[show abstract][hide abstract] ABSTRACT: Infection with human papillomaviruses (HPVs) characterizes a distinct subset of head and neck squamous cell cancers (HNSCCs). HPV-positive HNSCC preferentially affect the oropharynx and tonsils. Localized HPV-positive HNSCCs have a favorable prognosis and treatment outcome. However, the impact of HPV in advanced or metastatic HNSCC remains to be defined. In particular, it is unclear whether HPV modulates the response to cetuximab, an antibody targeting the epidermal growth factor receptor (EGFR), which is a mainstay of treatment of advanced HNSCC. To this end, we have examined the sensitivity of HPV-positive and -negative HNSCC models to cetuximab and cytotoxic drugs in vitro and in vivo. In addition, we have stably expressed the HPV oncogenes E6 and E7 in cetuximab-sensitive cancer cell lines to specifically investigate their role in the antibody response. The endogenous HPV status or the expression of HPV oncogenes had no significant impact on cetuximab-mediated suppression of EGFR signaling and proliferation in vitro. Cetuximab effectively inhibited the growth of E6- and E7-expressing tumors grafted in NOD/SCID mice. In support, formalin-fixed, paraffin-embedded tumor samples from cetuximab-treated patients with recurrent or metastatic HNSCC were probed for p16(INK4a) expression, an established biomarker of HPV infection. Response rates (45.5% versus 45.5%) and median progression-free survival (97 versus 92 days) following cetuximab-based therapy were similar in patients with p16(INK4A)-positive and p16(INK4A)-negative tumors. In conclusion, HPV oncogenes do not modulate the anti-EGFR antibody response in HSNCC. Cetuximab treatment should be administered independently of HPV status.
Cell Death & Disease 01/2014; 5:e1091. · 6.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: ABSTRACT Background: A high incidence of anastomotic leakage (37.5%) is reported after low anterior rectal resection (LAR) and circular double-stapled anastomosis without protective ileostoma. Since the pathomechanism of anastomosis leakage is still unclear, a suitable animal model would be most desirable. Methods: The objective was to assess the incidence of clinically apparent and inapparent leakage after LAR in pigs (n = 20). Endpoints were radiological, clinical, macroscopic, and histologic proof of anastomotic leakage on the 9th postoperative day. Integrity of anastomosis was assessed by double-contrast barium examination on 9th postoperative day. Animals were sacrificed and anastomoses were resected for histopathological investigation. In case of earlier clinical apparent anastomotic leakage, radiologic double-contrast barium was performed immediately. Results: LAR with a circular double-stapled anastomosis without protective ileostoma was performed in 20 pigs (m:f = 8:12). Length of resection was 10-20 cm, anastomosis was performed 7 cm ab ano. Five animals (25%) developed clinical apparent anastomotic leakage (no appetite, fever, inactivity, tachypnea, discomfort, pain) between the 6th (n = 1) and 9th (n = 4) postoperative day, proven by double-contrast barium radiographs. Additionally in 1 animal clinical inapparent anastomotic insufficiency was observed radiologically. Total rate of leakage was 30% (n = 6). These results were confirmed by leucocytosis, low potassium levels, in two cases high ALT and AST and local peritonitis in all cases. Conclusion: Including one additional case of clinical inapparent leakage, total rate of anastomotic leakage was 30% (6/20). Thus we managed to establish a new experimental model of anastomotic leakage after low rectal resection comparable to the human situation.
Journal of Investigative Surgery 08/2013; · 1.32 Impact Factor
[show abstract][hide abstract] ABSTRACT: Benign epithelial tumors of the tracheobronchial system and the lungs are exceedingly rare. These entities encompass squamous and glandular papillomas (as well as their mixed forms) and adenomas (alveolar adenoma, papillary adenoma, salivary gland-like pleomorphic and mucinous adenomas and mucinous cystadenomas). These tumors are considered to be biologically benign neoplasms; however, they can pose considerable diagnostic difficulties, especially during frozen section evaluation, as they can mimic malignant tumors and in particular they can resemble well differentiated papillary adenocarcinomas. As a result of the extreme rarity of these tumors only a few descriptive diagnostic series exist and a systematic investigation including molecular data does not exist. This article presents the case of a 64-year-old patient with a glandular papilloma of the right main bronchus including the immunohistochemical and molecular work-up as well as a review of the current literature.
[show abstract][hide abstract] ABSTRACT: BACKGROUND: Neoadjuvant treatment is thought to improve resection with margin-negative surgery in locally advanced soft-tissue sarcomas (STS). Treatment-induced alterations of the tumor peripheryhave not yet been microscopically evaluated. OBJECTIVE: This histopathological study compared limb STS with primary resection and those that had undergone neoadjuvant treatment, emphasizing microscopic changes of the fibrous capsule (FC) and reactive zone (RZ) after neoadjuvant treatment. PATIENTS AND METHODS: Patients with primary high-grade limb sarcomas (N = 76) which have not previously been treated were included. Of those, 37 were primarily resected and 39 were treated with one of the following neoadjuvant treatment modalities: 7x chemotherapy (CTX), 3x radiotherapy (RT), 15x isolated limb perfusion (ILP), 8x CTX + RT, and 6x CTX + ILP. Sizes of the FC and RZ were microscopically measured, and FC-integrity was documented. Histopathologic regression was expressed as a percent. RESULTS: Only 35.1% of untreated sarcomas showed an intact FC. We observed significantly higher capsular integrity after treatment (76.9%). Additionally, the average width of the FC (0.21 mm vs. 0.61 mm) and RZ (0.67 mm vs. 1.48 mm) increased significantly. The extent of histopathologic regression showed a correlation with capsular integrity and width. The combination of two treatment modalities (CTX + RT or ILP) showed strongest effects at the tumor periphery. CONCLUSIONS: Neoadjuvant treatment stabilizes the tumor periphery in STS (e.g., the capsule). Concerning local treatment strategies, these novel histopathologic insights might significantly influence the decision as to whether primary resection is advisable in advanced local soft-tissue sarcoma.
European journal of surgical oncology: the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 10/2012; · 2.56 Impact Factor
[show abstract][hide abstract] ABSTRACT: Monoclonal antibodies against the epidermal growth factor receptor (EGFR) are effective cancer therapeutics, but tumors harboring RAS mutations are resistant. To functionally dissect RAS-mediated resistance, we have studied clinically approved anti-EGFR antibodies, cetuximab and panitumumab, in cancer models. Both antibodies were equally cytotoxic in vitro. However, cetuximab, which also triggers antibody-dependent cellular cytotoxicity (ADCC), was more effective than panitumumab in vivo. Oncogenic RAS neutralized the activity of both antibodies in vivo. Mechanistically, RAS upregulated BCL-XL in cancer cell lines and in primary colorectal cancers. Suppression of BCL-XL by short hairpin RNA or treatment with a BH3 mimetic overcame RAS-mediated antibody resistance. In conclusion, RAS-mutant tumors escape anti-EGFR antibody-mediated receptor blockade as well as ADCC in vivo. Pharmacological targeting of RAS effectors can restore sensitivity to antibody therapy.Oncogene advance online publication, 16 July 2012; doi:10.1038/onc.2012.302.
[show abstract][hide abstract] ABSTRACT: Endobronchial ultrasound-guided transbronchial fine needle aspiration (EBUS-TBNA) has become an important tool in the diagnosis and staging of malignant tumors of the lungs and mediastinum. Rapid on-site evaluation (ROSE) denotes a cytomorphological diagnostic procedure that allows assessment of the adequacy and accuracy of the material obtained during bronchoscopy within a few minutes in or near the bronchoscopy suite (on-site) using a quick staining of smears. This results in a significant decrease in the number of repeated bronchoscopy procedures required to recover an adequate biopsy sample and is therefore both time and cost effective. The obtained material can be further assessed as conventional cytological specimens or alternatively using the thin-prep technique for definitive cytopathology diagnosis and/or embedded in paraffin for immunohistochemical or molecular analyses such as DNA sequencing or flow cytometry.
Der Pathologe 07/2012; 33(4):308-15. · 0.62 Impact Factor
[show abstract][hide abstract] ABSTRACT: The Bethesda system for reporting thyroid cytopathology was published in 2008 (Baloch et al. 2008, Cytojournal 5:6; Baloch et al. 2008, Diagn Cytopathol 36:425-437) offering a classification system which is closely related to clinical data. The aim was to ensure adequate terminology without risk of errors in understanding, to advise clinicians concerning therapeutic options in relationship to cytological diagnoses as well as to facilitate the comparison of cytology data at national and international levels. However, mainly due to specific US American (both medical and legal) demands, this classification system is not yet fully appreciated in most European countries. The reasons are various: (a) Criteria for representative material are much more restrictive than those commonly used and in Germany a higher number of (unnecessary) repunctures would be the consequence. (b) It remains doubtful whether the introduction of a new and rather heterogeneous category of "atypia of undetermined significance or follicular lesion of undetermined significance" would contribute to a substantial decrease of findings classified as "follicular neoplasia". Furthermore it is unlikely that clinicians would be willing to accept the recommended conservative approach with repuncture if a new diagnostic category is associated with a calculated risk of malignancy in 5-15% cases. (c) Until now an integration of new developments in molecular markers into the Bethesda system is missing. Thus, for experienced cytologists the Bethesda system for reporting thyroid cytopathology offers very limited benefits in comparison to the currently used, established and highly accepted classification systems. However, a positive argument remains the fact that an internationally accepted classification system may improve the comparability of the results of national and international studies on thyroid findings.
Der Pathologe 06/2012; 33(4):324-30. · 0.62 Impact Factor
[show abstract][hide abstract] ABSTRACT: Zusammenfassung Der hyalinisierende trabekuläre Tumor der Schilddrüse ist ein seltener Tumor, der von den Follikelepithelzellen der Schilddrüse
ausgeht und durch eine prominente intratrabekuläre Hyalinisierung gekennzeichnet ist. Aufgrund des Wachstumsmusters besteht
eine Ähnlichkeit zum medullären Schilddrüsenkarzinom. Auffällige Kernatypien wie Kerninklusionen lassen an ein papilläres
Schilddrüsenkarzinom denken. Deswegen ist die Dignitätsbeurteilung nach wie vor umstritten. Nachdem er aufgrund eindeutig
fehlender Malignitätskriterien initial als Tumor mit benignem Verhalten eingestuft wurde, führten erste molekularpathologische
Untersuchungen (Nachweis eines RET / PTC-Rearrangements) zu der Annahme, dass es sich um eine Variante des papillären Schilddrüsenkarzinoms handeln könnte. Neuere
molekularpathologische Methoden wie die Bestimmung der microRNA, kurzer, nichtkodierender RNA, widerlegen jedoch diese Annahme.
Der vorliegende Beitrag fasst die zur Diagnose wichtigen histomorphologischen Kriterien einschließlich neuer molekularpathologischer
[show abstract][hide abstract] ABSTRACT: Heterotopic gastric mucosa is a rare finding in the rectum. Apart from two other hypotheses, a misdifferentiation of entodermal stem cells is the most widely accepted aetiopathogenetic assumption today. Due to acid secretion, the lesions predominantly manifest with hematochezia. Therapeutic options include medicinal therapy and particularly (endoscopic) removal. From the pathologist's point of view a careful evaluation is required also in terms of basically possible dysplastic or malignant changes.
Der Pathologe 07/2011; 32(6):521-3. · 0.62 Impact Factor
[show abstract][hide abstract] ABSTRACT: Total mesorectal excision (TME) refers to the anatomically accurate surgical resection of the rectum from its surrounding fascias and has become the gold standard for treating rectal cancer. The pathologist plays a key role in the assessment of these specimens and good pathological reporting of rectal cancer is essential to achieving the optimum possible results for patients with rectal cancer. In experienced hands, these techniques result in a dramatic improvement in cancer-related cure rates from 45% to 75% and a reduction in pelvic recurrences from 40% to 5%-10%. Moreover, preservation of sexual and urinary functions is possible in the majority of cases. This article reviews the pathological assessment of the TME specimen in detail with regards to current international guidelines and describes its anatomical background. In addition, particular issues relating to margins, lymph node dissection and effects of neoadjuvant therapy are discussed.
Der Pathologe 06/2011; 32(4):321-9. · 0.62 Impact Factor
[show abstract][hide abstract] ABSTRACT: For the clinical management of adrenocortical neoplasms it is crucial to correctly distinguish between benign and malignant tumours. Even histomorphologically based scoring systems do not allow precise separation in single lesions, thus novel parameters are desired which offer a more accurate differentiation. The tremendous potential of microRNAs (miRNAs) as diagnostic biomarkers in surgical pathology has recently been shown in a broad variety of tumours.
In order to elucidate the diagnostic impact of miRNA expression in adrenocortical neoplasms, a cohort of 20 adrenocortical specimens including normal adrenal tissue (n=4), adrenocortical adenomas (ACAs) (n=9), adrenocortical carcinomas (ACCs) (n=4) and metastases (n=3) was analysed using TaqMan low density arrays to identify specific miRNA profiles in order to distinguish between benign and malignant adrenocortical lesions. Results were validated in a validation cohort (n=16).
Concerning the differential diagnosis of ACAs and ACCs, 159 out of 667 miRNAs were up- and 89 were down-regulated in ACAs. Using real-time PCR analysis of three of the most significantly expressed single key miRNAs allowed separation of ACAs from ACCs. ACCs exhibited significantly lower levels of miR-139-3p (up to 8.49-fold, p<0.001), miR-675 (up to 23.25-fold, p<0.001) and miR-335 (up to 5.25-fold, p<0.001). A validation cohort of 16 specimen with known Weiss score showed up-regulation of miR-335 and miR-675 in the majority of cases with probable malignant course, although overlapping values exist.
miRNA profiling of miR-675 and miR-335 helps in discriminating ACCs from ACAs. miRNA analysis may indicate malignant behaviour in cases with indeterminate malignant potential.
Journal of clinical pathology 04/2011; 64(6):529-35. · 2.43 Impact Factor
[show abstract][hide abstract] ABSTRACT: Zusammenfassung Eine Magenschleimhautheterotopie ist im Rektum ein äußerst seltener Befund. Es existieren 3 ätiopathogenetische Hypothesen,
wobei man heute von einer Fehldifferenzierung entodermaler Stammzellen ausgeht. Klinisch imponieren durch Salzsäurebildung
zumeist peranale Blutabgänge. Therapeutisch steht neben konservativ-medikamentösen Methoden die (endoskopische) Resektion
im Vordergrund. Aus pathologischer Sicht erfordern Biopsien und Resektate solcher Läsionen auch aufgrund der grundsätzlich
möglichen dysplastischen bzw. malignen Transformation eine sorgfältige Begutachtung.
[show abstract][hide abstract] ABSTRACT: Die totale mesorektale Exzision bezeichnet die chirurgische, anatomisch korrekte Resektion des Rektums aus seinen Hüllfaszien
und ist heute als der Goldstandard der chirurgischen Therapie des Rektumkarzinoms zu betrachten. Dem Pathologen kommt die
Schlüsselrolle bei der Beurteilung der Qualität der Operationspräparate zu. Ein präziser histopathologischer Befund ist essenziell
für das bestmögliche klinische Management von Patienten mit Rektumkarzinomen. Ausgeführt von darin spezialisierten Chirurgen
führt die totale mesorektale Exzision zu einer dramatischen Verbesserung der Heilungsraten von 45% auf bis zu 75% und zu einer
Reduktion der pelvinen Lokalrezidive von 40% bis auf 5–10%. Zusätzlich gelingt in der Mehrzahl der Fälle eine Erhaltung der
Harnkontinenz sowie der Sexualfunktionen. Dieser Artikel handelt die detaillierte pathologische Aufarbeitung von Präparaten
der totalen mesorektalen Exzision unter Berücksichtigung aktueller internationaler Leitlinien und der zugrunde liegenden Anatomie
ab. Im Speziellen wird auf die Problematik von Resektionsgrenzen, Lymphknotenpräparation und Effekten einer neoadjuvanten
Total mesorectal excision (TME) refers to the anatomically accurate surgical resection of the rectum from its surrounding
fascias and has become the gold standard for treating rectal cancer. The pathologist plays a key role in the assessment of
these specimens and good pathological reporting of rectal cancer is essential to achieving the optimum possible results for
patients with rectal cancer. In experienced hands, these techniques result in a dramatic improvement in cancer-related cure
rates from 45% to 75% and a reduction in pelvic recurrences from 40% to 5%–10%. Moreover, preservation of sexual and urinary
functions is possible in the majority of cases. This article reviews the pathological assessment of the TME specimen in detail
with regards to current international guidelines and describes its anatomical background. In addition, particular issues relating
to margins, lymph node dissection and effects of neoadjuvant therapy are discussed.
SchlüsselwörterMesorektale Exzision–Levator-/Analkanalresektion–Resektionsgrenzen–Lymphknotenstatus–Prognose und Therapieempfehlungen
KeywordsMesorectal excision–Levator/anal canal resection–Resection borders–Lymph nodes status–Prognosis and therapy recommendations
Der Pathologe 01/2011; 32(4):321-329. · 0.62 Impact Factor
[show abstract][hide abstract] ABSTRACT: Zusammenfassung In der Differenzialdiagnose primärer und sekundärer (Adeno-)Karzinome der Lunge werden häufig Antikörper gegen TTF-1 (thyreoidaler
Transkriptionsfaktor 1) eingesetzt, wofür zwei verschiedene Klone (8G7G3/1 bzw. SPT24) zur Verfügung stehen. Für den Klon
SPT24 und zuletzt auch für den Klon 8G7G3/1 wurden in einer geringen Anzahl von nichtpulmonalen Adenokarzinomen positive Reaktionen
beschrieben. Wir berichten nun von einem Patienten mit TTF-1- (8G7G3/1) positivem Kolonkarzinom mit intraokulären sowie pulmonalen
Metastasen und stellen Überlegung zum diagnostischen Einsatz von TTF-1-Antikörpern an.
[show abstract][hide abstract] ABSTRACT: Immunohistochemical evaluation of primary and secondary (adeno-) carcinomas of the lung often includes utilisation of two different clones (8G7G3/1 or SPT24) of TTF-1 (thyroid transcription factor 1) antibodies. In a subgroup of adenocarcinomas with a primary site other than the lung a positive reaction of clone SPT24 and also of clone 8G7G3/1 is described. We report on a patient with TTF-1 (clone 8G7G3/1) positive adenocarcinoma of the colon with metastases to the eye and lung and discuss TTF-1 based diagnostic considerations.
Der Pathologe 12/2010; 32(4):349-51. · 0.62 Impact Factor
[show abstract][hide abstract] ABSTRACT: The essentially desirable standardisation of various European and American guidelines for the evaluation of thyroid nodules has led to the recommendation to perform fine-needle biopsy (FNB) in all nodules >1 cm in order to detect clinically occult thyroid carcinoma early. However, in iodine-deficient areas such as Germany (where thyroid nodules are found in approximately 25% of the adult population) this recommendation would substantially increase both the number of FNB and thyroid operations without significantly increasing the cancer detection rate. The recommendation for FNB in Germany, therefore, should be restricted to hypofunctioning ("cold") nodules >1 cm.
Der Pathologe 11/2010; 32(2):169-72. · 0.62 Impact Factor
[show abstract][hide abstract] ABSTRACT: Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant inherited cancer syndrome with the major components medullary thyroid carcinoma, pheochromocytoma and hyperparathyroidism. Due to the clinical course three distinct subtypes are distinguished, MEN 2A, MEN 2B and familial medullary thyroid carcinoma. The disease is caused by germ-line mutations of the RET proto-oncogene and the localization of these mutations correlates with the onset of the development of medullary thyroid carcinoma, which is crucial for the clinical course and outcome of the disease. It therefore has a substantial influence on the clinical management of the affected patients and their relatives. This review summarizes the morphology and clinic of MEN 2-associated tumors and their respective precursor lesions.
Der Pathologe 10/2010; 31(6):449-54. · 0.62 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background: Once metastasized, despite a variety of therapeutic options, the prognosis of patients with malignant melanoma (MM) is still poor. Therefore, the search for reliable markers to identify patients with high risk of disease progression is of high clinical importance. We have recently shown that TT genotypes of the single-nucleotide polymorphism (SNP) T393C in the gene GNAS1 are significantly associated with better outcome in a variety of carcinomas. - Patients: In the present study we assessed whether the T393C SNP is also related to the clinical course in MM. 328 patients with MM were retrospectively genotyped and genotypes were correlated with clinical outcome. - Results: While the allele frequency in the MM group (fC 0.52) did not significantly differ from that of healthy blood donors, the T393C SNP was associated with tumor progression of MM. Carriers of the C-allele showed a significantly more severe tumor progression as estimated from the time period to develop metastasis (HR 2.2, 95% CI 1.1-3.2, p = 0.017). Proportions of 5-year metastasis-free intervals were 87.1% for TT genotypes and 66.0% for C-allele carriers. Moreover, multivariable Cox regression analysis including tumor stage and melanoma subtype proved the T393C polymorphism to be an independent factor for metastasis (p = 0.012). - Conclusions: In summary, the GNAS1 T393C SNP represents a genetic host factor for predicting tumor progression also in patients with MM; genotyping of this SNP may contribute to better define patients who could benefit from an early individualized therapy.
European journal of medical research 10/2010; 15(10):422-7. · 1.10 Impact Factor
[show abstract][hide abstract] ABSTRACT: Multiple endocrine neoplasia type I (MEN1) is a rare hereditary cancer syndrome, which is manifested as a variety of endocrine and non-endocrine tumours and lesions caused by specific germline mutations of the MEN1 gene, a tumour suppressor gene. The detection of these germline mutations allows the early identification of affected, possibly still asymptomatic patients. The combined use of genetic and clinical tools for the diagnosis of MEN1-associated tumours substantially improves both the course of the disease and the quality of life of affected patients. This review summarizes the relevant morphological and clinical features of MEN1-associated endocrine and non-endocrine neoplasms and lesions.
Der Pathologe 10/2010; 31(6):445-8. · 0.62 Impact Factor