Virchows Archiv

Bertelsen, Bjørn; Kugarajh, Kalaiarasy; Skar, Robert; Laerum, Ole

doi: 10.1007/s00428-006-0232-3pmid: 16767449

Our objective was to investigate the practicability of sequencing DNA from formalin fixed, paraffin embedded tissue stored for up to 75 years and to study human papillomavirus subtype distribution in cervical neoplasias between 1931 and 2004. Three protocols for DNA retrieval were tested, and magnetic bead DNA extraction proved advantageous, as it gave superior specimen purity and effortless sequencing. Successful sequencing was achieved in more than 70% of the specimens from 1931 to 1960. This technique was utilized in the study of papillomavirus subtypes using general primer pair PCR with sequencing of the products in a series of 97 cases of neoplastic and non-neoplastic cervical specimens from 1931 to 1960 and 73 similar cases from 1992 to 2004. HPV was detected in 61% of neoplastic specimens from 1931 to 1960, and in 89% of those from 1992 to 2004. In specimens from 1931 to 1934, only HPV type 16 was detected, whereas in the specimens from 1940 and up, other HPV subtypes were identified in one-third of the cases. The difference was significant and suggests an increase in papillomavirus subtype heterogeneity in Western Norway during 1930–2000. The results strongly support the feasibility of using DNA from paraffin-embedded specimens for studying cancer etiology and genotypes over extended time periods.

Shia, Jinru; Chen, Wen; Tang, Laura; Carlson, Diane; Qin, Jin; Guillem, Jose; Nobrega, Jennifer; Wong, W.; Klimstra, David

doi: 10.1007/s00428-006-0231-4pmid: 16758173

It has been more than 10 years since follicular dendritic cell (FDC) sarcoma was first reported to occur in extranodal sites, yet extranodal FDC sarcoma still appears underrecognized, and its clinical and pathological characteristics remain to be defined. This study analyzed the clinical and pathological findings of three such cases that the authors encountered recently and 43 previously reported cases identified in the literature. Assessment of all 46 cases showed a slight female predominance (1.2:1) with a median age of 41.5 years. One-third of the cases were misdiagnosed at initial evaluation mainly because the possibility of FDC sarcoma was not considered. When considered, this disease had distinct pathological characteristics that allowed an accurate diagnosis. Staining for FDC markers, CD21, CD35, and clusterin was particularly helpful. The pathogenesis of the disease appeared heterogeneous, and associated factors included Epstein–Barr virus infection (in hepatic cases) and inflammatory pseudotumor-like conditions. Treatment modality varied widely although surgical resection was often included. With a median follow-up of 18 months, 43% of the cases recurred and 7% died of disease. The 5-year recurrence-free survival was 27.4%. From data available at the current time, we were not able to identify prognostically significant pathologic factors.

Ihrler, Stephan; Sendelhofert, Andrea; Weiler, Christoph; Hagedorn, Hjalmar; Harrison, John

doi: 10.1007/s00428-006-0208-3pmid: 16673121

Preinvasive intraductal neoplasia of the salivary glands has only been identified in the rare salivary-duct carcinoma, whereas, it is an established feature of carcinomas of other glands. A fortuitous observation of what appeared to be intraductal tumor in a salivary adenocarcinoma, not otherwise specified, led to the present investigation to determine whether intraductal neoplasia is a significant feature of this carcinoma. Intraductal tumor confined by normal CK14-positive, actin-negative ductal basal cells was identified in 15 of 22 cases (68%). The degree of cellular atypia and the pattern of growth of intraductal tumor was similar to that of the invasive tumor. Cases with intraductal tumor devoid of invasive tumor were not found. Intraductal tumor is identified as the pre-invasive precursor of adenocarcinoma, not otherwise specified, and apparently develops in excretory ducts. The findings support the possibility that different salivary tumors arise from different types of parenchymal cell. Possibly intraductal neoplasia is a universal feature of many types of salivary tumor, but has been overlooked because of the need to use immunohistology to demonstrate it and because it may no longer be present as such when the tumor presents as a clinical lesion.

Akyürek, Nalan; Memiş, Leyla; Ekinci, Özgür; Köktürk, Nurdan; Öztürk, Can

doi: 10.1007/s00428-006-0239-9pmid: 16810543

Survivin is an inhibitor of apoptosis protein, which is overexpressed in many carcinomas, including lung carcinoma. The aim of this immunohistochemical study was to investigate the role of survivin in the early steps of lung carcinogenesis and non-small cell lung carcinomas (NSCLC), and its relationship with expression of p53 protein, a tumor suppressor gene involved in cell cycle control. In the normal bronchial epithelium, low-grade atypical adenomatous hyperplasia (AAH) and non-neoplastic lung parenchyma adjacent to tumor, survivin was found completely negative. Expression of survivin was detected in the areas of squamous metaplasia and dysplasia as well as high-grade AAH lesions adjacent to tumor. Survivin was expressed in 50 (64%) and p53 in 41 (53%) NSCLC. Survivin expression was significantly correlated with lymph node metastasis (p=0.02). There was no correlation between survivin and p53 expression. The patients with expression of survivin had significantly worse prognosis (Log-rank test, p=0.003). Multivariate Cox regression analysis showed TNM stage (p<0.001) and survivin expression (p=0.003) as independent prognostic indicators. In conclusion, survivin expression might be an early step in lung carcinogenesis. Survivin expression might also be used as a prognostic indicator predicting the worse outcome in NSCLC, and might be a novel target for the treatment of patients with preinvasive lesions of lung and NSCLC.

Guertl, Barbara; Leuschner, Ivo; Harms, Dieter; Hoefler, Gerald

doi: 10.1007/s00428-006-0225-2pmid: 16715229

Nephroblastomas are embryonal tumors exhibiting a wide variety of different morphological features and genetic changes. Some of the genetic aberrations were associated with a certain histological subtype. It is generally assumed that nephroblastomas develop as subclonal proliferations from nephrogenic rests. However, so far, a very limited amount of tumors from only part of the morphological spectrum of nephroblastomas was investigated. We therefore investigated the clonality of 45 tumors of all different histological subtypes. The number of each subtype was in accordance with the percentage of occurrence of the respective subtype. We analyzed a highly polymorphic locus of the human androgen receptor gene for nonrandom X-inactivation of genomic DNA using a methylation-sensitive restriction enzyme. Data were obtained for 39 tumors. Eighteen of the tumors included were noninformative in the genetic locus examined, the remaining 21 tumors were monoclonal regardless of the histological subtype. Our findings therefore support the hypothesis that Wilms’ tumors are monoclonal proliferations despite their large variety of morphological features.

Moll, Roland; Holzhausen, Hans-Jürgen; Mennel, Hans-Dieter; Kuhn, Caecilia; Baumann, Renate; Taege, Christiane; Franke, Werner

doi: 10.1007/s00428-006-0220-7pmid: 16715231

The two sarcomeric isoforms of actins, cardiac and skeletal muscle α-actin, are highly homologous so that their immunohistochemical distinction is extremely difficult. Taking advantage of monoclonal antibodies distinguishing the two conservative amino acid exchanges near the aminoterminus, we have performed an extended immunohistochemical analysis of the cardiac α-actin (CAA) isoform in normal, regenerating, diseased and neoplastic human muscle tissues. Intense and uniform CAA staining is seen in fetal and adult myocardium and in fetal skeletal muscle while adult skeletal muscle is essentially negative, except for muscle spindle myocytes and a few scattered muscle fibres with overall reduced diameter. By contrast, CAA synthesis is markedly induced in regenerating skeletal muscle cells, in Duchenne muscular dystrophy and upon degenerative atrophy. CAA has also been detected in certain vascular and visceral smooth muscle cells. Among tumors, CAA has consistently been seen in rhabdomyosarcomas and rhabdomyomatous cells of nephroblastomas, whereas, smooth muscle tumors have shown only occasional staining. While the synthesis of this actin isoform is less restricted than previously thought, monoclonal antibodies against CAA provide a well-defined, reliable and sensitive diagnostic tool for the definition and detection of aberrant differentiation in diseased skeletal muscle and of striated muscle differentiation in rhabdomyosarcomas.

August, Christian; Brockmann, Jens; Vowinkel, Thorsten; Wolters, Heiner; Dietl, Karl-Heinz; Levkau, Bodo; Heidenreich, Stefan; Lang, Detlef; Baba, Hideo

doi: 10.1007/s00428-006-0216-3pmid: 16738898

Light microscopic alterations reflecting both previous and preservation-induced changes in the donor organ are usually not very distinctive. The ischemia/reperfusion-associated injury depends primarily on the conditions of donor organ preservation. The present study examined human kidney biopsies with special attention paid to the molecular mechanisms of preservation-induced injury preceding reperfusion. Stress-associated proteins hemeoxygenase-1 (HO-1), heat shock protein 70 (HSP 70), and metallothionein (MT) were studied in human zero-hour biopsies of transplanted kidneys prior to reperfusion in 29 patients. Protein expression was evaluated by semiquantitative immunohistochemistry and Western blotting for HO-1 and HSP 70. These findings were correlated with terminal deoxynucleotidyltransferase-mediated 2′-deoxyuridine 5′-triphosphate-digoxigenin nick end labeling (TUNEL) staining and follow up. Compared to controls, MT and HSP 70 expression was significantly higher at zero hour. In contrast, HO-1 and the number of TUNEL-positive cells were not elevated. MT and HO-1 immunoexpression were inversely associated with graft function, and hence, were of prognostic relevance. MT and HSP 70 were sensitive to the duration of cold ischemia. MT and HO-1 are suitable indicators for tissue injury during ischemia and may serve as new predictive markers that need to be validated in further independent studies.

Sonne, Si; Herlihy, Amy; Hoei-Hansen, Christina; Nielsen, John; Almstrup, Kristian; Skakkebaek, Niels; Marks, Alexander; Leffers, Henrik; Rajpert-De Meyts, Ewa

doi: 10.1007/s00428-006-0223-4pmid: 16736189

Amann, Kerstin; Hofstetter, Jürgen; Câmpean, Valentina; Koch, Andreas; Gross, Marie-Luise; Veelken, Roland; Ritz, Eberhard

doi: 10.1007/s00428-006-0219-0pmid: 16691425

Renal failure causes sympathetic overactivity and inadequate capillary growth in response to cardiomyocyte hypertrophy in experimental renal failure, as well as in uremic patients. In nonuremic animals, sympathetic overactivity was shown to suppress capillary growth. The purpose of this study was to examine whether blockade with α- and β-adrenoblockers ameliorates the capillary deficit that was documented in the hearts of rats with moderate renal failure. Male Sprague–Dawley rats, 3 days after surgical ablation [subtotal nephrectomy (SNX)] or sham operation (sham), were treated with phenoxybenzamine, metoprolol, or a combination of both: After 12 weeks, the hearts were investigated using morphometric and stereologic techniques. The length density of myocardial capillaries was lower (p<0.05) in untreated SNX than in sham (2,786±372 vs 3,397±602 mm/mm3); the decrease was abrogated by metoprolol (3,305±624 mm/mm3), but not by phenoxybenzamin (2,628±480 mm/mm3). The intercapillary distance increased (p<0.05) in SNX (20.5±1.5 μm) and tended to be lower after metoprolol treatment (19.0±1.9 μm). The media area of intramyocardial arterioles was significantly higher in untreated SNX (1,158±1,343 vs 686±771 μm2 in sham). Metoprolol in nonhypotensive doses prevents the capillary deficit in the hearts of rats with moderate renal failure and presents an argument for an important role of sympathetic overactivity in the genesis of the capillary deficit in moderate chronic renal insufficiency.

Ueo, Tetsuya; Kashima, Kenji; Daa, Tsutomu; Kondo, Yoshiyuki; Yokoyama, Shigeo

doi: 10.1007/s00428-006-0193-6pmid: 16609909

Epstein–Barr virus (EBV)-associated gastric carcinoma (EBV-GC) is not rare, accounting for 5 to 18% of all gastric carcinomas. Recently, we encountered two cases of EBV-GC of ordinary histopathological type coexistent with malignant lymphoma. One patient was a 71-year-old Japanese man who had two lesions, one in the cardia and the other in the antrum of the stomach. The former was EBV-GC without lymphoma, and antral one was EBV-GC with diffuse large B-cell lymphoma (DLBCL). The other patient was a 49-year-old Japanese man who had received chemotherapy for pelvic DLBCL 3 years earlier. He had EBV-GC with follicular lymphoma in the fundus of the stomach. In both cases, gastric carcinomas were positive for EBV-encoded small RNA by in situ hybridization, whereas the lymphoma cells, infiltrating nonneoplastic lymphocytes, and nonneoplastic epithelial cells were negative. The present cases suggest that focal immunosuppression by adjacent gastric lymphomas might be related to the alteration of the microenvironment and development of EBV-GC.