[Cutaneous adnexal and salivary gland tumours. Similarities and differences]. / Hautadnex- vs. Speicheldrüsentumoren. Analoges und Divergentes.

Despite major discrepancies in basic microscopic anatomy, remarkable similarities are manifest within the wide spectrum of cutaneous adnexal and salivary gland tumors. In this study salivary gland and adnexal tumors were identified and investigated with respect to similarities in histology, terminology and pathogenesis. Histological similarities of certain types of salivary gland tumors relate to eccrine, apocrine and rarely sebaceous (but not trichofollicular) types of adnexal tumors. The most striking similarity was found with salivary gland pleomorphic adenoma and cutaneous mixed tumor. Multistep carcinogenesis starting with intraductal carcinoma, identified in carcinoma ex pleomorphic adenoma is identical to that found in cutaneous carcinoma ex spiradenoma. Further histological and terminological similarities are shown for mucinous and mucoepidermoid carcinoma, for lymphadenoma and lymphoepithelial carcinoma, for sebaceous adenoma and carcinoma, for adenoid-cystic carcinoma, as well as for salivary gland basal cell adenoma versus cutaneous spiradenoma. Manifest diagnostic problems related to histologically similar salivary gland and adnexal tumors are rare and are topographically limited to the parotid and oral areas.

[In situ analysis of pathomechanisms of human intervertebral disc degeneration]. / In-situ-Analyse von Pathomechanismen der humanen Bandscheibendegeneration.

BACKGROUND: Low back pain is one of the major causes of pain and disability in the western world, with a constantly rising life-time prevalence of approximately 60-85 %. Degeneration of the intervertebral disc is believed to be a major cause of low back pain. MATERIALS AND METHODS: Semiquantitative macroscopic and microscopic changes of the intervertebral disc were assessed and classified. Furthermore additional methods, such as immunohistochemistry, in situ hybridization and in situ zymography were used to analyze phenotypic cellular and matrix changes. RESULTS: We have developed and tested a practicable, valid and reliable histological classification system for lumbar discs which can serve as a morphological reference framework to allow more sophisticated molecular biological studies on the pathogenesis of ageing and degeneration of discs. Secondly, we were able to demonstrate that intrinsic (genetic) and extrinsic (e.g. overweight) factors have a profound effect on the process of disc degeneration. Cells with a notochord-like phenotype are present in a considerable fraction of adult lumbar intervertebral discs. The presence of these cells is associated with distinct features of (early) age-related disc degeneration. During the process of disc degeneration, the intervertebral disc shows a progressive and significant reduction in height due to tissue resorption. This matrix loss is related to an imbalance between matrix synthesis and degradation. During this process an inflammatory reaction takes place and resident disc cells are causatively involved. CONCLUSIONS: In summary, disc degeneration is a multifactorial disease with a strong intrinsic (hereditary) and extrinsic (e.g. mechanical factors) background. The process starts as early as in the second decade of life and shows high interindividual differences. The loss of regenerative capacity in the intervertebral disc is probably related to the loss of stem cells, e.g. notochord-like cells. Resident disc cells are involved in the inflammatory reaction with increased matrix degradation, resorption and reduced matrix synthesis.

Treatment of hypereosinophilic syndromes--the first 100 years.

Treatment of the hypereosinophilic syndrome (HES) has advanced rapidly and prevention of end organ damage previously associated with the disorders is now possible in most patients who have had a timely diagnosis. Tried and true medications such as prednisone, hydroxyurea, and interferon-alpha (IFN-aα) continue to play a valuable role in treating HES and their cost is modest. Newer medications included pegylated forms of IFN-aα and IFN-α2b, first- and second-generation tyrosine kinase inhibitors (imatinib mesylate, nilotinib), and monoclonal antibodies to interleukin (IL)-5 and CD52. The combination of better understanding of HES and better medications now provide the clinician with an improved ability to control unregulated proliferation of eosinophils.

Age-related changes in human cervical, thoracal and lumbar intervertebral disc exhibit a strong intra-individual correlation.

INTRODUCTION: Intervertebral disc (IVD) degeneration is characterized as a multifactorial disease, in which the hereditary background is thought to be of high importance. Accordingly, one would expect all spinal levels (lumbar/cervical/thoracal) to be affected by above-average disc degeneration in genetically predisposed individuals. The aim of this study, therefore, was to analyze the amount of degenerative changes in different spine levels in humans from different ages. MATERIALS AND METHODS: In detail, the presence, localization and abundance of histomorphological changes in the annulus fibrosus (AF) and nucleus pulposus (NP) in the cervical (C5/C6), thoracic (T2/T3) and lumbar (L2/L3) spine were investigated in complete autopsy IVD specimens (47 individuals) covering a complete age range (0-95 years). RESULTS: Results indicate that the highest degree of histo-degenerative changes were observed in the NP in all spine levels and showed an age-related expression pattern. With regard to the different spine levels, lumbar disc specimen showed significantly more degenerative changes compared to cervical and thoracic discs, whereas no statistical difference was observed between cervical and thoracic discs. In summary, highest grades of degeneration were observed in lumbar discs (especially in the NP). Intra-individual correlations between the degeneration score in the different levels showed a significant individual concordance. CONCLUSIONS: The intra-individual correlation of degenerative changes in all three examined spine regions further supports the notion that individual, i.e. genetic factors are strong predisposing factor for the development of age-related disc alterations.

[Unilateral maxillary sinusitis: a cavernous haemangioma with bone destruction]. / Einseitige Sinusitis maxillaris : Kavernöses Hämangiom mit knöchernen Arrosionen.

Haemangioma originating in the paranasal sinuses are a rare entity. In the case of unilateral sinusitis the differential diagnosis should include tumors. The following case of a 30-year-old female patient with a therapy-resistant sinusitis showed bone destruction and a maxillary shadow on computed tomography. The histological exam resulted in a cavernous haemangioma.

Intraductally applied contrast-enhanced ultrasound (IA-CEUS) for evaluating obstructive disease and secretory dysfunction of the salivary glands.

Obstructive diseases of the salivary glands are a common problem, usually based on sialolithiasis, duct stenosis, foreign bodies or other more rare causes. Secretory dysfunction, often associated with Sjögren syndrome or post radiation treatment, is also a frequent problem. Several diagnostic tools exist to classify the disease; however conventional radiological imaging or ultrasound does not provide a diagnosis in 5-10% of all cases. Intraductally applied contrast-enhanced ultrasound (IA-CEUS) improves the visualization of obstructive diseases of the salivary glands. IA-CEUS is a promising tool for assessing the ductal system and to diagnose and characterize abnormalities. This study describes the assessment of IA-CEUS in diagnosing different obstructive and chronic inflammatory conditions of the salivary glands.

[Pleomorphic adenoma: pitfalls and clinicopathological forms of progression]. / Das pleomorphe Adenom: Pitfalls in der Diagnostik und klinisch-pathologische Progressionsformen.

In the majority of cases the diagnosis of pleomorphic adenoma (PA) is straightforward. In "monomorphic" types of PA problems may result: Epithelial-rich PA need to be distinguished from basal cell adenoma or canalicular adenoma. PA dominated by mesenchymal, spindle-shaped differentiation need to be distinguished from myoepithelioma or soft tissue tumours like schwannoma. Focal biphasic-tubular differentiation with CK7/18-positive ductal cells is good evidence for a tumour within the wide spectrum of PA. Focal peripheral pseudoinfiltration can represent physiological growth pattern of PA; this may render a difficult distinction from low-malignant carcinomas like adenoid-cystic or epithelial-myoepithelial carcinoma, harbouring also tubular structures. The different progression steps of carcinoma ex pleomorphic adenoma (CEPA), starting with intraductal carcinoma, are highly relevant with respect to prognosis and therapy. Early stages including CEPA with minor extracapsular invasion show favourable prognosis, while cases with extensive extracapsular invasion carry a dismal prognosis.

[Pattern recognition in the differential diagnosis of salivary lymphoepithelial lesions]. / Mustererkennung zur Differenzialdiagnose lymphoepithelialer Läsionen der Speicheldrüsen.

The prototype of a salivary lymphoepithelial lesion is the autoimmune disease Sjögren's syndrome with the characteristic lymphoepithelial duct lesions (LEL). The distinction of Sjögren's syndrome from cases with initial transformation into associated marginal zone B-cell lymphoma (MALT type) can be very challenging, whereby the presence of small "halos" can lead to over-diagnosis. The HIV-associated cystic lymphoepithelial lesion can be histologically almost identical to Sjögren's syndrome and often needs clinical correlation. The sporadic lymphoepithelial cyst of the parotid gland is a frequent finding and has no clinical consequence; however, this entity needs to be identified and distinguished from the above-mentioned entities. The most frequent diagnosis in resected submandibular glands is chronic-fibrosing sialadenitis, so-called Küttner's tumour. Altogether, there is a wide spectrum of lymphoepithelial interaction in the area of salivary glands, including biphasic lymphoepithelial tumours with an obligate lymphoid component, epithelial tumours with facultative tumour-associated lymphoid proliferation, and different processes of intraparotid lymph nodes. The immunohistological reaction for pan-keratin can be very helpful for a thorough pattern analysis of the different lymphoepithelial lesions. The relative frequency of the lesions in different salivary glands can also be diagnostically helpful.

[Reduced bone density and bone pain :osteomalacia with hypophospatemia and hypophosphaturia]. / Erniedrigte Knochendichte und Knochenschmerzen : Osteomalazie mit Hypophosphatämie und Hyperphosphaturie.

Two patients aged 24 and 64 years presented at our hospital with similar symptoms including bone pain and muscle weakness. Basic laboratory tests and urinary diagnostics, bone densitometry and bone histology revealed severe osteomalacia with renal phosphate wasting. After the exclusion of other causes an extensive tumor search was performed due to suspected tumor-induced osteomalacia. In one patient a mesenchymal tumor was found in the thigh and completely resected. After surgery the patient showed a rapid recovery from osteomalacia. Because the search was unsuccessful in the other patient phosphorus supplementation in combination with calcitriol was started. Despite continuing renal phosphate wasting a significant increase in bone mineral density was observed.

[Cholesterol ester storage disease: a rare disease or a rare diagnosis?]. / Cholesterinesterspeicherkrankheit: Eine seltene, weil zu selten diagnostizierte Krankheit?

We report the case of a 13-year-old boy with a longstanding history of unspecific hepatomegaly. The morphological investigations were diagnostic of a cholesterol ester storage disease (CESD), a rare autosomal recessive inherited disease with deficient activity of lysosomal acid lipase (LAL). The combination of hepatomegaly with accumulation of macrophages and ultrastructural evidence of lysosomal lipid storage are groundbreaking for the diagnosis. The probability of a underdiagnosis or false disease classification, for example as nonalcoholic steatohepatitis (NASH), is high, particularly with regard to genetic data which indicate a higher incidence of the disease.

Dose-dependent new bone formation by extracorporeal shock wave application on the intact femur of rabbits.

BACKGROUND: Whereas various molecular working mechanisms of shock waves have been demonstrated, no study has assessed in detail the influence of varying energy flux densities (EFD) on new bone formation in vivo. METHODS: Thirty Chinchilla bastard rabbits were randomly assigned to 5 groups (EFD 0.0, 0.35, 0.5, 0.9 and 1.2 mJ/mm2) and treated with extracorporeal shock waves at the distal femoral region (1,500 pulses; 1 Hz frequency). To investigate new bone formation, animals were injected with oxytetracycline at days 5-9 after shock wave application and sacrificed on day 10. Histological sections of all animals were examined using broad-band epifluorescent illumination, contact microradiography and Giemsa-Eosin staining. RESULTS: Application of shock waves induced new bone formation beginning with 0.5 mJ/mm2 EFD and increasing with 0.9 mJ/mm2 and 1.2 mJ/mm2. The latter EFD resulted in new bone formation also on the dorsal cortical bone; cortical fractures and periosteal detachment also occurred. CONCLUSION: Here, for the first time, a threshold level is presented for new bone formation after applying shock waves to intact bone in vivo. The findings of this study are of considerable significance for preventing unwanted side effects in new approaches in the clinical application of shock waves.

Intraductal carcinoma is the precursor of carcinoma ex pleomorphic adenoma and is often associated with dysfunctional p53.

AIMS: Although intraductal carcinoma has been demonstrated in intracapsular carcinoma ex pleomorphic adenoma (CEPA), the morphological and genetic stages of transformation of pleomorphic adenoma (PA) to CEPA are not fully understood. The aim of this study was to investigate the morphology of intracapsular CEPA. METHODS AND RESULTS: The largest series of intracapsular CEPA studied was subject to immunohistochemical double-staining to detect p53 protein and cellular proliferation in different types of cell combined with mutational analysis of the p53 gene in laser-microdissected material. Intraductal carcinoma with high-grade cellular atypia and frequent accumulation of p53 protein was found in 15/19 cases. Purely intraductal carcinoma was found in eight cases. Mutation of p53 was found in 7/19 cases, of which it was found in intraductal carcinoma in 5/15 cases. CONCLUSIONS: The frequent demonstration of intraductal carcinoma indicates that this preinvasive lesion is likely to be a constant feature in the malignant transformation of PA to CEPA. It appears to be a feature of CEPA developing from both primary and recurrent PA. The combined immunohistochemical and genetic data show that 14/19 cases of CEPA and 11/15 cases with intraductal carcinoma showed genetic or morphological evidence of dysfunctional p53, indicating that this is an early event in malignant transformation.

Selective antibody immune deficiency in a patient with Smith-Lemli-Opitz syndrome.

Smith-Lemli-Opitz syndrome is a rare autosomal recessive disorder characterized by multiple congenital anomalies and various degrees of cognitive deficits. This condition results from a deficiency of 7-dehydrocholesterol reductase, a critical step in cholesterol biosynthesis. Children with Smith-Lemli-Opitz syndrome have frequent infections, particularly of the respiratory tract. Immunodeficiency, however, is not recognized as a part of this metabolic condition. Frequent infections are usually attributed to a decreased patient mobility and reduced respiratory effort secondary to muscular hypotonia and mental retardation, which are often present in affected individuals. We describe a patient with Smith-Lemli-Opitz syndrome and recurrent respiratory infections who was found to have a selective antibody deficiency. The immunological diagnosis was based on an absent immune response to Pneumovax. She also had no immunological response to hepatitis B vaccine and was unable to break down red cells with isoagglutinin B. Therapy with intravenous IgG (IVIG) was initiated. Infections were less severe, although they still occurred in a high frequency after initiation of the IVIG therapy. This finding prompts the need for a higher index of suspicion for an underlying immune deficiency in patients with Smith-Lemli-Opitz syndrome who present with recurrent and chronic infections. Early recognition and appropriate therapeutic interventions may decrease the severity of infections, prevent potentially fatal infections, and eventually improve the quality of life in these patients.

[New bone formation by extracorporeal shock waves. Dependence of induction on energy flux density]. / Knochenneubildung durch extrakorporale Stosswellen. Einfluss der Energieflussdichte.

BACKGROUND: The purpose of this study was to test the hypothesis that shock waves can induce new bone formation even without cortical fractures and periosteal detachment as suggested in the literature. METHODS: Extracorporeal shock waves with energy flux densities between 0 mJ/mm(2) (sham treatment) and 1.2 mJ/mm(2) were applied in vivo to the distal femoral region of rabbits (1500 pulses at 1 Hz frequency each). Oxytetracycline was injected on days 5-9 and the animals were sacrificed on day 10. Sections of both femora of all animals were investigated with broadband fluorescence microscopy and contact microradiography for new periosteal and endosteal bone, periosteal detachment, cortical fractures, and trabecular bone with callus. RESULTS: Shock waves with energy flux densities of 0.9 mJ/mm(2) and 1.2 mJ/mm(2) resulted in new periosteal bone formation in the presence of cortical fractures and periosteal detachment. After application of shock waves with energy flux density of 0.5 mJ/mm(2), clearly detectable signs of new periosteal bone formation were observed without cortical fractures or periosteal detachment. CONCLUSIONS: The results of this study challenge the current view in the literature that the creation of cortical fractures and periosteal detachment are prerequisites for new bone formation mediated by extracorporeal shock waves.

2002 SSE Award Competition in Basic Science: expression of major matrix metalloproteinases is associated with intervertebral disc degradation and resorption.

During the process of degeneration, the intervertebral disc (IVD) shows a progressive and significant reduction in height due to tissue resorption. Intradiscal clefts and tears are major hallmarks of disc degeneration. Matrix-degrading enzymes such as matrix metalloproteinases (MMPs) are assumed to play a pivotal role in disc tissue degradation and resorption. The objective of this study was therefore to investigate the potential role of MMPs in extracellular matrix degradation leading to disc degeneration. This study was conducted on 30 formalin-fixed and EDTA-decalcified complete cross-sections of lumbar IVDs from cadavers of individuals aged between 0 and 86 years. Tissue sections were used for the immunolocalization of MMPs-1, -2, -3 and -9. The number of labeled cells was assessed by morphometric analyses, and was statistically correlated with the formation of clefts and tears, cellular proliferation, granular matrix changes and mucous degeneration. Furthermore, 30 disc specimens obtained during spinal surgery were used for in situ hybridization of MMP-2 and -3-mRNA. In addition, the enzymatic gelatinolytic activity was determined by in situ zymography in autopsy material. Immunohistochemistry showed the intradiscal expression of all four MMPs, which was confirmed by in situ hybridization, providing clear evidence for the synthesis of the enzymes within nucleus pulposus and annulus fibrosus cells. Gelatinolytic enzymatic activity was verified by in situ zymography. IVDs from infants and young adolescents remained almost completely unlabeled for all MMPs tested, while more MMPs-1 and -3 were seen in disc cells of younger adults than in those of a more advanced age; MMP-2 remained unchanged over the adult age periods, and MMP-9 was expressed in only relatively few cells. This pattern significantly correlated with the occurrence of clefts and tears. This correlation was strongest for MMP-1 ( P<0.0001), MMP-2 ( P<0.0017) and MMP-3 ( P<0.0005) in the nucleus, and MMP-1 ( P<0.0001) and MMP-2 ( P<0.038) in the annulus. In parallel, the proliferation of disc cells and matrix degeneration (granular changes and mucous degeneration) were related to MMP expression. Likewise, enzymatic activity was seen in association with cleft formation. Our data suggest that major MMPs play an important role in the degradation of the IVD. This is evidenced by the high correlation of MMP expression with the formation of clefts and tears. These findings implicate a leading function for MMPs in IVD degeneration resulting in the loss of normal disc function, eventually leading to low-back pain.

Influence of extracorporeal shock-wave application on normal bone in an animal model in vivo. Scintigraphy, MRI and histopathology.

There is little information about the effects of extracorporeal shock-wave application (ESWA) on normal bone physiology. We have therefore investigated the effects of ESWA on intact distal rabbit femora in vivo. The animals received 1500 shock-wave pulses each of different energy flux densities (EFD) on either the left or right femur or remained untreated. The effects were studied by bone scintigraphy, MRI and histopathological examination. Ten days after ESWA (0.5 mJ/mm2 and 0.9 mJ/mm2 EFD), local blood flow and bone metabolism were decreased, but were increased 28 days after ESWA (0.9 mJ/mm2). One day after ESWA with 0.9 mJ/mm2 EFD but not with 0.5 mJ/mm2, there were signs of soft-tissue oedema, epiperiosteal fluid and bone-marrow oedema on MRI. In addition, deposits of haemosiderin were found epiperiosteally and within the marrow cavity ten days after ESWA. We conclude that ESWA with both 0.5 mJ/mm2 and 0.9 mJ/mm2 EFD affected the normal bone physiology in the distal rabbit femur. Considerable damaging side-effects were observed with 0.9 mJ/mm2 EFD on periosteal soft tissue and tissue within the bone-marrow cavity.

Peptide-based analysis of amino acid sequences important to the biological activity of eosinophil granule major basic protein.

Synthetic peptides corresponding to amino acid sequences in eosinophil granule major basic protein (MBP) were evaluated for cytotoxic activity toward K562 cells and for ability to stimulate basophil mediator release. Results obtained using 14 peptides spanning the 117-amino acid sequence of MBP in overlapping fashion indicated that the activities mapped to peptide sequences near the amino and carboxy termini of MBP. The activity of these regions was confirmed using two peptides corresponding to MBP residues 18-45 and 89-117. A 20-h incubation with 5 microM peptide 18-45 or peptide 89-117 caused approximately the same levels (>60%) of cytotoxicity in K562 cells as 5 microM MBP. Similarly, a 30-min incubation with peptides 18-44 and 89-117 stimulated basophil histamine release in a concentration-dependent manner over the range of 5-20 microM. The level of release stimulated by 20 microM peptide 89-117 approached that stimulated by 2 microM MBP. A 20 microM concentration of peptide 89-117 also stimulated leukotriene C4 (LTC4) production by the basophils. Neither peptide 18-45 nor peptide 89-117 was cytotoxic for basophils under the experimental conditions for histamine and LTC4 release, as determined by 51Cr release. These results indicate that two MBP peptide sequences, including one (89-117) that contains a unique carbohydrate-binding region, share the biologic activities of MBP.

Cockroach allergen-induced eosinophilic airway inflammation in HLA-DQ/human CD4(+) transgenic mice.

Airway eosinophilic inflammation is a characteristic feature of allergic asthma. Exposure to allergens produced by the German cockroach (Blattella germanica) is a risk factor for allergic disease in genetically predisposed individuals, and has been linked to an increase in asthma morbidity among cockroach-sensitive inner city children. To determine the role and contribution of specific HLA class II in the pathogenesis of allergic airway inflammation in cockroach-induced asthma, we generated double-transgenic, double-knockout mice expressing human HLA-DQ8, HLA-DQ6, and CD4 molecules in the absence of mouse class II and mouse CD4. Mice were actively immunized and later challenged intranasally with cockroach allergen extract. These mice developed bronchoalveolar lavage fluid (BALF) eosinophilia and pulmonary eosinophilia. This was accompanied by an increase in total protein levels, IL-5, and IL-13 in BALF. There were also elevated levels of cockroach-specific serum IgG1 and total serum IgE. Histological analysis revealed peribronchial and perivascular eosinophilic inflammation in cockroach-treated mice. Other pathologic changes in the airways were epithelial cell hypertrophy and mucus production. Treatment with anti-DQ mAb significantly reduced pulmonary and BALF eosinophilia in cockroach allergen-sensitized mice. Abeta(0) mice and transgenic mice expressing human CD4 molecule alone (without class II) or human HLA-DQ8 molecule (without CD4) treated in the same fashion showed no eosinophilia in bronchoalveolar fluid and no pulmonary parenchymal inflammation. Our results provide direct evidence that HLA-DQ molecules and CD4 T cells mediate cockroach-induced eosinophilic inflammation in the airways.

In situ compressive stiffness, biochemical composition, and structural integrity of articular cartilage of the human knee joint.

OBJECTIVE: Reduction of compressive stiffness of articular cartilage has been reported as one of the first signs of cartilage degeneration. For the measurement of in situ compressive stiffness, a hand-held indentation probe has recently been developed and baseline data for macroscopically normal knee joint cartilage were provided. However, the histological stage of degeneration of the measured cartilage was not known. The purpose of this study was to investigate whether there is a relationship between the in situ measured compressive stiffness, the histological stage of degeneration, and the biochemical composition of articular cartilage. DESIGN: Instantaneous compressive stiffness was measured for the articular cartilage of 24 human cadaver knees. Additionally, biochemical composition (total proteoglycan and collagen content) and histological appearance (according to the Mankin score) were assessed for each measurement location. RESULTS: Despite visually normal surfaces, various histological signs of degeneration were present. A high correlation between Mankin score and cartilage stiffness was observed for the lateral patellar groove (R(2)=0.81), the medial (R(2)=0.83) and the lateral femoral condyle (R(2)=0.71), whereas a moderate correlation was found for the medial patellar groove (R(2)=0.44). No correlation was observed between biochemical composition and cartilage compressive stiffness. CONCLUSIONS: Our results are in agreement with others and show that the instantaneous compressive stiffness is primarily dependent on the integrity of the extracellular matrix, and not on the content of the major cartilage constituents. The high correlation between stiffness and Mankin score in mild osteoarthrosis suggests that the stage of cartilage degeneration can be assessed quantitatively with the hand-held indentation probe. Moderate and severe case of osteoarthrosis remains to be investigated.