[Non-seminomatous germ cell tumours]. / Nichtseminomatöse Keimzelltumoren.

The group of non-seminomatous germ cell tumors can be morphologically and therapeutically distinguished from the group of seminomas. The group of non-seminomatous germ cell tumors includes embryonal carcinoma, yolk sac tumor, choriocarcinoma and teratoma. All entities can occur rarely in pure form or much more commonly in mixed germ cell tumors consisting of more than one histological type. The non-seminomatous germ cell tumors are also characterized by the appearance of an isochromosome 12p, i(12p) and arise from a common precursor lesion called intratubular germ cell neoplasia of the unclassified type (ITGCNU). Various immunohistochemical markers are used to distinguish the different tumor components in addition to morphological characteristics.

[Sex cord gonadal stromal tumors]. / Tumoren des Gonadenstromas.

According to the World Health Organization (WHO) classification from 2004, sex cord gonadal stromal tumors are divided into Leydig cell tumors, Sertoli cell tumors, granulosa cell tumors, tumors of the thecoma-fibroma group, incompletely differentiated sex cord gonadal stromal tumors, mixed forms of sex cord gonadal stromal tumors and tumors containing both germ cell and sex cord gonadal stromal elements. These tumors can appear sporadically or in combination with hereditary syndromes. To diagnose these rare tumors the combination of characteristic morphological aspects and various immunohistochemical markers is useful. Latest investigations demonstrate the potential role of mutation analyses in the diagnosis of this heterogeneous group of tumors.

Myoglobin expression in renal cell carcinoma is regulated by hypoxia.

Myoglobin is a member of the hemoprotein superfamily, which additionally includes hemoglobin, neuroglobin and cytoglobin. Cytoplasmic localized myoglobin functions as a radical scavenger and prevents hypoxia. Besides muscle tissue MB expression could also be observed in other tissues as well as in different types of cancer. For the correlation between the expression of myoglobin, hypoxia-inducible-factor-1α, and capillary density tissue of 86 different renal cell carcinomas were immunohistochemically stained with myoglobin-specific and hypoxia-inducible-factor-1α-specific antibodies as well as with CD31 antibody. Four different renal carcinoma cell lines were cultivated under hypoxic conditions and the expression of myoglobin and hypoxia-inducible-factor-1α was evaluated by real-time PCR and Western blot. Renal cell carcinoma including clear cell, papillary, and chromophobe subtypes expressed myoglobin with an inverse relationship to capillary density being highly significant for clear cell renal cell carcinoma. For hypoxia-inducible-factor-1α a significant correlation with capillary density could also be observed in clear cell RCC. In renal cell carcinoma cell lines hypoxia induced a significant increase of myoglobin expression up to 62 fold, whereas hypoxia-inducible-factor-1α only increased up to 5 fold. The PCR results of myoglobin expression could be confirmed by Western blot. Myoglobin seems to be a sensitive marker for hypovascularized tumor entities especially during the early phase of hypoxia. Such neoplasias may benefit from an antiangiogenic therapy.

[Amyloidosis--a rare differential diagnosis of an orbital tumour]. / Amyloidose--ein seltene Differenzialdiagnose orbitaler Raumforderungen.

BACKGROUND: Amyloidosis is a disorder caused by a misfoulding of proteins. The deposition of these proteins in tissues and organs can affect the normal function of those tissues and organs. MATERIALS AND METHODS: Two patients are presented and an overview over the so far published cases with a localised orbital amyloidosis is given. RESULTS: The first case is a 50-year-old woman with progressive ptosis since half a year, progressive proptosis since three months and deterioration of motility and deviation of the left globe. The second case is a 68-year-old man with progressive ptosis since four years and with affection of the subtarsal conjunctiva of the right eye. Macroscopically a yellow-brown, gelatinous, easily crumbled material was seen during operation. CONCLUSION: the histological proof of amyloidosis can be made visually in intense unidirectional polarised light after congo red staining. This should be done in suspected cases every time. The orbita can also be involved in systemic forms of amyloidosis, so a systemic form should be excluded. The localised amyloidosis has no effect on the survival time in contrast to the systemic forms does have an effect. An untreated systemic form may be associuated with a prognosis of only 9 to 13 months.

The role of beta-catenin mutation and SOX9 expression in sex cord-stromal tumours of the testis.

The WHO classification of testis tumours includes the group of sex cord-stromal tumours. They are divided into several histological types, i.e. Leydig cell (LCT) and Sertoli cell tumours (SCT). Based on the physiological expression of ß-catenin in normal testis/Sertoli cells, it was previously shown that SCT can carry a ß-catenin mutation, causing a nuclear positivity for ß-catenin and cyclin D1. Furthermore, it could be shown that the stabilization of ß-catenin in Sertoli cells causes the loss of the Sertoli cell marker SOX9. We wanted to know whether the stabilization of ß-catenin in sex cord-stromal tumours influences SOX-9 expression and thus could be used in the diagnosis of sex cord-stromal tumours. Therefore, 53 cases of sex cord-stromal tumours and tumour-like lesions were investigated for their immunohistochemical expressions of ß-catenin, cyclin D1 and SOX9. In addition, mutation analyses of the ß-catenin gene (exon 3; CTNNB1) were performed. ß-catenin mutation in SCT results in nuclear ß-catenin and cyclin-D1 expressions on immunohistochemical analysis. The nuclear expression/stabilization of ß-catenin causes the loss of SOX9 in these tumours. In contrast, SOX9 is considerably expressed in non-mutated SCT as well as in Sertoli cells of non-neoplastic testes. In summary, immunohistochemical analyses of ß-catenin and SOX9 are useful to distinguish SCT from other sex cord-stromal tumours of the testis. Furthermore, the presence of SOX9 indicates that the cells of origin may be Sertoli cells.

[Lymph node metastases in ypT1/2 rectal cancer after neoadjuvant chemoradiotherapy : The Achilles heel of organ-preserving operative procedures?]. / Lymphknotenmetastasen beim ypT1/2-Rektumkarzinom nach neoadjuvanter Radiochemotherapie : Die Achillesferse organerhaltender Operationsverfahren?

BACKGROUND: For patients with rectal cancer and complete remission (ypT0) or with good response and residual tumor restricted only to the bowel wall (ypT1-2) after neoadjuvant chemoradiotherapy (CRT), local excision has been suggested as an alternative to avoid the significant morbidity and functional deficits associated with total mesorectal excision (TME). The aim of this investigation was to investigate the incidence, distribution and tumor-related localization of mesorectal lymph node (LN) metastases in TME specimens with complete remission (ypT0), intramural (ypT1-2) and extramural (ypT3-4) residual tumor tissue. PATIENTS AND METHODS: Specimens of TME from 81 patients with locally advanced rectal cancer (UICC II-III) undergoing neoadjuvant CRT within the phase III German rectal cancer trial CAO/ARO/AIO-04 were prospectively evaluated. The entire mesorectal compartment was microscopically screened after complete paraffin embedding. The number and localization of all detectable LN metastases were documented in relation to the primary tumor. RESULTS: Whereas 50 patients (62 %) had ypT3-4 rectal cancer after neoadjuvant CRT, 20 patients (25 %) presented with residual tumor within the bowel wall (ypT1-2), 11 patients (14 %) had pathological complete remission (ypT0), an average of 28 ± 13.7 LN were detected per specimen and 25 patients (31 %) had residual LN metastases after CRT. Although the incidence of LN metastases was higher in the ypT3-4 group (40 %), 25 % of patients in the ypT1-2 group with intramural residual tumor had a mean number of 2.2 residual LN metastases of which 55 % were located far from the primary lesion in the proximal mesorectum. None of the patients with ypT0 status (complete response) had residual LN metastases. CONCLUSION: Even in patients with good response and post-CRT tumor tissue restricted only to the bowel wall (ypT1-2), there is still a considerable risk for residual LN metastases. Local excision of residual rectal cancer was accompanied by a higher rate of local failure and radical surgery with TME should remain the standard treatment in these patients. To date, valid selection criteria for patients eligible for organ-sparing surgery are still lacking.

Switch of cadherin expression as a diagnostic tool for Leydig cell tumours.

Leydig cell tumours comprise about 3% of all testicular tumours. The pathogenesis of Leydig cell tumours is still poorly understood. We investigated testis with Leydig cell hyperplasia and Leydig cell tumours for their expression pattern of P- and N-cadherin. We could show a switch of expression of P- and N-cadherin in Leydig cell hyperplasia and Leydig cell tumours in comparison with normal Leydig cells. Cadherins could be established as a new immunohistochemical marker for this testicular tumour entity; their possible role in tumour genesis will be discussed.

Expression and function of the vitamin D receptor in malignant germ cell tumour of the testis.

Testicular germ cell tumours (TGCTs) are the most common malignancy in young men aged 18-35 years. They are clinically and histologically subdivided into seminomas and non-seminomas. 1,25-Dihydroxyvitamin D (1,25(OH)(2)D(3)) is the active form of vitamin D and exerts its actions via a specific intracellular vitamin D receptor (VDR). Several investigations in the recent years have revealed, in addition to a physiological occurrence of the VDR in various tissues, VDR expression in different human malignancies. Furthermore, 1,25(OH)(2)D(3) plays an important role in the regulation of cell proliferation and differentiation. In different normal and malignant cell types, antiproliferative and pro-differentiating effects of 1,25(OH)(2)D(3) are described. We investigated whether TGCT express the VDR, wether differences exist between the histological subtypes and if vitamin D has a function on the proliferation of tumour cells. Furthermore, we investigated the potential function of the vitamin D-regulated genes nuclear receptor co-repressor 1(NCOR1), nuclear receptor co-repressor 2 (NCOR2), thyroid receptor interacting protein 15 (TRIP15), Growth Arrest and DNA Damage (GADD45), MAP kinase-activated protein kinase 2 (MAPKAPK2), Cytochrome P450, family 24, subfamily A, polypeptide 1 (CYP24A1) and Cytochrome P450, family 27, subfamily B, polypeptide 1 (CYP27B1) in the pathogenesis of TGCT. We demonstrate, for the first time, that primary TGCT as well as TGCT cell lines, express VDR mRNA and protein. Vitamin D and VDR may play a role in the pathogenesis of TGCTs. Furthermore, vitamin D inhibits proliferation of TGCT cell-lines, potentially via an increase in expression of GADD45. Our data suggest that vitamin D could play a role in antitumour therapy.

Beneficial effects of CCR1 blockade on the progression of chronic renal allograft damage.

The biology of chemokines and their receptors have been linked to the development of chronic allograft damage. Effects of CCR1 antagonist BX 471 were studied in a Fischer to Lewis renal transplantation model at days 10, 21 and 42 after transplantation. BX 471 treatment did not effectively reduce signs of acute rejection at day 10 but significantly improved allograft function and morphology at day 21 posttransplantation. When therapy was initiated on day 21 after transplantation, glomerulosclerosis and tubulointerstitial fibrosis were significantly inhibited by day 42 posttransplantation. Parallel decrease in infiltrating and proliferating mononuclear cells (ED1, CD8 and Ki67) was observed in treated allografts. Expression of acute phase reactive and proinflammatory genes (HO-1, osteopontin) and molecules associated with fibrosis (PAI-1, TGF-beta1, biglycan) was downregulated at day 21; reduced collagen deposition was observed, parallel to a significant lower number of alpha-SMA+ interstitial myofibroblasts. In situ hybridization demonstrated that biglycan expression was reduced following CCR1 blockade in interstitium of treated allografts. CCR1 antagonism was found to inhibit CCL5-induced secretion of biglycan by macrophages in vitro. CCR1 blockade significantly inhibited development and progression of chronic allograft damage. CCR1 antagonists may represent a therapeutic option for chronic inflammation and fibrosis in renal grafts.