Anette Weber

SOCS-3 is frequently methylated in head and neck squamous cell carcinoma and its precursor lesions and causes growth inhibition.

The suppressors of cytokine signaling (SOCS) are inhibitors of cytokine signaling that function via the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway. Recently, methylation of SOCS-1 and SOCS-3 has been implicated in the tumorigenesis of liver and lung cancer. This study was performed to elucidate the role of SOCS-1 and SOCS-3 in squamous cell carcinoma of the head and neck (HNSCC) and its precursor lesions. HNSCC of 94 patients and corresponding normal mucosa, lymph node metastases as well as 16 high- and 21 low-grade squamous cell dysplasias were studied by using methylation-specific PCR (MSP) for the SOCS-1 and SOCS-3 promoter after microdissection. The presence of SOCS-3 mRNA transcripts was confirmed by semiquantitative real-time PCR, and the SOCS-3 protein was analysed immunohistochemically. SOCS-3 hypermethylation was found in 85/94 HNSCC (90%) and in 10/16 high-grade and 9/21 low-grade dysplasias (63 and 43%, respectively). SOCS-1 promoter hypermethylation was detected in 10/94 HNSCC samples (11%) and in 2/16 high-grade and 1/21 low-grade dysplasias (13 and 5%, respectively). Lymph node metastases exhibited an identical methylation status as the primary tumors. Methylation of the SOCS-3 promoter correlated with downregulation of SOCS-3 transcripts and protein expression in these tumors and various cell lines. In the cell lines tested, SOCS-3 and SOCS-1 transcripts increased upon treatment with the demethylation compound 5-aza-2-deoxycytidine (5-AZA-DC). Overexpression of wild-type SOCS-3 in carcinoma cells with methylated SOCS-3 resulted in the induction of apoptosis and growth suppression as well as downregulation of STAT3, bcl-2 as well as bcl-xL. Our data suggest that promoter methylation and subsequent transcript downregulation of SOCS-3 transcripts and, to a much lesser extent, SOCS-1 are involved in the multistep carcinogenesis of HNSCC. During its involvement in tumor growth, restoration of SOCS-3 may hold treatment potential for HNSCC.

Mutations of the BRAF gene in squamous cell carcinoma of the head and neck

The RAF/MEK/ERK (MAPK) signal transduction cascade is an important mediator of a number of cellular fates including growth, proliferation and survival. The BRAF gene, one of the human isoforms of RAF, is activated by oncogenic RAS, leading to cooperative effects in cells responding to growth factor signals. This study was performed to elucidate a possible function of BRAF in squamous cell carcinoma of the head and neck (HNSCC). Mutations of BRAF and KRAS2 were evaluated in 89 HNSCC and corresponding normal mucosa by direct DNA sequencing analyses after microdissection. The results obtained were correlated with histopathological variables. Activating BRAF missense mutations were identified in 3/89 HNSCC (3%). KRAS2 mutations were found in five out of 89 (6%) HNSCC examined. There were no mutations of KRAS2 and BRAF in non-neoplastic mucosa. We failed to observe a correlation between BRAF or KRAS2 mutations and histopathological factors. Our data indicate that BRAF gene mutations are relatively rare events in HNSCC. Although uncommon, BRAF mutations may identify a subset of patients with HNSCC sensitive to targeted therapy.

Absence of Mutations of the BRAF Gene and Constitutive Activation of Extracellular-Regulated Kinase in Malignant Melanomas of the Uvea

The v-raf murine sarcoma viral homolog B1 (BRAF) gene, one of the human isoforms of RAF, is activated by Ras, leading to cooperative effects in cells responsive to growth factor signals. Recently, somatic missense mutations of the BRAF gene have been detected in more than 66% of malignant melanomas of the skin. We analyzed 42 malignant melanomas of the uvea, 3 corresponding liver metastases, and 10 cutaneous melanomas for possible BRAF mutations: after microdissection, mutation analysis of BRAF and KRAS was performed. The expression of extracellular-regulated kinase 1 and 2 (ERK1/2), an important downstream point of convergence in the Ras-RAF-MEK-Erk pathway, was analyzed immunohistochemically. Interestingly, we failed to detect activating BRAF mutations in uvea melanomas and their corresponding liver metastases. There were no mutations of BRAF in corresponding non-neoplastic uvea specimens, although we detected three BRAF mutations in sporadic cutaneous melanoma that led to a substitution of valine by glutamic acid at position 599 (V599E). KRAS mutations were detected in 1 of 10 cutaneous melanoma but not in uveal or metastatic melanoma. Despite the lack of activating mutations in the BRAF gene, we identified constitutively activated ERK in almost all (86%) uveal melanoma tissues tested but not in corresponding normal retina or uveal cells. Our data indicate that BRAF gene mutations are rare to absent events in uveal melanoma. The finding of activated Erk suggests a causative role for MAPK activation in uveal melanoma independent of activating BRAF or RAS mutations.

Methylation of SOCS-3 and SOCS-1 in the carcinogenesis of Barrett’s adenocarcinoma

Background: The suppressors of cytokine signalling (SOCS) are inhibitors of cytokine signalling; methylation of SOCS-3 has been implicated in the tumorigenesis of liver as well as head and neck cancer. Aims: This study was performed to elucidate the role of SOCS-1 and SOCS-3 in Barrett’s adenocarcinoma and its precursor lesions. Methods: DNA of specimens from 19 Barrett’s adenocarcinomas, 56 Barrett’s intraepithelial neoplasias (n = 29 low grade and n = 27 high grade), 30 Barrett’s mucosa without neoplasia, 20 samples of normal squamous and gastric epithelium and four cell lines were studied using methylation specific PCR for the SOCS-1 and SOCS-3 promoter following microdissection. The presence of SOCS-3 mRNA transcripts was confirmed by semiquantitative real time PCR, and the SOCS-3 protein was analysed immunohistochemically. Results: In normal squamous epithelium and normal gastric mucosa, neither SOCS-3 nor SOCS-1 methylation was observed. In Barrett’s mucosa without intraepithelial neoplasia, SOCS-3 methylation occurred in 4/30 cases (13%) whereas SOCS-1 was unmethylated. A hypermethylated SOCS-3 promoter was found in 14/19 Barrett’s adenocarcinomas (74%) and in 20/29 high and 6/27 low grade intraepithelial neoplasias (69% and 22%, respectively). SOCS-1 promoter hypermethylation occurred in 8/19 adenocarcinomas (42%) and in 6/29 high grade and 1/27 low grade intraepithelial neoplasias (21% and 4%, respectively). Methylation of the SOCS-3 promoter correlated with downregulation of SOCS-3 transcripts and protein expression in these tumours and various cell lines. In the cell lines tested, SOCS-3 and SOCS-1 transcripts increased after treatment with the demethylation compound 5-aza-2-deoxycytidine. Conclusions: These data indicate that promoter methylation and subsequent transcript downregulation of SOCS-3 transcripts and, to a much lesser extent, SOCS-1 are involved in the multistep carcinogenesis of Barrett’s adenocarcinoma.

Endemische Syphilis an den rekognoszierten Reliquien des Gottfried von Cappenberg Eine paläopathologische Studie

ZusammenfassungPaläopathologische Untersuchungen erlauben Rückschlüsse auf Erkrankungen früherer Populationen. Am Beispiel des westfälischen Ritters und Grafen Gottfried von Cappenberg werden die Möglichkeiten der Paläopathologie aufgezeigt. An knöchernen Skelettresten aus der Stiftskirche Cappenberg konnte insbesondere durch die histomorphometrische Methode nach Kerley eine genaue Lebensaltersbestimmung eines männlichen Skeletts erfolgen, die entscheidend unter Berücksichtigung zusätzlicher auch historischer Vorgaben zur Identifizierung (Rekognoszierung) der Knochen des Grafen Gottfried von Cappenberg (AD 1097–1127) führte. Die Unterschenkelknochen dieses frühadulten Mannes ließen zusätzlich pathologische Befunde erkennen, die insgesamt dem Krankheitsbild der endemischen Syphilis (d. h. einer nichtvenerischen Form der Syphilis) zuzuordnen waren. Die Paläopathologie ist somit in der Lage, neben wichtigen Fragestellungen wie z. B. der Identifizierung knöcherner Funde Krankheitsbilder zu erkennen, die auch noch heutzutage in der Differentialdiagnose knöcherner Läsionen – wenn auch nur selten – berücksichtigt werden sollten.

Neuerungen der TNM-Klassifikation der Kopf-Hals-Tumoren

ZusammenfassungBei den Plattenepithelkarzinomen im Kopf-Hals-Bereich wurden kleinere Änderungen nur bei der Einteilung von Tumoren des Oro- und Hypopharynx vorgenommen, in Form geänderter Definitionen einzelner T- und N-Kategorien. Neu eingeführt wurde eine TNM-Klassifikation für die malignen Melanome der Schleimhäute des oberen Aerodigestivtrakts. Bei den Schilddrüsenkarzinomen wurde eine Ramifikation der T1-Kategorie aus dem TNM-Supplement übernommen, leider nicht die Unterteilung der T3-Kategorie. Ebenfalls neu vorgestellt wurde eine TNM-Klassifikation der Merkel-Zell-Karzinome der Haut, die in diesem Beitrag auch aufgeführt werden, weil diese Tumoren im Kopfbereich nicht selten vorkommen.AbstractOnly minor modifications were introduced in the classification of squamous cell carcinomas of the oro- and hypopharynx, namely in the definition of some T and N categories. A new TNM classification has been introduced for mucosal melanoma of the head and neck. Some proposals for ramification of the T1 categories of thyroid tumours have been adopted from the TNM Supplement, unfortunately not those proposed for the T3 categories. The new TNM classification of Merkel cell carcinomas, which frequently occur in the head and neck region, is also discussed.Only minor modifications were introduced in the classification of squamous cell carcinomas of the oro- and hypopharynx, namely in the definition of some T and N categories. A new TNM classification has been introduced for mucosal melanoma of the head and neck. Some proposals for ramification of the T1 categories of thyroid tumours have been adopted from the TNM Supplement, unfortunately not those proposed for the T3 categories. The new TNM classification of Merkel cell carcinomas, which frequently occur in the head and neck region, is also discussed.

Changes in the TNM classification of head and neck tumors

ZusammenfassungBei den Plattenepithelkarzinomen im Kopf-Hals-Bereich wurden kleinere Änderungen nur bei der Einteilung von Tumoren des Oro- und Hypopharynx vorgenommen, in Form geänderter Definitionen einzelner T- und N-Kategorien. Neu eingeführt wurde eine TNM-Klassifikation für die malignen Melanome der Schleimhäute des oberen Aerodigestivtrakts. Bei den Schilddrüsenkarzinomen wurde eine Ramifikation der T1-Kategorie aus dem TNM-Supplement übernommen, leider nicht die Unterteilung der T3-Kategorie. Ebenfalls neu vorgestellt wurde eine TNM-Klassifikation der Merkel-Zell-Karzinome der Haut, die in diesem Beitrag auch aufgeführt werden, weil diese Tumoren im Kopfbereich nicht selten vorkommen.AbstractOnly minor modifications were introduced in the classification of squamous cell carcinomas of the oro- and hypopharynx, namely in the definition of some T and N categories. A new TNM classification has been introduced for mucosal melanoma of the head and neck. Some proposals for ramification of the T1 categories of thyroid tumours have been adopted from the TNM Supplement, unfortunately not those proposed for the T3 categories. The new TNM classification of Merkel cell carcinomas, which frequently occur in the head and neck region, is also discussed.Only minor modifications were introduced in the classification of squamous cell carcinomas of the oro- and hypopharynx, namely in the definition of some T and N categories. A new TNM classification has been introduced for mucosal melanoma of the head and neck. Some proposals for ramification of the T1 categories of thyroid tumours have been adopted from the TNM Supplement, unfortunately not those proposed for the T3 categories. The new TNM classification of Merkel cell carcinomas, which frequently occur in the head and neck region, is also discussed.

Neuerungen der TNM-Klassifikation der Kopf-Hals-Tumoren@@@Changes in the TNM classification of head and neck tumors

ZusammenfassungBei den Plattenepithelkarzinomen im Kopf-Hals-Bereich wurden kleinere Änderungen nur bei der Einteilung von Tumoren des Oro- und Hypopharynx vorgenommen, in Form geänderter Definitionen einzelner T- und N-Kategorien. Neu eingeführt wurde eine TNM-Klassifikation für die malignen Melanome der Schleimhäute des oberen Aerodigestivtrakts. Bei den Schilddrüsenkarzinomen wurde eine Ramifikation der T1-Kategorie aus dem TNM-Supplement übernommen, leider nicht die Unterteilung der T3-Kategorie. Ebenfalls neu vorgestellt wurde eine TNM-Klassifikation der Merkel-Zell-Karzinome der Haut, die in diesem Beitrag auch aufgeführt werden, weil diese Tumoren im Kopfbereich nicht selten vorkommen.AbstractOnly minor modifications were introduced in the classification of squamous cell carcinomas of the oro- and hypopharynx, namely in the definition of some T and N categories. A new TNM classification has been introduced for mucosal melanoma of the head and neck. Some proposals for ramification of the T1 categories of thyroid tumours have been adopted from the TNM Supplement, unfortunately not those proposed for the T3 categories. The new TNM classification of Merkel cell carcinomas, which frequently occur in the head and neck region, is also discussed.Only minor modifications were introduced in the classification of squamous cell carcinomas of the oro- and hypopharynx, namely in the definition of some T and N categories. A new TNM classification has been introduced for mucosal melanoma of the head and neck. Some proposals for ramification of the T1 categories of thyroid tumours have been adopted from the TNM Supplement, unfortunately not those proposed for the T3 categories. The new TNM classification of Merkel cell carcinomas, which frequently occur in the head and neck region, is also discussed.

Chronic Parotitis: Not Another SPINKosis

Introduction: Pancreatitis and parotitis share several etiological, pathohistological and functional similarities. It arose from recent pancreatitis research that some cases of chronic pancreatitis are associated with mutations of the serine protease inhibitor, Kazal type-1 (SPINK1). We tested the hypothesis that the pancreatitis-associated N34S mutation of SPINK1 is also a risk factor for chronic parotitis. Methods: Reverse-transcriptase polymerase chain reaction was used to investigate SPINK1 transcription in the parotid gland. Forty-five blocks of formalin-fixed, paraffin wax-embedded tissues with chronic parotitis of unknown cause were analyzed for the SPINK1-N34S mutation. Results: The SPINK1 gene is transcribed in the parotid gland. Two of the 45 patients (4.4%) with chronic parotitis carried the N34S mutation heterozygously. Of 82 healthy blood donors, 3 subjects (3.7%) were identified as carrying this mutation heterozygously (p = 0.83). Conclusion: The SPINK1-N34S mutation is not associated with chronic parotitis.

Das epitheloide Osteosarkom Differentialdiagnostische Problematik

The case of a 23-year-old female patient suffering from a rare variety of osteosarcoma of the distal femur with epithelial differentiation and only traces of osteoid is reported. The tumour cells reacted strongly to antibodies against vimentin. Metastases were found in the fifth rib and the right kidney. There was no response to chemotherapy. One year after implantation of a tumour prothesis of the knee a thigh amputation was necessary because of a local failure. The patient died 2.5 years after the tumour had initially been diagnosed. Other reports of this rare type of epitheloid osteosarcoma illustrate the difficulties involved in reaching a correct diagnosis. This tumour can be mistaken for a skeletal metastasis of an epithelial tumour.ZusammenfassungEs wird uber ein epitheloid-differenziertes Osteosarkom des distalen Oberschenkels mit nur minimaler Osteoidbildung and positiver Immunreaktion mit Antikörpern gegen das mesenchymale Zytoskelettprotein Vimentin bei einer 23jährigen Patientin berichtet. Metastasenverddchtige Areale fanden sich in der 5. Rippe sowie oberhalb des rechten Nierenpols. Bei fehlendem Ansprechen auf eine adjuvante Chemotherapie mußte aufgrund eines Lokalrezidivs 1 Jahr nach Tumorprothesenimplantation eine Oberschenkelamputation vorgenommen werden. Die Patientin verstarb 2,5 Jahre nach der Erstdiagnosestellung. Die Literaturberichte uber das seltener “epitheloide Osteosarkom” zeigen die Schwierigkeiten der differentialdiagnostischen Abgrenzung von der Metastase eines epithelialen Tumors.