

Reduced HBME‐1 immunoreactivity of papillary thyroid carcinoma and papillary thyroid carcinoma‐related neoplastic lesions with Hürthle cell and/or apocrine‐like changes

Background: We have recently observed that Hürthle cell tumours and papillary thyroid carcinoma with tumour cells showing decapitation of luminal portion of the cytoplasm (apocrine‐like changes) display negative or decreased immunoreactivity for HBME. The purpose of this study is to correlate papillary thyroid carcinoma with positive and negative immunoreactivity for HBME with the histopathological features.

Methods and results: Two hundred and five thyroid neoplasms including carcinoma and adenomas were grouped into Hürthle cell tumours, tumours with or without some features of Hürthle cells, tumours with apocrine‐like changes and adenomas with or without limited nuclear features of papillary thyroid carcinoma but not diagnostic for papillary thyroid carcinoma. All neoplasms were submitted for immunostaining with cytokeratin 19 (CK19) and HBME. Papillary thyroid carcinoma, follicular carcinoma and follicular adenoma that have areas of limited nuclear features but not diagnostic for papillary thyroid carcinoma showed stronger immunostaining for HBME than their respective counterparts with Hürthle cell changes. All Hürthle cell tumours showed negative to focal reactivity. This decrease of reactivity for HBME was proportional to the levels of Hürthle cell changes. In addition, focal to extensive apocrine‐like changes were seen in most Hürthle cell neoplasms and rarely seen in non‐Hürthle cell neoplasms. Apocrine‐like changes abolished or decreased HBME immunoreactivity of papillary thyroid carcinoma and tumours with limited nuclear features. Immunostaining for cytokeratin AE3 was not affected by Hürthle cell or apocrine‐like changes.

Conclusions: All papillary thyroid carcinomas without Hürthle cell or apocrine‐like differentiation are reactive for HBME. Hürthle cell tumours and tumours with Hürthle cell or apocrine‐like changes show negative or focal reactivity for HBME. Except for this limitation, HBME is a sensitive marker for papillary thyroid carcinoma and tumours with limited nuclear features.
Comparative evaluation of the prognostic value of MUC1, MUC2, sialyl‐Lewisa and sialyl‐Lewisx antigens in colorectal adenocarcinoma
Authors: Baldus S E , Mönig S P , Hanisch F‐G , Zirbes T K , Flucke U , Oelert S , Zilkens G , Madejczik B , Thiele J , Schneider P M , Hölscher A H , Dienes H P
Published: March 2003

Comparative evaluation of the prognostic value of MUC1, MUC2, sialyl‐Lewisa and sialyl‐Lewisx antigens in colorectal adenocarcinoma

Aims: The significance of MUC1, MUC2 and sialylated Lewis blood group antigens as prognostic markers in colorectal adenocarcinoma was investigated in a large series of patients because previous investigations revealed inconsistent results due to unrelated tumour samples from different patient groups and methodological differences.

Methods and results: Tissues from 243 patients with colorectal adenocarcinoma were stained immunohistochemically. MUC1 showed a strong immunoreactivity (in more than 35% of the tumour area) in 32.5%, MUC2 in 51.0%, sialyl‐Lewisx in 67.9% and sialyl‐Lewisa in 73.7% of the cases, respectively. MUC1 immunoreactivity displayed a significant correlation with tumour progression as reflected by advancing pTNM staging and poor differentiation. MUC2 expression was significantly stronger in mucinous adenocarcinomas. Sialyl‐Lewisx immunostaining correlated with the extent of lymph node metastasis as well as low cytological differentiation. According to univariate and multivariate analysis (P < 0.0001) only MUC1 reactivity represented a marker of worse survival probability, opposed to the sialylated Lewis antigens that did not exert a predictive value.

Conclusions: According to our data, MUC1 and sialyl‐Lewisx immunoreactivity exhibit statistically significant correlations with established markers of tumour progression. However, only MUC1 presents as an independent prognostic factor of colorectal adenocarcinoma.
Frequent alteration of MDM2 and p53 in the molecular progression of recurring non‐Hodgkin's lymphoma
Authors: Møller M B , Nielsen O , Pedersen N T
Published: March 2003

Aims: Recurrence of non‐Hodgkin's lymphoma with or without transformation is often associated with increased clinical drug resistance and poor prognosis indicating molecular progression. The study addresses the currently poorly understood molecular mechanisms underlying relapsing non‐Hodgkin's lymphoma.

Methods and results: We have analysed sequential biopsies from 42 non‐Hodgkin's lymphoma patients immunohistochemically for p53 alterations (based on p53 and p21Waf1 expression), as well as for expression of MDM2, p27Kip1 and cyclin D3. Relapse of follicle centre lymphoma was associated with p53 alterations as 5/6 (83%) follicle centre lymphomas with normal p53 at diagnosis showed p53 alterations at relapse. Of these cases, three showed transformation to diffuse large B‐cell lymphoma. p53 alteration was also associated with relapse of de novo diffuse large B‐cell lymphoma and T‐cell non‐Hodgkin's lymphoma, as 2/5 (40%) diffuse large B‐cell lymphomas and 3/9 (33%) T‐cell non‐Hodgkin's lymphomas with normal p53 at diagnosis showed p53 alterations at relapse. No indolent non‐Hodgkin's lymphoma case showed MDM2 over‐expression at diagnosis, whereas 4/5 (80%) transformed diffuse large B‐cell lymphomas developed MDM2 over‐expression.

Conclusion: Our data are consistent with the notion that p53 alterations are important for the histological transformation of follicle centre lymphoma. However, the data also suggest that relapsing follicle centre lymphomas without overt transformation often have p53 alterations and increased risk of transformation, and that relapse of de novo diffuse large B‐cell lymphomas and T‐cell non‐Hodgkin's lymphomas is associated with p53 alterations. Furthermore, our results are consistent with an association of MDM2 over‐expression with histological transformation of both follicle centre lymphoma and marginal zone B‐cell lymphoma.
Cathepsin G enhances human natural killer cytotoxicity
Authors: Yamazaki  , Aoki
Published: March 2003

Cathepsin G is a serine protease located in the azurophil granules of neutrophils. In this study, we investigated the effect of cathepsin G on the functions of human natural killer (NK) cells in vitro. Cathepsin G enhanced NK cytotoxicity rapidly in a dose‐dependent fashion. The ability to augment NK cytotoxicity was markedly reduced in the presence of the inhibitor, phenylmethanesulphonyl fluoride (PMSF) or chymostatin, demonstrating that the proteolytic activity of cathepsin G is essential for the induction of NK cytotoxicity. Granulocyte exocytosis is required for NK cell‐dependent target killing. Cathepsin G induced the release of the granule enzyme, N‐acetyl‐β–glucosaminidase, from human NK cells. Moreover, an increase in the cytosolic‐free Ca2+ concentration was observed in NK cells after stimulation with cathepsin G. When human granulocytes were stimulated with cytochalasin B and N‐formyl‐methionyl‐leucyl‐phenylalanine (fMLP), cathepsin G was released. The cathepsin G released from granulocytes also caused enhancement of NK cytotoxicity. In the presence of serine protease inhibitor the supernatant including cathepsin G obtained from stimulated granulocytes did not enhance NK cytotoxicity, but the stimulated granulocytes did. Highly purified human NK cells treated with cathepsin G enhanced NK cytotoxicity, but NK‐depleted lymphocytes did not, demonstrating that cathepsin G regulates NK cytotoxicity independently of other factors. We have shown recently that human cathepsin G binds to human NK cells. These combined data indicate that cathepsin G released from granulocytes binds to NK cells and augments NK cytotoxicity through its protease activity.
Interleukin‐4 and interleukin‐10 are chondroprotective and decrease mononuclear cell recruitment in human rheumatoid synovium in vivo
Authors: JORGENSEN  , APPARAILLY  , COURET  , CANOVAS  , JACQUET  , SANY
Published: March 2003

We used the severe combined immunodeficient (SCID) mouse model to assess the effect of interleukin‐4 (IL‐4) or IL‐10 injection on cartilage degradation and mononuclear cell (MNC) recruitment to human rheumatoid synovium in vivo. Human rheumatoid synovium and cartilage from five rheumatoid arthritis patients, obtained after joint replacement surgery, were engrafted subcutaneously to 6–8‐week‐old SCID CB17 mice. Synovial tissues were injected with recombinant human IL‐4 (rhIL‐4, 100 ng; rhIL‐10, 100 ng), both cytokines, or tumour necrosis factor‐α (TNF‐α) (1000 U), or phosphate‐buffered saline twice a week for 4 weeks. The graft was removed and immunochemical analysis was carried out to assess intracellular adhesion molecule‐1 (ICAM‐1), vascular cell adhesion molecule‐1 (VCAM‐1) and E‐selectin expression. Moreover, cartilage degradation was assessed through the quantification of the erosion surface on a computerized image of the engrafted cartilage at high power view. MNC recruitment in the synovial tissue was determined by labelling blood MNC with indium‐111 before their intraperitoneal injection. The activity obtained in the region of the graft were determined with a gamma camera 72 hr postinjection. The results are expressed as a percentage of initial injected activity. After 4 weeks we observed a decrease of cartilage area in controls (77±8%), inhibited after injection of IL‐4, IL‐10, or both cytokines (90±3%, 89·1±4%, 89·2±5% respectively), and 57±17% after TNF‐α injection. The % MNC activity in the graft decreased to 77±81% (NS), 9±4% (P<0·003) and 19±6% (P<0·007) compared with untreated synovial tissue after treatment with IL‐4, IL‐10, or both cytokines, respectively. Moreover, IL‐10 but not IL‐4 decreased the expression of ICAM‐1 but not VCAM‐1 or E‐selectin by synovial cells. These results suggest that IL‐10 and IL‐4 could have chondroprotective properties, and that IL‐10 but not IL‐4 inhibits MNC traffic towards the synovial tissue efficiently.
Activation of complement by human IgG1 and human IgG3 antibodies against the human leucocyte antigen CD52
Authors: REDPATH†  , MICHAELSEN  , SANDLIE  , CLARK
Published: March 2003

Activation of the complement cascade by immunoglobulin G (IgG) plays a major role in the host defence against pathogens. Using recombinant human antibodies specific for the leucocyte antigen CD52, different allotypes of human IgG1 subclass were compared for their ability to activate human complement. In addition the roles of the different length hinge regions of IgG1 and IgG3 were investigated. It was found that the naturally occurring allotypes G1m(a,z) and G1m(f), and one artificially created isoallotype, G1m(null), did not significantly differ in their overall ability to cause cell lysis. However, some differences in binding of individual components of the classical activation pathway were detected. More of the complement component C1s seemed to be associated with the allotype G1m(f), although this did not result in an overall improvement in lytic potency. In this system the wild‐type IgG3 was found to be less effective in complement lysis than IgG1. By shortening the hinge region of IgG3 to resemble that of an IgG1 antibody, increased complement binding was observed compared with that of wild‐type IgG3 and the IgG1 allotypes. The overall lytic potency of the antibody was also improved compared with wild type IgG3 and it was also slightly more effective than the IgG1 allotypes.
Expression of the TrkB neurotrophin receptor by thymic macrophages
Authors: García‐Suárez* O. , Hannestad* J. , Esteban I. , Sainz R. , Naves F. J. , Vega J. A.
Published: March 2003

Increasing evidence suggests that some members of the neurotrophic factor family of neurotrophins could be implicated in the regulation of immune responses. Neurotrophins, as well as their tyrosine kinase signal‐transducing receptors (the so‐called Trk neurotrophin receptors), have been detected in different lymphoid tissues, although their cellular localization is not well known. In this study we used single and double immunohistochemistry to localize TrkB in situ in the rat thymus (in animals from 0 days to 2 years of age), in cytospin preparations of rat thymic cells, and in two mouse monocyte–macrophage cell lines (RAW 264.7 and J774A.1). We found TrkB protein expression in a subpopulation of cells in the corticomedullary junction, which simultaneously expressed the rat macrophage marker ED1. The density of TrkB‐expressing cells increased with age, reaching maximal values at 2 years. Conversely, no evidence of TrkB protein expression could be found in dendritic cells, epithelial cells or thymocytes. Thymic macrophages in cytospin preparations, as well as in the mouse monocyte–macrophage cell lines, also expressed TrkB protein. Although the possible function of TrkB in the thymic macrophage remains to be clarified, present findings add further evidence to the proposed role of neurotrophins in the immune system.
Peroxynitrite‐induced thymocyte apoptosis: the role of caspases and poly (ADP‐ribose) synthetase (PARS) activation
Authors: VIRÁG L. , SCOTT G. S. , CUZZOCREA S. , MARMER D. , SALZMAN A. L. , SZABÓ C.
Published: March 2003

The mechanisms by which immature thymocyte apoptosis is induced during negative selection are poorly defined. Reports demonstrated that cross‐linking of T‐cell receptor leads to stromal cell activation, expression of inducible nitric oxide synthase (iNOS) and, subsequently, to thymocyte apoptosis. Therefore we examined, whether NO directly or indirectly, through peroxynitrite formation, causes thymocyte apoptosis. Immuno‐histochemical detection of nitrotyrosine revealed in vivo peroxynitrite formation in the thymi of naive mice. Nitrotyrosine, the footprint of peroxynitrite, was predominantly found in the corticomedullary junction and the medulla of naive mice. In the thymi of mice deficient in the inducible isoform of nitric oxide synthase, considerably less nitrotyrosine was found. Exposure of thymocytes in vitro to low concentrations (10 μm) of peroxynitrite led to apoptosis, whereas higher concentrations (50 μm) resulted in intense cell death with the characteristics of necrosis. We also investigated the effect of poly (ADP‐ribose) synthetase (PARS) inhibition on thymocyte apoptosis. Using the PARS inhibitor 3‐aminobenzamide (3‐AB), or thymocytes from PARS‐deficient animals, we established that PARS determines the fate of thymocyte death. Suppression of cellular ATP levels, and the cellular necrosis in response to peroxynitrite were prevented by PARS inhibition. Therefore, in the absence of PARS, cells are diverted towards the pathway of apoptotic cell death. Similar results were obtained with H2O2 treatment, while apoptosis induced by non‐oxidative stimuli such as dexamethasone or anti‐FAS antibody was unaffected by PARS inhibition. In conclusion, we propose that peroxynitrite‐induced apoptosis may play a role in the process of thymocyte negative selection. Furthermore, we propose that the physiological role of PARS cleavage by apopain during apoptosis may serve as an energy‐conserving step, enabling the cell to complete the process of apoptosis.
Inhibition of sCD23 and immunoglobulin E release from human B cells by a metalloproteinase inhibitor, GI 129471
Authors: WHEELER  , PARVEEN  , POLLOCK  , WILLIAMS
Published: March 2003

Soluble CD23 (sCD23) has been proposed to play an important role in the up‐regulation of immunoglobulin E (IgE) synthesis. Production of sCD23 is dependent on the proteolytic cleavage of membrane CD23, but the protease(s) involved in this process remain unknown. Preliminary data, obtained by testing a panel of protease inhibitors, suggested that this enzyme may be a zinc‐dependent metalloproteinase. Therefore, we investigated the effect of a standard hydroxamate‐type Zn2+ metalloproteinase inhibitor (GI 129471) on both sCD23 and IgE release from human tonsillar B cells, stimulated with interleukin‐4 (IL‐4) and anti‐CD40. Incubation of cells for 3 days with GI 129471 inhibited the production of sCD23 with an IC50 of 602 nm±3 nm (n=3), but by 14 days the activity of the compound against sCD23 had decreased by greater than threefold (IC50 2±0·26 μm; n=3). On the other hand, GI 129471 caused a potent inhibition of IgE production, with no apparent loss of activity over the culture period (14 days: IC50 250 nm±72 nm; n=3). Time‐course studies showed that, despite loss of activity against sCD23, inhibition of sCD23 production early in the culture was able to cause a potent and long‐lasting inhibitory effect on IgE. Furthermore, we also showed that the activity of GI 129471 is selective for IgE, as no effect was seen on immunoglobulin G1 (IgG1) or IgG4 production at test concentrations as high as 10 μm. These results support the hypothesis that metalloproteinases may be involved in the proteolytic cleavage of CD23 and subsequent regulation of IgE synthesis. Inhibition of the protease(s) responsible for such cleavage may be of value in the treatment of allergic disease.
Oral tolerance induced to house dust mite extract in naive and sensitized mice: evaluation of immunoglobulin G anti‐immunoglobulin E autoantibodies and IgG–IgE complexes
Authors: SATO  , CARVALHO  , SILVA  , MACIEL JR  , FUSARO  , DUARTE
Published: March 2003

We investigated the effect on specific antibody response of naive and sensitized mice orally administrated with low (0·25 mg) or high (10·0 mg) doses of Dermatophagoides pteronyssinus (Dp) extract. We also examined the effect of oral administration of Dp on the production of autoantibodies to immunoglobulin G (IgG) and immunoglobulin E (IgE). Naive and sensitized mice both showed a marked down‐regulation of IgE antibody production, regardless of the dose of Dp. We also detected an inhibitory effect of the total IgE levels and the allergen‐specific IgG1, IgG2a and IgG2b antibody response in sensitized mice given the low dose of Dp. In contrast, high doses of Dp stimulated IgG1 antibody production in both naive and sensitized animals. In addition, the oral tolerance induction protocol stimulated anti‐F(ab′)2γ and anti‐Fcγ autoantibody production. Evaluation of IgG anti‐IgE autoantibodies by a direct enzyme immunoassay (EIA) revealed the presence of these autoantibodies, predominantly of the IgG1 isotype, specifically in those animals fed with the high dose. In contrast, IgG–IgE complexes, determined by EIA using immobilized anti‐IgE antibodies, were detected mainly in sera of control animals. The autoantibody anti‐IgE specificity was tested against IgE‐TNP and IgE‐DANSYL murine proteins and revealed different inhibition profiles, suggesting the action of heterogeneous subpopulations of autoantibodies. Taken together, our results show that the oral tolerance protocol with Dp was able to modulate the production of allergen‐specific IgE antibodies in both naive and sensitized animals. In addition, we suggest that anti‐IgE autoantibodies participate in the modulation of allergic response triggered by oral tolerance protocols.