Implications of bevacizumab on vascular endothelial growth factor and endostatin in human choroidal neovascularisation.

AIM: To evaluate the implications of intravitreal bevacizumab on proangiogenic vascular endothelial growth factor (VEGF) with regard to the endogenous angiogenesis inhibitor endostatin in human choroidal neovascularisation (CNV) secondary to age-related macular degeneration. METHODS: Retrospective review of an interventional case series of 48 patients who underwent full macular translocation surgery with removal of CNV. Twenty-five patients were treated with intravitreal bevacizumab injection 1 to 154 days prior to surgery (bevacizumab CNV). Twenty-three CNV without any kind of previous treatment were used as controls (control CNV). CNV were stained for CD34, cytokeratin18, VEGF, endostatin and E-selectin. A "predominance score of VEGF over endostatin" (PS) was defined by the difference between VEGF and endostatin staining scores. RESULTS: Bevacizumab CNV revealed a weaker VEGF expression in endothelial cells (p = 0.0245) but significantly more intense endostatin in retina pigment epithelium (RPE) (p = 0.0001) and stroma (p<0.0001). Consequently, PS was significantly lower in RPE (p = 0.02), vessels (p = 0.03) and stroma (p = 0.0004) in bevacizumab CNV. The intensity of E-selectin expression in bevacizumab CNV was comparable with that in control CNV. CONCLUSIONS: A shift within the angiogenic balance in terms of decreased VEGF predominance over endostatin is detected in human CNV treated with bevacizumab.

Massive cavernous lymphangioma of the breast and thoracic wall: case report and literature review.

Lymphangiomas are benign lesions but are associated with high morbidity when they become very large, occur in critical locations, or when surgically removed, develop secondary wound infections. Almost all lesions require surgical treatment. Complete excision is curative; however, relapses must be anticipated with incomplete excision. We report the case of a patient with a long history of massive cavernous lymphangioma of the breast and thoracic wall extending into the axilla in whom complete excision was not possible.

Paraadrenal Castleman disease presenting with adrenal hyperandrogenism.

Castleman disease, or angiofollicular lymph node hyperplasia, is a rare benign lymphoproliferative disorder. We report an uncommon case of retroperitoneal Castleman syndrome associated with adrenal hyperandrogenism and with interleukin-6 as the possible link in the pathophysiology of both disturbances. Four years after surgical resection of the paraadrenal mass, the patient is free of signs of recurrence of Castleman disease and adrenal hyperandrogenism.

[Cell reactions to amber: amber lung in experimental animals]. / Zelluläre Reaktionen auf Bernstein : Zum tierexperimentellen Nachweis einer "Bernsteinlunge".

UNLABELLED: Workers in the amber-processing industry are heavily exposed to amber dust during the cutting and grinding. Nothing is known about the effect on the lung of inhalation of amber dust. We studied the histological changes after subcutaneous injection of amber dust in man and the rat and after inhalation of amber dust in the rat. RESULTS: 1. The subcutaneous injection of amber dust led to acute inflammation and later to inflammation with large numbers of macrophages and giant cells, forming giant cell granulomas. 2. There was brisk phagocytosis of the amber dust by macrophages. Digestion of amber could not be identified with certainty. 3. Moderate inhalation of amber led to intraalveolar and intrabronchial phagocytosis, predominantly by macrophages. 4. After intense, repeated inhalation (4 and 6 1/2 months post-inhalation) peribronchiolar foreign body granulomas and fibroblasts were seen. In contrast to the findings in the skin (probably related to grinding paste), no epithelioid cell granulomas were found in the lung. The tissue reactions in man are similar to those in the rat. The inflammatory and fibrotic interstitial reactions observed in the rat lung after prolonged intense exposure to amber dust suggest that chronic pulmonary damage ("chronic amber lung") could occur as a result of occupational exposure to amber dust during cutting/polishing.

Neoplasm of hepatic stellate cells (spongiotic pericytoma): a new tumor entity in human liver.

The purpose of this investigation was to classify a previously unknown tumor entity in human liver observed in a 35-year-old woman. It was characterized by an unusual accumulation of fusiform CD34-positive cells and was initially misconceived as a tumor of the liver sinusoids. The tissue was examined by light and electron microscopy and by immunocytochemical techniques with a broad spectrum of antibodies. The polycyclic tumor contained multiple nodular cell aggregates. The tumor cells possessed extensive cytoplasmic processes, rough endoplasmic reticulum, a prominent Golgi complex, and, in isolated cases, fat droplets. They expressed vimentin, CD34, CD105, CD99, CD56, and sm-actin. The matrix surrounding these cells was reactive for collagen types I, III and V, and fibronectin. The unusual aspect of this tumor is that it contained collections of cells that appeared to be hepatic stellate cells (Ito cells). It also contained hepatic cells arranged in plates, lobules, and capillarized sinuses. These findings suggest that the tumorous proliferation of hepatic stellate cells is functionally linked to the hepatocytes. It is unclear whether there is a link between the tumor and the patient's use of oral contraceptives. Referring to animal studies, different hepatocarcinogens may cause neoplastic Ito cell proliferation. The patient has remained recurrence-free during the 12 months since operation.

Valproic acid-associated sialadenosis of the parotid and submandibular glands: diagnostic and therapeutic aspects.

Sialadenosis has been defined as a non-inflammatory, parenchymatous salivary gland disease causing recurrent, bilateral swelling of the salivary glands. As an adverse drug reaction of valproic acid, sialadenosis is very rare. To our knowledge, it has been reported only once in the world literature to date. We present herein the case of a patient with valproic acid-associated sialadenosis of both the parotid and submandibular glands. This appears to be the first published case of a patient who received surgical treatment. On light and electron microscopy of all the affected salivary glands, granular sialadenosis with predominantly moderate electron-dense secretory cytoplasmatic granules was observed. No relevant degenerative alterations were seen. There was no histological evidence of peripheral neuropathy of the nerve supply, leading to disordered activity of acinar cells by loss of neurosecretory granules. Lateral parotidectomy, performed under neuromonitoring control for safety reasons, is the treatment of choice for chronic recurrent parotitis that does not respond to conservative therapy, particularly if the cosmetic deformity is unacceptable to the patient. If the submandibular glands are involved, partial removal is recommended.

[Oral manifestation of miliary tuberculosis]. / Orale Manifestation einer miliaren Tuberkulose.

CASE REPORT: We report on the clinical course of a 40-year-old patient with an oral manifestation of miliary tuberculosis. In addition to oral mucosa and lung, the colon and ileum were also infested. The oral lesions may resemble malignant tumors and are difficult to diagnose, especially because tuberculosis has become a rare disease in industrialized countries. DISCUSSION: Oral lesions and concomitant pulmonary complaints can be a sign for existing tuberculosis. Patients with these problems should undergo a chest X-ray and a biopsy from the oral mucosa. In addition, tests should be conducted to determine if mycobacteria are present in the sputum, gastric fluid, and urine and cultures grown. In cases with negative results PCR may detect DNA of Mycobacterium tuberculosis.

[Immunohistochemical identification of lymph vessels with D2-40 in diagnostic pathology]. / Immunhistochemische Darstellung von Lymphgefässen mit D2-40 in der diagnostischen Pathologie.

D2-40 is an antibody that reliably detects human lymphatic endothelial cells. Because little is known about the extent to which other cells are stained, we have investigated this question in various tissues. Normal, reactive and neoplastic lymphatics (including lymphangiomas and Stewart-Treves syndrome) were stained by D2-40. Published findings indicate that some angiosarcomas and Kaposi are positive. Staining was also found in the following non-endothelial cells: mesothelial cells, follicular dendritic reticulum cells, Cajal cells, a few epithelial cells in the dermis, myoepithelial cells (e. g. breast), and basal cells (e. g. prostata), various mesenchymal cells. The following tumours were reactive: myofibroblastic tumours, gastrointestinal stromal tumour, mesothelioma, adenomatoid tumour, traumatic neuroma, seminoma, seminoma in situ and other testicular tumours, pleomorphic adenoma (one of two tumours positive), and follicular dendritic reticulum cell sarcoma. Despite this relatively broad spectrum of reactivity, we consider D2-40 to be the best commercially available antibody for the delineation of normal, reactive and neoplastic lymphatic endothelial cells.

[Malabsorption syndrome. Rare differential diagnosis in a young patient]. / Malassimilationsyndrom. Seltene Differenzialdiagnose bei einer jungen Patientin.

In a young female patient originally coming from Albany, immunoproliferative small intestinal disease (IPSID) could be diagnosed as a cause for severe maladsorption. Considering clinical and histological criteria an early disease stage of IPSID could be diagnosed. Under the continuous treatment of doxycycline for more than 3 1/2 years, all disease manifestations like watery diarrhea, vomiting, pain in the upper abdomen and loss of weight disappeared. After discontinuation of the antibiotic therapy the patient reached a sustained response.

[Calcium pyrophosphate dihydrate deposition disease]. / Kalziumpyrophosphat-Arthropathie des Kiefergelenks.

Calcium pyrophosphate dihydrate deposition disease (CPPD) of the temporomandibular joint is rare. The disorder is characterized by the presence of crystal deposits within the affected joint. The deposition of crystals in adjacent soft tissue may lead to the formation of pseudotumors. This form of the disease is called tophaceous pseudogout and typically affects the temporomandibular joint. It is difficult to differentiate the disease, particularly from malignant tumors, on the clinical and radiographic findings alone. The diagnosis is based on histological identification of the calcium pyrophosphate crystals. We present an unusually advanced case of tophaceous pseudogout of the temporomandibular joint. The etiology, clinical and diagnostic criteria as well as treatment options are discussed on the basis of our own experience and a review of the literature.

Lymphatic vessels in the colonic mucosa in ulcerative colitis.

In the normal colonic mucosa, lymphatics are found only in a narrow band associated with the muscularis mucosae and are absent from the rest of the mucosa. This study examined whether this arrangement of lymphatics is also valid in ulcerative colitis. Histological sections of colon from 15 long-standing cases were investigated with antibodies against CD 34 (negative for lymphatics; positive for blood vessel endothelium) and, in selected cases, podoplanin (positive for lymphatic endothelium; negative for blood vessel endothelium). Whereas inflammation of the mucosa was not associated with changes in lymphatics, an increase in intramucosal lymphatics was seen when the pathological changes included widening of the muscularis mucosae or penetration of the mucosa by muscle fibers, filiform changes in the mucosa, and hyperplasia of the mucosa-associated lymphoid tissue (MALT). In specimens with epithelial dysplasia, an association between the dysplastic epithelium and ectatic and quantitatively increased lymphatics was observed. With superimposed carcinoma, no relationship between the malignant tumor and lymphatics was identifiable. Nevertheless, pre-existing lymphatics in the muscularis mucosae were involved in lymphatic tumor spread. The immunohistochemical findings demonstrated that lymphatics occurred in all areas of the mucosa in ulcerative colitis (or, in effect, at sites which were not normally found under physiological conditions) and in regions that favored lymphatic tumor dissemination. Whether these lymphatics were actually involved in metastasis remains to be defined.

Small epithelial cells in human liver cirrhosis exhibit features of hepatic stem-like cells: immunohistochemical, electron microscopic and immunoelectron microscopic findings.

AIMS: To investigate whether cells with features similar to those of the oval cells of rodents and the small epithelial cells (SEC) recently described in certain human liver diseases, i.e. hepatic progenitor cells, also occur in human liver cirrhosis. METHODS AND RESULTS: Surgical specimens from 35 cases of hepatitis B virus-positive cirrhosis (30 cases containing hepatocellular carcinoma) were investigated by immunohistochemical staining for cytokeratin 7 and albumin. Electron microscopic investigations, and immunoelectron microscopic investigations using the same antibodies and a double-labelling technique were performed in 15 and seven cases, respectively. SEC were observed in proliferated bile ductules, at the margins of regenerating nodules and in the fibrous septa in all cases of cirrhosis. The SEC were morphologically similar to the SEC described previously, and to the oval cells seen in experimental hepatocarcinogenesis. They were characterized by their small size, oval shape, scanty electron-dense or electron-lucent cytoplasm, a high nucleo-cytoplasmic ratio, tonofilaments and intercellular junctions. Immunoelectron microscopy revealed that the SEC co-expressed cytokeratin 7 and albumin. Both relatively undifferentiated SEC and SEC with morphological and immunophenotypical signs of differentiation towards biliary epithelial cells and hepatocytes were found. CONCLUSIONS: SEC that exhibit morphological and immunophenotypical features of the SEC seen in certain other liver diseases are found in cirrhosis. These findings further support the hypothesis that a bipotent hepatic stem cell that may give rise to biliary epithelial cells and hepatocytes exists in the human liver.

Extranodal marginal zone B cell lymphoma of MALT type involving the mucosa of both the urinary bladder and stomach.

Primary lymphoma of the urinary bladder is a very rare tumour. A bladder tumour was found in a 57 year old man with obstructive dysuria. It was found by histological and immunohistohistochemical investigation to be an extranodal marginal zone B cell lymphoma. Lymphoepithelial lesions were absent, but were found in a clinically silent gastric lymphoma discovered four weeks later during staging investigations; this gastric lymphoma was negative for Helicobacter pylori by breath test and molecular biological analysis. Sequencing of the clonal immunoglobulin heavy chain gene in both tumours indicated the same precursor cell, of follicular or post follicular origin. In synopsis, the data suggested that this was a case of primary lymphoma of the bladder with involvement of the stomach. The application of a chromosome 3 specific alpha satellite probe revealed trisomy 3. A tumour with these characteristics arising as a lymphoma of the bladder with a metachronous involvement of the gastric mucosa has not been described previously.

Human cytomegalovirus as a direct pathogen: correlation of multiorgan involvement and cell distribution with clinical and pathological findings in a case of congenital inclusion disease.

The human cytomegalovirus (HCMV), a member of the Herpesviridae, is the most frequent cause of congenital virus infections and a major cause of morbidity and mortality in immunocompromised patients. Due to the lack of an appropriate animal model, insight into the pathogenesis of HCMV infections originates primarily from in situ examination of HCMV-infected tissues. Although in immunocompromised adults such tests are complicated frequently by the presence of additional misleading pathogens, the absence of additional pathogens renders congenital inclusion disease the most suitable access for investigation of pathogenetic aspects of HCMV infections. Immunohistochemical examination of tissue sections from a boy with fatal congenital inclusion disease was undertaken to detect the extent of multiorgan and cell involvement. Adrenal gland, bone marrow, diencephalon, heart, kidney, liver, lung, pancreas, placenta, small bowel and spleen were included in this study. Detection of virus antigens from different phases of viral replication revealed that all investigated organs were infected by HCMV. Simultaneous detection of cell type specific marker molecules showed that a variety of cell types stained positive for HCMV antigens including endothelial cells, epithelial cells, smooth muscle cells, mesenchymal cells, hepatocytes, monocytes/macrophages and granulocytes. The lung, the pancreas, the kidneys and the liver were the major target organs with a high number of HCMV infected cells. This correlated with multiorgan failure as the cause of death and strongly indicates direct pathogenetic effects of HCMV.

Molecular pathogenesis of Epstein-Barr virus associated posttransplant lymphomas: new insights through latent membrane protein 1 fingerprinting.

BACKGROUND: Fingerprint amino acid patterns within the carboxy terminus of the latent membrane protein (LMP1) oncoprotein of Epstein-Barr virus (EBV) allow individual strain identification at the molecular level. LMP1 is expressed in the tumor cells of EBV-associated posttransplant lymphomas (PTLs) and the LMP1 genome is also identified in lymphocytes of most donors of allogeneic bone marrow. Therefore, LMP1 genotyping in donor lymphocytes and PTL tumor cells, together with sex chromatin determination of tumor cells, allows to determine the origin of PTL tumor cells and the origin of individual EBV strains harboured by them. METHODS: We traced the origin of aggressive PTLs occurring in six patients after allogeneic T cell-depleted stem cell transplantation (allo-SCT). DNA was extracted from donor lymphocytes and PTLs of recipients and amplified with LMP1-specific primers in each case. A comparative sequence analysis of the fingerprint LMP1 region identified in donor lymphocytes and lymphoma was performed. RESULTS: One lymphoma of donor origin occurred after highly selected CD34+ PBSCT and contained the same LMP1 genotype as the donor lymphocytes. Three lymphomas of recipient origin had deletions within the carboxy terminus of LMP1, not identified in the donor strains. All lymphomas occurred in the setting of allo-SCT and had a rapid clinical course. CONCLUSIONS: These results show that highly selected CD34+ PBSCT does not protect against transfer of EBV positive founder cells of donor type PTL and that, after allo-SCT, recipient type PTLs are not uncommon. Outgrowth of recipient type lymphoma may be favoured by LMP1 deletion variant strains present in recipient lymphocytes.

High-grade lymphoma mimicking bone crisis in Gaucher's disease.

A 33-year-old woman with type 1 Gaucher's disease developed painful swelling of her right tibia. Initial diagnostics suggested a typical bone crisis. However, clinical course and subsequent imaging pointed to malignant disease, which was specified as high-grade lymphoma. Chemotherapy was applied together with enzyme replacement and resulted in complete remission of the lymphoma. We conclude that osseous lesions, although suggestive of common manifestations of Gaucher's disease, should be discriminated very carefully from neoplastic infiltration to maintain curative treatment options.

Newly-formed lymph nodes in the submucosa in chronic inflammatory bowel disease.

BACKGROUND AND AIMS: Routine diagnostic work revealed cell aggregates reminiscent of lymph nodes in the bowel submucosa in occasional cases of chronic inflammatory bowel disease. We therefore investigated whether they fulfill criteria for classification as lymph nodes. METHODS: Colon with terminal ileum from a patient with florid Crohn's disease and a colectomy specimen from a patient with ulcerative colitis were investigated. Sections were immunostained with antibodies that recognize endothelial and sinus-lining cells, immune-accessory cells, and lymphoid cells. RESULTS: Circumscribed collections of cells that fulfill all the major criteria for classification as lymph nodes were found in the large and small bowel. They had marginal and intermediate sinuses (positive for BMA 120, CD34, CD31, X-11, and von Willebrand's factor), afferent lymph vessels, T- and B-regions, and a capsule. Small collections composed predominantly of B cells that had only a marginal sinus were also occasionally observed. CONCLUSION: Secondary mucosa-associated lymphoid tissue, typically seen as follicular lymphoid hyperplasia, also appears to occur as secondary submucosal lymph nodes. This phenomenon seems inconsistent with the notion that lymph nodes do not develop after birth. We have also noted secondary development of lymph nodes in lymphangioma and lymphangioleiomyomatosis. It is possible that local lymph vessel proliferation, possibly with chronic lymphedema of the tissue involved, is an important prerequisite for lymph node neogenesis.

Primary lymph node plasmacytomas (plasmacytic lymphomas).

To determine whether primary lymph node plasmacytoma (PLNP) is a distinct entity among other types of plasma cell neoplasia, we analyzed a large series of PLNPs from 2 large lymphoma registries to compare histologic, immunophenotypic, and clinical features of PLNPs, nonnodal extramedullary plasmacytomas, and multiple myeloma. Twenty-five PLNPs (clinical data on 15 cases) were compared with 10 non-lymph node plasmacytomas and 51 cases of multiple myeloma; 36 cases of reactive plasmacytoses were used as controls. The histologic features of PLNP and other extramedullary plasmacytomas were similar. The histologic features of PLNPs were more immature than those of reactive plasmacytoses and less immature than in multiple myeloma. The immunophenotype of PLNPs significantly differed from that of reactive plasmacytoses, other extramedullary plasmacytomas, and multiple myeloma. PLNPs did not progress to multiple myeloma, unlike other extramedullary plasmacytomas, even though survival in PLNPs and other extramedullary plasmacytomas was similar. Our findings suggest that PLNPs may be distinct from other plasma cell dyscrasias.