Glomeruloid Bodies Research Articles

Disproportion in Pericyte/Endothelial Cell Proliferation and Mechanisms of Intussusceptive Angiogenesis Participate in Bizarre Vessel Formation in Glioblastoma.

Glioblastoma (GBM) is the most malignant tumor in the brain. In addition to the vascular pattern with thin-walled vessels and findings of sprouting angiogenesis, GBM presents a bizarre microvasculature (BM) formed by vascular clusters, vascular garlands, and glomeruloid bodies. The mechanisms in BM morphogenesis are not well known. Our objective was to assess the role of pericyte/endothelial proliferation and intussusceptive angiogenic mechanisms in the formation of the BM. For this purpose, we studied specimens of 66 GBM cases using immunochemistry and confocal microscopy. In the BM, the results showed (a) transitional forms between the BM patterns, mostly with prominent pericytes covering all the abluminal endothelial cell (EC) surface of the vessels, (b) a proliferation index high in the prominent pericytes and low in ECs (47.85 times higher in pericytes than in ECs), (c) intravascular pillars (hallmark of intussusceptive angiogenesis) formed by transcapillary interendothelial bridges, endothelial contacts of opposite vessel walls, and vessel loops, and (d) the persistence of these findings in complex glomeruloid bodies. In conclusion, disproportion in pericyte/EC proliferation and mechanisms of intussusceptive angiogenesis participate in BM formation. The contributions have morphogenic and clinical interest since pericytes and intussusceptive angiogenesis can condition antiangiogenic therapy in GBM.

Tissue factor pathway inhibitor is required for cerebrovascular development in mice

AbstractTissue factor pathway inhibitor (TFPI) inhibits proteases in the blood coagulation cascade that lead to the production of thrombin, including prothrombinase (factor Xa [FXa]/FVa), the catalytic complex that directly generates thrombin. Thus, TFPI and FV are directly linked in regulating the procoagulant response. Studies using knockout mice indicate that TFPI and FV are necessary for embryogenesis, but their contributions to vascular development are unclear. We performed extensive histological analyses of Tfpi−/− and Tfpi−/−F5−/− mouse embryos to investigate the importance of the interplay between TFPI and FV in regulating hemostasis and vascular development during embryogenesis. We observed normal tissue development throughout Tfpi−/− embryos, except in the central nervous system (CNS). The CNS displayed stunted brain growth, delayed development of the meninges, and severe vascular pathology characterized by the formation of glomeruloid bodies surrounding areas of cellular death, fibrin deposition, and hemorrhage. Removing FV from Tfpi−/− embryos completely ameliorated their brain pathology, suggesting that TFPI dampens FV-dependent procoagulant activity in a manner that modulates cerebrovascular development. Thus, we have identified a previously unrecognized role for TFPI activity within the CNS. This TFPI activity likely diminishes an effect of excess thrombin activity on signaling pathways that control cerebral vascular development.

Endothelial trans-differentiation in glioblastoma recurring after radiotherapy

We hypothesized that in glioblastoma recurring after radiotherapy, a condition whereby the brain endothelium undergoes radiation-induced senescence, tumor cells with endothelial phenotype may be relevant for tumor neovascularization. Matched glioblastoma samples obtained at primary surgery and at surgery for tumor recurrence after radiotherapy, all expressing epidermal growth factor receptor variant III (EGFRvIII), were assessed by a technique that combines fluorescent in situ hybridization (FISH) for the EGFR/CEP7 chromosomal probe with immunostaining for endothelial cells (CD31) and activated pericytes (α Smooth Muscle Actin). Five EGFRvIII-expressing paired primary/recurrent glioblastoma samples, in which the tumor cells showed EGFR/CEP7 amplification, were then assessed by CD31 and α Smooth Muscle Actin immunofluorescence. In glomeruloid bodies, the ratio between CD31+ cells with amplified EGFR/CEP7 signal and the total CD31+ cells was 0.23 ± 0.09 (mean ± sem) and 0.63 ± 0.07 in primary tumors and in recurrent ones, respectively (p < 0.002, Student-t test). In capillaries, the ratio of CD31+ cells with amplified EGFR/CEP7 over the total CD31+ cells lining the capillary lumen was 0.21 ± 0.06 (mean ± sem) and 0.42 ± 0.07 at primary surgery and at recurrence, respectively (p < 0.005, Student-t test). Expression of α Smooth Muscle Actin by cells with EGFR/CEP7 amplification was not observed. Then, in glioblastoma recurring after radiotherapy, where the brain endothelium suffers from radiation-induced cell senescence, tumor-derived endothelium plays a role in neo-vascularization.

Diagnostic pitfalls of differentiating desmoplastic small round cell tumor (DSRCT) from Wilms tumor (WT): overlapping morphologic and immunohistochemical features.

Desmoplastic small round cell tumor (DSRCT) and blastemal-predominant Wilms tumor (WT) share overlapping histologic features, yet accurate distinction is critical because of differing prognosis and treatment. We encountered a neck mass in a young adult with a concomitant abdominal mass. The neck mass was initially concerning for DSRCT on the basis of the poorly differentiated morphology, desmoplastic stroma, and immunoreactivity for desmin and cytokeratin. However, focal triphasic elements and glomeruloid bodies were identified on deeper sections, WT1 immunoreactivity was seen with antibodies to both the amino-terminus and carboxy-terminus, and EWSR1-WT1 rearrangement studies were negative, supporting the ultimate diagnosis of WT. On the basis of the overlapping histologic features of DSRCT and blastemal-predominant WT, we undertook a comparison study of desmin and cytokeratin reactivity patterns. We found that, whereas desmin reactivity was more frequent in DSRCT (11 of 12) than in WT blastema (11 of 22, P=0.024), dot-like perinuclear reactivity was seen with equal frequency in desmin-reactive DSRCT (10 of 11) and WT blastema (10 of 11), illustrating an important diagnostic pitfall. Moreover, we demonstrate coexpression of desmin and cytokeratin in both DSRCT (9 of 12) and WT blastema (11 of 22). Importantly, although dot-like desmin reactivity and coexpression of desmin and cytokeratin are historically associated with DSRCT, we demonstrate that these features can be seen in either DSRCT or blastemal-predominant WT. In these challenging cases, detection of an EWSR1-WT1 rearrangement and selective WT1 carboxy-terminus immunoreactivity (characteristic of DSRCT) or dual immunoreactivity for the WT1 amino-terminus and carboxy-terminus (characteristic of WT) remain the most discriminating diagnostic tools.

Cutaneous collagenous vasculopathy associated with intravascular occlusive fibrin thrombi

Cutaneous collagenous vasculopathy (CCV) is a rare cutaneous microangiopathy that clinically resembles generalized essential telangiectasia with only 12 cases reported to date. The perivascular fibrosis is thought to be due to production of abnormal collagen by veil cells in the outer vessel walls as a result of unknown factors. This report is of an 84-year-old male with progressive telangiectasia. Biopsies showed characteristic features of CCV. In addition, there were multiple intravascular fibrin thrombi, some organizing and associated with endothelial cell hyperplasia with recanalization reminiscent of glomeruloid bodies and simulating reactive angioendotheliomatosis (RAE). Histochemically and ultrastructurally fibrin was noted within the vessel walls integrating into the fibrous tissue around the vessels; however, the patient had no evidence of coagulation disorder, cryoglobulinemia or cold agglutinemia. Immunofluorescence showed fibrinogen within the vessel walls but no immunoglobulins or C3. As well, there were minimal inflammatory cells. This suggests pauci-inflammatory injury to the endothelial cells by unknown angiogenic factors causing local intravascular fibrin thrombi with fibrin leaking and incorporating into the vessel walls, eventually leading to reparative perivascular fibrosis. This case suggests that some cases of CCV are related to a primary local intravascular occlusive thrombotic microangiopathy. However, the primary triggering factor causing the endothelial cell damage has yet to be elucidated.

Metanephric adenoma and solid variant of papillary renal cell carcinoma: common and distinctive features

To evaluate morphological and immunohistochemical (IHC) features helpful in distinguishing metanephric adenoma (MA) from solid papillary renal cell carcinoma (s-PRCC). We present a detailed study of 21 MA and 23 s-PRCC. The two entities exhibited significant similarities, both being well-circumscribed tumours composed of tightly packed small cells arranged in solid sheets or ill-defined tubules, often presenting glomeruloid bodies, psammoma bodies and dystrophic calcification, and showing overlapping immunoreactivity for S100, CD57 and CK7. Conversely, most MA were non-encapsulated, whereas most s-PRCC showed a thick fibrous pseudocapsule; MA cells had scanty cytoplasm and a high nuclear:cytoplasmic ratio in comparison to s-PRCC, where occasional tumour cells showed abundant cytoplasm and high nuclear grade. Polypoid branching fronds were common in MA, but absent in s-PRCC; multifocality and papillary hyperplasia/adenoma were seen only in s-PRCC. MA were positive for WT1 and negative for EMA and alpha-methylacyl-CoA racemase (AMACR); s-PRCC were positive for EMA and AMACR and negative for WT1. Despite overlapping features, careful morphological and architectural evaluation should result in accurate diagnosis of most MA and s-PRCC. In challenging cases, IHC stains for WT1, EMA and AMACR may help in distinguishing these two entities.

Immunohistochemical Study of Porcine Nephroblastoma

Nephroblastoma, a relatively common renal neoplasm of young swine, represents the animal counterpart of Wilms' tumour of children. Five porcine nephroblastomas were examined histologically, and immunohistochemically with antibodies against vimentin (VIM), cytokeratins (CKs), smooth-muscle actin, Factor VIII, and laminin. Histologically all showed the three components typical of this tumour: mesenchymal blastema, epithelium (tubuli, and glomeruloid bodies) and stroma. The only antibody recognizing mesenchymal cells was VIM. One-third of tubular structures were positive for VIM. All of the tubules were positive for CK19, two-thirds expressed CK AE1/AE3, and only one-third expressed CKs 8-18. Small round tubuli, located in the stromal septa, were positive for CK7 (ureteric branches). Stromal cells expressed both VIM and actin, demonstrating myofibroblastic differentiation. The kidney originates from mesenchymal blastema, which changes to epithelium, losing VIM and acquiring CK expression. In the adult mammalian kidney, CK 19 is expressed only by the parietal epithelium of Bowman's capsule and the distal tubules. Nevertheless, CK19 is also considered a "transient" CK, expressed by different kinds of epithelia during differentiation. CK 19 was also detected in several undifferentiated neoplasms. This finding, together with the co-expression of VIM detected in some tubules, demonstrates the embryonic origin of nephroblastoma.

Expression and adhesive activity of SC1, an Ig superfamily cell adhesion molecule, in sporadic nephroblastomas of chicken

SC1, an immunoglobulin superfamily cell adhesion molecule, is transiently expressed during avian embryogenesis by a variety of cell types. This molecule has a homophilic binding activity with SC1 itself and promotes neurite projection from embryonic neurons. However, the potential role of this molecule in pathologic tissue specimens from chickens has yet to be elucidated. In this study, we examined the expression and functional role of SC1 in the sporadic nephroblastomas of chickens. Western blot analysis showed SC1 to be recognized as approximately 100 kDa and enriched in embryonic metanephros with a lower level in the adult kidney, while it was overexpressed in nephroblastomas. Immunohistochemically, SC1 was abundantly found in the tubular epithelia and blastemal cells of embryonic metanephros. In contrast, it had almost completely disappeared in the adult kidney; parts of the distal convoluted and intermediated tubules, collecting ducts, and Bowman's capsule slightly expressed SC1. In all 32 cases of nephroblastoma, SC1 was overexpressed in most characteristic components in tumors such as neoplastic epithelia with various types of differentiation, blastemal cell condensations, and glomeruloid bodies. Primary culture cells from a nephroblastoma expressed SC1 on the cell surface, whereas cells from the adult kidney showed only weak expression. A cell aggregation assay revealed that the dissociated cells from a nephroblastoma have strong aggregation activity, which was inhibited by anti-SC1 antibody. In contrast, the self-aggregation of adult chicken kidney cells was weaker than that of the tumor and not inhibited by the antibody. These findings suggest that the expression of SC1 might play a potential role in both the structural formation of nephroblastomas, based on its adhesive activity, and normal renal development.

Current practice of diagnosis and reporting of prostate cancer on needle biopsy among genitourinary pathologists

As there is a lack of hard data in the literature about many of the issues relating to diagnosing and reporting prostate cancer, we sought to survey current practices. A questionnaire was sent to 93 genitourinary pathologists with a response rate of 69%. Almost all respondents (95%) used formalin as fixative for needle biopsies. Unstained intervening sections were retained by 47%. Three levels of needle biopsies were used routinely by 63%. For verification of a diagnosis of cancer, high-molecular-weight cytokeratin was still the most commonly used immunohistochemical marker (91%), followed by p63 (58%) and alpha-methylacyl-CoA-racemase (50%). Features considered pathognomonic for cancer were glomeruloid bodies (58%), collagenous micronodules (64%), circumferential perineural invasion (84%), and growth in fat (36%). With none of these present, 39% required a minimum of 2 to 10 glands (median, 3) to diagnose cancer, whereas the others had no lower limit. A Gleason score was always given to even minute cancer foci by 86% and typically a Gleason score 6 was assigned (77%). Perineural invasion was mentioned by 86%. The extent of cancer on needle biopsies was quantified by all respondents with number of involved cores (80%) being the most commonly used measure. Linear extent was estimated by almost all, either as a percentage (80%) or millimeters of cancer length (41%) or both (22%). Measuring cancer from end to end or subtracting intervening benign tissue were almost equally common. For those general pathologists who would like to be in the mainstream of most urological pathologists, our survey data provide a guideline on how to diagnose and report prostate cancer.

Regulation of the Pathological Vasculature of Malignant Astrocytomas by Angiopoietin-1

Malignant astrocytomas are the most common and highly vascularized of all primary adult brain tumors. The histopathological hallmarks of malignant astrocytomas are microvascular proliferation and formation of vascular entities, which are referred to as “glomeruloid bodies.” The significance of glomeruloid bodies and the molecular mechanisms driving the abnormal vascular architecture in malignant astrocytomas are not understood. We have observed that overexpression of angiopoietin-1 (Ang1) in both subcutaneous and intracranial xenograft models of malignant astrocytomas reproduces many of the vascular features of these tumors, including glomeruloid bodies. To confirm that the formation of glomeruloid bodies was directly dependent on Ang1, we performed experiments where levels of Ang1 expression were regulated under tetracycline control, and we found a direct correlation between levels of Ang1 expression and the occurrence of glomeruloid bodies in xenografts. Additionally, we inhibited the action of Ang1 by blocking its cognate receptor Tie2, and we found that the formation of glomeruloid bodies was inhibited. Collectively, these results support our hypothesis that Ang1 is a key molecular regulator of pathological vascularization characteristic of malignant astrocytomas.

A Model for ex vivo Renal Angiogenesis

Attempts to study renal angiogenesis have been hampered by the lack of an appropriate model. Here we present data on a successful ex vivo culture of renal medullary explants in three-dimensional collagen 1 or Matrigel lattices and characterize the dynamics of capillary formation by sprouting endothelial cells. Initially, endothelial cells represented 71 ± 3% among the sprouting cells, but within a week growing capillaries were comprised exclusively of endothelial cells. The quantitative analysis showed that the number of sprouting capillaries progressively increased until 12 days in culture, after which capillaries underwent involution. Occasional formation of glomeruloid bodies was noted. Capillaries were characterized by a well-defined lumen, whereas glomeruloid bodies showed cellular debris occupying the luminal space. In view of the existing controversy regarding angiogenic competence in diabetic nephropathy, we applied this ex vivo culture system to Zucker diabetic rat model of diabetes mellitus. Comparative analysis of capillary sprouting in Zucker diabetic fat and lean nondiabetic control rats showed no differences in angiogenic properties of renal explants obtained at the age of 11 weeks. However, when kidneys were obtained from rats at age of 21 weeks, the capillary sprouting was significantly reduced in Zucker diabetic rats compared to age-matched lean rats. The rate of capillary involution was unaffected in Zucker diabetic rats. In conclusion, the data presented herein delineate the first successful ex vivo model of angiogenesis initiated from the renal medullary explants of adult rats and provide evidence of impaired angiogenesis in Zucker diabetic rats with the established, but not with incipient diabetes mellitus.

Review of metanephric adenoma of the kidney with focus on clinical and pathobiological aspects.

The concept of metanephric adenoma has become established in recent years. Metanephric adenoma is a rare neoplasm. Macroscopically, the cut surface of the tumor displays a tan to gray or yellow color, and tumors generally form well-circumscribed masses. Histologically, tumors are composed of small epithelial cells that form small acini. Glomeruloid bodies, which are composed of lobulated papillary projections, are occasionally seen. Although there have been few studies using chromosomal analysis, two recent studies have shown partial monosomy or LOH of 2p. On the other hand, the concept of metanephric tumors has recently become broadened. These tumors include metanephric adenomas, adenofibromas and stromal tumors, and they compose a continuous histological spectrum. Therefore, further studies on various aspects are needed to identify the gene responsible for the occurrence of metanephric tumors and, furthermore, to clarify the association among the three types of metanephric tumors.

Glomeruloid Microvascular Proliferation Follows Adenoviral Vascular Permeability Factor/Vascular Endothelial Growth Factor-164 Gene Delivery

Glomeruloid bodies are a defining histological feature of glioblastoma multiforme and some other tumors and vascular malformations. Little is known about their pathogenesis. We injected a nonreplicating adenoviral vector engineered to express vascular permeability factor/vascular endothelial growth factor-164 (VPF/VEGF(164)) into the ears of athymic mice. This vector infected local cells that strongly expressed VPF/VEGF(164) mRNA for 10 to 14 days, after which expression gradually declined. Locally expressed VPF/VEGF(164) induced an early increase in microvascular permeability, leading within 24 hours to edema and deposition of extravascular fibrin; in addition, many pre-existing microvessels enlarged to form thin-walled, pericyte-poor, "mother" vessels. Glomeruloid body precursors were first detected at 3 days as focal accumulations of rapidly proliferating cells in the endothelial lining of mother vessels, immediately adjacent to cells expressing VPF/VEGF(164). Initially, glomeruloid bodies were comprised of endothelial cells but subsequently pericytes and macrophages also participated. As they enlarged by endothelial cell and pericyte proliferation, glomeruloid bodies severely compromised mother vessel lumens and blood flow. Subsequently, as VPF/VEGF(164) expression declined, glomeruloid bodies devolved throughout a period of weeks by apoptosis and reorganization into normal-appearing microvessels. These results provide the first animal model for inducing glomeruloid bodies and indicate that VPF/VEGF(164) is sufficient for their induction and necessary for their maintenance.

Heterogeneity of the Angiogenic Response Induced in Different Normal Adult Tissues by Vascular Permeability Factor/Vascular Endothelial Growth Factor

Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) is an angiogenic cytokine with potential for the treatment of tissue ischemia. To investigate the properties of the new blood vessels induced by VPF/VEGF, we injected an adenoviral vector engineered to express murine VPF/VEGF164 into several normal tissues of adult nude mice or rats. A dose-dependent angiogenic response was induced in all tissues studied but was more intense and persisted longer (months) in skin and fat than in heart or skeletal muscle (≤3 weeks). The initial response (within 18 hours) was identical in all tissues studied and was characterized by microvascular hyperpermeability, edema, deposition of an extravascular fibrin gel, and the formation of enlarged, thin-walled pericyte-poor vessels (“mother” vessels). Mother vessels developed from preexisting microvessels after pericyte detachment and basement membrane degradation. Mother vessels were transient structures that evolved variably in different tissues into smaller daughter vessels, disorganized vessel tangles (glomeruloid bodies), and medium-sized muscular arteries and veins. Vascular structures closely resembling mother vessels and each mother vessel derivative have been observed in benign and malignant tumors, in other examples of pathological and physiological angiogenesis, and in vascular malformations. Together these data suggest that VPF/VEGF has a role in the pathogenesis of these entities. They also indicate that the angiogenic response induced by VPF/VEGF is heterogeneous and tissue specific. Finally, the muscular vessels that developed from mother vessels in skin and perimuscle fat have the structure of collaterals and could be useful clinically in the relief of tissue ischemia.

Pericardial Involvement by Thymomas: Entirely Intrapericardial Thymoma and a Pericardial Metastasis of Thymoma with Glomeruloid Vascular Proliferations

Thymomas are usually found in the anterior mediastinum, the normal location of the thymus. Involvement of the pericardium by thymic tumors is seen in invasive or metastasized thymoma. Very rarely, thymomas arise primarily in the pericardium. These tumors are believed to derive from thymic tissue which was misplaced in the pericardium during embryologic development. In contrast to patients with orthotopic thymoma who commonly suffer from paraneoplastic diseases, especially myasthenia gravis, patients with intrapericardial thymoma manifestations mainly have symptoms of congestive heart failure which are caused by local complications of tumor growth. In this study, we present two cases of thymoma involving the pericardium. Both tumors were polygonal-oval cell thymomas. In one of the cases diagnosis of an entirely intrapericardial thymoma was established by autopsy. In the other case, explorative thoracotomy revealed massive pericardial and pleural tumor manifestations. The latter tumor showed a peculiar histological pattern with multiple glomeruloid bodies, a finding reported only once for thymomas. Copyright 1999 W.B. Saunders Company Ltd on behalf of the Arányi Lajos Foundation

Immunohistochemical demonstration of wilms tumour gene product WT1 in a canine “Neuroepithelioma” providing evidence for its classification as an extrarenal nephroblastoma

An intradural extramedullary tumour, surgically removed from the spinal canal of a young dog with paraplegia, had the histological appearance of a nephroblastoma. Subsequent necropsy revealed no evidence of a renal primary tumour or of any other tumour. Similar tumours of the spinal canal have been described previously under a variety of names, in particular neuroepithelioma. With an antibody to the human Wilms tumour (nephroblastoma) gene product WT1, labelling of glomeruloid bodies, similar to glomerular podocytes in human fetal kidney, was demonstrated in the tumour. This finding strengthened the suggestion that it was a nephroblastoma.

The detection of CR1 mRNA and CR1 antigen identifies the presence of immature podocytes in a case of Wilms' tumor (nephroblastoma).

Wilms' tumors (nephroblastomas) are heterogeneous tumors consisting of proliferating epithelial cells in glomeruloid bodies and tubule formations and of proliferating blastemal cells. Using a specific CR1 35S-labeled cDNA probe and CR1 antibodies, CR1 mRNA and CR1 antigen-expressing cells were detected in glomeruloid bodies in one case of Wilm's tumor. The concomitant expression of CR1 mRNA and CR1 antigen and the high level of CR1 mRNA expression that characterize podocytes at an early stage of glomerular maturation in the normal human fetal kidneys indicates that glomeruloid bodies are composed of immature podocytes.

Deduction from Wilms' tumour that glomerular podocytes produce the basement membrane material bearing goodpasture determinants

Using an indirect immunoperoxidase technique, we tested frozen specimens from one Wilms' tumour composed of numerous glomeruloid bodies devoid of blood vessels, with monoclonal antibodies directed against vimentin, cytokeratin, CALLA/CD10, CD24, CR1/CD35, endothelium factor VIII, class I and II MHC molecules, laminin, fibronectin, and non-collagenic domain NC1 of type IV collagen. Two reagents against Goodpasture determinants were used: P1 monoclonal antibody and serum IgG (GP antibodies) from a biopsy-proven Goodpasture patient. Glomeruloid bodies comprised two cell types: a peripheral layer of parietal epithelial cells (cytokeratin and CD24-positive) and central cell clumps of podocytes (vimentin and CALLA-positive). The basal lamina surrounding the glomeruloid bodies contained laminin and NC1 domain of type IV collagen, while that present between the podocytes reacted strongly with laminin, and P1 and GP antibodies. Endothelium factor VIII was not detected within the glomeruloid bodies and CR1 molecules bound to the basement membrane material within them. These data favour the hypothesis that podocytes produce the basement membrane material which bears Goodpasture determinants recently identified as a novel chain, named the alpha 3 chain, of type IV collagen.

Cell differentiation in Wilms' tumor (nephroblastoma): An immunohistochemical study

Using an indirect immunoperoxidase technique, we tested frozen spectimens from 12 Wilms' tumors with monoclonal antibodies (MoAbs) reacting against a large panel of molecules including laminin, fibronectin, cytokeratin, vimentin, villin, CD24, CALLA/CD10, CR1, CD26, class I and class II major histocompatibility complex (MHC) molecules, and endothelium factor VIII. These molecules were chosen because they are markers of specific segments of the mature kidney and because their loss or acquisition is indicative of different steps of human nephrogenesis. KI67 MoAb was used to evaluate the proliferating activity of the cells. The blastemal component (cell compact areas) of Wilms' tumors consisted of vimentin-positive cells with a fibronectin network. However, signs of epithelial maturation were present in compact areas where cytokeratin-positive cells producing laminin were observed. The cells exhibited a high degree of proliferating activity. The tubule formations consisted of cytokeratin-positive cells and had a defined laminin border. All the cells, whether in compact areas or in tubules, were strongly CD24-positive. Some tubular formations showed signs of proximal maturation with the presence of CALLA, CD26, and even villin. In four cases class I-MHC molecules were expressed by some tubular cells. Large cystic cavities present in five cases were edged by cytokeratin, CD24-positive cells, or by vimentin, CALLA, CR1-positive cells. Some glomeruloid bodies, present in two cases, were also composed of vimentin, CALLA, and CR1-positive cells which correspond to the mature podocyte phenotype. The interstitial tissue contained mainly laminin and fibronectin network with macrophages and few CD3 lymphocytes. The presence of large cells with muscular differentiation was noted; round vimentin and CD26-positive cells were also seen. The endothelial cells of the vessels exhibited vimentin, factor VIII, and class I and class II MHC molecules as do mature cells, but in some cases the endothelial cells lacked class II molecule expression and were CALLA-positive. These results which confirmed and extended those previously described show that cell differentiation in Wilms' tumor mimics that observed during metanephros development. Moreover, this study shows that tumoral cells in nephroblastoma share several antigens with cells from lymphoid lineage (CD24, CALLA, and CD26) as do developing and mature kidney cells. Such cell phenotype dissection provides a useful and reliable tool for testing the influence of various factors on the development of hetero-transplanted or cultured Wilms' tumors.

Demonstration of both primary and secondary reninism in renal tumors in children

Two infants with renal tumors and associated hypertension are presented. By using an antibody to purified human renal renin, the sites of renin production were localized immunohistochemically in each tumor. The first case was a 9-month-old girl with Beckwith-Wiedemann syndrome. She presented with bilateral renal masses and hypertension (140/90 mm Hg). Following a left nephrectomy and chemotherapy and radiotherapy, her BP returned to normal. Her tumor was a Wilms' tumor of favorable histology, composed predominantly of glomeruloid structures. Renin was localized within a part of these neoplastic glomeruloid bodies. We therefore designated this as a Wilms' tumor with glomeruloid differentiation having primary reninism. The second case was a 24-day-old girl with hypertension (140/70 mm Hg). A renal tumor was found and successfully removed. Her BP returned to normal. The tumor was histologically confirmed as a congenital mesoblastic nephroma. By indirect immunoperoxidase staining, renin was localized only in the hypertrophied juxtaglomerular cells adjacent to the residual glomeruli entrapped by the tumor. None was seen in the tumor cells. We concluded that this was a case of secondary reninism--a case of hypertension secondary to the local ischemia at the entrapped glomeruli.