Virchows Archiv

Klöppel, Günter

doi: 10.1007/s00428-007-0464-xpmid: 17684759

Mascarel, Isabelle; MacGrogan, Gaëtan; Mathoulin-Pélissier, Simone; Vincent-Salomon, Anne; Soubeyran, Isabelle; Picot, Véronique; Coindre, Jean-Michel; Mauriac, Louis

doi: 10.1007/s00428-007-0408-5pmid: 17551752

This study analyzes the occurrence of epithelial atypia in 2,833 serially sectioned surgical breast biopsies (SB) performed for microcalcifications (median number of blocks per SB:26) and the occurrence of subsequent cancer after an initial diagnosis of epithelial atypia (median follow-up 160 months). Epithelial atypia (flat epithelial atypia, atypical ductal hyperplasia, and lobular neoplasia) were found in 971 SB, with and without a concomitant cancer in 301 (31%) and 670 (69%) SB, respectively. Thus, isolated epithelial atypia were found in 670 out of the 2,833 SB (23%). Concomitant cancers corresponded to ductal carcinomas in situ and micro-invasive (77%), invasive ductal carcinomas not otherwise specified (15%), invasive lobular carcinomas (4%), and tubular carcinomas (4%). Fifteen out of the 443 patients with isolated epithelial atypia developed a subsequent ipsilateral (n = 14) and contralateral (n = 1) invasive cancer. The high slide rating might explain the high percentages of epithelial atypia and concomitant cancers and the low percentage of subsequent cancer after a diagnosis of epithelial atypia as a single lesion. Epithelial atypia could be more a risk marker of concomitant than subsequent cancer.

Klöppel, Günter; Dege, Katherine; Remmele, Wolfgang; Kapran, Yersu; Tuzlali, Sitki; Modlin, Irvin

doi: 10.1007/s00428-007-0462-zpmid: 17684760

In 1907 Siegfried Oberndorfer published his observations and interpretations on tumorlets (“Geschwulstchen”) in the small intestine, which he called carcinoids (“karzinoide Tumoren”). This article pursues the questions why this discovery was so unique and what role it played in the later life of Siegfried Oberndorfer.

Klöppel, Günter; Rindi, Guido; Anlauf, Martin; Perren, Aurel; Komminoth, Paul

doi: 10.1007/s00428-007-0461-0pmid: 17684761

The gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are composed of cells with a neuroendocrine phenotype. Well-differentiated tumors, well-differentiated carcinomas, poorly differentiated carcinomas, functioning tumors (with a hormonal syndrome), and nonfunctioning tumors are identified. To predict their clinical behavior, these neuroendocrine tumors are classified on the basis of their clinicopathological features, including size, local invasion, angioinvasion, proliferative activity, histological differentiation, and metastases, into neoplasms with benign, uncertain, low-grade malignant and high-grade malignant behavior. In addition, a tumor/nodes/metastases classification and a grading system are presented. In the light of these criteria, the various GEP-NET entities are reviewed.

Park, Daehoon; Kåresen, Rolf; Noren, Tove; Sauer, Torill

doi: 10.1007/s00428-007-0435-2pmid: 17554555

Proliferative activity of tumour cells assessed by immunohistochemical Ki-67 expression is one of several prognostic indicators in breast cancer. The major objective of this study was to investigate the prognostic impact of Ki-67 proliferative activity in the axillary lymph node metastases and in the matched primary breast carcinoma from 194 patients. There was a statistically significant up-regulation of Ki-67 protein in the metastatic deposit compared to where the primary tumour was found (p = 0.001). A low Ki-67 index in both the primary and the metastatic tumours was a favorable prognostic factor. A high index in both primary and metastatic lesion and an up-regulation from a low index in the primary tumour to a high index in the metastatic deposit represented an unfavorable prognostic factor. Multivariate analysis showed that Ki-67 expression in the metastases was a superior independent prognostic factor of clinical outcomes compared to that in the primary tumours. Ki-67 expression in ≥10% of carcinoma cells in the primary tumours and ≥15% in the nodal metastases seems to be optimal cut-off levels. Ki-67 is of value as an independent prognostic factor in breast cancer.

Dietel, M.; Ellis, I.; Höfler, H.; Kreipe, H.; Moch, H.; Dankof, A.; Kölble, K.; Kristiansen, G.

doi: 10.1007/s00428-007-0424-5pmid: 17562074

HER2 is an important tumour marker in breast cancer. However, there is controversy regarding which method reliably measures HER2 status. This study evaluates the concordance between HER2 gene amplification in invasive breast cancer determined by fluorescence in situ hybridisation (FISH) and a new silver enhanced in situ hybridisation (SISH) technique. Ninety-nine cases were analysed by direct-labelled manual FISH (PathVysion®, Abbott/Vysis) and bright field automated SISH (INFORM®, Ventana). For comparison, all specimens were stained by immunohistochemistry (Dako-HercepTest™ and Ventana-PATHWAY®4B5). Evaluation was performed by five pathologists following the algorithms of the manufacturers and the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines. Concordance was calculated and the value of κ statistics estimated. Overall concordance between FISH and SISH was 96.0% (κ = 0.754, 95%CI). Discrepancies were mostly seen in tumours with intra-tumoural heterogeneity of HER2 amplification. In conclusion, HER2 gene copy status can be reliably determined by SISH. The 96% concordance with FISH fulfils the ASCO/CAP requirement of greater than 95% concordance for amplified vs non-amplified cases. There was a low inter-observer variability in the interpretation of SISH, suggesting that SISH is equally reliable in determining HER2 amplification as FISH. Because SISH combines bright field microscopy with molecular analysis and full automation, it appears to be particularly suited for routine application in surgical pathology.

Yamamoto, Sohei; Tsuda, Hitoshi; Kita, Tsunekazu; Maekawa, Kazunari; Fujii, Kazuyuki; Kudoh, Kazuya; Furuya, Kenichi; Tamai, Seiichi; Inazawa, Johji; Matsubara, Osamu

doi: 10.1007/s00428-007-0433-4pmid: 17594113

Anlauf, Martin; Garbrecht, Nele; Bauersfeld, Juliane; Schmitt, Anja; Henopp, Tobias; Komminoth, Paul; Heitz, Philipp; Perren, Aurel; Klöppel, Günter

doi: 10.1007/s00428-007-0450-3pmid: 17684762

Approximately 5–10% of neuroendocrine tumors (NETs) of the gastroenteropancreatic system (GEP) have a hereditary background. The known inherited syndromes include multiple endocrine neoplasia type 1, neurofibromatosis type 1, von Hippel–Lindau disease, and the tuberous sclerosis complex. This review discusses for each of these syndromes the: (1) involved genes and specific types of mutations, (2) disease prevalence and penetrance, (3) affected neuroendocrine tissues and related clinical syndromes, (4) special morphological features of NETs and their putative precursor lesions. In addition, GEP-NETs clustering in individual families or associated with other malignancies without known genetic background are discussed.

Pellegata, Natalia; Quintanilla-Martinez, Leticia; Keller, Gisela; Liyanarachchi, Sandya; Höfler, Heinz; Atkinson, Michael; Fend, Falko

doi: 10.1007/s00428-007-0431-6pmid: 17554557

Pheochromocytomas are neuroendocrine tumors arising in the neural crest-derived chromaffin cells of the adrenal gland or in extra-adrenal sympathetic ganglia (paragangliomas). In a rat model of multiple endocrine neoplasia (MEN), absence of functional p27Kip1 protein predisposes to pheochromocytoma and paraganglioma development. As no data is available regarding the involvement of p27Kip1 in human pheochromocytoma and/or paraganglioma, we set out to determine the expression pattern of p27Kip1 in those tumor types. A panel of 25 pheochromocytomas and 23 paragangliomas was collected. Two pheochromocytomas were from MEN2 patients. The paragangliomas included 15 tumors that developed at the carotid bifurcation, three in the jugulo–tympanic area, and five at other sites. Except for the MEN2 cases, all others were apparently sporadic. Immunohistochemistry for p27Kip1 and the proliferation marker Ki67 was performed. We found that p27Kip1 expression is reduced/lost in 56% of pheochromocytomas, but only in 18.1% of paragangliomas. Downregulation of p27Kip1 was not associated with increased proliferation. Cases showing reduced/lost p27Kip1 expression were screened for the presence of somatic mutations in CDKN1B (p27Kip1) and for allelic imbalance at the p27Kip1 locus. Three cases had allelic imbalance but none had mutations. In conclusion, pheochromocytomas display extreme reduction/loss of p27Kip1 expression at high frequency.

Perren, Aurel; Anlauf, Martin; Komminoth, Paul

doi: 10.1007/s00428-007-0449-9pmid: 17684763

Neuroendocrine tumors of the gastroenteropancreatic system are defined by their endocrine phenotype and share many histopathological and clinical features. However, the fact that the hormone production of tumors depends on their site of origin, that the tumors differ in their biology, and that the association with familial syndromes is nonrandom suggests heterogeneity. It is therefore conceivable that the gastroenteropancreatic neuroendocrine tumors also differ in their molecular profile. This review summarizes and discusses the available data in this field.