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Steinestel K.,University of Federal Defense Munich | Steinestel K.,Institute of Pathology and Molecular Pathology | Lennerz J.K.,University of Ulm | Eder S.,University of Federal Defense Munich | And 2 more authors.
Virchows Archiv | Year: 2014

KRAS/BRAF mutation testing and mismatch repair (MMR) protein immunohistochemistry have an established role in routine diagnostic evaluation of colorectal carcinoma (CRC). However, since the exact impact of these molecular characteristics on tumor morphology and behavior is still subject to research, the aim of our study was to examine associations between molecular and morphologic features that had not been analyzed in this combination before. KRAS (codons 12, 13, and 61) and BRAF (codon 600) mutation status and MMR protein expression were analyzed in a consecutive series of 117 CRC samples using DNA pyrosequencing and immunohistochemistry. Tumor cell budding, infiltration pattern, and peritumoral lymphocytic (PTL) reaction was assessed applying established criteria. Molecular and morphological findings were correlated applying chi-square and Fisher's exact test. We found KRAS or BRAF mutations in 40 and 8 % of samples, while loss of MMR protein expression was observed in 11 %. Tumor budding was significantly associated with infiltrative growth, absence of PTLs, and blood and lymph vessel infiltration. Neither KRAS nor BRAF mutations were associated with a certain growth pattern or budding intensity of CRC, but loss of MMR protein expression was found in context with BRAF mutation, expanding growth, and presence of PTLs. Our results confirm an association between loss of MMR protein expression, presence of activating BRAF mutation, expanding growth, and PTL reaction as well as between tumor budding, infiltrative growth pattern, and tumor aggressiveness; however, there was no such association between the presence of an activating KRAS or BRAF mutation and a distinct invasion pattern or tumor aggressiveness in CRC. © 2014 Springer-Verlag.


Steinestel J.,Muenster University Medical Center | Al Ghazal A.,University of Ulm | Arndt A.,Institute of Pathology and Molecular Pathology | Schnoeller T.J.,University of Ulm | And 3 more authors.
BMC Cancer | Year: 2015

Background: Up to 50% of penile squamous cell carcinomas (pSCC) develop in the context of high-risk human papillomavirus (HR-HPV) infection. Most of these tumours have been reported to show basaloid differentiation and overexpression of tumour suppressor protein p16INK4a. Whether HPV-triggered carcinogenesis in pSCC has an impact on tumour aggressiveness, however, is still subject to research. Methods: In tissue specimens from 58 patients with surgically treated pSCC between 1995 and 2012, we performed p16INK4a immunohistochemistry and DNA extraction followed by HPV subtyping using a PCR-based approach. The results were correlated with histopathological and clinical parameters. Results: 90.4% of tumours were of conventional (keratinizing) subtype. HR-HPV DNA was detected in 29.3%, and a variety of p16INK4a staining patterns was observed in 58.6% of samples regardless of histologic subtype. Sensitivity of basaloid subtype to predict HR-HPV positivity was poor (11.8%). In contrast, sensitivity and specificity of p16INK4a staining to predict presence of HR-HPV DNA was 100% and 57%, respectively. By focussing on those samples with intense nuclear staining pattern for p16INK4a, specificity could be improved to 83%. Both expression of p16INK4a and presence of HR-HPV DNA, but not histologic grade, were inversely associated with pSCC tumour invasion (p=0.01, p=0.03, and p=0.71). However, none of these correlated with nodal involvement or distant metastasis. In contrast to pathological tumour stage, the HR-HPV status, histologic grade, and p16INK4a positivity failed to predict cancer-specific survival. Conclusions: Our results confirm intense nuclear positivity for p16INK4a, rather than histologic subtype, as a good predictor for presence of HR-HPV DNA in pSCC. HR-HPV / p16INK4a positivity, independent of histological tumour grade, indicates a less aggressive local behaviour; however, its value as an independent prognostic indicator remains to be determined. Since local invasion can be judged without p16INK4a/HPV-detection on microscopic evaluation, our study argues against routine testing in the setting of pSCC. © Steinestel et al.; licensee BioMed Central.


Saravakos P.,Head and Neck Surgery | Hartwein J.,Head and Neck Surgery | Fayyazi A.,Institute of Pathology and Molecular Pathology
European Archives of Oto-Rhino-Laryngology | Year: 2016

Malignant salivary gland sarcomas represent a clinically and histologically diagnostic challenge. Primary unclassified sarcomas of the parotid gland consist a rare salivary gland tumor. We report an unusual case of such a tumor, which occurred in the right parotid gland of a 54-year-old male and presented as an asymptomatic painless mass. The pathologoanatomical examination revealed a rhabdoid large-cell unclassified sarcoma. The patient was treated with superficial parotidectomy and adjuvant radiotherapy. No recurrence was noted in a 10-year follow-up period. Due to the rare occurrence of primary unclassified sarcomas, there is no evidence-based treatment of choice. An optimal approach is best planned in a multidisciplinary setting, taking into consideration the resectability of the tumor, individual patient characteristics, presence of local or distant metastatic activity, local infiltrative behavior and tumor stage. A close follow-up of the patient is strongly recommended. © 2016 Springer-Verlag Berlin Heidelberg


Steinestel K.,University of Federal Defense Munich | Steinestel K.,University of Ulm | Bruderlein S.,University of Ulm | Lennerz J.K.,University of Ulm | And 5 more authors.
Molecular Cancer | Year: 2014

Background: The Abelson tyrosine kinase (c-Abl) inhibitor STI571 (Glivec®) has been shown to effectively inhibit colorectal cancer cell migration and invasion. The c-Abl substrate abelson interactor 1 (Abi1) is a key regulator of actin reorganization and upregulated in colorectal carcinoma. The specific role of Abi1 in relation to extracellular matrix degradation and effects of targeting Abi1 phosphorylation have not yet been examined. Here, we investigated the role of Abi1 in relation to invasive properties in colorectal cancer.Methods and results: In 56 primary human colorectal carcinoma samples, we found overexpression of Abi1 in 39% at the invasive edge of the tumour, associated with an infiltrative phenotype and high-grade tumour cell budding (p = 0.001). To explore the role of Abi1 in vitro, we employed the Abi1 expressing and KRAS-mutated CHD1 model and performed matrix degradation assays that showed Abi1 localization at specific sites of matrix degradation. Moreover, quantification of matrix dissolution demonstrated suppression after RNAi knockdown of Abi1 by 95% (p = 0.001). Importantly, treatment with STI571 did abolish Abi1 Y435-phosphorylation, suppressed the matrix dissolution, decreased fibronectin attachment, and suppressed cell invasion through reconstituted extracellular matrix.Conclusion: Our data indicate that phosphorylated Abi1 contributes to the invasive properties of colorectal cancer. © 2014 Steinestel et al.; licensee BioMed Central Ltd.


Steinestel K.,University of Munster | Eder S.,University of Federal Defense Munich | Ehinger K.,University of Ulm | Schneider J.,Institute of Pathology and Molecular Pathology | And 5 more authors.
Tumor Biology | Year: 2015

Metastasis is the survival-determining factor in urothelial carcinoma (UC) of the urinary bladder. The small conductance calcium-activated potassium channel 3 (SK3) enhances tumor cell invasion in breast cancer and malignant melanoma. Since Edelfosine, a glycerophospholipid with antitumoral properties, effectively inhibits SK3 channel activity, our goal was to evaluate SK3 as a potential molecular target to inhibit the gain of an invasive phenotype in UC. SK3 protein expression was analyzed in 208 tissue samples and UC cell lines. Effects of Edelfosine on SK3 expression and intracellular calcium levels as well as on cell morphology, cell survival and proliferation were assessed using immunoblotting, potentiometric fluorescence microscopy, and clonogenic/cell survival assay; furthermore, we analyzed the effect of Edelfosine and SK3 RNAi knockdown on tumor cell migration and invasion in vitro and in vivo. We found that SK3 is strongly expressed in muscle-invasive UC and in the RT112 cellular tumor model. Higher concentrations of Edelfosine have a strong antitumoral effect on UC cells, while 1 μM effectively inhibits migration/invasion of UC cells in vitro and in vivo comparable to the SK3 knockdown phenotype. Taken together, our results show strong expression of SK3 in muscle-invasive UC, consistent with the postulated role of the protein in tumor cell invasion. Edelfosine is able to effectively inhibit migration and invasion of UC cells in vitro and in vivo in an SK3-dependent way, pointing towards a possible role for Edelfosine as an antiinvasive drug to effectively inhibit UC cell invasion and metastasis. © 2015 International Society of Oncology and BioMarkers (ISOBM)

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