Histopathologie des Nierenzellkarzinoms

By integrating genetic data into the traditional histology and immunohistochemistry-based classification system, the revised WHO classification of malignant tumors (2004) defined additional renal cell carcinoma subtypes, thereby enabling the application of additional diagnostic procedures.     

Immuntherapie des Nierenzellkarzinoms

Interleukin-2 (IL-2) and/or interferon-alpha (IFN-alpha) induce remissions and prolong life in patients with metastatic renal cell carcinoma when carefully selected for a possibly toxic treatment. However, better-tolerated and more effective therapies are needed, especially in the elderly and patients with comorbidities. Recent achievements in the treatment of advanced renal cell carcinoma highlight potentially significant improvements. Immune cells within the tumor correlate with response and survival indicating the importance of local immune modulation. Such modulation has allowed introducing well-tolerated treatments such as inhalation of IL-2 to control lung metastases, which results in a significant survival benefit for high-risk patients as suggested by a recent cohort study in 200 patients. Antibody-based tumor targeting against cG250, specifically expressed on RCC, seems to stabilize progressive metastatic disease and does not induce toxicity. Vaccination strategies are also well tolerated, but have not shown convincing results in advanced disease so far. Other approaches have not fulfilled expectations. Stem cell transplantation still has significant toxicity and cannot be recommended for the elderly.     

Immuntherapie des fortgeschrittenen Nierenzellkarzinoms

Zusammenfassung Beim Nierenzellkarzinom hat sich die Überlebenszeit der Patienten in frühen Stadien durch verbesserte chirurgische Therapie deutlich erhöht. Für Patienten mit fortgeschrittenen Stadien hat sich die Prognose aber nur unwesentlich verändert. Behandlung mit IFN- führte zur moderaten Verlängerung des Überlebens, zusätzlich kann eine Nephrektomie dazu beitragen. Die Kombination IFN-, 5-FU und Interleukin-2 führte ebenfalls in einer Studie zu verlängerter Überlebenszeit. Die häufig erhebliche Toxizität dieser Strategien machen jedoch eine sorgfältige Risiko-Nutzen-Abwägung im Einzelfall erforderlich. Auch wenn die Erwartungen an die Immuntherapie bisher nur teilweise erfüllt sind, zeigen erste Ergebnisse mit spezifischen Immuntherapien, dass eine immunologische Kontrolle des metastasierten Nierenzellkarzinoms möglich ist. Die Hoffnung auf effektive Behandlungsverfahren in naher Zukunft erscheint realistisch.     

Systemtherapie des metastasierten Nierenzellkarzinoms

In the last 5 years the paradigms for the treatment of metastatic renal cell cancer have fundamentally changed. Until 2005 systemic therapy was limited to the immunomodulating cytokines interferon-alfa and interleukin-2, in recent years, however, tyrosine kinase inhibitors, mTor inhibitors and monoclonal antibodies have been established for this therapeutic situation. Without validated predictive biomarkers it is currently not possible to select patients who are likely to benefit from a certain therapy. Therefore, most current guidelines stratify the patients into risk groups according to the MSKCC risk score. The resulting treatment algorithm for first-line therapy is limited to these new drugs within all risk groups. Since approval for more tyrosine kinase inhibitors and mTOR inhibitors is currently awaited, the number of treatment options will expand further in the near future. The present paper reviews the present study data and aims to provide practical advice for the treatment of patients suffering from metastatic renal cell cancer.     

Paraneoplastische Syndrome des Nierenzellkarzinoms

Renal cell carcinoma associated paraneoplastic symptoms include constitutional symptoms as well as specific metabolic and biochemical abnormalities. These are present in up to 40% of patients with renal cell carcinoma during the course of the disease. This report provides information on the most common manifestations and their therapy; some rare variants are also mentioned. The importance of paraneoplasia lies partly in the fact that paraneoplastic symptoms may be the precursor of either primary or recurrent disease. The presence of paraneoplastic manifestations does not necessarily imply a poor prognosis or metastatic disease.     

Operative Therapie des Nierenzellkarzinoms

Renal cell carcinoma represents the fifth most frequent malignant tumor in humans. At the time of diagnosis, 20% of the patients already manifest metastases. A further 20–30% of the patients develop systemic metastases in the postoperative course. Despite continued advances in pharmacological treatment options, cancer surgery tailored to the individual tumor findings constitutes the only curative treatment option.     

Systemische Therapie des metastasierten Nierenzellkarzinoms

Cytokine-based immunotherapy was the only viable option in metastatic, nonresectable renal cell carcinoma (RCC) for many years. Systemic immunotherapy has become increasingly established as a standard therapy during the last 15 years. In this context, interleukin-2 (IL-2) and interferon-alpha (IFN-alpha) turned out to be the most effective single agents in RCC. Subsequently, the approved subcutaneous application of these compounds was the preferred administration route in Germany. Response rates with cytokine combination therapy were almost similar to those of more aggressive concepts using additional chemotherapeutic agents.Currently, new compounds targeting specific signaling pathways are readily available and have passed clinical testing. Such small molecules like tyrosine kinase inhibitors, monoclonal antibodies, or the mTOR inhibitor CCI-779 may dramatically change the established concepts of systemic RCC treatment. This paper gives an overview of established, current, and evolving concepts of systemic therapy in RCC.     

Systemische Therapie des metastasierten Nierenzellkarzinoms

Once surgical options have been exhausted, systemic therapy is indicated for metastasizing renal cell carcinoma. Until recently this was carried out using mainly immunotherapeutic concepts with unsatisfactory results. Since the majority of clear cell renal cell carcinomas are well vascularised, angiogenetic inhibition offered an alternative therapy goal. To date, four substances have been approved to control angiogenesis in the therapy of renal cell carcinoma: sunitinib, sorafenib, temsirolimus, as well as a combination of bevacizumab and interferon alpha. Other substances, such as everolimus, pazopanib and axitinib, are currently the subject of clinical trials. Initial data on tolerance and efficacy was presented at this years annual conference of the American Society of Clinical Oncology (ASCO). This article examines current therapy options and ASCO data and discusses future trends.     

Systemische Behandlung des metastasierten Nierenzellkarzinoms

Introduction

The goal of this work was to describe the change of treatment paradigms for metastatic renal cell carcinoma (mRCC) since 2006.

Patients and methods

We retrospectively investigated all mRCC patients who were treated with targeted therapy between June 2006 and June 2012 at the University of Münster.

Results

In all, 50 of 158 (31.6?%) patients were initially treated with immunotherapy. The most often used second line treatment after immunotherapy was sorafenib (29 patients, 58.0?%). The first line treatment chosen for therapy-naïve patients was sunitinib (68 patients, 63.0?%). There was no statistically significant difference between the two groups (572 vs. 554 days, p?=?0.745). A total of 77 patients had synchronous metastasis (48.8?%), 55 of whom underwent cytoreductive nephrectomy. There was a significant survival benefit in favor of surgically treated patients (510 vs. 186 days, p?=?0.002).

Conclusion

After introduction of the new agents treatment paradigms have changed substantially. Immunotherapy is used only rarely. Cytoreductive nephrectomy may continue to be regarded as standard treatment until prospective data are available.     

Geschlechtsspezifische Charakteristika und Prognose des Nierenzellkarzinoms

BACKGROUND: Renal cell carcinoma (RCC) occurs twice as often in men as in women; however, the influence of gender on stage, grade, subtype and prognosis has not been studied in detail. METHODS: This study included 780 patients treated by (partial) nephrectomy at our institution in Marburg between 1990 and 2005. The mean follow-up was 5.44 years. RESULTS: Of the 780 patients, 486 (62%) were men and 294 (38%) were women. Women were significantly older (mean, 65.3 vs. 62.2 years; p<0.001, t-test), presented at lower T stages (p=0.046, chi(2)) and suffered metastasis less frequently at diagnosis (p=0.026, chi(2)). In addition, women more frequently had clear cell tumours (85.2% vs. 78.3%) and less frequently papillary tumours (11.0% vs. 18.8%) than men (p=0.026, chi(2)). In contrast, men had an increased risk of death from RCC (HR 1.23, CI 0.92-1.63); Kaplan-Meier curves revealed a significant difference in tumour-specific survival between men and women (p=0.033, log rank; 5-year survival 74% vs. 83%). However, unlike tumour stage and tumour grade, gender could not be retained as a significant independent prognostic marker in multivariate analysis. CONCLUSION: In general, RCC in men is characterized by higher tumour stages and more frequent metastasis at diagnosis along with inferior tumour-specific survival. However, as gender failed to qualify as an independent prognostic marker for tumour-specific survival, delayed diagnosis due to insufficient routine medical check-up and/or a more aggressive tumour biology might be be a concurrent cause. Thorough regular medical check-ups for men, also with regard to RCC, are thus mandatory.     

Die postoperative Prognose des chromophoben Nierenzellkarzinoms

Background

The chromophobe subtype represents the third most common histological subtype of renal cell carcinoma (chRCC). Due to the rarity of this subtype only one publication regarding the specific analysis of clinical and histopathological criteria as well as survival analysis of more than 200 patients with chRCC is known to date.

Materials and methods

A total of 6,234 RCC patients from 11 centres who were treated by (partial) nephrectomy are contained in the database of this multinational study. Of the patients 259 were diagnosed with chRCC (4.2?%) and thus formed the study group for this retrospective investigation. These subjects were compared to 4,994 patients with a clear cell subtype (80.1?%) with respect to clinical and histopathological criteria. The independent influence of the chromophobe subtype regarding tumor-specific survival and overall survival was determined using analysis by Cox proportional hazards regression models. The median follow-up was 59 months (interquartile range 29-106 months).

Results

The chRCC patients were significantly younger (60 vs. 63.2 years, p?<?0.001), more often female (50 vs. 41?%, p?=?0.005) and showed simultaneous distant metastases to a lesser extent (3.5 vs. 7.1?%, p?=?0.023) compared to patients with a clear cell subtype. Despite a comparable median tumor size a ≥?pT3 tumor stage was diagnosed in only 24.7?% of the patients compared to of 30.5?% in patients with a clear cell subtype (p?=?0.047). In addition to the clinical criteria of age, sex and distant metastases, the histological variables pTN stage, grade and tumor size showed a significant influence on tumor-specific and overall survival. However, in the multivariable Cox regression analysis no independent effect on tumor-specific mortality (HR 0.88, p?=?0.515) and overall mortality (HR 1.00, p?=?0.998) due to the histological subtype was found (c-index 0.86 and 0.77, respectively).

Conclusions

Patients with chRCC and clear cell RCC differ significantly concerning the distribution of clinical and histopathological criteria. Patients with chRCC present with less advanced tumors which leads to better tumor-specific survival rates in general; however, this advantage could not be verified after adjustment for the established risk factors.     

Palliative und supportive Therapie des Nierenzellkarzinoms

At the time of diagnosis, 25-30% of all patients with renal cell carcinoma already present with metastatic disease. Furthermore, 20-30% of patients with renal cell carcinoma will have progressive disease despite radical nephrectomy with complete tumor resection.In this review, we discuss the current therapeutic options for patients with metastatic renal cell carcinoma: These include palliative radical nephrectomy, surgery of metastasis, tumor embolisation and medical treatment options (e.g. immunotherapy, chemotherapy and targeted therapy), as well as supportive pain treatment.     

Aktuelles zur Systemtherapie des metastasierten Nierenzellkarzinoms

The past 5 years were marked by fundamental changes in the systemic therapy of metastatic renal cell carcinoma. Up to the end of the last decade cytokine-based chemotherapy was the only, even if only moderately effective systemic therapy for metastatic renal cell carcinoma. Currently there are five new approved drug releases of so-called targeted substances, which function on a molecular based therapeutic mechanism. Sunitinib (Sutent®) and sorafenib (Nexavar®) as multikinase inhibitors, everolimus (Afinitor®) and temsirolimus (Torisel®) as mTOR inhibitors, and bevacizumab as an antibody against VEGF in combination with interferon-alpha (IFN-α). The following article will give an overview of the currently available substances and critically discuss therapy plans and future trends.     

Kontroversen in der operativen Therapie des Nierenzellkarzinoms

Dabei stehen haupts?chlich folgende Aspekte im Vordergrund: 1. Zugangswege 2. Lymphadenektomie 3. Adrenalektomie 4. Operationsindikation beim Cavathrombus 5. Organerhaltende Therapie      

Systemische und operative Therapie des metastasierten Nierenzellkarzinoms

Several targeted therapies have become available for first-line (sunitinib, bevacizumab, pazopanib, temsirolimus) and second-line (sorafenib, pazopanib, everolimus) use in recent years. The superior outcomes achieved with these targeted agents have led to replacement of the formerly administered cytokines. New developments have raised the question of whether patients benefit from sequential therapies with tyrosine kinase inhibitors and/or whether combination regimes can improve clinical outcomes. This review gives an overview of the current therapeutic options for first- and second-line treatment in metastatic RCC as well as sequential and combination therapies. Adjuvant and neoadjuvant treatment options are being discussed. Furthermore, this review addresses surgical alternatives in the treatment of RCC.     

Entwicklung antiangiogener Kombinationstherapien zur Behandlung des Nierenzellkarzinoms

Ohne Zusammenfassung     

Bildgebung der aseptischen Femurkopfnekrose des Erwachsenen

The aim of diagnostic imaging procedures in avascular femoral head necrosis is to provide the patient with a stage-adapted therapy. Therefore, a differentiated diagnostic work-up is needed. Native radiography of the hip in two planes is still the first step. Over the past years, the diagnosis of femoral head necrosis has experienced tremendous improvement due to the use of MRI and CT scans. Because of these improvements the correct stage can be diagnosed early and the appropriate therapy can be initiated immediately. Today, MRI is the most sensitive diagnostic imaging procedure. CT scans can be particularly useful to exclude subchondral fractures. The use of bone scintigraphy is restricted to exceptional cases. In Europe, the ARCO classification of avascular femoral head necrosis has been widely accepted. It is essential here to define subtypes according to the localisation and the extent of the necrosis, because both have major influence on the prognosis of the disease and therefore also for the therapeutic strategy. In this overview, we describe the specific characteristics of the different diagnostic imaging procedures and illustrate them with appropriate imaging material. At the end of the article an algorithm for diagnostic imaging procedures in avascular femoral head necrosis for daily orthopaedic practice is proposed.