[Non-small cell lung cancer. New biomarkers for diagnostics and therapy]. / Nicht-kleinzelliges Lungenkarzinom. Neue Biomarker für Diagnostik und Therapie.

Although advances in targeted therapies have recently been achieved, lung cancer remains a major health burden worldwide. It is therefore pivotal to investigate the biology of lung cancers in order to design new therapeutic strategies. To address this a multi-antibody assay has been developed for the classification of non-small cell lung cancer (NSCLC). Using this assay the pathologist is able to reliably subtype NSCLC into adenocarcinoma, squamous cell carcinoma, large cell neuroendocrine carcinoma (LCNEC) and NSCLC not otherwise specified (NOS) large cell carcinoma, as required by the new World Health Organization (WHO) classification of 2015, on a single glass slide. In our cohort this classification algorithm showed significant differences in overall survival of the therapeutically important subgroups, which reflects the accuracy of the assay. To investigate the biology of NSCLC subtypes further, several proteins involved in carbohydrate metabolism were analyzed. In a hierarchical cluster analysis it could be shown that adenocarcinoma and squamous cell carcinoma harbor different metabolic shifts and, furthermore, that two distinct groups of squamous cell carcinoma seem to exist, a hypoxia and a transporter type. These results could be verified by analysis of mRNA data obtained from the TCGA database. As a close association between tumor metabolism and anti-tumor immune response has been reported, the lymphocytic infiltrates were characterized with respect to T-cells and their location within the tumor. Besides a negative correlation of lymphocyte density and expression of lactate dehydrogenase, it could be shown that depending on the location and type a high lymphocyte density indicates a significantly better overall survival of NSCLC patients. Investigating the expression of PD-L1 in NSCLC cells, a significant correlation with lymphocyte density was detected. In conclusion, the multi-antibody assay is a new and economically attractive tool for a reliable subclassification of NSCLC. This subtyping results in a better biological stratification of NSCLC and is the basis not only for palliative treatment options but also for further investigations on NSCLC biology. It was discovered that metabolic changes during malignant transformation are different in adenocarcinoma and squamous cell carcinoma. The latter group can be further divided into a hypoxia and a transporter type. Anti-tumor immune responses are influenced by the metabolic shift in NSCLC and lymphocyte density with respect to the location within the tumor is of prognostic significance in NSCLC. Therefore, the results contribute to a better biological understanding of NSCLC and may lead to new treatment options by targeting metabolic enzymes or triggering anti-tumor responses.

Downregulation of MTSS1 expression is an independent prognosticator in squamous cell carcinoma of the lung.

BACKGROUND: The metastasis suppressor 1 (MTSS1) is a newly discovered protein putatively involved in tumour progression and metastasis. MATERIAL AND METHODS: Immunohistochemical expression of MTSS1 was analysed in 264 non-small-cell lung carcinomas (NSCLCs). RESULTS: The metastasis suppressor 1 was significantly overexpressed in NSCLC compared with normal lung (P=0.01). Within NSCLC, MTSS1 expression was inversely correlated with pT-stage (P=0.019) and histological grading (P<0.001). NSCLC with MTSS1 downregulation (<20%) showed a significantly worse outcome (P=0.007). This proved to be an independent prognostic factor in squamous cell carcinomas (SCCs; P=0.041), especially in early cancer stages (P=0.006). CONCLUSION: The metastasis suppressor 1 downregulation could thus serve as a stratifying marker for adjuvant therapy in early-stage SCC of the lung.

Cancer cell invasion and EMT marker expression: a three-dimensional study of the human cancer-host interface.

Cancer cell invasion takes place at the cancer-host interface and is a prerequisite for distant metastasis. The relationships between current biological and clinical concepts such as cell migration modes, tumour budding and epithelial-mesenchymal transition (EMT) remains unclear in several aspects, especially for the 'real' situation in human cancer. We developed a novel method that provides exact three-dimensional (3D) information on both microscopic morphology and gene expression, over a virtually unlimited spatial range, by reconstruction from serial immunostained tissue slices. Quantitative 3D assessment of tumour budding at the cancer-host interface in human pancreatic, colorectal, lung and breast adenocarcinoma suggests collective cell migration as the mechanism of cancer cell invasion, while single cancer cell migration seems to be virtually absent. Budding tumour cells display a shift towards spindle-like as well as a rounded morphology. This is associated with decreased E-cadherin staining intensity and a shift from membranous to cytoplasmic staining, as well as increased nuclear ZEB1 expression.

[Granulomatous lung and systemic diseases]. / Granulomatöse Lungen- und Systemerkrankungen.

Granuloma formation occurs in the human body if there is a particle which persists in phagocytes and which the immune system cannot eliminate. The immune reaction of granuloma formation evolved in order to combat mycobacteria with the aim of localizing mycobacteria and to avoid spreading of mycobacteria throughout the body. Granulomatous lung diseases are often accompanied by severe, systemic inflammation. However, acute phase proteins may be only slightly elevated. The spectrum of granulomatous lung diseases is broad. Sarcoidosis is the most common granulomatous lung disease. To diagnose sarcoidosis, other infectious granulomatous lung diseases such as tuberculosis, atypical mycobacterial and fungal infection have to be ruled out. Pulmonary granuloma also evolve in the context of autoimmune diseases such as rheumatoid arthritis, granulomatosis with polyangiitis (GBA, Wegener's) and eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss syndrome). Furthermore, immunodeficiencies such as common variable immunodeficiency (CVID) and immune reconstitution syndrome in HIV can be associated with systemic granulomatous inflammation. Finally, occupational lung disease, particularly hypersensitivity pneumonitis, silicosis, hard metal lung, and chronic berylliosis are associated with pulmonary granuloma formation.

[Synchronous schwannoma of the vagus nerve and the cervical sympathetic chain]. / Synchrones Schwannom des N. vagus und des zervikalen sympathischen Grenzstrangs.

Schwannomas are rare neural sheath tumors which are generally benign. Up to 45% of all schwannomas originate in the head and neck region. In the parapharyngeal space (PPS) they may arise from any of the lower cranial nerves IX, X, XI and XII or from the cervical sympathetic chain. We report a unique case of a synchronous schwannoma of the vagal nerve and the cervical sympathetic chain in a patient without neurofibromatosis.

Relapsing high grade mucoepidermoid carcinoma. Long-lasting complete response following reirradiation and EGFR blockade.

BACKGROUND AND PURPOSE: The treatment strategy for inoperable recurrent mucoepidermoid carcinoma (MEC) is not well established. Here, we present a case of a relapsed high grade MEC of the salivary glands of the hard palate that was successfully treated with a reirradiation (re-RT) and cetuximab, an antibody against epidermal growth factor receptor (EGFR). CASE REPORT: Twelve years after resection and adjuvant radiotherapy for high grade MEC of the salivary glands, a patient presented with inoperable recurrent disease. She received another 59.4 Gy. In addition, 400 mg/m(2) cetuximab was administered in the first week, followed by six additional weekly courses at 250 mg/m(2). RESULTS: Treatment was well tolerated. The patient is doing well and continuous radiological complete response (CR) is documented for 25 months after completion of the combined treatment. CONCLUSION: Combined re-RT and targeted inhibition of EGFR with cetuximab may be a valuable therapeutic strategy in patients with recurrent localized high grade MEC who are not candidates for radical surgery.

[Large cystic tumor of the right neck]. / Große zystische Raumforderung zervikal rechts.

A 32-year-old patient presented to our department with a large cystic lesion in the right lateral neck (diameter 6 cm). After complete resection, the histopathological examination revealed a lymph node metastasis of a papillary thyroid carcinoma. We performed total thyroidectomy and bilateral selective neck dissection. There was a papillary microcarcinoma in the right lobe of the thyroid. The postoperative course was uneventful. Therapy with radioiodine was conducted. At 30 months after surgery the patient is free of disease.

[Chondrosarcoma of the larynx. Experience gained in Freiburg since 1999]. / Chondrosarkome des Larynx. Freiburger Erfahrungen seit 1999.

BACKGROUND: Chondrosarcomas are rare tumors of the head and neck. Nevertheless, they display the most common non-epithelial malignancy of the larynx. MATERIALS AND METHODS: Between 1999 and February 2010 we treated six patients with laryngeal chondrosarcoma. The group included two female and four male patients ranging in age from 54 to 82 years. RESULTS: An 82-year-old female patient died 3 months after diagnosis and tracheostomy due to other underlying diseases. An 82-year-old male patient underwent primary radiation therapy. In the other patients, we performed a modified hemilaryngektomy in three cases and a laryngectomy in one. In those four cases, there were no signs of recurrent disease 50, 85, 87 and 95 months after surgery, respectively. There were no local or distant metastases. CONCLUSIONS: Chondrosarcomas of the larynx are slow growing neoplasms. Metastases occur in less than 3% of cases. Complete resection is the therapy of choice. Function-preserving surgical approaches should be favoured.

[Exophytic tumor of the parotid gland]. / Exophytischer Parotistumor.

An 81-year-old male patient presented at our department with a large (diameter 10 cm), exophytic lesion in the right parotid region. Magnetic resonance imaging showed the tumor to derive from the lateral part of the parotid gland. We performed complete tumor resection with selective ipsilateral neck dissection. The facial nerve could be preserved. The postoperative course was uneventful. Histopathologic and immunohistochemical examinations revealed a malignant fibrous histiocytoma. We present the diagnostic and therapeutic options of this unusual malignancy of the parotid gland.

[Disseminated histoplasmosis with involvement of mediastinum and skin in an immunocompetent patient]. / Disseminierte Histoplasmose mit Befall des Mediastinums und der Haut bei immunkompetenter Patientin.

HISTORY AND ADMISSION FINDINGS: A 29-years-old Brazilian woman was admitted to hospital because of progressive dyspnoea, shivering and fever. She reported a noticeable swelling at the right mandible and an ulcerative tumor at the side of the nose. INVESTIGATIONS: Laboratory tests showed normocytic, normochromic anemia with an elevation of the inflammatory parameters. Radiology showed an enlargement of the upper mediastinum. Computed tomography revealed extensive, confluent lymphoma. There were groups of cervical lymph nodes, especially in the area of the right jaw. Bronchoscopy showed extensive space-occupying lesions with severe inflammation of the trachea. DIAGNOSIS: Bronchial biopsy revealed necrotizing, granulomatous inflammation with dense infiltration of lymphatic cells. Small and spheroidal pathogens were seen within giant cells. Grocott-silver stain was positive, indicating histoplasmosis. Histological work-up of the ulcerating tumor at the side of the nose also showed Histoplasma capsulatum. TREATMENT AND COURSE: 8 weeks after starting specific treatment with oral itraconazole the inflammatory parameters had fallen to normal and computed tomography showed regression of the mediastinal bulge. CONCLUSION: Large mediastinal and cervical lymphatic masses with space-occupying bronchial lesions suggest should, in the differential diagnosis, consider not only malignant tumor but also infections. If the patient had been abroad (in this case in Brazil), pathogens like Histoplasma capsulatum, which is not present in Europe, have to be considered. In this immunocompetent patient the severe progression and dissemination of the disease, involving mediastinum, throat and skin, is most unusual.

[Value and utility of minimal-invasive automatic cutting-needle biopsy as a diagnostic technique in the head and neck]. / Stellenwert und Einsatz der minimal-invasiven automatischen Grobnadelinzisionsbiopsie im Kopf-Hals-Bereich.

BACKGROUND: Lymphadenopathies and unclear masses in the head and neck often require tissue sampling to establish a diagnosis and to guide therapy. Open biopsy and lymph node excision is invasive and may entail general anaesthesia. Fine needle aspiration cytology is minimal-invasive and widely used but includes a high rate of non diagnostic samples and false negative results. Cutting needle biopsy is an established technique outside the head and neck but has found little attention among otorhinolaryngologists up to now. PATIENTS AND METHODS: Between April 2003 and May 2007 we performed a total of 307 cutting-needle biopsies in 143 patients with unclear cervicofacial masses, using side-notch-needles with a diameter of 12-16 Gauge. RESULTS: High-quality tissue cores without crushing artefacts for histopathological studies were obtained without complications from all patients. The target tissue was obtained in 132 of 143 patients, in these cases the sensitivity and accuracy rate for the diagnosis of malignant lesions was 98.9% and 99.2%, respectively. CONCLUSIONS: Ultrasound-guided Cutting-needle biopsy in the head and neck is a safe and reliable biopsy tool with an excellent diagnostic efficacy, which can be performed as an outpatient procedure with low expenditure of time and manpower. Performing the procedure requires substantiated experience in topographic head and neck anatomy as well as sonography of this body region.

[Malignancies arising in sinonasal inverted papillomas]. / Malignome auf dem Boden invertierter Papillome der Nase und Nasennebenhöhlen *

BACKGROUND: Inverted papillomas are primarily benign neoplasms that occur in the nasal cavity and paranasal sinuses. Many aspects of sinonasal inverted papillomas are still controversial and active fields of research. Inverted papillomas generate considerable interest because they are locally aggressive, have a propensity to recur and are associated with malignancy. However, neither the etiology and pathogenesis of these tumors nor the putative role as a precursor to carcinoma and the factors responsible for associated malignancy have been clarified. Whether carcinomas in inverted papillomas arise meta- or synchronous is also still unknown. PATIENTS AND METHODS: In a retrospective study we reviewed the charts of 93 patients with sinonasal inverted papillomas who were treated at our department between 1990 and 2007. Comparison was made between the group of patients with inverted papillomas and associated squamous cell carcinomas and the group of patients with benign inverted papillomas. We undertook a critical analysis of our results compared with the international medical literature. RESULTS: Associated malignancy was found in 11 patients (11.8 %). In each one case a metachronous carcinoma with and without recurrent inverted papilloma was diagnosed, the remaining 9 carcinomas were determined to be synchronous malignancies. Our data suggest, that the association between carcinoma and inverted papilloma is indirect and that the gradual progression from inverted papilloma to a malignant neoplasm is if at all infrequent. Male gender, advanced age and recurrent inverted papilloma do not per se present risk factors for the development of associated malignancies. CONCLUSIONS: Sinonasal carcinomas arise in about 10 % of patients with inverted papillomas, but the ratio of metachronous carcinomas has possibly been overrated up to now. Nevertheless, regular follow-up investigations after surgical resection of inverted papillomas are mandatory. The assumption, that carcinomas in inverted papillomas are less aggressive than carcinomas alone and the definition of high-risk groups for the development of carcinomas seems hazardous.

[Thymoma--incidence, classification and therapy]. / Thymome--Inzidenz, Klassifikation und Therapie.

Thymomas are a rare tumor entity. However, they represent 50 % of all tumors of the anterior mediastinum. There are no specific early symptoms. Overall in 10 - 15 % of patients with myasthenia gravis a thymoma is evident. Two major classifications are relevant in clinical practise: the Masaoka-classification and the WHO-classification. For their clinical and prognostic significance both classifications should be used for patients with thymomas. Additional, only resection status (RO) is known as a significant prognostic factor. Thymomas are compulsory malignant tumors. Distant metastasis is found as well as local recurrence in all stages of the disease. The 5-year-mortality rate constitutes about 80 %, not meaning any healing because local recurrences occur as late as five years after surgery. 60 % of all patients die from tumor-independent reasons making a clear prognostic statement difficult. Surgical treatment remains the gold standard and must be performed whenever possible. The most common approach is a median sternotomy. When dealing with a thymuscarcinoma, radical lymph node dissection is advisable. With respect of treatment only adjuvant radiation can possibly improve long term survival and reduces local recurrence rates for incomplete resected patients. There is no evidence for a benefit in patients with thymoma receiving adjuvant chemotherapy. A neo-adjuvant chemotherapy in combination with an adjuvant radiotherapy improves outcome after surgical resection in stage III and IV and goes along with better survival rates. Larger studies have not been performed so far. A multimodal therapy strategy is advised when dealing with thymomas in stage III and IV.

A rare case of aortic coarctation and ventricular septal defect combined with alveolar capillary dysplasia.

We report a rare case of alveolar capillary dysplasia (ACD) associated with severe aortic coarctation, hypoplastic aortic arch, and mild hypoplasia of the left ventricle. After successful coarctation repair, pulmonary hypertension persisted, and despite only minor anomalies on the x-ray, chest computed tomography (CT) revealed the presence of primary lung disease. Review of the literature suggests that ACD may be associated with left heart obstructions. Chest CT is applicable to diagnose ACD precociously.

Surgery for cystic lymphangioma in Gorlin-Goltz syndrome.

INTRODUCTION: We present a case of three major lymphomesenteric cysts in a female patient with known basal cell nevus syndrome (BCNS or Gorlin-Goltz syndrome). DISCUSSION: Although those cysts have been reported to appear in this syndrome, the exact prevalence is not known. In this case, the patient suffered from severe and recurrent abdominal pain due to bowel obstruction. CONCLUSION: By causing severe symptoms, cystic lymphangiomas are an important complication of the BCNS despite of their seldom occurrence. Surgeons confronted with intraabdominal masses in a patient with BCNS should always be aware of this manifestation of the disorder and plan interdisciplinary operations.

Digitized pathology: theory and experiences in automated tissue-based virtual diagnosis.

AIMS: To describe the theory and develop an automated virtual slide screening system. Theoretical considerations. Tissue-based diagnosis separates into (a) sampling procedure to allocate the slide area containing diagnostic information, and (b) evaluation of diagnosis from the selected area. Nyquist's theorem broadly applied in acoustics, serves to presetting the sampling accuracy. Tissue-based diagnosis relies on two different information systems: (a) texture, and (b) object information. Texture information can be derived by recursive formulas without image segmentation. Object information requires image segmentation and feature extraction. Both algorithms complete another to a "self-learning" classification system. METHODS: Non-overlapping compartments of the original virtual slide (image) are chosen at random with predefined error-rate (Nyquist's theorem). The standardized image compartments are subject for texture and object analysis. The recursive formula of texture analysis computes median gray values and local noise distribution. Object analysis includes automated measurements of immunohistochemically stained slides. The computations performed at different magnifications (x 2, x 4.5, x 10, x 20, x 40) are subject to multivariate statistically analysis and diagnosis classification. RESULTS: A total of 808 lung cancer cases of diagnoses groups: cohort (1) normal lung (318 cases) - cancer (490 cases); cancer subdivided: cohort (2) small cell lung cancer (10 cases) - non-small cell lung cancer (480 cases); non-small cell lung cancer subdivided: cohort (3) squamous cell carcinoma (318 cases) - adenocarcinoma (194 cases) - large cell carcinoma (70 cases) was analyzed. Cohorts (1) and (2) were classified correctly in 100%, cohort (3) in more than 95%. The selected area can be limited to 10% of the original image without increased error rate. A second approach included 233 breast tissue cases (105 normal, 128 breast carcinomas) and 88 lung tissue cases (58 normal, 38 cancer). Texture analysis revealed a correct classification with only 10 training set cases in >92% for both, breast and lung tissue. CONCLUSIONS: The developed system is a fast and reliable procedure to fulfill all requirements for an automated "pre-screening" of virtual slides in tissue-based diagnosis.