bluuebunny/crossref_metadata_2025 huggingface dataset:
Small cell carcinoma of urinary bladder is differentiated from urothelial carcinoma by chromogranin expression, absence of CD44 variant 6 expression, a unique pattern of cytokeratin expression, and more intense γ‐enolase expression
Authors: Iczkowski K A , Shanks J H , Allsbrook W C , Lopez‐Beltran A , Pantazis C G , Collins T R , Wetherington R W , Bostwick D G
Published: March 2003

Aims

Small cell (neuroendocrine) carcinoma of the urinary bladder is clinically more aggressive than urothelial (transitional cell) carcinoma. We have investigated the immunohistochemical markers most useful in diagnosing small cell carcinoma in bladder.

Methods and results

We evaluated the expression of chromogranin A, CD44 variant 6 (CD44v6), cytokeratin (CAM 5.2), gamma‐enolase, synaptophysin, and CD45 in 46 small cell carcinomas of the bladder. Small cell and urothelial carcinoma were mixed in 21 (46%) cases. The two immunohistochemical markers with best ability to discriminate between small cell and urothelial carcinoma were chromogranin A and CD44v6. Chromogranin A had 97% specificity for small cell carcinoma, staining 65% of cases with 2+/3+ mean intensity; only one case (5%) of urothelial carcinoma was weakly (1+/3+) positive. CD44v6 was 80% specific for urothelial carcinoma, with immunoreactivity in 60% of cases, compared with 7% of small cell carcinoma cases. In cases positive for CD44v6, the mean percentage of reactive urothelial carcinoma cells was 75% (range 10–100%), greater than the 12% of cells in three cases of small cell carcinoma (P = 0.31); further, the pattern of immunoreactivity was membranous vs. focal cytoplasmic, respectively. All small cell carcinomas stained with one of the three neuroendocrine markers tested; 76% of cases were reactive for synaptophysin and 93% for gamma‐enolase, with specificities of 86% and 73% in comparison to urothelial carcinoma. γ‐enolase staining of small cell carcinoma was more intense (P = 0.01) than for urothelial carcinoma. Cytokeratin CAM 5.2 stained a mean 47% of cells in small cell carcinoma, always in a punctate perinuclear pattern, and 75% in urothelial carcinoma, in a membranous pattern.

Conclusions

CD44v6, chromogranin A, and possibly gamma‐enolase and cytokeratin (CAM 5.2) help differentiate small cell carcinoma from urothelial carcinoma.
High‐grade extraskeletal myxoid chondrosarcoma: a high‐grade epithelioid malignancy
Authors: Lucas  , Fletcher  , Adsay  , Zalupski
Published: March 2003

Aims

Extraskeletal myxoid chondrosarcoma is typically a low‐to‐intermediate grade sarcoma that is associated with a prolonged clinical course. High‐grade forms are rare and not well characterized. In this series we report the clinicopathological, immunohistochemical and ultrastructural findings in four cases of high‐grade extraskeletal myxoid chondrosarcoma.

Methods and results

The patients were three men and one woman (ages 34–73 years) with tumours located in the thigh (two cases), paraspinal soft tissue and perineum. Three patients had metastases, one at 12 weeks, one at 10 months, and one at presentation of recurrent tumour. In the latter case the original tumour was low grade and became high grade when it recurred 3.5 years later. All three patients died of disease. One patient was lost to follow‐up. The most striking histological feature in all four tumours was the presence of numerous large epithelioid cells. These cells were arranged in cords within myxoid matrix and in sheets devoid of matrix. Two tumours had areas of conventional extraskeletal myxoid chondrosarcoma intermixed with the high‐grade areas. One tumour showed transition to high‐grade spindle cell sarcoma. One tumour had cells with rhabdoid features. Immunohistochemically, two tumours focally expressed S100 protein, and one focally expressed EMA. All were negative with cytokeratin, desmin, smooth muscle actin, HMB45, CD31 and CD34. Ultrastructural features in three cases were compatible with chondrosarcoma; one tumour had aggregates of microtubules within rough endoplasmic reticulum, a characteristic feature of this tumour.

Conclusions

High‐grade extraskeletal myxoid chondrosaroma is a rare and aggressive soft tissue sarcoma, and should be included in the differential diagnosis of other epithelioid malignancies.
Genotypic and phenotypic alterations in Epstein–Barr virus‐associated lymphoma
Authors: Ohshima  , Suzumiya  , Kanda  , Haraoka  , Kawasaki  , Shimazaki  , Kikuchi
Published: March 2003

Aims

Epstein–Barr virus (EBV) is associated with numerous reactive and neoplastic lymphoproliferative disorders. In vitro, EBV infection can transform B‐lymphocytes and induce phenotypic alterations. This study presents the clinicopathological features of four cases with malignant lymphoma, which showed phenotypic and/or genotypic alterations during the course of the disease.

Methods and results

To determine the type of EBV genotype, we performed polymerase chain reaction (PCR) for lymphocyte‐defined membrane antigen (LYDMA) of EBV, subtype A/B and latent membrane protein (LMP)‐1 deletion. In addition, we analysed the terminal repeat (TR) band of EBV and receptor genes (T‐cell receptor gene, TCR; immunoglobulin gene heavy chain, IgH) for EBV‐infected cell clonality. Double staining of cell markers (B, T‐lymphocytes; histiocytes), and in‐situ hybridization (ISH) for EBV were performed using tissues obtained during the course of the disease. The first case showed genotypic and phenotypic alterations of T‐cell type to B‐cell type. The first TCR rearrangement and T‐cell markers (CD3+, CD4+, CD8−) were lost and IgH rearrangement and B‐cell markers (CD19+, CD20+) were identified. During the course of the disease, EBV‐TR bands changed in size; however, the EBV genotype type B, LMP1 deletion type, and single LYDMA band remained the same. The initial T‐cell lymphoma clone was considered to be different from the latter B‐cell lymphoma clone. The second case showed phenotypic alterations. The first B‐cell marker (CD19+, CD20+, CD68−) changed to histiocytic markers (CD19−, CD20−, CD68+). However, IgH rearrangement and EBV‐TR bands remained the same throughout the course of the disease and EBV genotype type A, LMP1 deletion type, and single LYDMA band remained unchanged. The third case showed phenotypic alterations. The B‐cell marker (CD20+) was lost; however, IgH rearrangement of PCR and EBV genotype remained the same. In the second and third cases, the initial lymphoma clones were considered to be same as the latter clones. The last case showed lineage alterations from Hodgkin's disease to natural killer (NK) cell leukaemia. However, EBV genotype did not change. The second case and Hodgkin's disease showed LMP expression, but the first and third cases showed no LMP, and EBNA2 was not detected in all cases.

Conclusions

We report the genotypic and/or phenotypic alterations in four patients with EBV‐associated lymphoma/leukaemia. However, EBV genotype did not change in all four. These findings suggest that EBV might induce the cell marker and lineage alteration in vivo, as in vitro.
Spinal melanotic schwannoma: a tumour with poor prognosis
Authors: Vallat‐Decouvelaere  , Wassef  , Lot  , Catala  , Moussalam  , Caruel  , Mikol
Published: March 2003

Aim

To clarify the prognosis of melanotic schwannoma. This is a rare tumour which is generally considered as a benign lesion, reported in many cases with a short follow‐up only.

Methods and results

Five cases of spinal melanotic schwannoma were retrospectively studied. The tumours were examined using standard histological, immunohistochemical and ultrastructural methods. No features of malignancy (high mitotic count, atypia or necrosis) were found in the primary tumours. The follow‐up period ranged from 3 to 7 years. Malignant clinical behaviour was clear‐cut in four cases: three patients died from metastases to various sites and one presented several discrete spinal tumours of the same type seven years after the first operation. Only one patient presented no recurrence and was free of disease 6 years after initial diagnosis. The review of 57 cases of the literature (including our cases), showed that 15% of the cases had recurrences and 26.3% were complicated by metastasis. Only 53% of the cases followed for more than 5 years, were free of disease vs. 67.5% of the cases with shorter follow‐up. Twenty additional cases had no follow‐up.

Conclusion

Appropriate long‐term follow‐up is required for all melanotic schwannomas, as it may recur or metastasize after more than 5 years, even in the absence of overt malignant histological features.
A neural network approach to the biopsy diagnosis of early acute renal transplant rejection
Authors: Furness  , Levesley  , Luo  , Taub  , Kazi  , Bates  , Nicholson
Published: March 2003

Aims

To develop and test a neural network to assist in the histological diagnosis of early acute renal allograft rejection.

Methods and results

We used three sets of biopsies to train and test the network: 100 ‘routine’ biopsies from Leicester; 21 selected difficult biopsies which had already been evaluated by most of the renal transplant pathologists in the UK, in a study of the Banff classification of allograft pathology and 25 cases which had been classified as ‘borderline’ according to the Banff classification in a review of transplant biopsies from Oxford. The correct diagnosis for each biopsy was defined by careful retrospective clinical review. Biopsies where this review did not provide a clear diagnosis were excluded. Each biopsy was graded for 12 histological features and the data was entered into a simple single layer perception network, designed using the MATLAB neural network toolbox. Results were compared with logistic regression using the same data, and with ‘conventional’ histological diagnosis. If the network was trained only with the 100 ‘routine’ cases, its performance with either of the other sets was poor. However, if either of the ‘difficult’ sets was added to the training group, testing with the other ‘difficult’ group improved dramatically; 19 of the 21 ‘Banff’ study cases were diagnosed correctly. This was achieved using observations made by a trainee pathologist. The result is better than was achieved by any of the many experienced pathologists who had previously seen these biopsies (maximum 18/21 correct), and is considerably better than that achieved by using logistic regression with the same data.

Conclusion

A neural network can provide a considerable improvement in the diagnosis of early acute allograft rejection, though further development work will be needed before this becomes a routine diagnostic tool. The selection of cases used to train the network is crucial to the quality of its performance. There is scope to improve the system further by incorporating clinical information. Other related areas where this approach is likely to be of value are discussed.
Variation in the histological pattern of nodal involvement by gamma/delta T‐cell lymphoma
Authors: Charton‐Bain  , Brousset  , Bouabdallah  , Gaulard  , Merlio  , Dubus  , Rostaing  , de Roux  , Weiller  , Hassoun  , Xerri
Published: March 2003

Aims

Gamma‐delta (γδ) T‐cell non‐Hodgkin's lymphomas (NHLs) usually present with liver, spleen and marrow infiltration. Lymph node involvement by γδ T‐cell NHL has been rarely documented so far; its histological pattern needs to be further defined.

Methods and results

Two cases of nodal γδ T‐cell NHL are reported: case 1, a 44‐year‐old man, presented with cytomegalovirus retinitis and superficial lymphadenopathies. Histological analysis of an inguinal lymph node showed complete destruction by a diffuse pleomorphic lymphoid proliferation, which was positive for CD2, CD3, CD43, CD45, TIA‐1 and granzyme B, and displayed a γδ phenotype (δTCR1+, Vδ1+, Vδ2−, Vδ3−, βF1−). Bone marrow was normal. Case 2, a male 24‐year‐old patient with a history of renal transplantation, presented with hepatosplenomegaly and supraclavicular lymph node enlargement. Lymph node architecture was globally preserved. Peripheral sinuses contained scattered nests of medium‐sized irregular lymphoid cells. Bone‐marrow was infiltrated. Phenotype showed positivity for CD2, CD3, CD45 and TIA1 and expression of γδ TCR (δTCR1+, δV1+, δV2−, δV3−, βF1−). Both patients died a short time after diagnosis.

Conclusions

These observations suggest that at least two forms of nodal γδ T‐cell NHL may be encountered: one mimicking classical αβ T‐cell NHL, with diffuse pleomorphic cell proliferation, and one displaying sinusoidal neoplastic infiltration suggesting a close relationship with hepatosplenic γδ T‐cell NHL.
Association of Helicobacter pylori‐dependent gastritis with gastric carcinomas in young Japanese patients: histopathological comparison of diffuse and intestinal type cancer cases
Authors: Koshida Y , Koizumi W , Sasabe M , Katoh Y , Okayasu I
Published: March 2003

Aims

: The causal relationship of H. pylori gastric colonization with gastric cancer development has not as yet been fully elucidated. The prevalence of H. pylori infection increases with age in the asymptomatic population in Japan, and reaches a high plateau in those older than 40 years. The objective of this study was to assess the link between H. pylori and gastric carcinomas in patients younger than 40 years.

Methods and results

: Detection of H. pylori and assessment of background mucosa based on the Sydney system was performed histopathologically for 40 Japanese gastric cancer cases younger than 40 years and compared with 40 age‐ and sex‐matched controls. H. pylori infection in gastric mucosa was detected significantly more frequently (P < 0.001) in patients with cancer (29/40; 72.5%) than in controls (11/40; 27.5%). Additionally, by histopathological comparison between intestinal (18 cases) and diffuse (70 cases) types of young gastric cancer patients, mucosal atrophy and intestinal metaplasia were found to coexist with acute and chronic inflammation in the background mucosa of both intestinal and diffuse types, being significantly more prevalent than in young controls.

Conclusions

: As well as the high prevalence of H. pylori in young subjects with gastric cancer, it is clear that persistent infection induces mucosal damage, resulting in atrophy and intestinal metaplasia. Thus, acute/chronic gastritis could play an essential role in the early development of neoplasia in the stomach.
Anti‐mesothelial markers in sarcomatoid mesothelioma and other spindle cell neoplasms
Authors: Attanoos R L , Dojcinov S D , Webb R , Gibbs A R
Published: March 2003

Aims

To undertake a comparative evaluation of three antimesothelial markers (thrombomodulin, cytokeratin 5/6 and calretinin) with broad spectrum cytokeratin (AE1/AE3) in differentiating between sarcomatoid mesothelioma and a spectrum of spindle cell neoplasms.

Methods and results

Thirty‐one malignant sarcomatoid mesotheliomas were studied. Calretinin expression was focally identified in 12 (39%) tumours and thrombomodulin and cytokeratin 5/6 immunoreactivity was seen in nine (29%) cases. In comparison there was strong diffuse cytoplasmic reactivity with the broad spectrum cytokeratin (AE1/AE3) in 24 of 31 (77%) tumours. Thirty mixed spindle cells neoplasms were studied. No calretinin expression was identified in any case. Thrombomodulin immunoreactivity was identified in four (16%) cases (two angiosarcomas, two high‐grade sarcomas, not otherwise specified). Cytokeratin 5/6 expression was seen in one high‐grade pulmonary sarcoma originally termed malignant fibrous histiocytoma. None of the antimesothelial markers was expressed in the four spindle cell carcinomas studied. In contrast, broad spectrum cytokeratin was diffusely expressed in all four spindle cell carcinomas (three pulmonary, one renal), both synovial sarcomas, both malignant mixed Müllerian tumours, one of three pulmonary leiomyosarcomas and two of nine sarcomas, not otherwise specified.

Conclusions

Immunohistochemistry has a more limited role in the diagnosis and distinction of sarcomatoid mesothelioma from other spindle cell neoplasms. The combination of a broad spectrum cytokeratin with calretinin combines both high sensitivity (77% for AE1/AE3) with high specificity (100% for calretinin) for sarcomatoid mesothelioma and can be diagnostically useful. The mesothelial markers, thrombomodulin and cytokeratin 5/6, are not useful alone in the diagnosis of sarcomatoid mesothelioma as each shows insufficient antibody sensitivity, although together they complement calretinin.
Changing patterns of histological subgroups during therapy of Ph1+ chronic myelogenous leukaemia
Authors: Thiele J , Kvasnicka H M , Schmitt‐Graeff A , Leder L D , Schaefer H E
Published: March 2003

Aims

Bone marrow histopathology reveals a striking heterogeneity at diagnosis of Philadelphia chromosome positive (Ph1+) chronic myelogenous leukaemia (CML). Based on semiquantitative evaluations of the number of megakaryocytes and the content of fibres, various histological subtypes have been postulated. However, little information exists on whether these groups represent stable categories of the different classification systems and whether therapeutic regimes exert any influence on the putative shift of histological patterns.

Methods and results

A retrospective clinicopathological study was performed on 396 bone marrow biopsies derived from 173 patients. There were at least two representative trephines taken at diagnosis and at median intervals of 16 months. Processing of the specimens involved immunostaining with CD61 (megakaryopoiesis) and Ret40f (erythropoiesis) and Gomori's silver impregnation technique. Based on morphometric analysis and in accordance with the general appearance of bone marrow histology three different histological subtypes were distinguished. These consisted of a granulocytic (51 patients), a predominantly megakaryocytic (73 patients) and a myelofibrotic pattern (49 patients). Follow‐up biopsies revealed that a significant transition of histological groups occurred and that, independently of treatment modalities, the myelofibrotic category was associated with an unfavourable prognosis. Of the 124 patients without myelofibrosis at onset, 42% later transformed into the myelofibrotic subtype. However, these patients showed no prevalence of either a pre‐existing granulocytic or megakaryocytic growth. Myelofibrotic changes were significantly associated with interferon (IFN) and busulfan (BU) therapy. On the other hand, a transition of a myelofibrotic into a nonfibrotic subtype was detectable in 17 of the 49 patients under study and related to hydroxyurea (HU) treatment.

Conclusions

Histological classification systems of bone marrow features in CML do not represent stable patterns, but may be significantly altered by therapy, in particular IFN and HU.
Borrelia burgdorferi‐associated cutaneous marginal zone lymphoma: a clinicopathological study of two cases illustrating the temporal progression of B. burgdorferi‐associated B‐cell proliferation in the skin
Authors: Goodlad J R , Davidson M M , Hollowood K , Batstone P , Ho‐Yen D O
Published: March 2003

A relationship between Borrelia burgdorferi and primary cutaneous B‐cell lymphoma (PCBCL) has recently been confirmed following demonstration of the organism in lesional skin of patients with PCBCL. We report herein two cases of B. burgdorferi‐associated PCBCL which strengthen this association by demonstrating the organism in cutaneous B‐cell infiltrates present at sites in which PCBCL subsequently developed.

All studies were performed on formalin‐fixed paraffin‐embedded tissues. These were examined by routine light microscopy and immunohistochemically by a standard streptavidin–biotin–complex technique. Genotypic studies were also undertaken using semi‐nested polymerase chain reaction (PCR) for immunoglobulin heavy chain gene rearrangement, and nested PCR for B. burgdorferi flagellin gene. Both patients presented with erythematous skin lesions, biopsy of which showed dense perivascular infiltrates comprising small T‐lymphocytes and collections of B‐blasts. Primary cutaneous marginal zone lymphoma (MZL) developed subsequently in both cases at the same site. PCR for B. burgdorferi flagellin gene was positive in the perivascular lymphocytic infiltrates and the succeeding lymphomas in both patients.

These results show that, at least in some instances, PCBCL arises from chronically stimulated lymphoid tissue acquired in the skin in response to B. burgdorferi infection. This may have significant therapeutic implications and warrant further studies on the extent of this association.
Expression of CD44 and its variant isoform v3 has no prognostic value in gastric cancer
Authors: Setälä L , Lipponen P , Tammi R , Tammi M , Eskelinen M , Alhava E , Kosma V‐M
Published: March 2003

To study the controversial role of transmembrane glycoprotein CD44 as a moderator of tumour spread and as a prognostic factor in gastric cancer.

The expression of all CD44 forms and that with exon v3 was assessed in 198 stage I‐IV gastric adenocarcinomas using immunohistochemistry. CD44 expression was found in 72% and CD44v3 in 55% of the cases. The intensity of CD44 expression was associated with the level of invasion and with hyaluronan expression, while the frequency of CD44 positive cells was not significantly related to any of the clinical or histological features of the tumours. CD44v3 expression failed to show any association with the clinical or histological variables examined. Neither total CD44 nor CD44v3 expression affected survival. The most important prognostic factors in this cohort were the level of invasion, lymph node status, tumour size and vascular or perineural invasion.

Changes in CD44 or CD44v3 expression level do not predict tumour spread or patient survival in gastric cancer.
Histological changes in the hypofunctional pituitary gland following conventional radiotherapy for adenoma
Authors: Nishioka H , Ito H , Haraoka J , Hirano A
Published: March 2003

Histological changes in the hypofunctional pituitary gland following conventional radiotherapy for adenoma

Aims: Although delayed hypopituitarism is a common complication of conventional radiotherapy of sellar tumours, histological changes that may account for it have been rarely reported. To elucidate the changes, hypofunctional pituitary glands following irradiation were studied.

Methods and results: Two pituitary glands obtained at autopsy from patients who had been irradiated for adenoma and exhibited hypopituitarism were examined. In both cases diffuse fibrosis was observed in the adenohypophysis, whereas the neurohypophysis remained unchanged. Immunohistochemistry showed that stellate‐shaped S100 protein‐positive cells were increased in number and distributed among the endocrine cells. Some irradiated endocrine cells showed dense granular immunoreactivity for mitochondrial protein, cytochrome oxidase and manganese‐superoxide dismutase. In addition to faint reactivity with anti‐cytokeratin 8, 18 antibody, many cells were densely positive with anti‐cytokeratin 1, 5, 10, 14 antibody.

Conclusions: These results indicate that radiation‐ induced fibrosis is associated with an increased number of folliculo‐stellate cells and the presence of metabolic dysfunctional mitochondria resembling mitochondria in oncocytes. Squamous metaplasia in the irradiated endocrine cells was also noted. Various intracellular changes may participate in delayed pituitary hypofunction following radiotherapy.
Histomorphometric assessment of bone turnover in uraemic patients: comparison between activation frequency and bone formation rate
Authors: Ballanti P , Coen G , Mazzaferro S , Taggi F , Giustini M , Calabria S , Ferrannini M , Bonucci E
Published: March 2003

Histomorphometric assessment of bone turnover in uraemic patients: comparison between activation frequency and bone formation rate

Aims: The histomorphometric assessment of bone formation rate (BFR/BS) in bone biopsies from uraemic patients is of crucial importance in differentiating low from high turnover types of renal osteodystrophy. However, since BFR/BS relies on osteoblasts, activation frequency (Ac.f), encompassing all remodelling phases, has recently been preferred to BFR/BS. This study was carried out to consider whether estimation of Ac.f is superior, in practical terms, to that of BFR/BS in distinguishing between different rates of bone turnover in uraemic patients.

Methods and results: Bone biopsies from 27 patients in predialysis (20 men and seven women; mean age 53 ± 12 years) and 37 in haemodialysis (22 men and 15 women; mean age 53 ± 12 years) were examined. The types of renal osteodystrophy were classified on the basis of morphology. Bone formation rate and Ac.f were evaluated according to standardized procedures. The Ac.f was calculated both as a ratio between BFR/BS and wall thickness (W.Th) and as a reciprocal of erosion, formation and quiescent periods (EP, FP and QP). Patients were affected by renal osteodystrophy with predominant hyperparathyroidism (two predialysis and 16 dialysis), predominant osteomalacia (three predialysis and seven dialysis) or that of advanced (nine predialysis and five dialysis) or mild (seven predialysis and four dialysis) mixed type or adynamic type (six predialysis and five dialysis). Activation frequency, which with either formula requires the measurement of W.Th, i.e. the thickness of bone structural units (BSUs), was not calculated in three dialysis patients with severe hyperparathyroidism and in one predialysis and four dialysis patients with severe osteomalacia, because only incomplete BSUs were found. In dialysis, EP was higher in the adynamic than in the other types of osteodystrophy. During both predialysis and dialysis, FP was higher in osteomalacia than in the other forms of osteodystrophy, and in adynamic osteopathy than in hyperparathyroidism or in advanced and mild mixed osteodystrophy. During predialysis and dialysis, QP was higher in the adynamic than in the other forms of osteodystrophy. Correlations were found between BFR/BS and Ac.f, during predialysis (r=0.97) and dialysis (r=0.95).

Conclusions: The superiority of Ac.f in assessing bone turnover, in comparison to BFR/BS, is conceptual rather than practical. The highest values for FP in osteomalacia and for QP in adynamic bone allow a clearer characterization of these low turnover conditions.
Follicular adenoma with papillary architecture: a lesion mimicking papillary thyroid carcinoma
Authors: Mai K T , Landry D C , Thomas J , Burns B F , Commons A S , Yazdi H M , Odell P F
Published: March 2003

Follicular adenoma with papillary architecture: a lesion mimicking papillary thyroid carcinoma

Aims: The purpose of this study was to investigate the significance of ‘benign’ encapsulated follicular thyroid nodules with papillary structures.

Methods and results: Twenty‐one cases of encapsulated neoplastic thyroid nodules with papillary structures and nuclear features not diagnostic of papillary thyroid carcinoma (PTC) were obtained. All cases were reviewed with particular attention to nuclear features (fine chromatin pattern, optical clearing, grooves and inclusions). Representative sections were submitted for measurement of the maximum diameter of 200 round or nearly round nuclei and for immunostaining for MIB1, CK19, HBME and Ret oncogene protein. Nine cases displayed scattered optically clear nuclei or nuclear grooves in less than 30% of total neoplastic cells. They were grouped in the category of thyroid nodules with limited nuclear features of papillary thyroid carcinoma (PTC), but not diagnostic of PTC. The other 12 cases had fine or coarse chromatin, but lacked other features of nuclei in PTC. The diameter of the nuclei ranged from 5.6 to 7.2 μm and were smaller than those of PTC (6.3–10.0 μm). Immunostaining revealed positive reactivity for MIB1 in the papillary structures. Immunostaining for CK19 and HBME varied from negative or focally weak to diffusely moderate reactivity. Ret oncogene protein immunostaining showed focal and weak reactivity in one case and was negative in other cases of the study. Clinical follow‐up from 6 months to 15 years revealed no evidence of metastasis.

Conclusions: The papillary structures in the study cases are unlikely to represent degenerative changes due to their proliferative activity. In view of (i) the encapsulation and the uniformity of the constituent cells, (ii) the varying degrees of immunoreactivity for CK19 and HBME and negative immunoreactivity for Ret oncogene protein, and (iii) the absence or insufficiency of nuclear criteria for the diagnosis of PTC and the absence of lymph node metastasis in all study cases, we believe that these lesions represent the papillary variant of follicular adenoma. Recognition of this pathological entity is important to avoid an over‐diagnosis of PTC.
Different patterns of β‐catenin expression in gastric carcinomas: relationship with clinicopathological parameters and prognostic outcome
Authors: Grabsch H , Takeno S , Noguchi T , Hommel G , Gabbert H E , Mueller W
Published: March 2003

Different patterns of β‐catenin expression in gastric carcinomas: relationship with clinicopathological parameters and prognostic outcome

Aims: The cadherin–catenin complex is known to play a critical role in maintenance of cell adhesion. Additionally β‐catenin (β‐ct) can also take part in signal transduction and nuclear β‐ct expression could be correlated with poor prognosis in several malignancies. Since, in gastric cancer, this role of β‐ct is still uncertain, we investigated the expression pattern of β‐ct as well as the possible prognostic role.

Methods and results: β‐catenin expression was immunohistochemically investigated in a retrospective series of 401 R0‐resected gastric carcinomas. Out of these cases, 54 tumours (13.5%) revealed a preserved membranous β‐ct expression similar to that in normal gastric mucosa. In 80 tumours β‐ct expression was moderately reduced and in 117 tumours highly reduced. In 150 tumours (37.4%), no or only a weak membranous β‐ct expression was found. Additionally, in 53 tumours, a strong β‐ct expression could be observed in the cytoplasm with a simultaneous nuclear β‐ct immunoreactivity in 17 of these 53 tumours, while nine tumours only showed nuclear immunoreactivity without cytoplasmic staining. There were no significant correlations between the degree of membranous β‐ct expression or the different staining pattern (membranous vs. cytoplasmic/nuclear) and the grade of tumour differentiation, the histological tumour type according to Lauren, as well as with the prognostic parameters pT, pN category and vascular invasion. No associations could be found with tumour cell proliferation and the expression of E‐cadherin, irrespectively of the different β‐ct staining pattern. Univariate analysis revealed no influence on survival, either for membranous or for cytoplasmic/nuclear β‐ct expression.

Conclusion: Our data on 401 tumours suggest that activation of the Wnt/β‐catenin signalling does also occur in a subset of gastric carcinomas. However, in gastric cancer, neither the presence of cytoplasmic/nuclear β‐ct expression nor the reduction or loss of membranous β‐ct expression is correlated with a specific histological tumour type, tumour progression or prognosis.
MLH1 and MSH2 protein immunohistochemistry is useful for detection of hereditary non‐polyposis colorectal cancer in young patients
Authors: Paraf F , Gilquin M , Longy M , Gilbert B , Gorry P , Petit B , Labrousse F
Published: March 2003

MLH1 and MSH2 protein immunohistochemistry is useful for detection of hereditary non‐polyposis colorectal cancer in young patients

Aims: Hereditary non‐polyposis colorectal cancer is related to germline mutations of DNA mismatch repair genes MLH1 and MSH2, which result in microsatellite instability and loss of protein expression of the corresponding mutated gene in the tumour tissue.

Methods and results: MLH1 and MSH2 protein expression was studied by immunohistochemistry in paraffin‐embedded surgical samples of 100 colorectal adenocarcinomas occurring before 50 years of age. Absence of tumour cell nuclear staining with positive internal control (normal mucosa, lymphoid follicles) was considered negative. Loss of MLH1 or MSH2 expression was found in 20 cases with microsatellite instability in 15 cases. Twelve of these patients had a family history of colorectal cancer. Compared with MLH1‐ and MSH2‐positive cases, MLH1‐ or MSH2‐deficient colorectal adenocarcinomas were significantly associated on multivariate analysis with a younger age (38 vs. 43 years, P;0.0224), a larger tumour size (60 ± 6 vs. 46 ± 2 mm, P=0.0291), an expanding margin (85% vs. 51%, P=0.0159), a higher number of tumour‐infiltrating lymphocytes assessed by CD3 immunostaining (202 ± 48 vs. 33 ± 4 CD3+ lymphocytes/10 high‐power fields, P=0.0039), and a grade 2 Crohn's like lymphoid reaction (70% vs. 9%, P=0.0037). The two groups were not different for tumour site, differentiation, pTNM stage, vascular and perineural invasion, peripheral adenomatous residue, and 5‐year survival rates.

Conclusions: MLH1‐ or MSH2‐deficient colorectal carcinomas of young patients exhibit pathological and molecular features similar to hereditary non‐polyposis colorectal cancer. This suggests that MLH1 and MSH2 immunohistochemistry is valuable for detecting hereditary non‐polyposis colorectal cancer in young patients.
Ber‐EP4 immunoreactivity depends on the germ layer origin and maturity of the squamous epithelium
Authors: Rossen K , Thomsen H K
Published: March 2003

Ber‐EP4 immunoreactivity depends on the germ layer origin and maturity of the squamous epithelium

Aim: To map the expression of Ber‐EP4 in well‐differentiated squamous epithelia, metaplastic squamous epithelia and dysplastic squamous epithelia of different origins.

Methods and results: Squamous epithelium of different origin was stained using a standard immunohistochemistry method applied to paraffin sections. We found that normal squamous epithelium of the oral cavity, oesophagus, uterine cervix, vagina, anal canal, and branchial cysts are Ber‐Ep4‐negative, as are the mature squamous metaplasia of bronchial mucosa, urinary bladder mucosa and uterine cervical mucosa. In contrast, immature squamous metaplasia of bronchial mucosa, or uterine cervical mucosa, and squamous dysplasia of oral mucosa of endodermal origin, or uterine cervical mucosa in most cases expressed Ber‐EP4.

Conclusion: Squamous epithelia of ectodermal origin never express Ber‐EP4, whether normal, hyperplastic, dysplastic or neoplastic. In contrast, squamous epithelium of endodermal origin sometimes contains the target glycoproteins of Ber‐EP4 when immature, metaplastic, dysplastic or neoplastic. The results indicate that the differences in expression of Ber‐EP4 in squamous epithelium depend primarily on germ layer origin, and on the maturity of the epithelium.
Expression of cell cycle regulatory proteins in the multistep process of oesophageal carcinogenesis: stepwise over‐expression of cyclin E and p53, reduction of p21WAF1/CIP1 and dysregulation of cyclin D1 and p27KIP1
Authors: Ohbu M , Kobayashi N , Okayasu I
Published: March 2003

Expression of cell cycle regulatory proteins in the multistep process of oesophageal carcinogenesis: stepwise over‐expression of cyclin E and p53, reduction of p21WAF1/CIP1 and dysregulation of cyclin D1 and p27KIP1

Aims: Cell cycle regulatory proteins were analysed by immunohistochemistry in order to clarify how their expression changes with the degree of atypia as oesophageal surface squamous epithelium progresses from normal mucosa, through reactive change, low‐grade dysplasia, and high‐grade dysplasia to mucosal invasive carcinoma.

Methods and results: Immunostaining for cyclin D1, cyclin E, p21, p27, p53 and Ki67 proteins was performed using 22 normal mucosa, 17 reactive change, 22 low‐grade dysplasia, 15 high‐grade dysplasia and 22 mucosal invasive carcinoma specimens. Normal mucosa, low‐grade dysplasia and high‐grade dysplasia samples were taken from patients without any oesophageal invasive carcinoma by endoscopic biopsy or endoscopic mucosal resection, and reactive change and mucosal invasive carcinoma were obtained from oesophagectomy material. Stepwise over‐expression of cyclin E (P < 0.0001) and p53 (P < 0.0001), reduction of p21 (P=0.0189) and dysregulation of cyclin D1 and p27 were observed in the multistep process of oesophageal carcinogenesis. Significant differences in expression of p27 (P < 0.0001), p53 (P=0.0299) and Ki67 (P=0.0101) were observed between reactive change and low‐grade dysplasia. Furthermore, expression of cyclin D1, cyclin E, p27 and p53 in mucosal invasive carcinoma were significantly different from those in high‐grade dysplasia (P=0.0079, P=0.0237, P=0.0042 and P= 0.0299, respectively).

Conclusions: Cell cycle regulatory proteins, cyclin E, p53 and p21 show stepwise over‐expression or reduction with progression of oesophageal carcinogenesis, correlating with the increased cell proliferation observed with Ki67 labelling. We conclude that immunohistochemical analysis for p27, p53 and Ki67 is practically useful for the discrimination between low‐grade dysplasia and reactive change. Cyclin D1, cyclin E, p27 and p53 help to distinguish high‐grade dysplasia from mucosal invasive carcinoma.
Fatty acid synthase is highly expressed in carcinoma, adenoma and in regenerative epithelium and intestinal metaplasia of the stomach
Authors: Kusakabe T , Nashimoto A , Honma K , Suzuki T
Published: March 2003

Fatty acid synthase is highly expressed in carcinoma, adenoma and in regenerative epithelium and intestinal metaplasia of the stomach

Aims: To investigate the relation of fatty acid synthase (FAS) expression to the clinicopathological characteristics of gastric cancers and gastric tumorigenesis.

Methods and results: FAS expression was examined immunohistochemically in 626 gastric cancers, 51 gastric adenomas, and non‐neoplastic epithelium contiguous with cancer tissue including normal foveolae, intestinal metaplasia, regenerative epithelium, and gastric glands. FAS expression was found in more than 70% of gastric cancers. Interestingly, it occurred preferentially in differentiated carcinomas, male cases, and in patients over 51 years old. Although previous reports showed that FAS expression is closely related to cancer progression, in gastric cancers FAS expression had no relationship with prognosis, cancer progression as indicated by depth of invasion, venous and lymphatic permeation, and distant metastasis. Gastric tubular adenoma and intestinal metaplasia, which are thought to be associated with well‐differentiated gastric carcinomas, showed a frequency of FAS expression similar to that of differentiated carcinomas; however, normal foveolae and gastric glands showed no or less FAS expression.

Conclusions: FAS expression occurs at the early stage of tumorigenesis and plays important roles in the formation of precancerous foci rather than in the progression of carcinoma of the stomach.
Splenic small B‐cell lymphoma with predominant red pulp involvement: a diffuse variant of splenic marginal zone lymphoma?
Authors: Mollejo M , Algara P , Mateo M S , Sánchez‐Beato M , Lloret E , Medina M T , Piris M A
Published: March 2003

Splenic small B‐cell lymphoma with predominant red pulp involvement: a diffuse variant of splenic marginal zone lymphoma?

Aims: Splenic marginal zone lymphoma (SMZL) has been characterized by a micronodular pattern of infiltration, biphasic cytology, follicular replacement and the presence of marginal zone differentiation. Here we describe four cases with some distinctive features, such as diffuse splenic infiltration, lack of micronodules, marginal zone cytology, p53 inactivation and cutaneous involvement.

Methods and results: In the course of a review of cases of SMZL, we recognized the existence of a subset of four cases of splenic B‐cell lymphoma, with predominantly red pulp involvement, absence of follicular replacement, and a monomorphous population of tumoral cells resembling marginal zone B‐cells, with scattered nucleolated blast cells. The immunophenotype (bcl2+, CD5−, CD10−, CD43−, CD23−, cyclin D1−, IgD− (3/4)) was consistent with SMZL. Bone marrow infiltration (4/4) and peripheral blood involvement (2/4) showed similar findings to those described for SMZL in these locations. However, unlike classical SMZL, 2/4 had cutaneous involvement, and 4/4 cases showed either p53 mutation or anomalous p53 staining (p53+, p21−).

Conclusions: In spite of a diffuse pattern of splenic infiltration, cutaneous involvement and p53 alterations, these cases have findings that overlap with those corresponding to classic SMZL (symptomatology, morphology of bone marrow, lymph nodes, peripheral blood involvement, and immunophenotype). We suggest that these cases be considered a putative variant of SMZL.
Ki67 protein: the immaculate deception?
Authors: Brown D C , Gatter K C
Published: March 2003

Ki67 protein: the immaculate deception?

This article updates our previous review of Ki67 published in Histopathology 10 years ago. In this period the numbers of papers published featuring this antibody has increased 10‐fold from 338 to 3489 indicating the considerable enthusiasm with which this antibody has been studied. This review attempts to provide an update on the characterization of the Ki67 protein, its function and its use as a prognostic or diagnostic tool.
Marginal zone cell lymphoma—an update on recent advances
Authors: Maes B , De Wolf‐Peeters C
Published: March 2003

Marginal zone cell lymphoma—an update on recent advances

The marginal zone represents one of the distinct compartments of the B‐cell area in lymphoid tissues. It is especially well developed in the spleen and in Peyer's patches of the gut, but not in lymph nodes, with the exception of the ones in the mesenterium. However, the pronounced proliferation of so‐called `monocytoid B‐cells' that may be seen in some inflammatory conditions of the lymph node may be regarded as a nodal reactive marginal zone cell expansion. The cellular compositions of the marginal zone and the monocytoid B‐cell proliferation are similar and both show a heterogeneous population of B‐cells, of which the functions are being slowly unravelled. Neoplasms originating in the marginal zone have been recognized in the past and are listed in the REAL classification as marginal zone B‐cell lymphomas including extranodal MALT‐type lymphomas, splenic marginal zone lymphomas and nodal (monocytoid) marginal zone lymphomas. Marginal zone cell lymphomas display a broad morphological spectrum, which is reflected by the heterogeneity of the cellular composition and the variation in the growth pattern of the lymphoma, but is independent of the anatomical site. All three marginal zone cell lymphomas share immunophenotypic, genetic and chromosomal similarities which will be discussed. The morphologic features are dealt with only briefly as they have been extensively discussed elsewhere.
Cytokeratin 19 and galectin‐3 immunohistochemistry in the differential diagnosis of solitary thyroid nodules
Authors: Beesley M F , McLaren K M
Published: March 2003

Aims : The immunohistochemical expression of cytokeratin 19 (CK19) and galectin‐3 was evaluated in 69 thyroid lesions to assess their potential asmarkers in the diagnosis and classification of thyroid malignancy. The following were studied: 26 cases of papillary carcinoma, 12 of follicular carcinoma, 20 follicular adenomas, two medullary carcinomas, one anaplastic carcinoma and eight multinodular goitres.

Methods and results : Formalin‐fixed paraffin‐embedded thyroid tissues were stained immunohistochemically for both CK19 and galectin‐3. CK19 expression was found in all 26 papillary carcinomas, five of 12 follicular carcinomas, two of two medullary carcinomas and one case of anaplastic carcinoma. Only five of 20 follicular adenomas were positive for CK19, and this was in a focal distribution. Two of eight multinodular goitres stained focally positive. Galectin‐3 expression was found in 22 of 26 papillary carcinomas, 12 of 12 follicular carcinomas and one of two cases of medullary carcinoma. Only two of 20 follicular adenomas were positive. Three of eight multinodular goitres showed focal galectin‐3 expression.

Conclusions : Our findings suggest that the immunohistochemical localization of CK19 and of galectin‐3 is a useful adjunct to the histopathological diagnosis of a solitary thyroid lesion. The expression of CK19 favours a diagnosis of papillary carcinoma in all its variant patterns. Galectin‐3 may serve as a marker for the recognition of follicular carcinoma, particularly the minimally invasive form.
Splenic marginal zone atrophy and progressive CD8+ T‐cell lymphocytosis in HIV infection: a study of adult post‐mortem spleens from Côte d'Ivoire
Authors: Wilkins B S , Davis Z , Lucas S B , Delsol G , Jones D B
Published: March 2003

Aims:  Progressive changes have been reported in lymph nodes in HIV infection, but few accounts describe altered splenic histology at different stages of the disease. Investigation of splenic changes accompanying the progressive CD4+ T‐cell depletion that occurs in HIV infection could shed light on normal immunological interactions in this organ. Therefore, we assessed the amount and distribution of lymphoid tissue in spleens from adults with documented early or advanced HIV disease.

Methods and results:  Immunohistochemistry was used to study splenic tissue collected in an extensive autopsy survey of HIV+ adults in West Africa. Compared with post‐mortem spleens from HIV– West African adults and control UK spleens, those from HIV‐infected patients showed severe atrophy of white pulp B‐ and T‐cell compartments. In early and advanced HIV disease, marginal zone atrophy was significant. Peri‐arteriolar lymphoid sheaths contained increased numbers of CD8+/CD45RO+ T‐cells in advanced HIV disease. In red pulp, early and advanced cases showed a lymphocytosis of CD8+/CD45RO– T‐lymphocytes.

Conclusions:  Atrophic changes were more extreme in advanced than early HIV infection. Reduced marginal zone function possibly explains the known predisposition of HIV+ patients to infection by encapsulated bacteria. Possible immunological consequences of these CD8+/CD45RO+ (peri‐arteriolar lymphoid sheaths) and CD8+/CD45RO– (red pulp) responses deserve further study. Comparison of West African and UK control spleens indicated that there were no major ethnic differences in spleen structure to prevent extrapolation of our results to European adults.
Tolerogenic activity of polyethylene glycol‐conjugated lysozyme distinct from that of the native counterpart
Authors: ITO  , SO  , HIRATA  , KOGA  , UEDA  , IMOTO
Published: March 2003

Conjugation of proteins with polyethylene glycol (PEG) has been reported to make the proteins tolerogenic. Native proteins are also potentially tolerogenic when given without adjuvants. We compared immunotolerogenic activities between PEG‐conjugated and native hen egg‐white lysozyme (HEL). BALB/c mice were given consecutive weekly intraperitoneal administrations of PEG‐conjugated HEL, unmodified HEL or phosphate‐buffered saline (PBS), for 3 weeks, then challenged with HEL in Freund’s complete adjuvant. The pretreatment with PEG–HEL tolerized both T‐cell and humoral responses, while native HEL tolerized only the T‐cell response. Immunoglobulin G1 (IgG1) antibody was already elevated in HEL‐pretreated mice prior to challenge immunization, followed by suppressed IgG2a and IgG2b, but spared IgG1 production after the antigen challenge, whereas PEG–HEL‐pretreated mice produced no antibody in all IgG subclasses prior and subsequent to the antigen‐challenge. Production of interleukin‐2 (IL‐2) and interferon‐γ (IFN‐γ) by lymphoid cells in response to HEL in vitro was markedly suppressed in both the antigen‐pretreated groups, while suppression of IL‐4 production was evident only in PEG–HEL‐, not in HEL‐pretreated animals. Involvement of suppressor cells in these tolerance states was found to be unlikely, and the immunological property of PEG–HEL differed from deaggregated HEL that was similar to the original HEL. These results suggest a unique immunotolerogenic activity of PEG‐conjugated proteins to suppress both T‐helper type‐1 (Th1)‐ and Th2‐type responses, the result being extensive inhibition of all IgG subclass responses, while tolerance induction by unconjugated soluble proteins tends to be targeted on Th1‐, but spares Th2‐type responses.